| Date | Panel | Item | Activity | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| BabyScreen+ newborn screening v1.114 | IDUA | Tommy Li Added phenotypes Mucopolysaccharidosis type 1, MONDO:0001586 for gene: IDUA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v1.103 | TRIM28 |
Zornitza Stark gene: TRIM28 was added gene: TRIM28 was added to BabyScreen+ newborn screening. Sources: Expert list Mode of inheritance for gene: TRIM28 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: TRIM28 were set to 30694527 Phenotypes for gene: TRIM28 were set to Wilms tumour, MONDO:0006058, TRIM28-related Review for gene: TRIM28 was set to GREEN Added comment: Established gene-disease association, more than 10 individuals reported. Onset in childhood. Included for completeness as managed similarly to WT1. Sources: Expert list |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v1.70 | IRF8 |
Zornitza Stark gene: IRF8 was added gene: IRF8 was added to BabyScreen+ newborn screening. Sources: Expert list treatable, immunological tags were added to gene: IRF8. Mode of inheritance for gene: IRF8 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: IRF8 were set to Immunodeficiency 32B, monocyte and dendritic cell deficiency, autosomal recessive, MIM# 226990 Review for gene: IRF8 was set to GREEN Added comment: At least 4 families reported with bi-allelic variants. Gene-disease association also proposed for mono-allelic variants but only two individuals reported. Recurrent infections presenting in infancy. Treatment: BMT Non-genetic confirmatory testing available Sources: Expert list |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v1.56 | F10 |
Zornitza Stark changed review comment from: Well established gene-disease association. Variable severity: for review. Affected individuals can manifest prolonged nasal and mucosal haemorrhage, menorrhagia, haematuria, and occasionally hemarthrosis. Treatment: plasma-derived factor 10 concentrate (Coagadex); to: Well established gene-disease association. Affected individuals can manifest prolonged nasal and mucosal haemorrhage, menorrhagia, haematuria, and occasionally hemarthrosis. Treatment: plasma-derived factor 10 concentrate (Coagadex) |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v1.30 | APOA5 |
Zornitza Stark gene: APOA5 was added gene: APOA5 was added to BabyScreen+ newborn screening. Sources: Expert list treatable tags were added to gene: APOA5. Mode of inheritance for gene: APOA5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: APOA5 were set to 23307945; 31390500 Phenotypes for gene: APOA5 were set to Hyperchylomicronaemia, late-onset, MIM# 144650 Review for gene: APOA5 was set to RED Added comment: Established gene-disease association. Variable age of onset, many of the reported individuals are adults. Treatment: Volanesorsen Sources: Expert list |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v1.28 | AP3D1 |
Zornitza Stark gene: AP3D1 was added gene: AP3D1 was added to BabyScreen+ newborn screening. Sources: Expert list treatable, haematological tags were added to gene: AP3D1. Mode of inheritance for gene: AP3D1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: AP3D1 were set to 26744459; 9697856; 30472485; 36445457 Phenotypes for gene: AP3D1 were set to Hermansky-Pudlak syndrome 10, MIM# 617050 Review for gene: AP3D1 was set to AMBER Added comment: Four individuals from two unrelated families and a mouse model. Borderline gene-disease association. New case report 36445457, proband presenting with SNHL and questionable other subtle features of HPS, homozygous missense variant (VOUS). Onset in infancy. Treatable: BMT for immunodeficiency. Sources: Expert list |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.2134 | TRDN |
Zornitza Stark changed review comment from: Rated as 'strong actionability' for paediatric patients by ClinGen. The mean age of onset of symptoms (usually a syncopal episode) of CPVT is between age seven and twelve years; onset as late as the fourth decade of life has been reported. Nearly 60% of patients have at least one syncopal episode before age 40. If untreated, CPVT is highly lethal, as approximately 30% of genetically affected individuals experience at least one cardiac arrest and up to 80% one or more syncopal spells. In untreated patients, the 8-year fatal or near-fatal event rates of 25% have been reported. Sudden death may be the first manifestation of the disease. Beta-blockers lacking intrinsic sympathomimetic activity are recommended as a first-line therapy in all patients with a clinical diagnosis of CPVT, including those with documented spontaneous, stress-induced VAs. Guidelines differ in their recommendations about utilizing beta-blocker therapy in phenotype negative individuals. Treatment with beta blockers is associated with a reduction in adverse cardiac events. However, variability in outcome with beta-blocker therapy is due to multiple factors, including dosing and compliance. In a study of 101 patients with CPVT (22 diagnosed clinically and 79 diagnosed molecularly), 81 were administered beta-blockers (57 symptomatic and 24 asymptomatic individuals). Estimated 4- and 8-year cardiac event rates were 8% and 27%, respectively in patients taking beta-blockers, and 33% and 58% in those not taking beta blockers (log-rank p=0.01). Corresponding statistics for fatal events were 1% and 11% with beta-blockers vs. 18% and 25% without (log-rank p=0.05). Event rates in asymptomatic patients with a positive genotype were similar to other patients. In multivariate models, absence of beta-blockers was an independent predictor of cardiac events (hazard ratio [HR], 5.48; 95% CI, 1.8 to 16.7, p=0.003) and of fatal events (HR, 5.54; 95% CI, 1.2 to 26.1, p=0.03). Of the 37 asymptomatic patients with a positive genotype, 9 (24%) had cardiac events. In patients with CPVT and recurrent sustained VT or syncope, while receiving adequate or maximally tolerated beta blocker, treatment intensification with either combination medication therapy (e.g., beta blocker with flecainide), left cardiac sympathetic denervation, and/or an ICD is recommended. Clinical penetrance ranges from 25 to 100%, with an average of 70 to 80%. Syncope appears to be the first symptom in more than half of the patients. When untreated, mortality from CPVT is high, reaching 30 to 50% by the age of 30 years. For review: age of onset and penetrance.; to: Rated as 'strong actionability' for paediatric patients by ClinGen. The mean age of onset of symptoms (usually a syncopal episode) of CPVT is between age seven and twelve years; onset as late as the fourth decade of life has been reported. Nearly 60% of patients have at least one syncopal episode before age 40. If untreated, CPVT is highly lethal, as approximately 30% of genetically affected individuals experience at least one cardiac arrest and up to 80% one or more syncopal spells. In untreated patients, the 8-year fatal or near-fatal event rates of 25% have been reported. Sudden death may be the first manifestation of the disease. Beta-blockers lacking intrinsic sympathomimetic activity are recommended as a first-line therapy in all patients with a clinical diagnosis of CPVT, including those with documented spontaneous, stress-induced VAs. Guidelines differ in their recommendations about utilizing beta-blocker therapy in phenotype negative individuals. Treatment with beta blockers is associated with a reduction in adverse cardiac events. However, variability in outcome with beta-blocker therapy is due to multiple factors, including dosing and compliance. In a study of 101 patients with CPVT (22 diagnosed clinically and 79 diagnosed molecularly), 81 were administered beta-blockers (57 symptomatic and 24 asymptomatic individuals). Estimated 4- and 8-year cardiac event rates were 8% and 27%, respectively in patients taking beta-blockers, and 33% and 58% in those not taking beta blockers (log-rank p=0.01). Corresponding statistics for fatal events were 1% and 11% with beta-blockers vs. 18% and 25% without (log-rank p=0.05). Event rates in asymptomatic patients with a positive genotype were similar to other patients. In multivariate models, absence of beta-blockers was an independent predictor of cardiac events (hazard ratio [HR], 5.48; 95% CI, 1.8 to 16.7, p=0.003) and of fatal events (HR, 5.54; 95% CI, 1.2 to 26.1, p=0.03). Of the 37 asymptomatic patients with a positive genotype, 9 (24%) had cardiac events. In patients with CPVT and recurrent sustained VT or syncope, while receiving adequate or maximally tolerated beta blocker, treatment intensification with either combination medication therapy (e.g., beta blocker with flecainide), left cardiac sympathetic denervation, and/or an ICD is recommended. Clinical penetrance ranges from 25 to 100%, with an average of 70 to 80%. Syncope appears to be the first symptom in more than half of the patients. When untreated, mortality from CPVT is high, reaching 30 to 50% by the age of 30 years. Reviewed with paediatric cardiologist: variable penetrance and age of onset, does not fulfil criteria for gNBS. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.2133 | TECRL |
Zornitza Stark changed review comment from: Rated as 'strong actionability' for paediatric patients by ClinGen. The mean age of onset of symptoms (usually a syncopal episode) of CPVT is between age seven and twelve years; onset as late as the fourth decade of life has been reported. Nearly 60% of patients have at least one syncopal episode before age 40. If untreated, CPVT is highly lethal, as approximately 30% of genetically affected individuals experience at least one cardiac arrest and up to 80% one or more syncopal spells. In untreated patients, the 8-year fatal or near-fatal event rates of 25% have been reported. Sudden death may be the first manifestation of the disease. Beta-blockers lacking intrinsic sympathomimetic activity are recommended as a first-line therapy in all patients with a clinical diagnosis of CPVT, including those with documented spontaneous, stress-induced VAs. Guidelines differ in their recommendations about utilizing beta-blocker therapy in phenotype negative individuals. Treatment with beta blockers is associated with a reduction in adverse cardiac events. However, variability in outcome with beta-blocker therapy is due to multiple factors, including dosing and compliance. In a study of 101 patients with CPVT (22 diagnosed clinically and 79 diagnosed molecularly), 81 were administered beta-blockers (57 symptomatic and 24 asymptomatic individuals). Estimated 4- and 8-year cardiac event rates were 8% and 27%, respectively in patients taking beta-blockers, and 33% and 58% in those not taking beta blockers (log-rank p=0.01). Corresponding statistics for fatal events were 1% and 11% with beta-blockers vs. 18% and 25% without (log-rank p=0.05). Event rates in asymptomatic patients with a positive genotype were similar to other patients. In multivariate models, absence of beta-blockers was an independent predictor of cardiac events (hazard ratio [HR], 5.48; 95% CI, 1.8 to 16.7, p=0.003) and of fatal events (HR, 5.54; 95% CI, 1.2 to 26.1, p=0.03). Of the 37 asymptomatic patients with a positive genotype, 9 (24%) had cardiac events. In patients with CPVT and recurrent sustained VT or syncope, while receiving adequate or maximally tolerated beta blocker, treatment intensification with either combination medication therapy (e.g., beta blocker with flecainide), left cardiac sympathetic denervation, and/or an ICD is recommended. Clinical penetrance ranges from 25 to 100%, with an average of 70 to 80%. Syncope appears to be the first symptom in more than half of the patients. When untreated, mortality from CPVT is high, reaching 30 to 50% by the age of 30 years. For review: age of onset and penetrance. Sources: ClinGen; to: Rated as 'strong actionability' for paediatric patients by ClinGen. The mean age of onset of symptoms (usually a syncopal episode) of CPVT is between age seven and twelve years; onset as late as the fourth decade of life has been reported. Nearly 60% of patients have at least one syncopal episode before age 40. If untreated, CPVT is highly lethal, as approximately 30% of genetically affected individuals experience at least one cardiac arrest and up to 80% one or more syncopal spells. In untreated patients, the 8-year fatal or near-fatal event rates of 25% have been reported. Sudden death may be the first manifestation of the disease. Beta-blockers lacking intrinsic sympathomimetic activity are recommended as a first-line therapy in all patients with a clinical diagnosis of CPVT, including those with documented spontaneous, stress-induced VAs. Guidelines differ in their recommendations about utilizing beta-blocker therapy in phenotype negative individuals. Treatment with beta blockers is associated with a reduction in adverse cardiac events. However, variability in outcome with beta-blocker therapy is due to multiple factors, including dosing and compliance. In a study of 101 patients with CPVT (22 diagnosed clinically and 79 diagnosed molecularly), 81 were administered beta-blockers (57 symptomatic and 24 asymptomatic individuals). Estimated 4- and 8-year cardiac event rates were 8% and 27%, respectively in patients taking beta-blockers, and 33% and 58% in those not taking beta blockers (log-rank p=0.01). Corresponding statistics for fatal events were 1% and 11% with beta-blockers vs. 18% and 25% without (log-rank p=0.05). Event rates in asymptomatic patients with a positive genotype were similar to other patients. In multivariate models, absence of beta-blockers was an independent predictor of cardiac events (hazard ratio [HR], 5.48; 95% CI, 1.8 to 16.7, p=0.003) and of fatal events (HR, 5.54; 95% CI, 1.2 to 26.1, p=0.03). Of the 37 asymptomatic patients with a positive genotype, 9 (24%) had cardiac events. In patients with CPVT and recurrent sustained VT or syncope, while receiving adequate or maximally tolerated beta blocker, treatment intensification with either combination medication therapy (e.g., beta blocker with flecainide), left cardiac sympathetic denervation, and/or an ICD is recommended. Clinical penetrance ranges from 25 to 100%, with an average of 70 to 80%. Syncope appears to be the first symptom in more than half of the patients. When untreated, mortality from CPVT is high, reaching 30 to 50% by the age of 30 years. Reviewed with a paediatric cardiologist: variable penetrance and age of onset, does not fulfil criteria for gNBS. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.2131 | PRKG1 |
Zornitza Stark changed review comment from: Assessed as 'strong actionability' in paediatric patients by ClinGen. FTAAD is a rare genetic vascular disease characterized by the familial occurrence of thoracic aortic aneurysm, dissection, or dilatation affecting one or more aortic segments (aortic root, ascending aorta, arch, or descending aorta). Variable age of clinical presentation. Prophylactic surgical repair of the aorta is recommended at 4.5-5.0 cm for patients with pathogenic variants in MYH11, SMAD3, and ACTA2 and at 4.0-4.5 cm for patients with pathogenic variants in TGFBR1 or TGFBR2. Beta adrenergic-blocking agents are recommended to reduce aortic dilation. Losartan was added as an alternative to beta adrenergic-blocking agents in FTAAD after studies showed its efficacy in children and young adults with MFS who were randomly assigned to losartan or atenolol. Penetrance: A study of 31 individuals with PRKG1 pathogenic variants indicated that 63% presented with an aortic dissection and 37% had aortic root enlargement. The cumulative risk of an aortic dissection or repair of an aortic aneurysm by age 55 has been estimated as 86% (95% CI: 70-95%). Sources: ClinGen; to: Assessed as 'strong actionability' in paediatric patients by ClinGen. FTAAD is a rare genetic vascular disease characterized by the familial occurrence of thoracic aortic aneurysm, dissection, or dilatation affecting one or more aortic segments (aortic root, ascending aorta, arch, or descending aorta). Variable age of clinical presentation. Prophylactic surgical repair of the aorta is recommended at 4.5-5.0 cm for patients with pathogenic variants in MYH11, SMAD3, and ACTA2 and at 4.0-4.5 cm for patients with pathogenic variants in TGFBR1 or TGFBR2. Beta adrenergic-blocking agents are recommended to reduce aortic dilation. Losartan was added as an alternative to beta adrenergic-blocking agents in FTAAD after studies showed its efficacy in children and young adults with MFS who were randomly assigned to losartan or atenolol. Penetrance: A study of 31 individuals with PRKG1 pathogenic variants indicated that 63% presented with an aortic dissection and 37% had aortic root enlargement. The cumulative risk of an aortic dissection or repair of an aortic aneurysm by age 55 has been estimated as 86% (95% CI: 70-95%). Discussed with a paediatric cardiologist: variable penetrance and age of onset, does not fulfil criteria for gNBS. Sources: ClinGen |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.2130 | MYH11 |
Zornitza Stark changed review comment from: Assessed as 'strong actionability' in paediatric patients by ClinGen. FTAAD is a rare genetic vascular disease characterized by the familial occurrence of thoracic aortic aneurysm, dissection, or dilatation affecting one or more aortic segments (aortic root, ascending aorta, arch, or descending aorta). Variable age of clinical presentation. Prophylactic surgical repair of the aorta is recommended at 4.5-5.0 cm for patients with pathogenic variants in MYH11, SMAD3, and ACTA2 and at 4.0-4.5 cm for patients with pathogenic variants in TGFBR1 or TGFBR2. Beta adrenergic-blocking agents are recommended to reduce aortic dilation. Losartan was added as an alternative to beta adrenergic-blocking agents in FTAAD after studies showed its efficacy in children and young adults with MFS who were randomly assigned to losartan or atenolol. Penetrance: A study of 12 individuals with MYH11 pathogenic variants indicated that 34% had an aortic dissection and one individual (8%) underwent prophylactic aortic aneurysm repair.; to: Assessed as 'strong actionability' in paediatric patients by ClinGen. FTAAD is a rare genetic vascular disease characterized by the familial occurrence of thoracic aortic aneurysm, dissection, or dilatation affecting one or more aortic segments (aortic root, ascending aorta, arch, or descending aorta). Variable age of clinical presentation. Prophylactic surgical repair of the aorta is recommended at 4.5-5.0 cm for patients with pathogenic variants in MYH11, SMAD3, and ACTA2 and at 4.0-4.5 cm for patients with pathogenic variants in TGFBR1 or TGFBR2. Beta adrenergic-blocking agents are recommended to reduce aortic dilation. Losartan was added as an alternative to beta adrenergic-blocking agents in FTAAD after studies showed its efficacy in children and young adults with MFS who were randomly assigned to losartan or atenolol. Penetrance: A study of 12 individuals with MYH11 pathogenic variants indicated that 34% had an aortic dissection and one individual (8%) underwent prophylactic aortic aneurysm repair. Reviewed with a paediatric cardiologist: variable penetrance and age of onset, does not meet criteria for gNBS. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.2129 | LOX |
Zornitza Stark changed review comment from: Assessed as 'strong actionability' in paediatric patients by ClinGen. FTAAD is a rare genetic vascular disease characterized by the familial occurrence of thoracic aortic aneurysm, dissection, or dilatation affecting one or more aortic segments (aortic root, ascending aorta, arch, or descending aorta). Variable age of clinical presentation. Prophylactic surgical repair of the aorta is recommended at 4.5-5.0 cm for patients with pathogenic variants in MYH11, SMAD3, and ACTA2 and at 4.0-4.5 cm for patients with pathogenic variants in TGFBR1 or TGFBR2. Beta adrenergic-blocking agents are recommended to reduce aortic dilation. Losartan was added as an alternative to beta adrenergic-blocking agents in FTAAD after studies showed its efficacy in children and young adults with MFS who were randomly assigned to losartan or atenolol. Penetrance: A study of 15 individuals with LOX pathogenic variants indicated that 73% had aortic aneurysms and 1 individual (7%) had an aortic dissection. Sources: ClinGen; to: Assessed as 'strong actionability' in paediatric patients by ClinGen. FTAAD is a rare genetic vascular disease characterized by the familial occurrence of thoracic aortic aneurysm, dissection, or dilatation affecting one or more aortic segments (aortic root, ascending aorta, arch, or descending aorta). Variable age of clinical presentation. Prophylactic surgical repair of the aorta is recommended at 4.5-5.0 cm for patients with pathogenic variants in MYH11, SMAD3, and ACTA2 and at 4.0-4.5 cm for patients with pathogenic variants in TGFBR1 or TGFBR2. Beta adrenergic-blocking agents are recommended to reduce aortic dilation. Losartan was added as an alternative to beta adrenergic-blocking agents in FTAAD after studies showed its efficacy in children and young adults with MFS who were randomly assigned to losartan or atenolol. Penetrance: A study of 15 individuals with LOX pathogenic variants indicated that 73% had aortic aneurysms and 1 individual (7%) had an aortic dissection. Discussed with paediatric cardiologist: variable penetrance and age of onset, does not fit with criteria for gNBS. Sources: ClinGen |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.2126 | CASQ2 |
