PanelApp (test)

Activity

Filter

Cancel
Date Panel Item Activity
203 actions
BabyScreen+ newborn screening v1.114 UCP2 Tommy Li Added phenotypes Hyperinsulinism, ORPHA:276556; Hyperinsulinism for gene: UCP2
Publications for gene UCP2 were updated from 28681398; 27967291 to 27967291; 28681398
BabyScreen+ newborn screening v1.114 TRPM2 Tommy Li Added phenotypes ALS and Parkinson's disease for gene: TRPM2
BabyScreen+ newborn screening v1.114 TCOF1 Tommy Li Added phenotypes Treacher Collins syndrome 1, MIM# 154500 for gene: TCOF1
BabyScreen+ newborn screening v1.114 PSAP Tommy Li Added phenotypes Parkinson disease; Encephalopathy due to prosaposin deficiency, MONDO:0012719; Metachromatic leukodystrophy due to SAP-b deficiency, MIM# 249900; Gaucher disease, atypical, MIM# 610539; Krabbe disease, atypical, MIM# 611722; Combined SAP deficiency, MIM# 611721 for gene: PSAP
BabyScreen+ newborn screening v1.114 PRKAG2 Tommy Li Added phenotypes Cardiomyopathy, hypertrophic; Glycogen storage disease of heart, lethal congenital; Wolff-Parkinson-White syndrome for gene: PRKAG2
BabyScreen+ newborn screening v1.114 PLA2G6 Tommy Li Added phenotypes Neurodegeneration with brain iron accumulation 2B MIM#610217; Infantile neuroaxonal dystrophy 1 MIM#256600; Parkinson disease 14, autosomal recessive MIM#612953 for gene: PLA2G6
BabyScreen+ newborn screening v1.114 PINK1 Tommy Li Added phenotypes Parkinson disease 6, early onset, MIM#605909 for gene: PINK1
BabyScreen+ newborn screening v1.114 NTRK1 Tommy Li Added phenotypes Congenital insensitivity to pain with anhidrosis MIM#256800 for gene: NTRK1
BabyScreen+ newborn screening v1.114 MAPT Tommy Li Added phenotypes Dementia, frontotemporal, with or without parkinsonism for gene: MAPT
BabyScreen+ newborn screening v1.114 LRRK2 Tommy Li Added phenotypes Parkinson disease for gene: LRRK2
BabyScreen+ newborn screening v1.114 IRS1 Tommy Li Added phenotypes Diabetes mellitus, noninsulin dependent for gene: IRS1
BabyScreen+ newborn screening v1.114 INSR Tommy Li Added phenotypes Leprechaunism, MIM# 246200; Hyperinsulinemic hypoglycemia, familial, 5, MIM# 609968; Rabson-Mendenhall syndrome, MIM# 262190 for gene: INSR
BabyScreen+ newborn screening v1.114 HPD Tommy Li Added phenotypes Hawkinsinuria , MIM#140350; Tyrosinaemia, type III 276710; Tyrosinemia, type III for gene: HPD
Publications for gene HPD were updated from 9343288; 32520295; 11916315 to 32520295; 9343288; 11916315
BabyScreen+ newborn screening v1.114 HOXA1 Tommy Li Added phenotypes Athabaskan brainstem dysgenesis syndrome for gene: HOXA1
BabyScreen+ newborn screening v1.114 FOXF1 Tommy Li Added phenotypes Alveolar capillary dysplasia with misalignment of pulmonary veins, MIM# 265380 for gene: FOXF1
BabyScreen+ newborn screening v1.114 CREBBP Tommy Li Added phenotypes Rubinstein-Taybi syndrome 1, MIM# 180849; Menke-Hennekam syndrome 1, MIM# 618332 for gene: CREBBP
BabyScreen+ newborn screening v1.114 COX4I2 Tommy Li Added phenotypes Exocrine pancreatic insufficiency, dyserythropoietic anemia, and calvarial hyperostosis for gene: COX4I2
BabyScreen+ newborn screening v1.114 ATP1A3 Tommy Li Added phenotypes Rapid-onset dystonia-parkinsonism for gene: ATP1A3
BabyScreen+ newborn screening v1.114 ATP1A2 Tommy Li Added phenotypes Developmental and epileptic encephalopathy 98, MIM# 619605; Alternating hemiplegia of childhood 1, MIM#104290; Fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies, MIM# 619602 for gene: ATP1A2
BabyScreen+ newborn screening v1.114 AR Tommy Li Added phenotypes Hypospadias 1, X-linked MIM#30063; Androgen insensitivity MIM#300068; Androgen insensitivity, partial, with or without breast cancer MIM#312300 for gene: AR
BabyScreen+ newborn screening v1.114 AKT2 Tommy Li Added phenotypes Severe insulin resistance and diabetes mellitus for gene: AKT2
BabyScreen+ newborn screening v1.114 ZBTB24 Tommy Li Added phenotypes Immunodeficiency-centromeric instability-facial anomalies syndrome 2 MIM#614069 for gene: ZBTB24