Zornitza Stark changed review comment from: Well established gene-disease association. ClinGen: 'strong actionability' both for adult and paediatric patients. Treatment: beta blockers first line; ICD. There are also numerous known arrhythmia triggers which can be avoided. The mean age of onset of symptoms (usually a syncopal episode) of CPVT is between age seven and twelve years; onset as late as the fourth decade of life has been reported. Nearly 60% of patients have at least one syncopal episode before age 40. If untreated, CPVT is highly lethal, as approximately 30% of genetically affected individuals experience at least one cardiac arrest and up to 80% one or more syncopal spells. In untreated patients, the 8-year fatal or near-fatal event rates of 25% have been reported. Sudden death may be the first manifestation of the disease. ; to: Well established gene-disease association. ClinGen: 'strong actionability' both for adult and paediatric patients. Treatment: beta blockers first line; ICD. There are also numerous known arrhythmia triggers which can be avoided. The mean age of onset of symptoms (usually a syncopal episode) of CPVT is between age seven and twelve years; onset as late as the fourth decade of life has been reported. Nearly 60% of patients have at least one syncopal episode before age 40. If untreated, CPVT is highly lethal, as approximately 30% of genetically affected individuals experience at least one cardiac arrest and up to 80% one or more syncopal spells. In untreated patients, the 8-year fatal or near-fatal event rates of 25% have been reported. Sudden death may be the first manifestation of the disease. Reviewed with paediatric cardiologist: variable penetrance and age of onset. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.2124 | CALM3 |
Zornitza Stark changed review comment from: Rated as 'strong actionability' for paediatric patients by ClinGen. The mean age of onset of symptoms (usually a syncopal episode) of CPVT is between age seven and twelve years; onset as late as the fourth decade of life has been reported. Nearly 60% of patients have at least one syncopal episode before age 40. If untreated, CPVT is highly lethal, as approximately 30% of genetically affected individuals experience at least one cardiac arrest and up to 80% one or more syncopal spells. In untreated patients, the 8-year fatal or near-fatal event rates of 25% have been reported. Sudden death may be the first manifestation of the disease. Instances of sudden infant death syndrome (SIDS) have been associated with pathogenic variants in RYR2. Individuals with pathogenic variants in CALM1, CALM2 or CALM3 can have a severe phenotype, with earlier onset, QT prolongation, and a high predilection for cardiac arrest and sudden death. Beta-blockers lacking intrinsic sympathomimetic activity are recommended as a first-line therapy in all patients with a clinical diagnosis of CPVT, including those with documented spontaneous, stress-induced VAs. Guidelines differ in their recommendations about utilizing beta-blocker therapy in phenotype negative individuals. Treatment with beta blockers is associated with a reduction in adverse cardiac events. However, variability in outcome with beta-blocker therapy is due to multiple factors, including dosing and compliance. In a study of 101 patients with CPVT (22 diagnosed clinically and 79 diagnosed molecularly), 81 were administered beta-blockers (57 symptomatic and 24 asymptomatic individuals). Estimated 4- and 8-year cardiac event rates were 8% and 27%, respectively in patients taking beta-blockers, and 33% and 58% in those not taking beta blockers (log-rank p=0.01). Corresponding statistics for fatal events were 1% and 11% with beta-blockers vs. 18% and 25% without (log-rank p=0.05). Event rates in asymptomatic patients with a positive genotype were similar to other patients. In multivariate models, absence of beta-blockers was an independent predictor of cardiac events (hazard ratio [HR], 5.48; 95% CI, 1.8 to 16.7, p=0.003) and of fatal events (HR, 5.54; 95% CI, 1.2 to 26.1, p=0.03). Of the 37 asymptomatic patients with a positive genotype, 9 (24%) had cardiac events. In patients with CPVT and recurrent sustained VT or syncope, while receiving adequate or maximally tolerated beta blocker, treatment intensification with either combination medication therapy (e.g., beta blocker with flecainide), left cardiac sympathetic denervation, and/or an ICD is recommended. Clinical penetrance ranges from 25 to 100%, with an average of 70 to 80%. Syncope appears to be the first symptom in more than half of the patients. When untreated, mortality from CPVT is high, reaching 30 to 50% by the age of 30 years. For review: age of onset and penetrance. Sources: ClinGen; to: Rated as 'strong actionability' for paediatric patients by ClinGen. The mean age of onset of symptoms (usually a syncopal episode) of CPVT is between age seven and twelve years; onset as late as the fourth decade of life has been reported. Nearly 60% of patients have at least one syncopal episode before age 40. If untreated, CPVT is highly lethal, as approximately 30% of genetically affected individuals experience at least one cardiac arrest and up to 80% one or more syncopal spells. In untreated patients, the 8-year fatal or near-fatal event rates of 25% have been reported. Sudden death may be the first manifestation of the disease. Instances of sudden infant death syndrome (SIDS) have been associated with pathogenic variants in RYR2. Individuals with pathogenic variants in CALM1, CALM2 or CALM3 can have a severe phenotype, with earlier onset, QT prolongation, and a high predilection for cardiac arrest and sudden death. Beta-blockers lacking intrinsic sympathomimetic activity are recommended as a first-line therapy in all patients with a clinical diagnosis of CPVT, including those with documented spontaneous, stress-induced VAs. Guidelines differ in their recommendations about utilizing beta-blocker therapy in phenotype negative individuals. Treatment with beta blockers is associated with a reduction in adverse cardiac events. However, variability in outcome with beta-blocker therapy is due to multiple factors, including dosing and compliance. In a study of 101 patients with CPVT (22 diagnosed clinically and 79 diagnosed molecularly), 81 were administered beta-blockers (57 symptomatic and 24 asymptomatic individuals). Estimated 4- and 8-year cardiac event rates were 8% and 27%, respectively in patients taking beta-blockers, and 33% and 58% in those not taking beta blockers (log-rank p=0.01). Corresponding statistics for fatal events were 1% and 11% with beta-blockers vs. 18% and 25% without (log-rank p=0.05). Event rates in asymptomatic patients with a positive genotype were similar to other patients. In multivariate models, absence of beta-blockers was an independent predictor of cardiac events (hazard ratio [HR], 5.48; 95% CI, 1.8 to 16.7, p=0.003) and of fatal events (HR, 5.54; 95% CI, 1.2 to 26.1, p=0.03). Of the 37 asymptomatic patients with a positive genotype, 9 (24%) had cardiac events. In patients with CPVT and recurrent sustained VT or syncope, while receiving adequate or maximally tolerated beta blocker, treatment intensification with either combination medication therapy (e.g., beta blocker with flecainide), left cardiac sympathetic denervation, and/or an ICD is recommended. Clinical penetrance ranges from 25 to 100%, with an average of 70 to 80%. Syncope appears to be the first symptom in more than half of the patients. When untreated, mortality from CPVT is high, reaching 30 to 50% by the age of 30 years. Exclude for CPVT: association has moderate evidence, there are issues with penetrance, and treatment is generally only recommended in symptomatic individuals. Sources: ClinGen |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.2123 | CALM2 |
Zornitza Stark changed review comment from: Rated as 'strong actionability' for paediatric patients by ClinGen. The mean age of onset of symptoms (usually a syncopal episode) of CPVT is between age seven and twelve years; onset as late as the fourth decade of life has been reported. Nearly 60% of patients have at least one syncopal episode before age 40. If untreated, CPVT is highly lethal, as approximately 30% of genetically affected individuals experience at least one cardiac arrest and up to 80% one or more syncopal spells. In untreated patients, the 8-year fatal or near-fatal event rates of 25% have been reported. Sudden death may be the first manifestation of the disease. Instances of sudden infant death syndrome (SIDS) have been associated with pathogenic variants in RYR2. Individuals with pathogenic variants in CALM1, CALM2 or CALM3 can have a severe phenotype, with earlier onset, QT prolongation, and a high predilection for cardiac arrest and sudden death. Beta-blockers lacking intrinsic sympathomimetic activity are recommended as a first-line therapy in all patients with a clinical diagnosis of CPVT, including those with documented spontaneous, stress-induced VAs. Guidelines differ in their recommendations about utilizing beta-blocker therapy in phenotype negative individuals. Treatment with beta blockers is associated with a reduction in adverse cardiac events. However, variability in outcome with beta-blocker therapy is due to multiple factors, including dosing and compliance. In a study of 101 patients with CPVT (22 diagnosed clinically and 79 diagnosed molecularly), 81 were administered beta-blockers (57 symptomatic and 24 asymptomatic individuals). Estimated 4- and 8-year cardiac event rates were 8% and 27%, respectively in patients taking beta-blockers, and 33% and 58% in those not taking beta blockers (log-rank p=0.01). Corresponding statistics for fatal events were 1% and 11% with beta-blockers vs. 18% and 25% without (log-rank p=0.05). Event rates in asymptomatic patients with a positive genotype were similar to other patients. In multivariate models, absence of beta-blockers was an independent predictor of cardiac events (hazard ratio [HR], 5.48; 95% CI, 1.8 to 16.7, p=0.003) and of fatal events (HR, 5.54; 95% CI, 1.2 to 26.1, p=0.03). Of the 37 asymptomatic patients with a positive genotype, 9 (24%) had cardiac events. In patients with CPVT and recurrent sustained VT or syncope, while receiving adequate or maximally tolerated beta blocker, treatment intensification with either combination medication therapy (e.g., beta blocker with flecainide), left cardiac sympathetic denervation, and/or an ICD is recommended. Clinical penetrance ranges from 25 to 100%, with an average of 70 to 80%. Syncope appears to be the first symptom in more than half of the patients. When untreated, mortality from CPVT is high, reaching 30 to 50% by the age of 30 years. For review: age of onset and penetrance. Sources: ClinGen; to: Rated as 'strong actionability' for paediatric patients by ClinGen. The mean age of onset of symptoms (usually a syncopal episode) of CPVT is between age seven and twelve years; onset as late as the fourth decade of life has been reported. Nearly 60% of patients have at least one syncopal episode before age 40. If untreated, CPVT is highly lethal, as approximately 30% of genetically affected individuals experience at least one cardiac arrest and up to 80% one or more syncopal spells. In untreated patients, the 8-year fatal or near-fatal event rates of 25% have been reported. Sudden death may be the first manifestation of the disease. Instances of sudden infant death syndrome (SIDS) have been associated with pathogenic variants in RYR2. Individuals with pathogenic variants in CALM1, CALM2 or CALM3 can have a severe phenotype, with earlier onset, QT prolongation, and a high predilection for cardiac arrest and sudden death. Beta-blockers lacking intrinsic sympathomimetic activity are recommended as a first-line therapy in all patients with a clinical diagnosis of CPVT, including those with documented spontaneous, stress-induced VAs. Guidelines differ in their recommendations about utilizing beta-blocker therapy in phenotype negative individuals. Treatment with beta blockers is associated with a reduction in adverse cardiac events. However, variability in outcome with beta-blocker therapy is due to multiple factors, including dosing and compliance. In a study of 101 patients with CPVT (22 diagnosed clinically and 79 diagnosed molecularly), 81 were administered beta-blockers (57 symptomatic and 24 asymptomatic individuals). Estimated 4- and 8-year cardiac event rates were 8% and 27%, respectively in patients taking beta-blockers, and 33% and 58% in those not taking beta blockers (log-rank p=0.01). Corresponding statistics for fatal events were 1% and 11% with beta-blockers vs. 18% and 25% without (log-rank p=0.05). Event rates in asymptomatic patients with a positive genotype were similar to other patients. In multivariate models, absence of beta-blockers was an independent predictor of cardiac events (hazard ratio [HR], 5.48; 95% CI, 1.8 to 16.7, p=0.003) and of fatal events (HR, 5.54; 95% CI, 1.2 to 26.1, p=0.03). Of the 37 asymptomatic patients with a positive genotype, 9 (24%) had cardiac events. In patients with CPVT and recurrent sustained VT or syncope, while receiving adequate or maximally tolerated beta blocker, treatment intensification with either combination medication therapy (e.g., beta blocker with flecainide), left cardiac sympathetic denervation, and/or an ICD is recommended. Clinical penetrance ranges from 25 to 100%, with an average of 70 to 80%. Syncope appears to be the first symptom in more than half of the patients. When untreated, mortality from CPVT is high, reaching 30 to 50% by the age of 30 years. Reviewed with paediatric cardiologist: not for inclusion due to issues with penetrance, plus guidelines only generally recommend treatment is symptomatic individuals. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.2123 | CALM1 |
Zornitza Stark changed review comment from: Rated as 'strong actionability' for paediatric patients by ClinGen. The mean age of onset of symptoms (usually a syncopal episode) of CPVT is between age seven and twelve years; onset as late as the fourth decade of life has been reported. Nearly 60% of patients have at least one syncopal episode before age 40. If untreated, CPVT is highly lethal, as approximately 30% of genetically affected individuals experience at least one cardiac arrest and up to 80% one or more syncopal spells. In untreated patients, the 8-year fatal or near-fatal event rates of 25% have been reported. Sudden death may be the first manifestation of the disease. Instances of sudden infant death syndrome (SIDS) have been associated with pathogenic variants in RYR2. Individuals with pathogenic variants in CALM1, CALM2 or CALM3 can have a severe phenotype, with earlier onset, QT prolongation, and a high predilection for cardiac arrest and sudden death. Beta-blockers lacking intrinsic sympathomimetic activity are recommended as a first-line therapy in all patients with a clinical diagnosis of CPVT, including those with documented spontaneous, stress-induced VAs. Guidelines differ in their recommendations about utilizing beta-blocker therapy in phenotype negative individuals. Treatment with beta blockers is associated with a reduction in adverse cardiac events. However, variability in outcome with beta-blocker therapy is due to multiple factors, including dosing and compliance. In a study of 101 patients with CPVT (22 diagnosed clinically and 79 diagnosed molecularly), 81 were administered beta-blockers (57 symptomatic and 24 asymptomatic individuals). Estimated 4- and 8-year cardiac event rates were 8% and 27%, respectively in patients taking beta-blockers, and 33% and 58% in those not taking beta blockers (log-rank p=0.01). Corresponding statistics for fatal events were 1% and 11% with beta-blockers vs. 18% and 25% without (log-rank p=0.05). Event rates in asymptomatic patients with a positive genotype were similar to other patients. In multivariate models, absence of beta-blockers was an independent predictor of cardiac events (hazard ratio [HR], 5.48; 95% CI, 1.8 to 16.7, p=0.003) and of fatal events (HR, 5.54; 95% CI, 1.2 to 26.1, p=0.03). Of the 37 asymptomatic patients with a positive genotype, 9 (24%) had cardiac events. In patients with CPVT and recurrent sustained VT or syncope, while receiving adequate or maximally tolerated beta blocker, treatment intensification with either combination medication therapy (e.g., beta blocker with flecainide), left cardiac sympathetic denervation, and/or an ICD is recommended. Clinical penetrance ranges from 25 to 100%, with an average of 70 to 80%. Syncope appears to be the first symptom in more than half of the patients. When untreated, mortality from CPVT is high, reaching 30 to 50% by the age of 30 years. For review: age of onset and penetrance. Sources: ClinGen; to: Rated as 'strong actionability' for paediatric patients by ClinGen. The mean age of onset of symptoms (usually a syncopal episode) of CPVT is between age seven and twelve years; onset as late as the fourth decade of life has been reported. Nearly 60% of patients have at least one syncopal episode before age 40. If untreated, CPVT is highly lethal, as approximately 30% of genetically affected individuals experience at least one cardiac arrest and up to 80% one or more syncopal spells. In untreated patients, the 8-year fatal or near-fatal event rates of 25% have been reported. Sudden death may be the first manifestation of the disease. Instances of sudden infant death syndrome (SIDS) have been associated with pathogenic variants in RYR2. Individuals with pathogenic variants in CALM1, CALM2 or CALM3 can have a severe phenotype, with earlier onset, QT prolongation, and a high predilection for cardiac arrest and sudden death. Beta-blockers lacking intrinsic sympathomimetic activity are recommended as a first-line therapy in all patients with a clinical diagnosis of CPVT, including those with documented spontaneous, stress-induced VAs. Guidelines differ in their recommendations about utilizing beta-blocker therapy in phenotype negative individuals. Treatment with beta blockers is associated with a reduction in adverse cardiac events. However, variability in outcome with beta-blocker therapy is due to multiple factors, including dosing and compliance. In a study of 101 patients with CPVT (22 diagnosed clinically and 79 diagnosed molecularly), 81 were administered beta-blockers (57 symptomatic and 24 asymptomatic individuals). Estimated 4- and 8-year cardiac event rates were 8% and 27%, respectively in patients taking beta-blockers, and 33% and 58% in those not taking beta blockers (log-rank p=0.01). Corresponding statistics for fatal events were 1% and 11% with beta-blockers vs. 18% and 25% without (log-rank p=0.05). Event rates in asymptomatic patients with a positive genotype were similar to other patients. In multivariate models, absence of beta-blockers was an independent predictor of cardiac events (hazard ratio [HR], 5.48; 95% CI, 1.8 to 16.7, p=0.003) and of fatal events (HR, 5.54; 95% CI, 1.2 to 26.1, p=0.03). Of the 37 asymptomatic patients with a positive genotype, 9 (24%) had cardiac events. In patients with CPVT and recurrent sustained VT or syncope, while receiving adequate or maximally tolerated beta blocker, treatment intensification with either combination medication therapy (e.g., beta blocker with flecainide), left cardiac sympathetic denervation, and/or an ICD is recommended. Clinical penetrance ranges from 25 to 100%, with an average of 70 to 80%. Syncope appears to be the first symptom in more than half of the patients. When untreated, mortality from CPVT is high, reaching 30 to 50% by the age of 30 years. Reviewed with paediatric cardiologist: not for inclusion due to issues with penetrance, plus guidelines only generally recommend treatment is symptomatic individuals. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.2063 | STIM1 |
Lilian Downie gene: STIM1 was added gene: STIM1 was added to Baby Screen+ newborn screening. Sources: Expert list Mode of inheritance for gene: STIM1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: STIM1 were set to PMID: 26469693, PMID: 30949876, PMID: 26560041 Phenotypes for gene: STIM1 were set to Immunodeficiency 10 MIM612783 Review for gene: STIM1 was set to GREEN Added comment: recurrent infections in childhood due to defective T- and NK-cell function, although the severity is variable. Affected individuals may also have hypotonia, hypohidrosis, or dental enamel hypoplasia consistent with amelogenesis imperfecta Rx bone marrow transpant Age of onset is consistently <5 but the severity of infections is highly variable - treatment if the phenotype is severe Sources: Expert list |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.2063 | SYT2 |
Lilian Downie gene: SYT2 was added gene: SYT2 was added to Baby Screen+ newborn screening. Sources: Expert list Mode of inheritance for gene: SYT2 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: SYT2 were set to PMID: 32250532, 32776697 Phenotypes for gene: SYT2 were set to Myasthenic syndrome, congenital, 7B, presynaptic, autosomal recessive MIM#619461 Review for gene: SYT2 was set to GREEN Added comment: Bi-allelic disease: 32250532 and 32776697, 8 individuals from 6 families, with biallelic loss of function variants in SYT2, clinically manifesting with severe congenital onset hypotonia and weakness, with variable degrees of respiratory involvement. Electrodiagnostic findings consistent with a presynaptic congenital myasthenic syndrome (CMS) in some. Treatment with an acetylcholinesterase inhibitor pursued in 4 indviduals showed clinical improvement with increased strength and function. Only report biallelic for newborn screening ? monoallelic causes a later onset distal weakness/neuropathy phenotype - still childhood but variable or not clear - not consistently <5yrs Sources: Expert list |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.2052 | TMEM165 |
Lilian Downie gene: TMEM165 was added gene: TMEM165 was added to Baby Screen+ newborn screening. Sources: Expert list Mode of inheritance for gene: TMEM165 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TMEM165 were set to PMID: 28323990, PMID: 35693943, PMID: 22683087 Phenotypes for gene: TMEM165 were set to Congenital disorder of glycosylation, type IIk MIM#614727 Review for gene: TMEM165 was set to AMBER Added comment: Affected individuals show psychomotor retardation and growth retardation, and most have short stature. Other features include dysmorphism, hypotonia, eye abnormalities, acquired microcephaly, hepatomegaly, and skeletal dysplasia. Serum transferrin analysis shows a CDG type II pattern Rx D-galactose (single paper, 2 unrelated patients and an in vitro study) ?inadequete evidence for treatment? Might need to check with JC if we would offer it maybe include Sources: Expert list |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.2051 | RNPC3 |
Zornitza Stark gene: RNPC3 was added gene: RNPC3 was added to Baby Screen+ newborn screening. Sources: Expert list treatable, endocrine tags were added to gene: RNPC3. Mode of inheritance for gene: RNPC3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: RNPC3 were set to 29866761; 32462814; 33650182 Phenotypes for gene: RNPC3 were set to Pituitary hormone deficiency, combined or isolated, 7, MIM# 618160 Review for gene: RNPC3 was set to GREEN Added comment: Three unrelated individuals reported with combined and isolated pituitary hormone deficiencies, including GH and TSH. Onset: congenital. Treatment: GH, thyroxine. Non-genetic confirmatory testing: hormone levels. Sources: Expert list |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.2046 | RAC2 |
Zornitza Stark gene: RAC2 was added gene: RAC2 was added to Baby Screen+ newborn screening. Sources: Expert list treatable, immunological tags were added to gene: RAC2. Mode of inheritance for gene: RAC2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Phenotypes for gene: RAC2 were set to Immunodeficiency 73B with defective neutrophil chemotaxis and lymphopaenia MIM# 618986 Review for gene: RAC2 was set to GREEN Added comment: Immunodeficiency 73B with defective neutrophil chemotaxis and lymphopaenia 13 individuals from 8 unrelated families; mono-allelic; gain of function; multiple mouse models Mono-allelic missense variants were reported in each individual (5 x De Novo) and resulted in a gain-of -function. (E62K, P34H, N92T, G12R) These individuals typically presented in infancy with frequent infections, profound leukopaenia, lymphopaenia diarrhoea and hypogammaglobulinaemia. SCID-like phenotype. Treatment: IVIG, BMT Note evidence for the other two immunodeficiency disorders associated with this gene is limited. Sources: Expert list |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.2040 | OAS1 |
Zornitza Stark gene: OAS1 was added gene: OAS1 was added to Baby Screen+ newborn screening. Sources: Expert list treatable, immunological tags were added to gene: OAS1. Mode of inheritance for gene: OAS1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: OAS1 were set to 34145065; 29455859 Phenotypes for gene: OAS1 were set to Immunodeficiency 100 with pulmonary alveolar proteinosis and hypogammaglobulinaemia, MIM#618042 Review for gene: OAS1 was set to GREEN Added comment: Immunodeficiency-100 with pulmonary alveolar proteinosis and hypogammaglobulinemia (IMD100) is primarily a lung disorder characterized by onset of respiratory insufficiency due to pulmonary alveolar proteinosis (PAP) in the first months of life. Affected individuals may have normal respiratory function at birth. Development of the disorder appears to be influenced or triggered by viral infection, manifest as progressive respiratory insufficiency, confluent consolidations on lung imaging, and diffuse collection of periodic acid-Schiff (PAS)-positive material in pulmonary alveoli associated with small and nonfoamy alveolar macrophages. Patients also have hypogammaglobulinemia, leukocytosis, and splenomegaly. Many patients die of respiratory failure in infancy or early childhood. Treatment: IVIG; BMT is curative. Non-genetic confirmatory testing: immunoglobulin levels. Sources: Expert list |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.2038 | NFKBIA |
Zornitza Stark gene: NFKBIA was added gene: NFKBIA was added to Baby Screen+ newborn screening. Sources: Expert list treatable, immunological tags were added to gene: NFKBIA. Mode of inheritance for gene: NFKBIA was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Phenotypes for gene: NFKBIA were set to Ectodermal dysplasia and immunodeficiency 2 MIM# 612132 Review for gene: NFKBIA was set to GREEN Added comment: 12 heterozygous variants were identified in 15 unrelated individuals (de novo in 14 individuals and somatic mosaicism in 1 individual). Functional studies & two mouse models; demonstrate reported NFKBIA gain-of-function variants resulting in impaired NFKB1 activity. The majority of individuals displayed recurrent infections, chronic diarrhoea, agammaglobulinaemia, increased IgM, and defects in teeth (hair, nail, sweat glands). Onset is generally in infancy. Treatment: BMT. Non-genetic confirmatory testing: no Sources: Expert list |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.2030 | MTHFD1 |
Zornitza Stark gene: MTHFD1 was added gene: MTHFD1 was added to Baby Screen+ newborn screening. Sources: Expert list treatable, immunological, haematological tags were added to gene: MTHFD1. Mode of inheritance for gene: MTHFD1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MTHFD1 were set to 32414565; 19033438 Phenotypes for gene: MTHFD1 were set to Combined immunodeficiency and megaloblastic anemia with or without hyperhomocysteinaemia MIM # 617780 Review for gene: MTHFD1 was set to GREEN Added comment: 8 individuals from 4 unrelated families have been reported; multiple mouse models 7 individuals were Compound heterozygous (nonsense & missense) and 1 was homozygous (missense) for MTHFD1 variants often resulting in alteration of highly conserved residues in binding-sites. Individuals typically present with megaloblastic anaemia, atypical hemolytic uremic syndrome, hyperhomocysteinaemia, microangiopathy, recurrent infections and autoimmune diseases. Treatment: hydroxocobalamin, folinic acid and betaine Non-genetic confirmatory testing: T and B Lymphocyte and Natural Killer Cell Profile, complete blood count with MCV, plasma homocysteine and methylmalonic acid levels, CSF Sources: Expert list |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.2026 | MALT1 |
Zornitza Stark gene: MALT1 was added gene: MALT1 was added to Baby Screen+ newborn screening. Sources: Expert list treatable, immunological tags were added to gene: MALT1. Mode of inheritance for gene: MALT1 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: MALT1 were set to Immunodeficiency 12 MIM# 615468 Review for gene: MALT1 was set to GREEN Added comment: 5 individuals from 3 unrelated families with immunodeficiency phenotype have reported variants in MALT1; two MALT1-knockout mouse models displaying primary T- and B-cell lymphocyte deficiency. Variants identified were homozygous missense variants resulting in the alteration of highly conserved residue domains. All individuals reported onset in infancy of recurrent bacterial/ fungal/ viral infections leading to bronchiectasis and poor T-cell proliferation. Treatment: prophylactic antibiotics, IVIG, BMT. Non-genetic confirmatory testing: no Sources: Expert list |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.2024 | MAGT1 |
Zornitza Stark gene: MAGT1 was added gene: MAGT1 was added to Baby Screen+ newborn screening. Sources: Expert list treatable, immunological tags were added to gene: MAGT1. Mode of inheritance for gene: MAGT1 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females Publications for gene: MAGT1 were set to 31036665; 31714901 Phenotypes for gene: MAGT1 were set to Immunodeficiency, X-linked, with magnesium defect, Epstein-Barr virus infection and neoplasia (MIM# 300853) Review for gene: MAGT1 was set to GREEN Added comment: XMEN is an X-linked recessive immunodeficiency characterized by CD4 lymphopenia, severe chronic viral infections, and defective T-lymphocyte activation. Affected individuals have chronic Epstein-Barr virus (EBV) infection and are susceptible to the development of EBV-associated B-cell lymphoproliferative disorders. Variable age of onset, including in early childhood. Treatment: Mg supplementation; IVIG, BMT. Non-genetic confirmatory testing: immunoglobulin levels, T and B Lymphocyte and Natural Killer Cell Profile, Carbohydrate deficient glycosylation profile Sources: Expert list |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.2013 | ITK |
Zornitza Stark gene: ITK was added gene: ITK was added to Baby Screen+ newborn screening. Sources: Expert list treatable, immunological tags were added to gene: ITK. Mode of inheritance for gene: ITK was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: ITK were set to Lymphoproliferative syndrome 1, MIM# 613011 Review for gene: ITK was set to GREEN Added comment: 7 individuals from 5 unrelated families reported homozygous (missense/ nonsense) ITK variants consistent with Lymphoproliferative syndrome phenotype. Triggered by EBV infection. Two ITK-deficient mouse models demonstrated reduced T cells (CD4+), causing decreased CD4 to CD8 ratio. Patients displayed early onset of features typically including fever, lymphadenopathy, autoimmune disorders, low immunoglobulins and high EBV viral load. Fatal without BMT. Non-genetic confirmatory testing: immunoglobulin levels, T and B Lymphocyte and Natural Killer Cell Profile. Sources: Expert list |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.2007 | IL2RA |
Zornitza Stark gene: IL2RA was added gene: IL2RA was added to Baby Screen+ newborn screening. Sources: Expert list treatable, immunological tags were added to gene: IL2RA. Mode of inheritance for gene: IL2RA was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: IL2RA were set to Immunodeficiency 41 with lymphoproliferation and autoimmunity, MIM# 606367 Review for gene: IL2RA was set to GREEN Added comment: Immunodeficiency-41 is a disorder of immune dysregulation. Affected individuals present in infancy with recurrent viral, fungal, and bacterial infections, lymphadenopathy, and variable autoimmune features, such as autoimmune enteropathy and eczematous skin lesions. Immunologic studies show a defect in T-cell regulation. At least 4 unrelated families reported. Treatment: rapamycin, bone marrow transplant. Confirmatory non-genetic testing: flow cytometric analysis. Sources: Expert list |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.2005 | IL21R |
Zornitza Stark gene: IL21R was added gene: IL21R was added to Baby Screen+ newborn screening. Sources: Expert list treatable, immunological tags were added to gene: IL21R. Mode of inheritance for gene: IL21R was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: IL21R were set to Immunodeficiency 56, MIM# 615207 Review for gene: IL21R was set to GREEN Added comment: Biallelic inactivating mutations in IL21R causes a combined immunodeficiency that is often complicated by cryptosporidium infections. More than 20 individuals reported. Recent series of 13 individuals: the main clinical manifestations were recurrent bacterial (84.6%), fungal (46.2%), and viral (38.5%) infections; cryptosporidiosis-associated cholangitis (46.2%); and asthma (23.1%). Inflammatory skin diseases (15.3%) and recurrent anaphylaxis (7.9%) constitute novel phenotypes of this combined immunodeficiency. Most patients exhibited hypogammaglobulinaemia and reduced proportions of memory B cells, circulating T follicular helper cells, MAIT cells and terminally differentiated NK cells. However, IgE levels were elevated in 50% of IL-21R-deficient patients. Onset: infancy/early childhood. Treatment: BMT. Non-genetic confirmatory testing: immunoglobulin levels. Sources: Expert list |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.2001 | IKZF1 |
Zornitza Stark gene: IKZF1 was added gene: IKZF1 was added to Baby Screen+ newborn screening. Sources: Expert list Mode of inheritance for gene: IKZF1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Phenotypes for gene: IKZF1 were set to Immunodeficiency, common variable, 13 MIM# 616873 Added comment: Over 25 individuals from 9 unrelated families with variants in IKZF1 displaying Immunodeficiency; three mouse models Heterozygous missense, frameshift and deletion variants in IKZF1 gene resulting in loss or alteration of a zinc finger DNA contact site cause LoF. Typically presents with recurrent bacterial respiratory infections, hypogammaglobulinaemia and low Ig levels; variable age of onset. PMID 35333544: Eight individuals harboring heterozygous IKZF1R183H or IKZF1R183C variants associated with GOF effects reported. The clinical phenotypes and pathophysiology associated with IKZF1R183H/C differ from those of previously reported patients with IKZF1HI, IKZF1DN, and IKZF1DD and should therefore be considered as a novel IKAROS-associated disease entity. This condition is characterized by immune dysregulation manifestations including inflammation, autoimmunity, atopy, and polyclonal PC proliferation. Included primarily for LoF phenotype. Treatment: IVIG and BMT. Non-genetic confirmatory testing: immunoglobulin levels Sources: Expert list |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.1991 | ICOS |
Zornitza Stark gene: ICOS was added gene: ICOS was added to Baby Screen+ newborn screening. Sources: Expert list treatable, immunological tags were added to gene: ICOS. Mode of inheritance for gene: ICOS was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: ICOS were set to Immunodeficiency, common variable, 1 MIM# 607594 Review for gene: ICOS was set to GREEN Added comment: 15 affected individuals from 8 unrelated families reported with ICOS variants and displayed immunodeficiency, common variable, 1 phenotype; three mouse models. Homozygous and compound heterozygous deletion and missense variants, with the most frequent variant being a 442 nucleotide deletion. Patients typically presented with recurrent bacterial respiratory & gastrointestinal infections and low IgG/IgA. Congenital onset. Treatment: replacement immunoglobulin treatment, bone marrow transplant. Non-genetic confirmatory testing: immunoglobulin levels. Sources: Expert list |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.1982 | TPK1 |
Lilian Downie gene: TPK1 was added gene: TPK1 was added to Baby Screen+ newborn screening. Sources: Expert list Mode of inheritance for gene: TPK1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TPK1 were set to PMID: 33086386, 32679198, 22152682, PMID: 33231275 Phenotypes for gene: TPK1 were set to Thiamine metabolism dysfunction syndrome 5 (episodic encephalopathy type) MIM#614458 Review for gene: TPK1 was set to GREEN Added comment: Strong gene disease association Variable age of onset but always under 5years Thiamine metabolism dysfunction syndrome-5 (THMD5) is an autosomal recessive metabolic disorder due to an inborn error of thiamine metabolism. The phenotype is highly variable, but in general, affected individuals have onset in early childhood of acute encephalopathic episodes associated with increased serum and CSF lactate. These episodes result in progressive neurologic dysfunction manifest as gait disturbances, ataxia, dystonia, and spasticity, which in some cases may result in loss of ability to walk. Cognitive function is usually preserved, although mildly delayed development has been reported. These episodes are usually associated with infection and metabolic decompensation. Some patients may have recovery of some neurologic deficits (Mayr et al., 2011). Biotin and thiamine therapy - newer evidence (2021) suggests early thiamine therapy may prevent any neurologic deficits. Sources: Expert list |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.1982 | TRNT1 |
Lilian Downie gene: TRNT1 was added gene: TRNT1 was added to Baby Screen+ newborn screening. Sources: Expert list Mode of inheritance for gene: TRNT1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TRNT1 were set to PMID: 25193871, PMID: 23553769, PMID: 33936027, PMID: 26494905 Phenotypes for gene: TRNT1 were set to Sideroblastic anemia with B-cell immunodeficiency, periodic fevers, and developmental delay MIM#616084 Review for gene: TRNT1 was set to AMBER Added comment: Onset infancy Strong gene disease association Sideroblastic anemia with B-cell immunodeficiency, periodic fevers, and developmental delay (SIFD) is an autosomal recessive syndromic disorder characterized by onset of severe sideroblastic anemia in the neonatal period or infancy. Affected individuals show delayed psychomotor development with variable neurodegeneration. Recurrent periodic fevers without an infectious etiology occur throughout infancy and childhood; immunologic work-up shows B-cell lymphopenia and hypogammaglobulinemia. Other more variable features include sensorineural hearing loss, retinitis pigmentosa, nephrocalcinosis, and cardiomyopathy. Death in the first decade may occur (summary by Wiseman et al., 2013). Bone marrow transplant (hematopoietic stem cell transplantation (HSCT)), replacement immunoglobulin treatment Allelic disease: Retinitis pigmentosa and erythrocytic microcytosis MIM#616959. Also AR. DeLuca et al. (2016) concluded that hypomorphic TRNT1 mutations can cause a recessive disease that is almost entirely limited to the retina - this has teenage onset and is not treatable. can we exclude these variants? Sources: Expert list |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.1967 | GPIHBP1 |
Zornitza Stark gene: GPIHBP1 was added gene: GPIHBP1 was added to Baby Screen+ newborn screening. Sources: Expert list Mode of inheritance for gene: GPIHBP1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: GPIHBP1 were set to 31390500 Phenotypes for gene: GPIHBP1 were set to Hyperlipoproteinemia, type 1D MIM#615947; familial chylomicronemia syndrome Review for gene: GPIHBP1 was set to GREEN Added comment: Well-established gene-disease association. Usually presents in childhood with episodes of abdominal pain, recurrent acute pancreatitis, eruptive cutaneous xanthomata, and hepatosplenomegaly. Approximately 25% of affected children develop symptoms before age one year and the majority develop symptoms before age ten years; however, some individuals present for the first time during pregnancy. Treatment: volanesorsen, dietary fat restriction Non-genetic confirmatory testing: triglyceride level Sources: Expert list |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.1958 | USP18 |
Lilian Downie gene: USP18 was added gene: USP18 was added to Baby Screen+ newborn screening. Sources: Expert list Mode of inheritance for gene: USP18 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: USP18 were set to PMID: 31940699, 27325888, 12833411 Phenotypes for gene: USP18 were set to Pseudo-TORCH syndrome 2 MIM#617397 Review for gene: USP18 was set to AMBER Added comment: antenatal onset of intracranial hemorrhage, calcification, brain malformations, liver dysfunction, and often thrombocytopenia. Affected individuals tend to have respiratory insufficiency and seizures, and die in infancy. The phenotype resembles the sequelae of intrauterine infection, but there is no evidence of an infectious agent. The disorder results from inappropriate activation of the interferon (IFN) immunologic pathway Treatment Ruxolitinib (single patient only) - is a single patient with successful treatment enough? Sources: Expert list |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.1949 | FCHO1 |
Zornitza Stark gene: FCHO1 was added gene: FCHO1 was added to Baby Screen+ newborn screening. Sources: Expert list treatable, immunological tags were added to gene: FCHO1. Mode of inheritance for gene: FCHO1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: FCHO1 were set to 32098969; 30822429 Phenotypes for gene: FCHO1 were set to Immunodeficiency 76, MIM# 619164 Added comment: More than 10 affected individuals with bi-allelic variants in this gene reported. Functional data. Immunodeficiency-76 (IMD76) is an autosomal recessive primary immunologic disorder characterized by onset of recurrent bacterial, viral, and fungal infections in early childhood. Laboratory studies show T-cell lymphopenia and may show variable B-cell or immunoglobulin abnormalities. More variable features found in some patients include lymphoma and neurologic features. Treatment: bone marrow transplant. Non-genetic confirmatory testing: T and B Lymphocyte and Natural Killer Cell Profile, immunoglobulin levels Sources: Expert list |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.1943 | DOCK2 |