BabyScreen+ newborn screening v1.114 SLC16A1 Tommy Li Added phenotypes Hyperinsulinemic hypoglycemia, familial, 7, MIM# 610021; Monocarboxylate transporter 1 deficiency for gene: SLC16A1
BabyScreen+ newborn screening v1.114 HNF4A Tommy Li Added phenotypes Fanconi renotubular syndrome 4, with maturity-onset diabetes of the young, MIM# 616026; MODY, type I, OMIM # 125850; Hypoglycaemia, hyperinsulinaemic, MIM#125850 for gene: HNF4A
BabyScreen+ newborn screening v1.114 SLC18A2 Tommy Li Added phenotypes Parkinsonism-dystonia, infantile, 2, MIM# 618049 for gene: SLC18A2
BabyScreen+ newborn screening v1.114 POMC Tommy Li Added phenotypes Obesity, adrenal insufficiency, and red hair due to POMC deficiency MIM#609734 for gene: POMC
BabyScreen+ newborn screening v1.114 NR5A1 Tommy Li Added phenotypes Adrenocortical insufficiency, (MIM#612964) for gene: NR5A1
BabyScreen+ newborn screening v1.114 KCNJ11 Tommy Li Added phenotypes Diabetes, permanent neonatal, with or without neurologic features 606176; Hyperinsulinemic hypoglycemia, familial, 2 601820; Diabetes mellitus, transient neonatal, 3 610582 for gene: KCNJ11
BabyScreen+ newborn screening v1.114 INS Tommy Li Added phenotypes Maturity-onset diabetes of the young, type 10, MIM# 613370; Diabetes mellitus, permanent neonatal 4, MIM# 618858; Diabetes mellitus, insulin-dependent, 2, MIM# 125852 for gene: INS
BabyScreen+ newborn screening v1.114 IGF1 Tommy Li Added phenotypes Insulin-like growth factor I deficiency, MIM# 608747 for gene: IGF1
BabyScreen+ newborn screening v1.114 HK1 Tommy Li Added phenotypes Hyperinsulinism MONDO:0002177, HK1-related for gene: HK1
BabyScreen+ newborn screening v1.114 HELLS Tommy Li Added phenotypes Immunodeficiency-centromeric instability-facial anomalies syndrome 4, MIM# 616911 for gene: HELLS
BabyScreen+ newborn screening v1.114 GLUD1 Tommy Li Added phenotypes Hyperinsulinism, MIM#606762 for gene: GLUD1
BabyScreen+ newborn screening v1.114 GIF Tommy Li Added phenotypes Intrinsic factor deficiency, MIM# 261000 for gene: GIF
BabyScreen+ newborn screening v1.114 GHR Tommy Li Added phenotypes Growth hormone insensitivity, partial, MIM# 604271; Laron dwarfism, MIM# 262500 for gene: GHR
BabyScreen+ newborn screening v1.114 GCK Tommy Li Added phenotypes Hyperinsulinemic hypoglycemia, familial, MIM#602485 for gene: GCK
BabyScreen+ newborn screening v1.114 FOXA2 Tommy Li Added phenotypes Hyperinsulinism MONDO:0002177 for gene: FOXA2
BabyScreen+ newborn screening v1.114 DNMT3B Tommy Li Added phenotypes Immunodeficiency-centromeric instability-facial anomalies syndrome 1, MIM# 242860 for gene: DNMT3B
BabyScreen+ newborn screening v1.114 CYP11A1 Tommy Li Added phenotypes Adrenal insufficiency, congenital, with 46XY sex reversal, partial or complete, MIM#613743 for gene: CYP11A1
BabyScreen+ newborn screening v1.114 CDCA7 Tommy Li Added phenotypes Immunodeficiency-centromeric instability-facial anomalies syndrome 3, MIM# 616910 for gene: CDCA7
BabyScreen+ newborn screening v1.114 AVPR2 Tommy Li Added phenotypes Diabetes insipidus, nephrogenic, MIM#304800 for gene: AVPR2
BabyScreen+ newborn screening v1.114 AVP Tommy Li Added phenotypes Diabetes insipidus, neurohypophyseal MIM#125700 for gene: AVP
Publications for gene AVP were updated from 32052034; 31238300 to 31238300; 32052034
BabyScreen+ newborn screening v1.114 AQP2 Tommy Li Added phenotypes Diabetes insipidus, nephrogenic, 2, MIM#125800 for gene: AQP2
Publications for gene AQP2 were updated from 7537761; 11536078 to 11536078; 7537761
BabyScreen+ newborn screening v1.114 ABCC8 Tommy Li Added phenotypes Hyperinsulinemic hypoglycemia, familial, MIM#256450 for gene: ABCC8
BabyScreen+ newborn screening v1.110 ELANE Zornitza Stark commented on gene: ELANE: ClinGen: there is little evidence for haploinsufficiency. gnomAD pLI score is zero and there are NMD predicted variants in the population.