Zornitza Stark gene: DOCK2 was added gene: DOCK2 was added to Baby Screen+ newborn screening. Sources: Expert Review Mode of inheritance for gene: DOCK2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: DOCK2 were set to 26083206; 29204803; 33928462; 30826364; 30838481; 11518968 Phenotypes for gene: DOCK2 were set to Immunodeficiency 40 MIM# 616433 Review for gene: DOCK2 was set to GREEN Added comment: 13 unrelated individuals; two mouse models; 10 biallelic mutations found (6 led to premature termination of the protein & 4 missense mutations affecting conserved residues) All patients presented with combined immunodeficiency in infancy (defective IFN-mediated immunity), early onset of invasive bacterial and viral infections, functional defects in T/B/NK cells and elevated IgM (normal IgG/IgA). Treatment: bone marrow transplant. Non-genetic confirmatory testing: T and B Lymphocyte and Natural Killer Cell Profile Sources: Expert Review |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.1929 | CORO1A |
Zornitza Stark gene: CORO1A was added gene: CORO1A was added to gNBS. Sources: Expert list Mode of inheritance for gene: CORO1A was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: CORO1A were set to Immunodeficiency 8 MIM# 615401 Review for gene: CORO1A was set to GREEN Added comment: 3 unrelated families and 1 unrelated individual reported with bi-allelic (deletion, missense, insertion) variants, resulting in premature stop codons and truncated protein/ alter a highly conserved residue in binding domain; one mouse model All patients displayed T−B+NK+ SCID or CID presenting in early-onset recurrent infections and additional features that included EBV-associated lymphoproliferative disease and low immunoglobulin levels. Congenital onset. Treatment: bone marrow transplant Non-genetic confirmatory testing: T and B Lymphocyte and Natural Killer Cell Profile Sources: Expert list |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.1926 | CD81 |
Zornitza Stark gene: CD81 was added gene: CD81 was added to gNBS. Sources: Expert Review Mode of inheritance for gene: CD81 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CD81 were set to 20237408 Phenotypes for gene: CD81 were set to Immunodeficiency, common variable, 6, MIM# 613496 Review for gene: CD81 was set to RED Added comment: CVID, which would be congenital, severe and treatable with replacement immunoglobulins. However, only a single individual reported. Sources: Expert Review |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.1918 | CD3G |
Zornitza Stark gene: CD3G was added gene: CD3G was added to gNBS. Sources: Expert list Mode of inheritance for gene: CD3G was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CD3G were set to 31921117 Phenotypes for gene: CD3G were set to Immunodeficiency 17; CD3 gamma deficient MIM# 615607 Added comment: 10 affected individuals from 5 unrelated families; homozygous and compound heterozygous variants (splicing, missense and small deletion variants) identified resulting in premature stop codons and truncated protein; multiple mouse models. All individuals displayed immune deficiency and autoimmunity of variable severity. Some individuals presented at birth with failure to thrive due to lethal SCID features. The most common immunologic profile includes partial T lymphocytopenia and low CD3, with normal B cells, NK cells, and immunoglobulins. Congenital onset. Treatment: replacement immunoglobulin Non-genetic confirmatory testing: immunoglobulin levels Sources: Expert list |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.1916 | CD27 |
Zornitza Stark gene: CD27 was added gene: CD27 was added to gNBS. Sources: Expert list Mode of inheritance for gene: CD27 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CD27 were set to 22197273; 22801960; 22365582; 25843314; 11062504 Phenotypes for gene: CD27 were set to CD27-deficiency MIM# 615122 Review for gene: CD27 was set to GREEN Added comment: 17 affected individuals from 9 unrelated families; homozygous (missense) and compound heterozygous (missense/ nonsense) variants identified in CD27; one mouse model. Affected individuals present with varied phenotypes (even within the same families); most commonly with lymphadenopathy, fever, hepatosplenomegaly, EBV-related infections, and immunodeficiency associated with hypogammaglobulinaemia. However, some CD27-deficient individuals are asymptomatic or display borderline-low hypogammaglobulinaemia. Treatment: replacement immunoglobulin treatment, rituximab, Bone marrow transplant. Non-genetic confirmatory testing: immunoglobulin levels Sources: Expert list |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.1883 | PRDX1 |
Lilian Downie gene: PRDX1 was added gene: PRDX1 was added to gNBS. Sources: Expert list Mode of inheritance for gene: PRDX1 was set to Other Publications for gene: PRDX1 were set to PMID: 20301503, PMID: 29396438, PMID: 34215320, PMID: 33982424 Phenotypes for gene: PRDX1 were set to Methylmalonic aciduria and homocystinuria, cblC type, digenic MIM#277400 Review for gene: PRDX1 was set to GREEN Added comment: Digenic inheritance with mutation in other allele of MMACHC On GUARDIAN and Rx genes list Recently, three individuals who are double heterozygous for pathogenic variants in MMACHC and PRDX1 have been identified. PRDX1 is a neighboring gene on chromosome 1 transcribed from the reverse strand. Variants identified in PRDX1 located at the intron 5 splice acceptor site caused skipping of exon 6, transcription of antisense MMACHC, and hypermethylation of the MMACHC promoter/exon 1, resulting in no gene expression from that allele [Guéant et al 2018]. Treatable with cobalamin, carnitine & diet. NB MMACHC is green on our list, on newborn screening. Sources: Expert list |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.1849 | TMEM43 |
Zornitza Stark changed review comment from: Rated as 'strong actionability' in paediatric patients by ClinGen together with other ARVC genes. ARVC is a progressive heart disease characterized by degeneration of cardiac myocytes and their subsequent replacement by fat and fibrous tissue primarily in the right ventricle, though the left ventricle may also be affected. It is associated with an increased risk of ventricular arrhythmia (VA) and sudden cardiac death (SCD) in young individuals and athletes. The VA is usually in proportion to the degree of ventricular remodeling and dysfunction, and electrical instability. The mechanism of SCD is cardiac arrest due to sustained ventricular tachycardia (VT) or ventricular fibrillation (VF). Age of onset is highly variable with a mean age of diagnosis of 31 years and a range of 4 to 64 years. Antiarrhythmic drugs and beta-blockers are not recommended in healthy gene carriers. In patients with ARVC and ventricular arrhythmia (VA), a beta-blocker or other antiarrhythmic is recommended. Recommendations for ICD placement in patients with ARVC differ across guidelines, both in terms of the indications for placement and whether recommendations are based on evidence or expert opinion. Recommendations based on non-randomized studies support ICD placement in patients with ARVC and an additional marker of increased risk of SCD (resuscitated SCA, sustained VT hemodynamically tolerated, and significant ventricular dysfunction with RVEF or LVEF ≤35%) and in patients with ARVC and syncope presumed to be due to VA if meaningful survival greater than 1 year is expected. The presence of a combination of other risk factors (e.g., male sex, frequent PVCs, syncope) may also be used to indicate implantation. Serial screening for the emergence of cardiomyopathy is recommended for clinically unaffected individuals who carry a variant associated with ARVC, including: • Medical history, with special attention to heart failure symptoms, arrhythmias, presyncope or syncope, and thromboembolism • Physical examination with special attention to cardiac and neuromuscular systems and examination of the integumentary system if ARVC is suspected • Electrocardiography • Cardiovascular imaging. Penetrance: In a study of 264 probands with genetic variants associated with ARVC who presented alive, 73% had sustained VA, 13% had symptomatic HF, and 5% had cardiac death (2% SCD, 2% HF, and 1% HF with VA) during median 8-year follow-up. Among 385 family members of the probands who also carried an ARVC variant, 32% met clinical criteria for ARVC, 11% experienced sustained VA, and 2% died during follow-up (1% from SCD, 0.5% from HF, and 0.5% non-cardiac issues). In a second study of 220 probands with genetic variants associated with ARVC who presented alive, 54% presented with sustained VT. In 321 family members of the probands who also carried an ARVC variant, 14% were symptomatic at presentation but 8% experienced VA during a mean 4-year follow-up. For all 541 cases, 60% met clinical criteria for ARVC, 30% had sustained VA, 14% developed ventricular dysfunction, 5% experienced HF, 4% had a resuscitated SCD/VF, and 2% died over a mean follow-up of 6 years.; to: Rated as 'strong actionability' in paediatric patients by ClinGen together with other ARVC genes. ARVC is a progressive heart disease characterized by degeneration of cardiac myocytes and their subsequent replacement by fat and fibrous tissue primarily in the right ventricle, though the left ventricle may also be affected. It is associated with an increased risk of ventricular arrhythmia (VA) and sudden cardiac death (SCD) in young individuals and athletes. The VA is usually in proportion to the degree of ventricular remodeling and dysfunction, and electrical instability. The mechanism of SCD is cardiac arrest due to sustained ventricular tachycardia (VT) or ventricular fibrillation (VF). Age of onset is highly variable with a mean age of diagnosis of 31 years and a range of 4 to 64 years. Antiarrhythmic drugs and beta-blockers are not recommended in healthy gene carriers. In patients with ARVC and ventricular arrhythmia (VA), a beta-blocker or other antiarrhythmic is recommended. Recommendations for ICD placement in patients with ARVC differ across guidelines, both in terms of the indications for placement and whether recommendations are based on evidence or expert opinion. Recommendations based on non-randomized studies support ICD placement in patients with ARVC and an additional marker of increased risk of SCD (resuscitated SCA, sustained VT hemodynamically tolerated, and significant ventricular dysfunction with RVEF or LVEF ≤35%) and in patients with ARVC and syncope presumed to be due to VA if meaningful survival greater than 1 year is expected. The presence of a combination of other risk factors (e.g., male sex, frequent PVCs, syncope) may also be used to indicate implantation. Serial screening for the emergence of cardiomyopathy is recommended for clinically unaffected individuals who carry a variant associated with ARVC, including: • Medical history, with special attention to heart failure symptoms, arrhythmias, presyncope or syncope, and thromboembolism • Physical examination with special attention to cardiac and neuromuscular systems and examination of the integumentary system if ARVC is suspected • Electrocardiography • Cardiovascular imaging. Penetrance: In a study of 264 probands with genetic variants associated with ARVC who presented alive, 73% had sustained VA, 13% had symptomatic HF, and 5% had cardiac death (2% SCD, 2% HF, and 1% HF with VA) during median 8-year follow-up. Among 385 family members of the probands who also carried an ARVC variant, 32% met clinical criteria for ARVC, 11% experienced sustained VA, and 2% died during follow-up (1% from SCD, 0.5% from HF, and 0.5% non-cardiac issues). In a second study of 220 probands with genetic variants associated with ARVC who presented alive, 54% presented with sustained VT. In 321 family members of the probands who also carried an ARVC variant, 14% were symptomatic at presentation but 8% experienced VA during a mean 4-year follow-up. For all 541 cases, 60% met clinical criteria for ARVC, 30% had sustained VA, 14% developed ventricular dysfunction, 5% experienced HF, 4% had a resuscitated SCD/VF, and 2% died over a mean follow-up of 6 years. Note founder variant in Newfoundland. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.1845 | CASQ2 |
Zornitza Stark changed review comment from: Well established gene-disease association. ClinGen: 'strong actionability' both for adult and paediatric patients. Treatment: beta blockers first line; ICD. There are also numerous known arrhythmia triggers which can be avoided. The mean age of onset of symptoms (usually a syncopal episode) of CPVT is between age seven and twelve years; onset as late as the fourth decade of life has been reported. Nearly 60% of patients have at least one syncopal episode before age 40. If untreated, CPVT is highly lethal, as approximately 30% of genetically affected individuals experience at least one cardiac arrest and up to 80% one or more syncopal spells. In untreated patients, the 8-year fatal or near-fatal event rates of 25% have been reported. Sudden death may be the first manifestation of the disease. For review.; to: Well established gene-disease association. ClinGen: 'strong actionability' both for adult and paediatric patients. Treatment: beta blockers first line; ICD. There are also numerous known arrhythmia triggers which can be avoided. The mean age of onset of symptoms (usually a syncopal episode) of CPVT is between age seven and twelve years; onset as late as the fourth decade of life has been reported. Nearly 60% of patients have at least one syncopal episode before age 40. If untreated, CPVT is highly lethal, as approximately 30% of genetically affected individuals experience at least one cardiac arrest and up to 80% one or more syncopal spells. In untreated patients, the 8-year fatal or near-fatal event rates of 25% have been reported. Sudden death may be the first manifestation of the disease. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.1834 | WT1 |
Zornitza Stark changed review comment from: Rated as 'moderate actionability' in paediatric patients by ClinGen. Individuals with germline WT1 pathogenic variants are more likely to have bilateral or multicentric tumors and to develop tumors at an early age. The median age of diagnosis is between 3 and 4 years and both kidneys are affected in ~5% of children. Significantly more females than males have the bilateral disease. Adult forms are very rare. In the majority of cases, the prognosis is favorable with a survival rate of over 90%. The goal of surveillance in individuals with a genetic predisposition to WT is to detect tumors while they are low-stage and require less treatment compared to advanced-stage tumors. Surveillance is not a one-time event and should continue through the period of risk. WTs can double in size every week, leading to the recommendation that evaluation with abdominal ultrasound be performed every 3-4 months, with and no less frequently than 3 times a year, until age five years. Even at this frequency, occasional tumors may present clinically between scans and families should be made aware of this. However, there is no evidence to suggest that such tumors have a worse outcome. No evidence was found on the effectiveness of surveillance in children with WT due to WT1 pathogenic variants. In addition, there is no clear evidence that surveillance results in a significant decrease in mortality or tumor stage generally. However, tumors detected by surveillance would be anticipated to be on average smaller than tumors that present clinically. There have been three small retrospective evaluations of WT surveillance published, only one of which reported a significant difference in stage distribution between screened and unscreened individuals. This report was a case series of children with Beckwith-Wiedemann syndrome and idiopathic hemihypertropy, where 0/12 screened children with WT had late-stage disease and 25/59 (42%) of unscreened children had late-stage WT (p<0.003). In addition, in Germany, where abdominal ultrasound in children is common and 10% of WT are diagnosed prior to symptoms, there are some data to suggest that asymptomatic tumors are of lower stage than those present due to clinical symptoms. Penetrance is unclear. For review.; to: Rated as 'moderate actionability' in paediatric patients by ClinGen. Individuals with germline WT1 pathogenic variants are more likely to have bilateral or multicentric tumors and to develop tumors at an early age. The median age of diagnosis is between 3 and 4 years and both kidneys are affected in ~5% of children. Significantly more females than males have the bilateral disease. Adult forms are very rare. In the majority of cases, the prognosis is favorable with a survival rate of over 90%. The goal of surveillance in individuals with a genetic predisposition to WT is to detect tumors while they are low-stage and require less treatment compared to advanced-stage tumors. Surveillance is not a one-time event and should continue through the period of risk. WTs can double in size every week, leading to the recommendation that evaluation with abdominal ultrasound be performed every 3-4 months, with and no less frequently than 3 times a year, until age five years. Even at this frequency, occasional tumors may present clinically between scans and families should be made aware of this. However, there is no evidence to suggest that such tumors have a worse outcome. No evidence was found on the effectiveness of surveillance in children with WT due to WT1 pathogenic variants. In addition, there is no clear evidence that surveillance results in a significant decrease in mortality or tumor stage generally. However, tumors detected by surveillance would be anticipated to be on average smaller than tumors that present clinically. There have been three small retrospective evaluations of WT surveillance published, only one of which reported a significant difference in stage distribution between screened and unscreened individuals. This report was a case series of children with Beckwith-Wiedemann syndrome and idiopathic hemihypertropy, where 0/12 screened children with WT had late-stage disease and 25/59 (42%) of unscreened children had late-stage WT (p<0.003). In addition, in Germany, where abdominal ultrasound in children is common and 10% of WT are diagnosed prior to symptoms, there are some data to suggest that asymptomatic tumors are of lower stage than those present due to clinical symptoms. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.1834 | GLA |