Entire gene deletion is not described in the context of neutropenia, including deletion of 19p terminal (encompassing ELANE) (PMID: 33968054).

Maturation arrest, the failure of the marrow myeloid progenitors to form mature neutrophils, is a consistent feature of ELANE associated congenital neutropenia. Knock-out of the mutant allele in hematopoietic stem cells derived from SCN patients restores neutrophils maturation (PMID: 3124897).
BabyScreen+ newborn screening v1.83 POMC Zornitza Stark Phenotypes for gene: POMC were changed from Proopiomelanocortin deficiency to Obesity, adrenal insufficiency, and red hair due to POMC deficiency MIM#609734
BabyScreen+ newborn screening v1.81 POMC Zornitza Stark reviewed gene: POMC: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Obesity, adrenal insufficiency, and red hair due to POMC deficiency MIM#609734; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v1.65 IGF1 Zornitza Stark Phenotypes for gene: IGF1 were changed from Insulin-like growth factor deficiency to Insulin-like growth factor I deficiency, MIM# 608747
BabyScreen+ newborn screening v1.63 IGF1 Zornitza Stark reviewed gene: IGF1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Insulin-like growth factor I deficiency, MIM# 608747; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
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 v0.2124 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 SGPL1 Lilian Downie gene: SGPL1 was added
gene: SGPL1 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: SGPL1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SGPL1 were set to PMID: 28165343
Phenotypes for gene: SGPL1 were set to Nephrotic syndrome, type 14 MIM#617575
Review for gene: SGPL1 was set to RED
Added comment: infancy or early childhood with progressive renal dysfunction associated with focal segmental glomerulosclerosis (FSGS), resulting in end-stage renal disease within a few years. Other infants present with primary adrenal insufficiency. Some patients present in utero with fetal hydrops and fetal demise. Additional features of the disorder can include ichthyosis, acanthosis, adrenal insufficiency, immunodeficiency, and neurologic defects

Rx Hydrocortisone, kidney transplant (treatment doesn't fit screening model as would need to have ESRD before you had it?)
Sources: Expert list
BabyScreen+ newborn screening v0.2063 SMARCD2 Lilian Downie gene: SMARCD2 was added
gene: SMARCD2 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: SMARCD2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SMARCD2 were set to PubMed: 28369036, 33279574, 33025377
Phenotypes for gene: SMARCD2 were set to Specific granule deficiency 2 MIM#617475
Review for gene: SMARCD2 was set to GREEN
Added comment: recurrent infections due to defective neutrophil development. Bone marrow findings include paucity of neutrophil granulocytes, absence of granule proteins in neutrophils, abnormal megakaryocytes, and features of progressive myelofibrosis with blasts. The disorder is apparent from infancy, and patients may die in early childhood unless they undergo hematopoietic stem cell transplantation. Most patients have additional findings, including delayed development, mild dysmorphic features, tooth abnormalities, and distal skeletal defects

Rx bone marrow transplant
Sources: Expert list
BabyScreen+ newborn screening v0.2062 SAR1B Zornitza Stark gene: SAR1B was added
gene: SAR1B was added to Baby Screen+ newborn screening. Sources: Expert list
treatable, gastrointestinal tags were added to gene: SAR1B.
Mode of inheritance for gene: SAR1B was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: SAR1B were set to Chylomicron retention disease, MIM# 246700
Review for gene: SAR1B was set to GREEN
Added comment: Chylomicron retention disease is an autosomal recessive disorder of severe fat malabsorption associated with failure to thrive in infancy. Well established gene-disease association.

Congenital onset.

Treatment: low-fat diet with supplementation of fat-soluble vitamins (A, D, E, and K) and oral essential fatty acid supplementation

Non-genetic confirmatory testing: total cholesterol, triglyceride, LDL-cholesterol, HDL-cholesterol
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 v0.2037 NAXE Zornitza Stark gene: NAXE was added
gene: NAXE was added to Baby Screen+ newborn screening. Sources: Expert list
treatable, metabolic tags were added to gene: NAXE.
Mode of inheritance for gene: NAXE was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NAXE were set to 27122014; 27616477; 31758406
Phenotypes for gene: NAXE were set to Encephalopathy, progressive, early-onset, with brain oedema and/or leukoencephalopathy, MIM# 617186
Review for gene: NAXE was set to RED
Added comment: Early-onset progressive encephalopathy with brain oedema and/or leukoencephalopathy-1 (PEBEL1) is an autosomal recessive severe neurometabolic disorder characterized by rapidly progressive neurologic deterioration that is usually associated with a febrile illness. Affected infants tend to show normal early development followed by acute psychomotor regression with ataxia, hypotonia, respiratory insufficiency, and seizures, resulting in coma and death in the first years of life. Brain imaging shows multiple abnormalities, including brain edema and signal abnormalities in the cortical and subcortical regions. More than 5 unrelated families reported.

Treatment: niacin

However, single case reported. Treatment not established.
Sources: Expert list
BabyScreen+ newborn screening v0.2028 MNX1 Zornitza Stark gene: MNX1 was added
gene: MNX1 was added to Baby Screen+ newborn screening. Sources: Expert list
treatable, endocrine tags were added to gene: MNX1.
Mode of inheritance for gene: MNX1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MNX1 were set to 36586106
Phenotypes for gene: MNX1 were set to Permanent neonatal diabetes mellitus, MONDO:0100164, MNX1-related
Review for gene: MNX1 was set to GREEN
Added comment: Three unrelated families reported. Presentation is in newborn period.

Treatment: insulin.

Non-genetic confirmatory testing: glucose tolerance test, hemoglobin A1C, insulin level, glucose level
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 v0.2013 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 v0.1993 IFITM5 Zornitza Stark gene: IFITM5 was added
gene: IFITM5 was added to Baby Screen+ newborn screening. Sources: Expert list
5'UTR, treatable, skeletal tags were added to gene: IFITM5.
Mode of inheritance for gene: IFITM5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: IFITM5 were set to 22863190; 22863195; 32383316; 24519609
Phenotypes for gene: IFITM5 were set to Osteogenesis imperfecta, type V MIM#610967
Review for gene: IFITM5 was set to GREEN
Added comment: A recurrent c.-14C>T variant has been reported in many patients with type V OI. It introduces an alternative in-frame start codon upstream that is stronger than the reference start codon in transfected HEK cells (PMIDs: 22863190, 22863195). However, the effect of mutant protein (5 amino acids longer) remains unknown but neomorphic mechanism is a widely accepted hypothesis (PMIDs: 25251575, 32383316).

Variable severity, including within families. However, severe perinatal presentations reported.

Treatment: bisphosphanates.

Non-genetic confirmatory testing: skeletal survey.
Sources: Expert list
BabyScreen+ newborn screening v0.1982 UCP2 Lilian Downie reviewed gene: UCP2: Rating: RED; Mode of pathogenicity: None; Publications: PMID: 28681398, PMID: 27967291; Phenotypes: UCP2 associated hyperinsulinism; Mode of inheritance: None
BabyScreen+ newborn screening v0.1973 HELLS Zornitza Stark gene: HELLS was added
gene: HELLS was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: HELLS was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: HELLS were set to Immunodeficiency-centromeric instability-facial anomalies syndrome 4, MIM# 616911
Review for gene: HELLS was set to GREEN
Added comment: Congenital onset.