Zornitza Stark changed review comment from: Assessed as 'moderate actionability' in paediatric patients by ClinGen. In classic FD, the first symptoms, including chronic neuropathic pain and episodic severe pain crises, emerge during childhood (typically age 3-10 years). Heterozygous females typically have a later median age of onset than males (9-13 years versus 13-23 years). Rarely, females may be relatively asymptomatic and have a normal life span or may have symptoms as severe as males with the classic phenotype. Cardiac and/or cerebrovascular disease is present in most males by middle age while ESRD usually develops during the third to fifth decade. Renal and cardiac failure represent major sources of morbidity, and account for the reduced lifespan among affected males (50-58 years) and females (70-75 years) compared to the normal population. A systematic review of RCTs of ERT reported on nine studies of 351 FD patients; however, many of these studies reported only on the effect of ERT on levels of enzyme substrate. Data from 2 trials (n=39 males) found no statistically significant differences in plasma enzyme substrate and one trial (n=24 males) found no statistical differences in renal function between individuals treated with agalsidase alfa and placebo (up to 6-month follow-up). Similar results were seen for agalsidase beta. One trial of 26 male patients found a statistically significant difference in pain, favoring agalsidase alfa compared to placebo at 5-6 months after treatment. No trial reported on the effect of agalsidase alfa on mortality or cardiac/cerebrovascular disease. One trial of agalsidase beta (n=82 males and females) found no difference in mortality, renal function, or symptoms or complications of cardiac or cerebrovascular disease over 18 months. The long-term influence of ERT on risk of morbidity and mortality related to FD remains to be established. Migalastat, an oral chaperone drug, is recommended as an option for treatment for some patients with FD who are over 16 years with an amenable genetic variant who would usually be offered ERT. For non-amenable genotypes, migalastat may result in a net loss of alpha-Gal A activity, potentially worsening the disease condition. A systematic review evaluated 2 phase III RCTs that both included males and females. One RCT randomized patients to switch from ERT to migalastat (n = 36) or continue with ERT (n = 24) during an 18-month period with a 12-month extension in which all patients received migalastat. During the treatment period, the percentage of patients who had a renal, cardiac, or cerebrovascular event or died was 29% of patients on migalastat compared to 44% of patients on ERT. However, this difference was not statistically significant. A second RCT compared migalastat (n=34) with placebo (n=33) over a 6-month period, with an 18-month extension study. The primary outcome was change from baseline in interstitial capillary inclusions of the enzyme substrate globotriaosylceramide (GL-3), which was not significantly different between groups. Results from both trials indicate that migalastat does not have a significant beneficial effect on pain, health-related quality of life outcomes, or glomerular filtration rate (results were uncertain due to large confidence intervals, small sample sizes, and/or short follow-up time). Migalastat did not influence left ventricular ejection fraction but did improve left ventricular mass over 18 months. There are a number of recommendations for surveillance and agents to avoid (amiodarone). There is no consensus as to when ERT should be started.; to: Assessed as 'moderate actionability' in paediatric patients by ClinGen. In classic FD, the first symptoms, including chronic neuropathic pain and episodic severe pain crises, emerge during childhood (typically age 3-10 years). Heterozygous females typically have a later median age of onset than males (9-13 years versus 13-23 years). Rarely, females may be relatively asymptomatic and have a normal life span or may have symptoms as severe as males with the classic phenotype. Cardiac and/or cerebrovascular disease is present in most males by middle age while ESRD usually develops during the third to fifth decade. Renal and cardiac failure represent major sources of morbidity, and account for the reduced lifespan among affected males (50-58 years) and females (70-75 years) compared to the normal population. A systematic review of RCTs of ERT reported on nine studies of 351 FD patients; however, many of these studies reported only on the effect of ERT on levels of enzyme substrate. Data from 2 trials (n=39 males) found no statistically significant differences in plasma enzyme substrate and one trial (n=24 males) found no statistical differences in renal function between individuals treated with agalsidase alfa and placebo (up to 6-month follow-up). Similar results were seen for agalsidase beta. One trial of 26 male patients found a statistically significant difference in pain, favoring agalsidase alfa compared to placebo at 5-6 months after treatment. No trial reported on the effect of agalsidase alfa on mortality or cardiac/cerebrovascular disease. One trial of agalsidase beta (n=82 males and females) found no difference in mortality, renal function, or symptoms or complications of cardiac or cerebrovascular disease over 18 months. The long-term influence of ERT on risk of morbidity and mortality related to FD remains to be established. Migalastat, an oral chaperone drug, is recommended as an option for treatment for some patients with FD who are over 16 years with an amenable genetic variant who would usually be offered ERT. For non-amenable genotypes, migalastat may result in a net loss of alpha-Gal A activity, potentially worsening the disease condition. A systematic review evaluated 2 phase III RCTs that both included males and females. One RCT randomized patients to switch from ERT to migalastat (n = 36) or continue with ERT (n = 24) during an 18-month period with a 12-month extension in which all patients received migalastat. During the treatment period, the percentage of patients who had a renal, cardiac, or cerebrovascular event or died was 29% of patients on migalastat compared to 44% of patients on ERT. However, this difference was not statistically significant. A second RCT compared migalastat (n=34) with placebo (n=33) over a 6-month period, with an 18-month extension study. The primary outcome was change from baseline in interstitial capillary inclusions of the enzyme substrate globotriaosylceramide (GL-3), which was not significantly different between groups. Results from both trials indicate that migalastat does not have a significant beneficial effect on pain, health-related quality of life outcomes, or glomerular filtration rate (results were uncertain due to large confidence intervals, small sample sizes, and/or short follow-up time). Migalastat did not influence left ventricular ejection fraction but did improve left ventricular mass over 18 months. There are a number of recommendations for surveillance and agents to avoid (amiodarone). There is no consensus as to when ERT should be started. Note ERT is licensed in Australia from age 7 years. However, carbamazepine relieves neuropathic pain, which has onset in early childhood. Overall, include. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.1833 | SMAD2 |
Zornitza Stark gene: SMAD2 was added gene: SMAD2 was added to gNBS. Sources: Expert Review Mode of inheritance for gene: SMAD2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Phenotypes for gene: SMAD2 were set to Loeys-Dietz syndrome 6, MIM# 619656 Review for gene: SMAD2 was set to GREEN Added comment: 9 individuals from 5 unrelated families reported with LDS phenotype. Gene-disease association rated 'moderate' by ClinGen but this gene is included in our diagnostic testing. LDS included in gNBS panel as in general medical actionability for the LDS group of disorders is considered established. Can manifest in early childhood. Treatment: different interventions, including beta-blockers, surgical and monitoring Non-genetic confirmatory test: characteristic clinical findings Sources: Expert Review |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.1821 | RET |
Zornitza Stark changed review comment from: Established gene-disease associations. Assessed as 'strong actionability' in paediatric patients by ClinGen. Onset of MEN2A is typically prior to age 35, usually between ages 5 and 25. MTC is generally the first manifestation in MEN2A with probands presenting with a neck mass or neck pain. Metastatic spread is common. MTC is the most common cause of death in patients with MEN2A. PHEOs usually present after MTC or concomitantly but are the first manifestation in 13-27% of individuals; they occur in about 50% of individuals. PHEOs are diagnosed at an earlier age, have subtler symptoms, and are more likely to be bilateral than sporadic tumors, with malignant transformation occurring in about 4% of cases. Even without malignant progression, PHEOs can be lethal from intractable hypertension or anesthesia-induced hypertensive crises. Depending on the risk category of the RET pathogenic variant, PHEOs have been observed as early as 5 years of age. For MEN2A children with a “high-risk” pathogenic variant, patients should undergo annual ultrasound and screening for increased calcitonin levels starting at 3 years of age and proceed to thyroidectomy when elevated levels are detected or at 5 years of age. For patients with a “moderate-risk” pathogenic variant, considering the clinical variability of disease expression in family members in this category, annual physical examination, cervical US, and measurement of serum calcitonin levels, should begin at 5 years of age. Biochemical surveillance for PHPT should begin at 11 years and 16 years of age for patients with high- and moderate-risk variants, respectively; this screening is recommended annually for “high-risk” patients and at least every 2-3 years in “moderate-risk” patients. Biochemical screening for PHEO should begin at age 11 for patients with high-risk variants and age 16 for patients with moderate-risk variants. For review: actionable in first 5 years of life?; to: Established gene-disease associations. Assessed as 'strong actionability' in paediatric patients by ClinGen. Onset of MEN2A is typically prior to age 35, usually between ages 5 and 25. MTC is generally the first manifestation in MEN2A with probands presenting with a neck mass or neck pain. Metastatic spread is common. MTC is the most common cause of death in patients with MEN2A. PHEOs usually present after MTC or concomitantly but are the first manifestation in 13-27% of individuals; they occur in about 50% of individuals. PHEOs are diagnosed at an earlier age, have subtler symptoms, and are more likely to be bilateral than sporadic tumors, with malignant transformation occurring in about 4% of cases. Even without malignant progression, PHEOs can be lethal from intractable hypertension or anesthesia-induced hypertensive crises. Depending on the risk category of the RET pathogenic variant, PHEOs have been observed as early as 5 years of age. For MEN2A children with a “high-risk” pathogenic variant, patients should undergo annual ultrasound and screening for increased calcitonin levels starting at 3 years of age and proceed to thyroidectomy when elevated levels are detected or at 5 years of age. For patients with a “moderate-risk” pathogenic variant, considering the clinical variability of disease expression in family members in this category, annual physical examination, cervical US, and measurement of serum calcitonin levels, should begin at 5 years of age. Biochemical surveillance for PHPT should begin at 11 years and 16 years of age for patients with high- and moderate-risk variants, respectively; this screening is recommended annually for “high-risk” patients and at least every 2-3 years in “moderate-risk” patients. Biochemical screening for PHEO should begin at age 11 for patients with high-risk variants and age 16 for patients with moderate-risk variants. For review: some actionability in first 5 years, variants can be stratified in terms of risk. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.1801 | MLH1 |
Zornitza Stark changed review comment from: Note mono-allelic variants are associated with adult-onset cancer risk. MMRCS rated as 'strong actionability' in paediatric patients by ClinGen. The hallmark of MMRCS is early onset cancer, most often in childhood or young adulthood. The median age of onset of the first tumor is 7.5 years, with a wide range observed (0.4-39 years). A large portion (up to 40%) of patients develop metachronous second malignancies. The median survival after diagnosis of the primary tumor is less than 30 months. Prognosis depends on the possibility of complete resection, making early detection paramount. It is unclear what tumor spectrum will emerge among adults with MMRCS. Brain tumors are frequent and often diagnosed in the first decade of life. The rate of progression appears to be rapid in the brain tumors. The median age at diagnosis of brain tumors is 9 years (range, 2-40 years). Brain tumors are by far the most common cause of death. Colonic adenomatous oligopolyposis typically is diagnosed between 5 and 10 years of age. The progression of adenomas to malignancy in MMRCS is the most rapid of any inherited colorectal cancer syndrome. Among MMRCS patients presenting with colorectal cancer (CRC), the median age at diagnosis was 16 years (range, 8-48 years) with more than half of patients classified as pediatric-onset CRC. The age of onset of small-bowel adenomas is later; they typically develop in the second decade of life. The median age at diagnosis of small-bowel cancer was 28 years, with a range of 11-42 years. The lifetime risk of gastrointestinal cancer among MMRCS patients is the highest reported of all gastrointestinal cancer predisposition syndromes as a function of age. The median age at diagnosis of hematologic malignancy is 6.6 years. Endometrial cancer has been diagnosed between 19 and 44 years. The age at diagnosis of urinary tract tumors has ranged from 10 to 22 years. The management of MMRCS is based on the current estimates of neoplasia risk and the early age of onset for the cancers, which have led to tentative guidelines for the management of these patients. The age at which to begin surveillance varies by guideline and is represented below as age ranges. In patients with MMRCS, the following surveillance is suggested: •Screening for CRC by colonoscopy is recommended annually beginning at age 6 to 8 years. Once polyps are identified, colonoscopy every 6 months is recommended. •Annual surveillance for small-bowel cancer by upper endoscopy and video capsule endoscopy is suggested beginning at 8 to 10 years of age. Monitoring of hemoglobin levels every 6 months also is suggested, beginning at 8 years of age. •Surveillance for brain tumors by brain MRI every 6 to 12 months is suggested starting at the time of diagnosis even in the first year of life to age 2 years. •Currently, no proven surveillance modalities for leukemia or lymphoma have been identified. Complete blood count to screen for leukemia is suggested every 6 months beginning at 1 year of age. Clinical examinations and abdominal ultrasounds to screen for lymphoma every 6 months may be considered by the treating physician. •For individuals with a uterus, surveillance for endometrial cancer is suggested by transvaginal ultrasound, pelvic examination, and endometrial sampling annually starting at age 20 years. •Surveillance for cancer of the urinary tract is suggested, with annual urinalysis starting at age 10 to 20 years. •To screen for other types of tumors, whole-body MRI could be considered once a year starting at 6 years of age or when anesthesia is not needed. This method should not replace the need for ultrasound and brain MRI. Estimated penetrance in MMRCS: •50% develop small-bowel adenomas •>90% develop colorectal adenomas •59 to 70% develop colorectal cancer •58 to 70% develop high-grade brain tumours •20-40% develop lymphoma •10-40% develop leukemia •10 to 18% develop small-bowel cancer •<10% develop endometrial cancer •<10% develop urinary tract cancer •<10% develop cancer of other sites; to: Note mono-allelic variants are associated with adult-onset cancer risk. MMRCS rated as 'strong actionability' in paediatric patients by ClinGen. The hallmark of MMRCS is early onset cancer, most often in childhood or young adulthood. The median age of onset of the first tumor is 7.5 years, with a wide range observed (0.4-39 years). A large portion (up to 40%) of patients develop metachronous second malignancies. The median survival after diagnosis of the primary tumor is less than 30 months. Prognosis depends on the possibility of complete resection, making early detection paramount. It is unclear what tumor spectrum will emerge among adults with MMRCS. Brain tumors are frequent and often diagnosed in the first decade of life. The rate of progression appears to be rapid in the brain tumors. The median age at diagnosis of brain tumors is 9 years (range, 2-40 years). Brain tumors are by far the most common cause of death. Colonic adenomatous oligopolyposis typically is diagnosed between 5 and 10 years of age. The progression of adenomas to malignancy in MMRCS is the most rapid of any inherited colorectal cancer syndrome. Among MMRCS patients presenting with colorectal cancer (CRC), the median age at diagnosis was 16 years (range, 8-48 years) with more than half of patients classified as pediatric-onset CRC. The age of onset of small-bowel adenomas is later; they typically develop in the second decade of life. The median age at diagnosis of small-bowel cancer was 28 years, with a range of 11-42 years. The lifetime risk of gastrointestinal cancer among MMRCS patients is the highest reported of all gastrointestinal cancer predisposition syndromes as a function of age. The median age at diagnosis of hematologic malignancy is 6.6 years. Endometrial cancer has been diagnosed between 19 and 44 years. The age at diagnosis of urinary tract tumors has ranged from 10 to 22 years. The management of MMRCS is based on the current estimates of neoplasia risk and the early age of onset for the cancers, which have led to tentative guidelines for the management of these patients. The age at which to begin surveillance varies by guideline and is represented below as age ranges. In patients with MMRCS, the following surveillance is suggested: •Screening for CRC by colonoscopy is recommended annually beginning at age 6 to 8 years. Once polyps are identified, colonoscopy every 6 months is recommended. •Annual surveillance for small-bowel cancer by upper endoscopy and video capsule endoscopy is suggested beginning at 8 to 10 years of age. Monitoring of hemoglobin levels every 6 months also is suggested, beginning at 8 years of age. •Surveillance for brain tumors by brain MRI every 6 to 12 months is suggested starting at the time of diagnosis even in the first year of life to age 2 years. •Currently, no proven surveillance modalities for leukemia or lymphoma have been identified. Complete blood count to screen for leukemia is suggested every 6 months beginning at 1 year of age. Clinical examinations and abdominal ultrasounds to screen for lymphoma every 6 months may be considered by the treating physician. •For individuals with a uterus, surveillance for endometrial cancer is suggested by transvaginal ultrasound, pelvic examination, and endometrial sampling annually starting at age 20 years. •Surveillance for cancer of the urinary tract is suggested, with annual urinalysis starting at age 10 to 20 years. •To screen for other types of tumors, whole-body MRI could be considered once a year starting at 6 years of age or when anesthesia is not needed. This method should not replace the need for ultrasound and brain MRI. Estimated penetrance in MMRCS: •50% develop small-bowel adenomas •>90% develop colorectal adenomas •59 to 70% develop colorectal cancer •58 to 70% develop high-grade brain tumours •20-40% develop lymphoma •10-40% develop leukemia •10 to 18% develop small-bowel cancer •<10% develop endometrial cancer •<10% develop urinary tract cancer •<10% develop cancer of other sites |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.1781 | PRKG1 |
Zornitza Stark gene: PRKG1 was added gene: PRKG1 was added to gNBS. Sources: ClinGen for review, cardiac, treatable tags were added to gene: PRKG1. Mode of inheritance for gene: PRKG1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Phenotypes for gene: PRKG1 were set to Aortic aneurysm, familial thoracic 8, MIM#615436 Penetrance for gene: PRKG1 were set to Incomplete Review for gene: PRKG1 was set to AMBER Added comment: Assessed as 'strong actionability' in paediatric patients by ClinGen. FTAAD is a rare genetic vascular disease characterized by the familial occurrence of thoracic aortic aneurysm, dissection, or dilatation affecting one or more aortic segments (aortic root, ascending aorta, arch, or descending aorta). Variable age of clinical presentation. Prophylactic surgical repair of the aorta is recommended at 4.5-5.0 cm for patients with pathogenic variants in MYH11, SMAD3, and ACTA2 and at 4.0-4.5 cm for patients with pathogenic variants in TGFBR1 or TGFBR2. Beta adrenergic-blocking agents are recommended to reduce aortic dilation. Losartan was added as an alternative to beta adrenergic-blocking agents in FTAAD after studies showed its efficacy in children and young adults with MFS who were randomly assigned to losartan or atenolol. Penetrance: A study of 31 individuals with PRKG1 pathogenic variants indicated that 63% presented with an aortic dissection and 37% had aortic root enlargement. The cumulative risk of an aortic dissection or repair of an aortic aneurysm by age 55 has been estimated as 86% (95% CI: 70-95%). Sources: ClinGen |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.1778 | LOX |
Zornitza Stark gene: LOX was added gene: LOX was added to gNBS. Sources: ClinGen for review, cardiac, treatable tags were added to gene: LOX. Mode of inheritance for gene: LOX was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Phenotypes for gene: LOX were set to Aortic aneurysm, familial thoracic 10, MIM#617168 Penetrance for gene: LOX were set to Incomplete Review for gene: LOX was set to AMBER Added comment: Assessed as 'strong actionability' in paediatric patients by ClinGen. FTAAD is a rare genetic vascular disease characterized by the familial occurrence of thoracic aortic aneurysm, dissection, or dilatation affecting one or more aortic segments (aortic root, ascending aorta, arch, or descending aorta). Variable age of clinical presentation. Prophylactic surgical repair of the aorta is recommended at 4.5-5.0 cm for patients with pathogenic variants in MYH11, SMAD3, and ACTA2 and at 4.0-4.5 cm for patients with pathogenic variants in TGFBR1 or TGFBR2. Beta adrenergic-blocking agents are recommended to reduce aortic dilation. Losartan was added as an alternative to beta adrenergic-blocking agents in FTAAD after studies showed its efficacy in children and young adults with MFS who were randomly assigned to losartan or atenolol. Penetrance: A study of 15 individuals with LOX pathogenic variants indicated that 73% had aortic aneurysms and 1 individual (7%) had an aortic dissection. Sources: ClinGen |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.1772 | RUNX1 |