Immunodeficiency-centromeric instability-facial anomalies syndrome-4 is characterized by recurrent infections in childhood and variable dysmorphic facial features. Laboratory studies show hypomethylation of certain chromosomal regions. Additional features, including delayed development, are variable. At least 4 unrelated families reported.

Treatment: bone marrow transplant.
Sources: Expert list
BabyScreen+ newborn screening v0.1965 GHRHR Zornitza Stark gene: GHRHR was added
gene: GHRHR was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: GHRHR was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GHRHR were set to 8528260; 10084571; 11232012
Phenotypes for gene: GHRHR were set to Growth hormone deficiency, isolated, type IV, MIM# 618157
Review for gene: GHRHR was set to GREEN
Added comment: IGHD type IV is characterized by early and severe growth failure (height SDS up to -7.4), a blunted growth hormone (GH) response to different provocation tests and low insulin-like growth factor-I and IGF-binding protein-3 concentrations, and a good response to growth hormone treatment. At least three unrelated families reported.

Non-genetic confirmatory testing: growth hormone stimulation test
Sources: Expert list
BabyScreen+ newborn screening v0.1963 GHR Zornitza Stark gene: GHR was added
gene: GHR was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: GHR was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Phenotypes for gene: GHR were set to Growth hormone insensitivity, partial, MIM# 604271; Laron dwarfism, MIM# 262500
Review for gene: GHR was set to GREEN
Added comment: Well established gene-disease association.

Congenital onset.

Treatment: growth hormone.

Non-genetic confirmatory testing: growth hormone stimulation test
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 v0.1953 ZBTB24 Zornitza Stark reviewed gene: ZBTB24: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Immunodeficiency-centromeric instability-facial anomalies syndrome 2 MIM#614069; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1952 ZBTB24 Lilian Downie gene: ZBTB24 was added
gene: ZBTB24 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: ZBTB24 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZBTB24 were set to PMID: 28128455, 21906047, 21596365, 23486536
Phenotypes for gene: ZBTB24 were set to Immunodeficiency-centromeric instability-facial anomalies syndrome 2 MIM#614069
Review for gene: ZBTB24 was set to AMBER
Added comment: INfant onset
Agammaglobulinemia, facial anomalies, and mental retardation. Facial anomalies included broad, flat nasal bridge, hypertelorism, and epicanthal folds.
Treat immunoglobulin and bone marrow transplant however, this only treats the immune deficiency
Consider exclusion due to untreatable ID phenotype?
Sources: Expert list
BabyScreen+ newborn screening v0.1939 DNAJC21 Zornitza Stark gene: DNAJC21 was added
gene: DNAJC21 was added to Baby Screen+ newborn screening. Sources: Expert Review
Mode of inheritance for gene: DNAJC21 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DNAJC21 were set to 29700810; 28062395; 27346687
Phenotypes for gene: DNAJC21 were set to Bone marrow failure syndrome 3, MIM# 617052
Review for gene: DNAJC21 was set to GREEN
Added comment: Onset of pancytopenia in early childhood; variable nonspecific somatic abnormalities, including poor growth, microcephaly, and skin anomalies.

Treatment: oral pancreatic enzymes, fat-soluble vitamins, blood and/or platelet transfusions, granulocyte-colony stimulation factor, bone marrow transplant

Confirmatory non-genetic testing: no; FBE as pancytopenia evolves.
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 v0.1927 CDCA7 Zornitza Stark gene: CDCA7 was added
gene: CDCA7 was added to gNBS. Sources: Expert Review
Mode of inheritance for gene: CDCA7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CDCA7 were set to 26216346
Phenotypes for gene: CDCA7 were set to Immunodeficiency-centromeric instability-facial anomalies syndrome 3, MIM# 616910
Review for gene: CDCA7 was set to GREEN
Added comment: Congenital onset, severe disorder. At least 4 unrelated families reported.

Treatment: replacement immunoglobulins, bone marrow transplant

Non-genetic confirmatory testing: immunoglobulin levels, cytogenetic analysis for centromeric instability, DNA methylation studies
Sources: Expert Review
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 v0.1849 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 v0.1837 AGPAT2 Zornitza Stark gene: AGPAT2 was added
gene: AGPAT2 was added to gNBS. Sources: Expert list
for review, treatable, endocrine tags were added to gene: AGPAT2.
Mode of inheritance for gene: AGPAT2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AGPAT2 were set to 29704234
Phenotypes for gene: AGPAT2 were set to Lipodystrophy, congenital generalized, type 1, MIM# 608594
Review for gene: AGPAT2 was set to AMBER
Added comment: Established gene-disease association.

Congenital generalized lipodystrophy (CGL), or Berardinelli-Seip syndrome, is a rare autosomal recessive disease characterized by a near absence of adipose tissue from birth or early infancy and severe insulin resistance. Other clinical and biologic features include acanthosis nigricans, muscular hypertrophy, hepatomegaly, altered glucose tolerance or diabetes mellitus, and hypertriglyceridemia.

Leptin replacement therapy (metreleptin) has been found to improve metabolic parameters in many patients with lipodystrophy. Metreleptin is approved in the United States as replacement therapy to treat the complications of leptin deficiency in patients with congenital or acquired generalized lipodystrophy and has been submitted for approval elsewhere.

For review regarding availability and use of treatment locally.
Sources: Expert list
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 v0.1825 PMM2 Zornitza Stark changed review comment from: Well established gene-disease association.

Two clinical presentations - solely neurologic form and a neurologic-multivisceral form
Mortality approximately 20% in first 2 years

Treatment: epalrestat

PMID 31636082: Epalrestat increased PMM2 enzymatic activity in four PMM2-CDG patient fibroblast lines with genotypes R141H/F119L, R141H/E139K, R141H/N216I and R141H/F183S. PMM2 enzyme activity gains ranged from 30% to 400% over baseline, depending on genotype. Pharmacological inhibition of aldose reductase by epalrestat may shunt glucose from the polyol pathway to glucose-1,6-bisphosphate, which is an endogenous stabilizer and coactivator of PMM2 homodimerization. Epalrestat is a safe, oral and brain penetrant drug that was approved 27 years ago in Japan to treat diabetic neuropathy in geriatric populations.

For review: uncertain if in use for CDG; to: Well established gene-disease association.

Two clinical presentations - solely neurologic form and a neurologic-multivisceral form
Mortality approximately 20% in first 2 years

Treatment: epalrestat

PMID 31636082: Epalrestat increased PMM2 enzymatic activity in four PMM2-CDG patient fibroblast lines with genotypes R141H/F119L, R141H/E139K, R141H/N216I and R141H/F183S. PMM2 enzyme activity gains ranged from 30% to 400% over baseline, depending on genotype. Pharmacological inhibition of aldose reductase by epalrestat may shunt glucose from the polyol pathway to glucose-1,6-bisphosphate, which is an endogenous stabilizer and coactivator of PMM2 homodimerization. Epalrestat is a safe, oral and brain penetrant drug that was approved 27 years ago in Japan to treat diabetic neuropathy in geriatric populations.

Treatment not well established in patients.
BabyScreen+ newborn screening v0.1753 OAT Zornitza Stark gene: OAT was added
gene: OAT was added to gNBS. Sources: ClinGen
for review, treatable, metabolic tags were added to gene: OAT.
Mode of inheritance for gene: OAT was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: OAT were set to Gyrate atrophy of choroid and retina with or without ornithinemia MIM#258870
Review for gene: OAT was set to GREEN
Added comment: Rated as 'moderate actionability' in paediatric patients by ClinGen.

GA due to deficiency of the enzyme ornithine aminotransferase (OAT) is characterized by a triad of progressive chorioretinal degeneration, early cataract formation, and type II muscle fiber atrophy. GA first presents as night blindness and constriction of the visual field caused by sharply demarcated circular areas of chorioretinal atrophy in the periphery. Atrophic areas progressively increase, coalesce, and spread towards the macula leading to central visual loss and blindness (vision less than 20/200).