Zornitza Stark gene: RUNX1 was added gene: RUNX1 was added to gNBS. Sources: ClinGen for review, treatable, haematological tags were added to gene: RUNX1. Mode of inheritance for gene: RUNX1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Phenotypes for gene: RUNX1 were set to Platelet disorder, familial, with associated myeloid malignancy, MIM# 601399 Review for gene: RUNX1 was set to AMBER Added comment: Assessed as 'moderate actionability' in paediatric patients by ClinGen. HTHCPS is characterized by mild to moderate thrombocytopenia with normal platelet size, abnormal platelet functioning (defective release of delta granules and/or aggregation defects), and an increased risk of developing a haematologic malignancy. Age of onset of bleeding can be highly variable, with some individuals presenting in early infancy and others not recognizing their symptoms until much later in life. Severe thrombocytopenia or profound platelet dysfunction can result in recognition during the perinatal or infancy period. Hematologic malignancies can occur in childhood or adulthood; the range of age of onset is wide with a median age of 33 years. Use of clotting promotors (e.g., desmopressin, epsilon aminocaproic acid, tranexamic acid) can be used for surgeries, injuries, or dental treatments. Platelet transfusions may be used for severe bleeding or procedures with a high bleeding risk. Though there is no specific treatment for HTHCPS, there are recommendations regarding the indications and timing of hematopoietic stem cell transplantation (HSCT) that vary. HSCT in pre-malignancy patients, particularly in the absence of any clonal progression, is debatable due to transplantation-associated risks and incomplete penetrance. Some suggested indications for HSCT include severe or symptomatic cytopenias, severe marrow dysplasia (particularly in the context of falling blood counts), complex or high-risk (e.g., monosomy 7) cytogenetic abnormalities (particularly if the clones are large or increasing in size) and increasing blasts >5%. Consider use of a medical alert bracelet for thrombocytopenia, platelet dysfunction, or hematologic malignancy as indicated. Sources: ClinGen |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.1770 | DICER1 |
Zornitza Stark gene: DICER1 was added gene: DICER1 was added to gNBS. Sources: ClinGen Mode of inheritance for gene: DICER1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Phenotypes for gene: DICER1 were set to DICER1 syndrome, MONDO:0017288 Penetrance for gene: DICER1 were set to Incomplete Review for gene: DICER1 was set to AMBER Added comment: Rated as 'moderate actionability' in paediatric patients by ClinGen. A multiple registry study examining neoplasm incidence in a cohort containing 102 non-probands with DICER1 pathogenic variants (3,344 person-years of observation in non-probands) found that by age 10 years, 5.3% (95% CI, 0.6% to 9.7%) of non-probands had developed a neoplasm (females, 4.0%; males, 6.6%). By age 50 years, 19.3% (95% CI, 8.4% to 29.0%) of non-probands had developed a neoplasm (females, 26.5%; males, 10.2%). Most individuals with pathogenic variants in DICER1 are healthy or have only minor DICER1-associaited conditions. The most severe manifestations tend to present in early childhood with adulthood characterized by good health. The majority of tumors in individuals with DICER1 pathogenic variants occur in individuals younger than 40. Many of these tumors typically only occur in childhood, including: PPB (before age 7), CN (before age 4), CBME typically occurs in young children, pituitary blastoma (before age 2), and childhood pineoblastoma (only one has been reported associated with a DICER1 mutation). Surveillance recommendations: In order to detect pulmonary cysts or PPB (one of the most important causes of DICER1-associated morbidity and mortality), chest x-rays are recommended every 6 months from birth to through age 7 years and then annually from 8-12 years. A chest computed tomography (CT) (with efforts to minimize radiation) should be obtained by 9 months of age, preferably between 3 and 6 months of age and repeated at approximately 2.5 years of age. Abdominal ultrasound is recommended for the detection in infancy or at the time of the first chest CT then every 6-12 months until at least 8 years of age. Annual ultrasound may be considered until 12 years of age. Beginning at ages 8-10 females should receive pelvic ultrasound performed in conjunction with abdominal ultrasound (every 6-12 months) until at least age 40 or as needed for signs and symptoms. Individuals should undergo thyroid ultrasound with assessment for regional adenopathy every 2 to 3 years starting at age 8 or as needed for signs and symptoms. An annual routine dilated ophthalmologic exam with visual acuity screening is recommended from age 3 to at least age 10 for detection of CBME. Sources: ClinGen |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.1748 | PRKAR1A |
Zornitza Stark edited their review of gene: PRKAR1A: Added comment: Rated as 'strong actionability' in paediatric patients by ClinGen, principally due to benefit from early detection of cardiac myxomas through surveillance. CNC is associated with skin pigmentary abnormalities, myxomas, endocrine tumors or overactivity, and schwannomas. Lentigines are the most common presenting feature of CNC and may be present at birth. Typically, they increase in number at puberty, fade after the fourth decade, but may still be evident in the eighth decade. Cutaneous myxomas appear between birth and the fourth decade. Cardiac myxomas may occur at a young age. Breast myxomas occur in females after puberty. Males and females may develop nipple myxomas at any age. In a minority of individuals, PPNAD presents in the first two to three years; in the majority, it presents in the second or third decade. LCCSCT often present in the first decade. Signs and symptoms of CNC may be present at birth, but the median age of diagnosis is 20 years. Most patients with CNC present with a mild increase in GH. However, clinically evident acromegaly is a relatively frequent manifestation of CNC, occurring in approximately 10% of adults at the time of presentation. Most individuals with CNC have a normal life span. However, because some die at an early age, the average life expectancy for individuals with CNC is 50 years. Causes of death include complications of cardiac myxoma (myxoma emboli, cardiomyopathy, cardiac arrhythmia, and surgical intervention), metastatic or intracranial PMS, thyroid carcinoma, and metastatic pancreatic and testicular tumors. The only preventive measure in an asymptomatic individual is surgical removal of a heart tumor (cardiac myxoma) prior to the development of heart dysfunction, stroke, or other embolism. Cardiac myxomas should be diagnosed early through regular screening. Development of metabolic abnormalities from Cushing syndrome or arthropathy and other complications from acromegaly may be prevented by medical or surgical treatment of the respective endocrine manifestations. The overall penetrance of CNC in those with a PRKAR1A pathogenic variant is greater than 95% by age 50 years. 30-60% have cardiac myxomas.; Changed rating: GREEN; Changed phenotypes: Carney complex, type 1, MIM# 160980 |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.1746 | MEN1 |
Zornitza Stark changed review comment from: For review re age of onset: surveillance starts age 5, disease onset generally later.; to: For review re age of onset: surveillance starts age 5, disease onset generally later. Rated as 'strong actionability' in paediatric patients by ClinGen. Parathyroid tumors, which cause PHPT, are the most common feature and the first clinical manifestation in 90% of individuals with MEN1 with onset typically between ages 20 and 25 years. Almost all (95-100%) individuals with MEN1 can expect to have PHPT by age 50 years. However, MEN1 affects all age groups, with a reported age range of 5 to 81 years; 17% of MEN1 tumors are diagnosed under age 21. Untreated patients with MEN1 have a decreased life expectancy with a 50% probability of death by age 50. The cause of death in 50-70% of cases is due to a malignant tumor process or sequelae of the disease, with malignancies accounting for 30% of all deaths. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.1740 | TGFB2 |
Zornitza Stark gene: TGFB2 was added gene: TGFB2 was added to gNBS. Sources: ClinGen Mode of inheritance for gene: TGFB2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Phenotypes for gene: TGFB2 were set to Loeys-Dietz syndrome 4, MIM# 614816 Review for gene: TGFB2 was set to GREEN Added comment: Rated as 'strong actionability' in paediatric patients by ClinGen. Individuals with LDS are predisposed to widespread and aggressive arterial aneurysms which are the major source of morbidity and mortality. Aortic growth can be faster than 10mm per year. Aortic dissection has been observed in early childhood, and the mean age of death is 26 years. Other life-threatening manifestations include spontaneous rupture of the spleen, bowel, and uterine rupture during pregnancy. Prophylactic surgical repair is typically recommended at an aortic diameter of ≥ 4.2 cm. Beta-blockers or other medications can be used to reduce hemodynamic stress. Consider Medicalert bracelet. Use of subacute bacterial endocarditis prophylaxis should be considered for individuals with connective tissue disorders and documented evidence of mitral and/or aortic regurgitation who are undergoing dental work or other procedures expected to contaminate the bloodstream with bacteria. Because of a high risk of cervical spine instability, a flexion and extension x-ray of the cervical spine should be performed prior to intubation or any other procedure involving manipulation of the neck. Sources: ClinGen |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.1736 | TECRL |
Zornitza Stark gene: TECRL was added gene: TECRL was added to gNBS. Sources: ClinGen for review, cardiac, treatable tags were added to gene: TECRL. Mode of inheritance for gene: TECRL was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: TECRL were set to Ventricular tachycardia, catecholaminergic polymorphic, 3, MIM# 614021 Review for gene: TECRL was set to GREEN Added comment: Rated as 'strong actionability' for paediatric patients by ClinGen. The mean age of onset of symptoms (usually a syncopal episode) of CPVT is between age seven and twelve years; onset as late as the fourth decade of life has been reported. Nearly 60% of patients have at least one syncopal episode before age 40. If untreated, CPVT is highly lethal, as approximately 30% of genetically affected individuals experience at least one cardiac arrest and up to 80% one or more syncopal spells. In untreated patients, the 8-year fatal or near-fatal event rates of 25% have been reported. Sudden death may be the first manifestation of the disease. Beta-blockers lacking intrinsic sympathomimetic activity are recommended as a first-line therapy in all patients with a clinical diagnosis of CPVT, including those with documented spontaneous, stress-induced VAs. Guidelines differ in their recommendations about utilizing beta-blocker therapy in phenotype negative individuals. Treatment with beta blockers is associated with a reduction in adverse cardiac events. However, variability in outcome with beta-blocker therapy is due to multiple factors, including dosing and compliance. In a study of 101 patients with CPVT (22 diagnosed clinically and 79 diagnosed molecularly), 81 were administered beta-blockers (57 symptomatic and 24 asymptomatic individuals). Estimated 4- and 8-year cardiac event rates were 8% and 27%, respectively in patients taking beta-blockers, and 33% and 58% in those not taking beta blockers (log-rank p=0.01). Corresponding statistics for fatal events were 1% and 11% with beta-blockers vs. 18% and 25% without (log-rank p=0.05). Event rates in asymptomatic patients with a positive genotype were similar to other patients. In multivariate models, absence of beta-blockers was an independent predictor of cardiac events (hazard ratio [HR], 5.48; 95% CI, 1.8 to 16.7, p=0.003) and of fatal events (HR, 5.54; 95% CI, 1.2 to 26.1, p=0.03). Of the 37 asymptomatic patients with a positive genotype, 9 (24%) had cardiac events. In patients with CPVT and recurrent sustained VT or syncope, while receiving adequate or maximally tolerated beta blocker, treatment intensification with either combination medication therapy (e.g., beta blocker with flecainide), left cardiac sympathetic denervation, and/or an ICD is recommended. Clinical penetrance ranges from 25 to 100%, with an average of 70 to 80%. Syncope appears to be the first symptom in more than half of the patients. When untreated, mortality from CPVT is high, reaching 30 to 50% by the age of 30 years. For review: age of onset and penetrance. Sources: ClinGen |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.1734 | CALM3 |
Zornitza Stark gene: CALM3 was added gene: CALM3 was added to gNBS. Sources: ClinGen for review, cardiac, treatable tags were added to gene: CALM3. Mode of inheritance for gene: CALM3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Phenotypes for gene: CALM3 were set to Ventricular tachycardia, catecholaminergic polymorphic 6 , MIM# 618782 Penetrance for gene: CALM3 were set to Incomplete Review for gene: CALM3 was set to GREEN Added comment: Rated as 'strong actionability' for paediatric patients by ClinGen. The mean age of onset of symptoms (usually a syncopal episode) of CPVT is between age seven and twelve years; onset as late as the fourth decade of life has been reported. Nearly 60% of patients have at least one syncopal episode before age 40. If untreated, CPVT is highly lethal, as approximately 30% of genetically affected individuals experience at least one cardiac arrest and up to 80% one or more syncopal spells. In untreated patients, the 8-year fatal or near-fatal event rates of 25% have been reported. Sudden death may be the first manifestation of the disease. Instances of sudden infant death syndrome (SIDS) have been associated with pathogenic variants in RYR2. Individuals with pathogenic variants in CALM1, CALM2 or CALM3 can have a severe phenotype, with earlier onset, QT prolongation, and a high predilection for cardiac arrest and sudden death. Beta-blockers lacking intrinsic sympathomimetic activity are recommended as a first-line therapy in all patients with a clinical diagnosis of CPVT, including those with documented spontaneous, stress-induced VAs. Guidelines differ in their recommendations about utilizing beta-blocker therapy in phenotype negative individuals. Treatment with beta blockers is associated with a reduction in adverse cardiac events. However, variability in outcome with beta-blocker therapy is due to multiple factors, including dosing and compliance. In a study of 101 patients with CPVT (22 diagnosed clinically and 79 diagnosed molecularly), 81 were administered beta-blockers (57 symptomatic and 24 asymptomatic individuals). Estimated 4- and 8-year cardiac event rates were 8% and 27%, respectively in patients taking beta-blockers, and 33% and 58% in those not taking beta blockers (log-rank p=0.01). Corresponding statistics for fatal events were 1% and 11% with beta-blockers vs. 18% and 25% without (log-rank p=0.05). Event rates in asymptomatic patients with a positive genotype were similar to other patients. In multivariate models, absence of beta-blockers was an independent predictor of cardiac events (hazard ratio [HR], 5.48; 95% CI, 1.8 to 16.7, p=0.003) and of fatal events (HR, 5.54; 95% CI, 1.2 to 26.1, p=0.03). Of the 37 asymptomatic patients with a positive genotype, 9 (24%) had cardiac events. In patients with CPVT and recurrent sustained VT or syncope, while receiving adequate or maximally tolerated beta blocker, treatment intensification with either combination medication therapy (e.g., beta blocker with flecainide), left cardiac sympathetic denervation, and/or an ICD is recommended. Clinical penetrance ranges from 25 to 100%, with an average of 70 to 80%. Syncope appears to be the first symptom in more than half of the patients. When untreated, mortality from CPVT is high, reaching 30 to 50% by the age of 30 years. For review: age of onset and penetrance. Sources: ClinGen |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.1732 | CALM2 |
Zornitza Stark gene: CALM2 was added gene: CALM2 was added to gNBS. Sources: ClinGen for review, cardiac, treatable tags were added to gene: CALM2. Mode of inheritance for gene: CALM2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Phenotypes for gene: CALM2 were set to Catecholaminergic polymorphic ventricular tachycardia MONDO:0017990 Review for gene: CALM2 was set to GREEN Added comment: Rated as 'strong actionability' for paediatric patients by ClinGen. The mean age of onset of symptoms (usually a syncopal episode) of CPVT is between age seven and twelve years; onset as late as the fourth decade of life has been reported. Nearly 60% of patients have at least one syncopal episode before age 40. If untreated, CPVT is highly lethal, as approximately 30% of genetically affected individuals experience at least one cardiac arrest and up to 80% one or more syncopal spells. In untreated patients, the 8-year fatal or near-fatal event rates of 25% have been reported. Sudden death may be the first manifestation of the disease. Instances of sudden infant death syndrome (SIDS) have been associated with pathogenic variants in RYR2. Individuals with pathogenic variants in CALM1, CALM2 or CALM3 can have a severe phenotype, with earlier onset, QT prolongation, and a high predilection for cardiac arrest and sudden death. Beta-blockers lacking intrinsic sympathomimetic activity are recommended as a first-line therapy in all patients with a clinical diagnosis of CPVT, including those with documented spontaneous, stress-induced VAs. Guidelines differ in their recommendations about utilizing beta-blocker therapy in phenotype negative individuals. Treatment with beta blockers is associated with a reduction in adverse cardiac events. However, variability in outcome with beta-blocker therapy is due to multiple factors, including dosing and compliance. In a study of 101 patients with CPVT (22 diagnosed clinically and 79 diagnosed molecularly), 81 were administered beta-blockers (57 symptomatic and 24 asymptomatic individuals). Estimated 4- and 8-year cardiac event rates were 8% and 27%, respectively in patients taking beta-blockers, and 33% and 58% in those not taking beta blockers (log-rank p=0.01). Corresponding statistics for fatal events were 1% and 11% with beta-blockers vs. 18% and 25% without (log-rank p=0.05). Event rates in asymptomatic patients with a positive genotype were similar to other patients. In multivariate models, absence of beta-blockers was an independent predictor of cardiac events (hazard ratio [HR], 5.48; 95% CI, 1.8 to 16.7, p=0.003) and of fatal events (HR, 5.54; 95% CI, 1.2 to 26.1, p=0.03). Of the 37 asymptomatic patients with a positive genotype, 9 (24%) had cardiac events. In patients with CPVT and recurrent sustained VT or syncope, while receiving adequate or maximally tolerated beta blocker, treatment intensification with either combination medication therapy (e.g., beta blocker with flecainide), left cardiac sympathetic denervation, and/or an ICD is recommended. Clinical penetrance ranges from 25 to 100%, with an average of 70 to 80%. Syncope appears to be the first symptom in more than half of the patients. When untreated, mortality from CPVT is high, reaching 30 to 50% by the age of 30 years. For review: age of onset and penetrance. Sources: ClinGen |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.1730 | CALM1 |
Zornitza Stark gene: CALM1 was added gene: CALM1 was added to gNBS. Sources: ClinGen for review, cardiac, treatable tags were added to gene: CALM1. Mode of inheritance for gene: CALM1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Phenotypes for gene: CALM1 were set to Ventricular tachycardia, catecholaminergic polymorphic, 4, MIM# 614916 Penetrance for gene: CALM1 were set to Incomplete Review for gene: CALM1 was set to GREEN Added comment: Rated as 'strong actionability' for paediatric patients by ClinGen. The mean age of onset of symptoms (usually a syncopal episode) of CPVT is between age seven and twelve years; onset as late as the fourth decade of life has been reported. Nearly 60% of patients have at least one syncopal episode before age 40. If untreated, CPVT is highly lethal, as approximately 30% of genetically affected individuals experience at least one cardiac arrest and up to 80% one or more syncopal spells. In untreated patients, the 8-year fatal or near-fatal event rates of 25% have been reported. Sudden death may be the first manifestation of the disease. Instances of sudden infant death syndrome (SIDS) have been associated with pathogenic variants in RYR2. Individuals with pathogenic variants in CALM1, CALM2 or CALM3 can have a severe phenotype, with earlier onset, QT prolongation, and a high predilection for cardiac arrest and sudden death. Beta-blockers lacking intrinsic sympathomimetic activity are recommended as a first-line therapy in all patients with a clinical diagnosis of CPVT, including those with documented spontaneous, stress-induced VAs. Guidelines differ in their recommendations about utilizing beta-blocker therapy in phenotype negative individuals. Treatment with beta blockers is associated with a reduction in adverse cardiac events. However, variability in outcome with beta-blocker therapy is due to multiple factors, including dosing and compliance. In a study of 101 patients with CPVT (22 diagnosed clinically and 79 diagnosed molecularly), 81 were administered beta-blockers (57 symptomatic and 24 asymptomatic individuals). Estimated 4- and 8-year cardiac event rates were 8% and 27%, respectively in patients taking beta-blockers, and 33% and 58% in those not taking beta blockers (log-rank p=0.01). Corresponding statistics for fatal events were 1% and 11% with beta-blockers vs. 18% and 25% without (log-rank p=0.05). Event rates in asymptomatic patients with a positive genotype were similar to other patients. In multivariate models, absence of beta-blockers was an independent predictor of cardiac events (hazard ratio [HR], 5.48; 95% CI, 1.8 to 16.7, p=0.003) and of fatal events (HR, 5.54; 95% CI, 1.2 to 26.1, p=0.03). Of the 37 asymptomatic patients with a positive genotype, 9 (24%) had cardiac events. In patients with CPVT and recurrent sustained VT or syncope, while receiving adequate or maximally tolerated beta blocker, treatment intensification with either combination medication therapy (e.g., beta blocker with flecainide), left cardiac sympathetic denervation, and/or an ICD is recommended. Clinical penetrance ranges from 25 to 100%, with an average of 70 to 80%. Syncope appears to be the first symptom in more than half of the patients. When untreated, mortality from CPVT is high, reaching 30 to 50% by the age of 30 years. For review: age of onset and penetrance. Sources: ClinGen |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.1728 | RPE65 |