Age at diagnosis ranges from 1 month to 44 years. The condition is characterized by the development of chorioretinal atrophic patches that start in the mid-peripheral retina in the first decade of life. Myopia, night blindness, changes in the macula (including cystic changes), and visual field affection usually start in the first or second decade. Most patients with GA have posterior subcapsular cataracts by the end of the second decade. Irreversible loss of vision and blindness generally occurs between 40 and 55 years of age but is highly variable.

Treatment of GA consists mainly of dietary modifications to help lower elevated systemic ornithine levels. Restriction of dietary arginine, a precursor of ornithine, appears to have therapeutic value. Pediatric patients undergoing arginine restriction should receive enough calories in their diet supplemented by essential amino acids, vitamins, and minerals to avoid malnutrition and excessive break down of endogenous proteins.

A long-term observational study of 27 patients with GA, 17 who complied with the arginine-restricted diet and 10 who were noncompliant, found that at 14 years follow-up the rates of vision loss were significantly slower in the compliant group for 3 of the 4 outcome measures, when adjusted for age.
Sources: ClinGen
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 ABCC8 David Amor reviewed gene: ABCC8: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: MIM 256450 Hyperinsulinemic hypoglycemia, familial, 1, MIM 618857 Diabetes mellitus, permanent neonatal 3, with or without neurologic features; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1710 ABCC8 David Amor commented on gene: ABCC8: Gene-disease association: strong. Note sporadic cases of Familial hyperinsulinemic hypoglycemiawith focal adenomatous hyperplasia due to paternally inherited variants focal loss of maternal allele.

ABCC8 associated permanent neonatal diabetes mellitus typically due to GoF missense variants. Fathers are at increased risk of T2DM also.

Severity: severe

Age of onset: congenital

Non-molecular confirmatory testing: yes
For hyperinsulinaemic hypoglycaemia: glucose, insulin, free fatty acid levels
For neonatal diabetes: glucose tolerance test, hemoglobin A1C, insulin level, glucose level

Treatment: as per rx-genes
For hyperinsulinaemic hypoglycaemia: Diazoxide, somatostatin analogs, nifedipine, glucagon, IGF-1, glucocorticoids, growth hormone, pancreatic resection, mTOR inhibitors, GLP-1 receptor antagonists, sirolimus

For neonatal diabetes: Insulin, glibenclamide, oral pancreatic enzymes
BabyScreen+ newborn screening v0.1710 ABCC8 David Amor edited their review of gene: ABCC8: Changed phenotypes: MIM 256450 Hyperinsulinemic hypoglycemia, familial, 1, MIM 618857 Diabetes mellitus, permanent neonatal 3, with or without neurologic features
BabyScreen+ newborn screening v0.1710 ABCC8 David Amor commented on gene: ABCC8: Gene-disease association: strong. Note sporadic cases of Familial hyperinsulinemic hypoglycemiawith focal adenomatous hyperplasia due to paternally inherited variants focal loss of maternal allele.

ABCC8 associated permanent neonatal diabetes mellitus typically due to GoF missense variants. Fathers are at increased risk of T2DM also.

Severity: severe

Age of onset: congenital

Non-molecular confirmatory testing: yes
For hyperinsulinaemic hypoglycaemia: glucose, insulin, free fatty acid levels
For neonatal diabetes: glucose tolerance test, hemoglobin A1C, insulin level, glucose level

Treatment: as per rx-genes
For hyperinsulinaemic hypoglycaemia: Diazoxide, somatostatin analogs, nifedipine, glucagon, IGF-1, glucocorticoids, growth hormone, pancreatic resection, mTOR inhibitors, GLP-1 receptor antagonists, sirolimus

For neonatal diabetes: Insulin, glibenclamide, oral pancreatic enzymes
BabyScreen+ newborn screening v0.1710 ABCC8 David Amor changed review comment from: Gene-disease association: strong. Note sporadic cases of Familial hyperinsulinemic hypoglycemiawith focal adenomatous hyperplasia due to paternally inherited variants focal loss of maternal allele.

ABCC8 associated permanent neonatal diabetes mellitus typically due to GoF missense variants. Fathers are at increased risk of T2DM also.