Zornitza Stark gene: RPE65 was added gene: RPE65 was added to gNBS. Sources: ClinGen for review, treatable, ophthalmological tags were added to gene: RPE65. Mode of inheritance for gene: RPE65 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: RPE65 were set to Leber congenital amaurosis 2 MIM#204100; Retinitis pigmentosa 20 MIM#613794 Review for gene: RPE65 was set to GREEN Added comment: Assessed as 'strong actionability' in paediatric patients by ClinGen. Biallelic RPE65 mutation-associated retinal dystrophy is a form of IRD caused by biallelic pathogenic variants in RPE65; it presents as a spectrum of disease with variable age of onset and progression of vision loss. Common clinical findings across the spectrum include night blindness, progressive loss of visual fields and loss of central vision. In LCA, night blindness often occurs from birth. Characteristically, these patients have residual cone-mediated vision in the first to third decades with progressive visual field loss until complete blindness is observed, most often in mid- to late-adulthood. A range of age of onset has been described for night blindness in RP, but it typically onsets in later childhood. In December 2017, the FDA approved LUXTURNA (voretigene neparvovec-rzyl) gene therapy for the treatment of patients with confirmed biallelic RPE65 mutation-associated retinal dystrophy. The FDA’s conclusion of efficacy is based on improvement in a functional vision score over 1 year in a single open-label controlled Phase 3 study of 31 affected patients. The average age of the 31 randomized patients was 15 years (range 4 to 44 years), including 64% pediatric subjects (n=20, age from 4 to 17 years) and 36% adults (n=11). Functional vision was scored by a patient’s ability to navigate a course in various luminance levels. Using both treated eyes of the 21 subjects in the LUXTURNA treatment group, 11 (52%) had a clinically meaningful score improvement, while only one of the ten (10%) subjects in the control group had a clinically meaningful score improvement. Using the first treated eye only, 15/21 (71%) had a clinically meaningful score improvement, while no comparable score improvement was observed in controls. Other secondary clinical outcomes were also examined. Analysis of white light full-field light sensitivity threshold testing showed statistically significant improvement at 1 year in the LUXTURNA treatment group compared to the control group. The change in visual acuity was not significantly different between the LUXTURNA and control groups. LUXTURNA is administered subretinally by injection. Per the FDA package insert, the most common adverse reactions (incidence ≥ 5%) in the clinical trials for LUXTURNA included conjunctival hyperemia, cataract, increased intraocular pressure, retinal tear, dellen (thinning of the corneal stroma), and macular hole. Several other ocular adverse effects were also reported, including risk of endophthalmitis. Safety data was included on the basis of 41 patients (81 eyes). For review: availability of therapy? Sources: ClinGen |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.1721 | F7 |
Zornitza Stark changed review comment from: Well established gene-disease association. Variable severity. Treatment: Recombinant coagulation Factor VIIa Non-genetic confirmatory testing: factor VII level; to: Well established gene-disease association. Variable severity. Treatment: Recombinant coagulation Factor VIIa Non-genetic confirmatory testing: factor VII level Rated as 'strong actionability' in paediatric patients by ClinGen. Clinical expression of factor VII deficiency is highly variable, and no consistent relationship has been found between the severity of the hemorrhagic syndrome and the residual levels of FVII activity. Individuals can be completely asymptomatic despite a very low FVII level. A bleeding history appears more predictive of further bleeding than the factor VII level. Factor VII levels increase during pregnancy, but levels usually remain insufficient for hemostasis in severely affected cases. Individuals with no history of bleeding do not appear to be at increased risk of PPH. Heterozygotes often have approximately half-normal levels of coagulation factors and are often asymptomatic. However, up to 2% of patients with severe bleeding phenotype are heterozygotes. Consider prophylaxis using rFVIIa in certain circumstances. Long term prophylaxis should be considered for cases with a personal or family history of severe bleeding or with FVII activity <0.01 IU/ml using rFVIIa, adjusting to maintain clinical response. Short term prophylaxis should be considered for cases for neonates without a personal or family history of severe bleeding but who have FVII activity 0.01-0.05 IU/ml up to 6-12 months of age. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.1710 | COL9A1 |
David Amor changed review comment from: Gene-disease association: strong but rare, prbably <1% of Sticller syndrome; Van Camp et al. (2006) described a consanguineous Moroccan family in which 4 of 10 sibs had features characteristic of Stickler syndrome, including moderate to severe sensorineural hearing loss, moderate to high myopia with vitreoretinopathy, and epiphyseal dysplasia. Nikopoulos et al. (2011) reported 2 sisters in a Turkish family and 1 boy in a Moroccan family with features of autosomal recessive Stickler syndrome. All 3 individuals had myopia, vitreous changes, sensorineural hearing loss, and epiphyseal dysplasia. They also had exudative rhegmatogenous retinal detachment. Severity: moderate-severe Age of onset: congenital Non-molecular confirmatory testing: Affected individuals have moderate-to-severe sensorineural hearing loss, moderate-to-high myopia with vitreoretinopathy, cataracts, and epiphyseal dysplasia Treatment: as per other Stickler syndrome; to: Gene-disease association: strong but rare, prbably <1% of Sticller syndrome; Van Camp et al. (2006) described a consanguineous Moroccan family in which 4 of 10 sibs had features characteristic of Stickler syndrome, including moderate to severe sensorineural hearing loss, moderate to high myopia with vitreoretinopathy, and epiphyseal dysplasia. Nikopoulos et al. (2011) reported 2 sisters in a Turkish family and 1 boy in a Moroccan family with features of autosomal recessive Stickler syndrome. All 3 individuals had myopia, vitreous changes, sensorineural hearing loss, and epiphyseal dysplasia. They also had exudative rhegmatogenous retinal detachment. Severity: moderate-severe Age of onset: congenital Non-molecular confirmatory testing: Affected individuals have moderate-to-severe sensorineural hearing loss, moderate-to-high myopia with vitreoretinopathy, cataracts, and epiphyseal dysplasia Treatment: as per other Stickler syndrome |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.1701 | GLA |
Zornitza Stark changed review comment from: For review: screen only for males or include both?; to: Assessed as 'moderate actionability' in paediatric patients by ClinGen. In classic FD, the first symptoms, including chronic neuropathic pain and episodic severe pain crises, emerge during childhood (typically age 3-10 years). Heterozygous females typically have a later median age of onset than males (9-13 years versus 13-23 years). Rarely, females may be relatively asymptomatic and have a normal life span or may have symptoms as severe as males with the classic phenotype. Cardiac and/or cerebrovascular disease is present in most males by middle age while ESRD usually develops during the third to fifth decade. Renal and cardiac failure represent major sources of morbidity, and account for the reduced lifespan among affected males (50-58 years) and females (70-75 years) compared to the normal population. A systematic review of RCTs of ERT reported on nine studies of 351 FD patients; however, many of these studies reported only on the effect of ERT on levels of enzyme substrate. Data from 2 trials (n=39 males) found no statistically significant differences in plasma enzyme substrate and one trial (n=24 males) found no statistical differences in renal function between individuals treated with agalsidase alfa and placebo (up to 6-month follow-up). Similar results were seen for agalsidase beta. One trial of 26 male patients found a statistically significant difference in pain, favoring agalsidase alfa compared to placebo at 5-6 months after treatment. No trial reported on the effect of agalsidase alfa on mortality or cardiac/cerebrovascular disease. One trial of agalsidase beta (n=82 males and females) found no difference in mortality, renal function, or symptoms or complications of cardiac or cerebrovascular disease over 18 months. The long-term influence of ERT on risk of morbidity and mortality related to FD remains to be established. Migalastat, an oral chaperone drug, is recommended as an option for treatment for some patients with FD who are over 16 years with an amenable genetic variant who would usually be offered ERT. For non-amenable genotypes, migalastat may result in a net loss of alpha-Gal A activity, potentially worsening the disease condition. A systematic review evaluated 2 phase III RCTs that both included males and females. One RCT randomized patients to switch from ERT to migalastat (n = 36) or continue with ERT (n = 24) during an 18-month period with a 12-month extension in which all patients received migalastat. During the treatment period, the percentage of patients who had a renal, cardiac, or cerebrovascular event or died was 29% of patients on migalastat compared to 44% of patients on ERT. However, this difference was not statistically significant. A second RCT compared migalastat (n=34) with placebo (n=33) over a 6-month period, with an 18-month extension study. The primary outcome was change from baseline in interstitial capillary inclusions of the enzyme substrate globotriaosylceramide (GL-3), which was not significantly different between groups. Results from both trials indicate that migalastat does not have a significant beneficial effect on pain, health-related quality of life outcomes, or glomerular filtration rate (results were uncertain due to large confidence intervals, small sample sizes, and/or short follow-up time). Migalastat did not influence left ventricular ejection fraction but did improve left ventricular mass over 18 months. There are a number of recommendations for surveillance and agents to avoid (amiodarone). There is no consensus as to when ERT should be started. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.1681 | COL4A4 |
Zornitza Stark changed review comment from: Assessed as 'strongly actionable' in paediatric patients by ClinGen. Treatment: ACE inhibitors alter long-term outcomes. Individuals with AR AS are recommended to be treated with ACEi at diagnosis (if older than 12-24 months), even before the onset of proteinuria.; to: Well established gene-disease association. Assessed as 'strongly actionable' in paediatric patients by ClinGen. Treatment: ACE inhibitors alter long-term outcomes. Individuals with AR AS are recommended to be treated with ACEi at diagnosis (if older than 12-24 months), even before the onset of proteinuria. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.1681 | COL4A4 |
Zornitza Stark changed review comment from: Assessed as 'strongly actionable' in paediatric patients by ClinGen. Treatment: ACE inhibitors alter long-term outcomes. Males with XLAS are recommended to be treated with ACEi at diagnosis (if older than 12-24 months), even before the onset of proteinuria. Guidelines differ slightly for the initiation of treatment in females with XLAS; one guideline recommends initiation of treatment at onset of microalbuminuria while a second recommends initiation at onset of microalbuminuria, hypertension, or renal impairment.; to: Assessed as 'strongly actionable' in paediatric patients by ClinGen. Treatment: ACE inhibitors alter long-term outcomes. Individuals with AR AS are recommended to be treated with ACEi at diagnosis (if older than 12-24 months), even before the onset of proteinuria. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.1451 | CIITA |
Zornitza Stark gene: CIITA was added gene: CIITA was added to gNBS. Sources: Expert Review Mode of inheritance for gene: CIITA was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: CIITA were set to Bare Lymphocyte Syndrome, type II, complementation group A MIM# 209920 Review for gene: CIITA was set to GREEN Added comment: 13 individuals of 11 unrelated families; two mouse models. Homozygous and compound heterozygous variants were identified in these individuals (missense, nonsense and splicing) resulting in premature stop codon and truncated protein, or inactive protein. Affected individuals typically present in infancy with severe (recurrent) respiratory and gastrointestinal tract infections and defective MHC II expression in PBMCs Treatment: BMT. Sources: Expert Review |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.1449 | RFXAP |
Zornitza Stark gene: RFXAP was added gene: RFXAP was added to gNBS. Sources: Expert Review Mode of inheritance for gene: RFXAP was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: RFXAP were set to Bare lymphocyte syndrome, type II, complementation group D MIM# 209920 Review for gene: RFXAP was set to GREEN Added comment: 9 unique RFXAP variants in 12 unrelated individuals have been reported; one mouse model The most frequent variant is a deletion c. delG484fsX525 which has been identified in 4 individuals of different origins (North African, Turkish and East Asian). Typically presents in infancy with recurrent bacterial infections, severe diarrhoea and failure to thrive. Treatment: BMT. Sources: Expert Review |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.1447 | RFX5 |
Zornitza Stark gene: RFX5 was added gene: RFX5 was added to gNBS. Sources: Expert Review Mode of inheritance for gene: RFX5 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: RFX5 were set to Bare lymphocyte syndrome, type II, complementation group C MIM# 209920; Bare lymphocyte syndrome, type II, complementation group E MIM# 209920 Review for gene: RFX5 was set to GREEN Added comment: Bare lymphocyte syndrome, type II, complementation group C 9 individuals from 8 unrelated families; multiple mouse models Homozygous and Compound heterozygous (Nonsense, missense, splice site, single bp del) variants were reported resulting in truncated protein and loss of function. All individuals presented with recurrent lower respiratory tract infection early in life, low CD4+ cells and/or failure to thrive, chronic diarrhoea, hepatosplenomegaly and low Ig levels. ---------- Bare lymphocyte syndrome, type II, complementation group E 2 siblings (twins) reported with RPX5 variants and new BLS group E phenotype; multiple functional studies Identified homozygous missense variant (R149Q) which resulted in altered DNA-binding domain and loss of function. These histo-identical twin brothers had normal numbers of CD4 + cells and are able to mount both cellular and humoral immune responses. They displayed absence of MHC class II surface expression on B cells and mononuclear cells. Presentation is typically in infancy. Treatment: BMT. Sources: Expert Review |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.1425 | KARS |
Zornitza Stark changed review comment from: Variants in this gene are associated with either isolated or complex deafness with leukoencephalopathy. The deafness tends to be congenital/pre-lingual. For review, likely meets criteria though some individuals will have leukoencephalopathy which does not have a specific treatment.; to: Variants in this gene are associated with either isolated or complex deafness with leukoencephalopathy. The deafness tends to be congenital/pre-lingual. For review, likely meets criteria though some individuals will have leukoencephalopathy which does not have a specific treatment. Reviewed: significant uncertainty regarding outcome, exclude. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.1425 | RYR1 |
Zornitza Stark changed review comment from: Well established association with susceptibility to malignant hyperthermia. However, variants in this gene also cause a range of muscular phenotypes, for which there is no specific treatment. Association with malignant hyperthermia is rated 'strongly actionable' in children by ClinGen. MH susceptibility (MHS) is a pharmacogenetic skeletal muscle disorder where exposure to certain volatile anesthetics (i.e., desflurane, enflurane, halothane, isoflurane, sevoflurane), either alone or with a depolarizing muscle relaxant (succinylcholine), may trigger uncontrolled skeletal muscle hypermetabolism. An MH episode may begin with hypercapnia, rapidly rising end-tidal CO2, and tachycardia followed by hyperthermia. Additional symptoms may include acidosis, muscle rigidity, compartment syndrome, rhabdomyolysis and subsequent increased creatine kinase, hyperkalemia with a risk for cardiac arrhythmia or even arrest, and myoglobinuria with a risk for renal failure. There is mounting evidence that some individuals with MHS may also develop episodes triggered by non-anesthetic conditions such as heat and/or exercise. These non-anesthetic-induced episodes, often called MH-like syndrome, may manifest as exertional rhabdomyolysis (ER). Surgical management recommendations include preparation of the anesthesia workstation to reduce or prevent exposure to triggering anesthetics (e.g., remove vaporizers from machine and replace all disposables), vigilant monitoring for signs and symptoms of MH during perioperative period, and close observation and monitoring postoperatively. MHS patients should carry identification of their susceptibility and inform those responsible for their care of their MH status. Do not use the following MH triggering drugs for MHS patients: inhaled general anesthetics (desflurane, enflurane, halothane, isoflurane, sevoflurane) and depolarizing muscle relaxants (succinylcholine). For review.; to: Well established association with susceptibility to malignant hyperthermia. However, variants in this gene also cause a range of muscular phenotypes, for which there is no specific treatment. Association with malignant hyperthermia is rated 'strongly actionable' in children by ClinGen. MH susceptibility (MHS) is a pharmacogenetic skeletal muscle disorder where exposure to certain volatile anesthetics (i.e., desflurane, enflurane, halothane, isoflurane, sevoflurane), either alone or with a depolarizing muscle relaxant (succinylcholine), may trigger uncontrolled skeletal muscle hypermetabolism. An MH episode may begin with hypercapnia, rapidly rising end-tidal CO2, and tachycardia followed by hyperthermia. Additional symptoms may include acidosis, muscle rigidity, compartment syndrome, rhabdomyolysis and subsequent increased creatine kinase, hyperkalemia with a risk for cardiac arrhythmia or even arrest, and myoglobinuria with a risk for renal failure. There is mounting evidence that some individuals with MHS may also develop episodes triggered by non-anesthetic conditions such as heat and/or exercise. These non-anesthetic-induced episodes, often called MH-like syndrome, may manifest as exertional rhabdomyolysis (ER). Surgical management recommendations include preparation of the anesthesia workstation to reduce or prevent exposure to triggering anesthetics (e.g., remove vaporizers from machine and replace all disposables), vigilant monitoring for signs and symptoms of MH during perioperative period, and close observation and monitoring postoperatively. MHS patients should carry identification of their susceptibility and inform those responsible for their care of their MH status. Do not use the following MH triggering drugs for MHS patients: inhaled general anesthetics (desflurane, enflurane, halothane, isoflurane, sevoflurane) and depolarizing muscle relaxants (succinylcholine). |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.1397 | RPS15 | Zornitza Stark changed review comment from: Single individual reported.; to: Single individual reported in 2008, no reports since. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.1384 | RPS28 |
Zornitza Stark changed review comment from: Congenital onset. DBA is a treatable disorder: corticosteroids, red blood cell transfusion, BMT.; to: Two individuals reported in 2014, none since. Congenital onset. DBA is a treatable disorder: corticosteroids, red blood cell transfusion, BMT. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.1272 | IDUA | John Christodoulou reviewed gene: IDUA: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 30143438; Phenotypes: coarse facie, corneal clouding, progressive neurodegeneration, dysostosis multiplex, hepatosplenomegaly, hernias, macrocephaly, cardiac valve involvement, SNHL, upper airways obstruction; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.1245 | IDUA | Zornitza Stark Marked gene: IDUA as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.1245 | IDUA | Zornitza Stark Gene: idua has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.1245 | IDUA | Zornitza Stark Phenotypes for gene: IDUA were changed from Mucopolysaccharidosis Ih, MIM#607014 to Mucopolysaccharidosis type 1, MONDO:0001586 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.1244 | IDUA |
Zornitza Stark Tag treatable tag was added to gene: IDUA. Tag metabolic tag was added to gene: IDUA. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.1244 | IDUA | Zornitza Stark reviewed gene: IDUA: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Mucopolysaccharidosis type 1, MONDO:0001586; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.869 | DFNB59 |
Zornitza Stark commented on gene: DFNB59: DEFINITIVE by ClinGen, over 50 affected individuals from more than 10 families reported, supportive functional data including animal models. New HGNC name is PJVK. Hearing loss is pre-lingual, therefore include. Treatment: hearing aids/cochlear implant. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.867 | DFNA5 |
Zornitza Stark commented on gene: DFNA5: Assessed as DEFINITIVE by ClinGen, over a 150 affected individuals reported, supportive functional data including animal models. New HGNC approved name is GSDME. However, age of onset is typically 11-50, therefore exclude. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.862 | PCBD1 |
Zornitza Stark changed review comment from: Well established gene-disease association. Presents in the neonatal period: characterized by mild transient hyperphenylalaninemia often detected by newborn screening. Patients also show increased excretion of 7-biopterin. Affected individuals are asymptomatic and show normal psychomotor development, although transient neurologic deficits in infancy have been reported. Patients may also develop hypomagnesemia and non-autoimmune diabetes mellitus during puberty. ; to: Well established gene-disease association. Presents in the neonatal period: characterized by mild transient hyperphenylalaninemia often detected by newborn screening. Patients also show increased excretion of 7-biopterin. Affected individuals are asymptomatic and show normal psychomotor development, although transient neurologic deficits in infancy have been reported. Patients may also develop hypomagnesemia and non-autoimmune diabetes mellitus during puberty. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.787 | PCBD1 |
John Christodoulou changed review comment from: is on the current VCGS newborn screening panel; to: is on the current VCGS newborn screening panel by virtue of phenylalanine being the primary first tier metabolite that is analysed. Hyperphenylalaninaemia when present in the newborn is transient. There doesn’t appear to be cognitive impairment if untreated, but some individuals develop diabetes and/or mild hypomagnesaemia later in adolescence. There does not appear to be any evidence that any treatments in infancy would have an effect on these two late effects. See: PMID: 32456656 So, I think we can take this one off the list. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.721 | PCBD1 |
Zornitza Stark changed review comment from: Well established gene-disease association. Presents in the neonatal period: characterized by mild transient hyperphenylalaninemia often detected by newborn screening. Patients also show increased excretion of 7-biopterin. Affected individuals are asymptomatic and show normal psychomotor development, although transient neurologic deficits in infancy have been reported. Patients may also develop hypomagnesemia and non-autoimmune diabetes mellitus during puberty. For review; to: Well established gene-disease association. Presents in the neonatal period: characterized by mild transient hyperphenylalaninemia often detected by newborn screening. Patients also show increased excretion of 7-biopterin. Affected individuals are asymptomatic and show normal psychomotor development, although transient neurologic deficits in infancy have been reported. Patients may also develop hypomagnesemia and non-autoimmune diabetes mellitus during puberty. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.662 | LDLR |
Zornitza Stark changed review comment from: ClinGen: 'strong actionability' in paediatric patients. For review as clinical manifestations are typically in adulthood. Statin therapy is recommended to be initiated as early as 8-12 years of age. However, there is also a severe, bi-allelic form with onset in early childhood. Elevated LDL-C levels can be detected from infancy and strongly predispose patients with FH to progressive atherosclerosis throughout childhood and premature CVD in adulthood. Although complications of atherosclerosis occur most commonly in individuals aged >50, the pathophysiological processes begin in childhood and are affected by additional risk factors: hypertension, diabetes, smoking, obesity, poor diet, and physical inactivity. By 12 years of age, children with FH have significant thickening of the carotid intima-media, and by 18 years have coronary stenosis. In natural history studies, 50% of males and 25% of females with FH develop clinical CVD by age 50 years, but up to 10% can have severe premature CVD by 40 years of age. On average, individuals with HeFH experience their first coronary event at age 42, 20 years younger than the general population. Statins have changed the prognosis of FH such that the rates of cardiovascular (CV) events are equal to the general population after 10 years of treatment.; to: ClinGen: 'strong actionability' in paediatric patients. For review as clinical manifestations are typically in adulthood. Statin therapy is recommended to be initiated as early as 8-12 years of age. However, there is also a severe, bi-allelic form with onset in early childhood. Elevated LDL-C levels can be detected from infancy and strongly predispose patients with FH to progressive atherosclerosis throughout childhood and premature CVD in adulthood. Although complications of atherosclerosis occur most commonly in individuals aged >50, the pathophysiological processes begin in childhood and are affected by additional risk factors: hypertension, diabetes, smoking, obesity, poor diet, and physical inactivity. By 12 years of age, children with FH have significant thickening of the carotid intima-media, and by 18 years have coronary stenosis. In natural history studies, 50% of males and 25% of females with FH develop clinical CVD by age 50 years, but up to 10% can have severe premature CVD by 40 years of age. On average, individuals with HeFH experience their first coronary event at age 42, 20 years younger than the general population. Statins have changed the prognosis of FH such that the rates of cardiovascular (CV) events are equal to the general population after 10 years of treatment. Include bi-allelic disease in gNBS. Continue considering if and when mono-allelic disease should be included. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.585 | CBS |
Zornitza Stark changed review comment from: Well established gene-disease association. Multi-system disorder, onset in infancy. In general, individuals appear normal at birth but have a progressive disease course if untreated. Clinical features typically manifest in the first or second decade of life. Intellectual disability may be the first recognizable sign and may present as developmental delay after the first to second year of life. Myopia typically occurs after age one with the majority of untreated individuals developing ectopia lentis by age 8. Roughly half of patients show signs of osteoporosis by their teens. Cerebrovascular events typically manifest during young adulthood, though they have been reported earlier. Thromboembolism is the major cause of early death and morbidity. Among B₆-responsive individuals, a vascular event in adolescence or adulthood is often the presenting feature. Treatment: vitamin B6 (pyridoxine), methionine-restricted diet, folate, vitamin B12, betaine. Management guidelines PMID 27778219. Non-genetic confirmatory testing: plasma total homocysteine and plasma amino acids Paediatric actionable gene by ClinGen. Note excluded from reproductive carrier screening tests due to poor mappability, for review.; to: Well established gene-disease association. Multi-system disorder, onset in infancy. In general, individuals appear normal at birth but have a progressive disease course if untreated. Clinical features typically manifest in the first or second decade of life. Intellectual disability may be the first recognizable sign and may present as developmental delay after the first to second year of life. Myopia typically occurs after age one with the majority of untreated individuals developing ectopia lentis by age 8. Roughly half of patients show signs of osteoporosis by their teens. Cerebrovascular events typically manifest during young adulthood, though they have been reported earlier. Thromboembolism is the major cause of early death and morbidity. Among B₆-responsive individuals, a vascular event in adolescence or adulthood is often the presenting feature. Treatment: vitamin B6 (pyridoxine), methionine-restricted diet, folate, vitamin B12, betaine. Management guidelines PMID 27778219. Non-genetic confirmatory testing: plasma total homocysteine and plasma amino acids Paediatric actionable gene by ClinGen. Note excluded from reproductive carrier screening tests due to poor mappability: downgraded to Amber for now. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.585 | BCHE |
Zornitza Stark changed review comment from: Well established gene-disease association. Individuals are asymptomatic unless exposed to triggering agents. Consider as a separate pharmacogenomic offering? For review.; to: Well established gene-disease association. Individuals are asymptomatic unless exposed to triggering agents. Consider as a separate pharmacogenomic offering? Group review: preventative intervention available by placing alerts in medical records. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.295 | CHRND |
Zornitza Stark changed review comment from: Well established gene-disease association. Severe disorder, perinatal onset. Treatment: 3,4-diaminopyridine, acetylcholine-esterase inhibitors; to: Well established gene-disease association for bi-allelic variants. Single individual only with mono-allelic variant reported. Severe disorder, perinatal onset. Treatment: 3,4-diaminopyridine, acetylcholine-esterase inhibitors |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.270 | CBS |
Zornitza Stark changed review comment from: Well established gene-disease association. Multi-system disorder, onset in infancy. In general, individuals appear normal at birth but have a progressive disease course if untreated. Clinical features typically manifest in the first or second decade of life. Intellectual disability may be the first recognizable sign and may present as developmental delay after the first to second year of life. Myopia typically occurs after age one with the majority of untreated individuals developing ectopia lentis by age 8. Roughly half of patients show signs of osteoporosis by their teens. Cerebrovascular events typically manifest during young adulthood, though they have been reported earlier. Thromboembolism is the major cause of early death and morbidity. Among B₆-responsive individuals, a vascular event in adolescence or adulthood is often the presenting feature. Treatment: vitamin B6 (pyridoxine), methionine-restricted diet, folate, vitamin B12, betaine. Management guidelines PMID 27778219. Non-genetic confirmatory testing: plasma total homocysteine and plasma amino acids Paediatric actionable gene by ClinGen.; to: Well established gene-disease association. Multi-system disorder, onset in infancy. In general, individuals appear normal at birth but have a progressive disease course if untreated. Clinical features typically manifest in the first or second decade of life. Intellectual disability may be the first recognizable sign and may present as developmental delay after the first to second year of life. Myopia typically occurs after age one with the majority of untreated individuals developing ectopia lentis by age 8. Roughly half of patients show signs of osteoporosis by their teens. Cerebrovascular events typically manifest during young adulthood, though they have been reported earlier. Thromboembolism is the major cause of early death and morbidity. Among B₆-responsive individuals, a vascular event in adolescence or adulthood is often the presenting feature. Treatment: vitamin B6 (pyridoxine), methionine-restricted diet, folate, vitamin B12, betaine. Management guidelines PMID 27778219. Non-genetic confirmatory testing: plasma total homocysteine and plasma amino acids Paediatric actionable gene by ClinGen. Note excluded from reproductive carrier screening tests due to poor mappability, for review. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.222 | LDLR |
Zornitza Stark changed review comment from: ClinGen: 'strong actionability' in paediatric patients. For review as clinical manifestations are typically in adulthood. Statin therapy is recommended to be initiated as early as 8-12 years of age. Elevated LDL-C levels can be detected from infancy and strongly predispose patients with FH to progressive atherosclerosis throughout childhood and premature CVD in adulthood. Although complications of atherosclerosis occur most commonly in individuals aged >50, the pathophysiological processes begin in childhood and are affected by additional risk factors: hypertension, diabetes, smoking, obesity, poor diet, and physical inactivity. By 12 years of age, children with FH have significant thickening of the carotid intima-media, and by 18 years have coronary stenosis. In natural history studies, 50% of males and 25% of females with FH develop clinical CVD by age 50 years, but up to 10% can have severe premature CVD by 40 years of age. On average, individuals with HeFH experience their first coronary event at age 42, 20 years younger than the general population. Statins have changed the prognosis of FH such that the rates of cardiovascular (CV) events are equal to the general population after 10 years of treatment.; to: ClinGen: 'strong actionability' in paediatric patients. For review as clinical manifestations are typically in adulthood. Statin therapy is recommended to be initiated as early as 8-12 years of age. However, there is also a severe, bi-allelic form with onset in early childhood. Elevated LDL-C levels can be detected from infancy and strongly predispose patients with FH to progressive atherosclerosis throughout childhood and premature CVD in adulthood. Although complications of atherosclerosis occur most commonly in individuals aged >50, the pathophysiological processes begin in childhood and are affected by additional risk factors: hypertension, diabetes, smoking, obesity, poor diet, and physical inactivity. By 12 years of age, children with FH have significant thickening of the carotid intima-media, and by 18 years have coronary stenosis. In natural history studies, 50% of males and 25% of females with FH develop clinical CVD by age 50 years, but up to 10% can have severe premature CVD by 40 years of age. On average, individuals with HeFH experience their first coronary event at age 42, 20 years younger than the general population. Statins have changed the prognosis of FH such that the rates of cardiovascular (CV) events are equal to the general population after 10 years of treatment. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.161 | ATP7A |
Zornitza Stark changed review comment from: Well established gene-disease association. ATP7A-related copper transport disorders are classically separated in three pathologies according to their severity, all inherited in an X-linked recessive manner: Menkes disease (MD, OMIM #309400) which represent more than 90% of cases; occipital Horn Syndrome (OHS, OMIM #304150) and ATP7A-related distal motor neuropathy also named X-linked distal spinal muscular atrophy-3 (SMAX3, OMIM #300489). Although there is no clear cut correlation between Cu and ceruloplasmin levels in ATP7A related disorders, these three entities probably represent a continuum partly depending on residual functional ATP7A protein. Menkes disease typically presents in infancy, and if untreated is fatal. Typical age at diagnosis is ~8 months. Females are typically asymptomatic. In Australia, the birth incidence of MD is reported to be much higher (1/40,000-100,000 cf 1 in 300,000 elsewhere), which may be due to a founder effect Treatment: subcutaneous injections of copper histidine or copper chloride ClinGen has assessed as moderate evidence for actionability. Neonatal treatment with subcutaneous copper-histidine (initiated before 30 days of life) is recommended for asymptomatic males with a diagnosis of MD, but is not recommended for symptomatic boys or after 30 days of life. Treatment should be continued indefinitely. In an open-label clinical trial, 12 patients with MD treated with copper-histidine within 22 days of life had 92% survival after a mean follow-up of 4.6 years compared to 13% in a historical control group of 15 patients treated after a late diagnosis (mean age at diagnosis: 163 ± 113 days, range: 42 to 390). Two of the 12 patients with earlier treatment had normal neurological development. A second open-label trial of 35 presymptomatic patients receiving copper-histidine at less than a month of age reported significant improvement of four major neurodevelopmental (gross motor, fine motor/adaptive, personal/social, and language) domains and a non-significant lower mortality (28.5% vs 50%) at age of 3 years (or age of death) compared to 22 patients treated later and after onset of symptoms.; to: Well established gene-disease association. ATP7A-related copper transport disorders are classically separated in three pathologies according to their severity, all inherited in an X-linked recessive manner: Menkes disease (MD, OMIM #309400) which represent more than 90% of cases; occipital Horn Syndrome (OHS, OMIM #304150) and ATP7A-related distal motor neuropathy also named X-linked distal spinal muscular atrophy-3 (SMAX3, OMIM #300489). Although there is no clear cut correlation between Cu and ceruloplasmin levels in ATP7A related disorders, these three entities probably represent a continuum partly depending on residual functional ATP7A protein. Menkes disease typically presents in infancy, and if untreated is fatal. Typical age at diagnosis is ~8 months. Females are typically asymptomatic. In Australia, the birth incidence of MD is reported to be much higher (1/40,000-100,000 cf 1 in 300,000 elsewhere), which may be due to a founder effect. Non-genetic confirmatory testing: serum ceruloplasmin and copper, plasma catechols Treatment: subcutaneous injections of copper histidine or copper chloride ClinGen has assessed as moderate evidence for actionability. Neonatal treatment with subcutaneous copper-histidine (initiated before 30 days of life) is recommended for asymptomatic males with a diagnosis of MD, but is not recommended for symptomatic boys or after 30 days of life. Treatment should be continued indefinitely. In an open-label clinical trial, 12 patients with MD treated with copper-histidine within 22 days of life had 92% survival after a mean follow-up of 4.6 years compared to 13% in a historical control group of 15 patients treated after a late diagnosis (mean age at diagnosis: 163 ± 113 days, range: 42 to 390). Two of the 12 patients with earlier treatment had normal neurological development. A second open-label trial of 35 presymptomatic patients receiving copper-histidine at less than a month of age reported significant improvement of four major neurodevelopmental (gross motor, fine motor/adaptive, personal/social, and language) domains and a non-significant lower mortality (28.5% vs 50%) at age of 3 years (or age of death) compared to 22 patients treated later and after onset of symptoms. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| BabyScreen+ newborn screening v0.0 | IDUA |
Zornitza Stark gene: IDUA was added gene: IDUA was added to gNBS. Sources: BeginNGS,BabySeq Category A gene,Expert Review Green Mode of inheritance for gene: IDUA was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: IDUA were set to Mucopolysaccharidosis Ih, MIM#607014 |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||