Severity: severe

Age of onset: congenital

Non-molecular confirmatory testing: yes
For hyperinsulinaemic hypoglycaemia: glucose, insulin, free fatty acid levels
For neonatal diabetes: glucose tolerance test, hemoglobin A1C, insulin level, glucose level

Treatment: as per rx-genes
For hyperinsulinaemic hypoglycaemia: Diazoxide, somatostatin analogs, nifedipine, glucagon, IGF-1, glucocorticoids, growth hormone, pancreatic resection, mTOR inhibitors, GLP-1 receptor antagonists, sirolimus

For neonatal diabetes: Insulin, glibenclamide, oral pancreatic enzymes
; to: Gene-disease association: strong. Note sporadic cases of Familial hyperinsulinemic hypoglycemiawith focal adenomatous hyperplasia due to paternally inherited variants focal loss of maternal allele.

ABCC8 associated permanent neonatal diabetes mellitus typically due to GoF missense variants. Fathers are at increased risk of T2DM also.

Severity: severe

Age of onset: congenital

Non-molecular confirmatory testing: yes
For hyperinsulinaemic hypoglycaemia: glucose, insulin, free fatty acid levels
For neonatal diabetes: glucose tolerance test, hemoglobin A1C, insulin level, glucose level

Treatment: as per rx-genes
For hyperinsulinaemic hypoglycaemia: Diazoxide, somatostatin analogs, nifedipine, glucagon, IGF-1, glucocorticoids, growth hormone, pancreatic resection, mTOR inhibitors, GLP-1 receptor antagonists, sirolimus

For neonatal diabetes: Insulin, glibenclamide, oral pancreatic enzymes
BabyScreen+ newborn screening v0.1710 ABCC8 David Amor changed review comment from: Gene-disease association: strong. Note sporadic cases with focal adenomatous hyperplasia due to paternally inherited variants focal loss of maternal allele

Severity: severe

Age of onset: congenital

Non-molecular confirmatory testing: yes, glucose, insulin, free fatty acid levels

Treatment: as per rx-genes, Diazoxide, somatostatin analogs, nifedipine, glucagon, IGF-1, glucocorticoids, growth hormone, pancreatic resection, mTOR inhibitors, GLP-1 receptor antagonists, sirolimus; to: Gene-disease association: strong. Note sporadic cases of Familial hyperinsulinemic hypoglycemiawith focal adenomatous hyperplasia due to paternally inherited variants focal loss of maternal allele.

ABCC8 associated permanent neonatal diabetes mellitus typically due to GoF missense variants. Fathers are at increased risk of T2DM also.



Severity: severe

Age of onset: congenital

Non-molecular confirmatory testing: yes
For hyperinsulinaemic hypoglycaemia: glucose, insulin, free fatty acid levels
For neonatal diabetes: glucose tolerance test, hemoglobin A1C, insulin level, glucose level

Treatment: as per rx-genes
For hyperinsulinaemic hypoglycaemia: Diazoxide, somatostatin analogs, nifedipine, glucagon, IGF-1, glucocorticoids, growth hormone, pancreatic resection, mTOR inhibitors, GLP-1 receptor antagonists, sirolimus

For neonatal diabetes: Insulin, glibenclamide, oral pancreatic enzymes
BabyScreen+ newborn screening v0.1710 ABCC8 David Amor reviewed gene: ABCC8: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: MIM 256450 Hyperinsulinemic hypoglycemia, familial, 1; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1708 KCNJ11 Zornitza Stark changed review comment from: Association with hyperinsulinism is well established.

Onset is congenital.

Treatment: Diazoxide, somatostatin analogs, nifedipine, glucagon, IGF-1, glucocorticoids, growth hormone, pancreatic resection, mTOR inhibitors, GLP-1 receptor antagonists, sirolimus

Association with neonatal diabetes is also well established.

Treatment: Insulin, glibenclamide, oral pancreatic enzymes.

Phenotypes are expected to be distinguishable clinically.; to: Association with hyperinsulinism is well established, mono-allelic variants.

Onset is congenital.

Treatment: Diazoxide, somatostatin analogs, nifedipine, glucagon, IGF-1, glucocorticoids, growth hormone, pancreatic resection, mTOR inhibitors, GLP-1 receptor antagonists, sirolimus

Association with neonatal diabetes is also well established, bi-allelic variants.

Treatment: Insulin, glibenclamide, oral pancreatic enzymes.

Phenotypes are expected to be distinguishable clinically.
BabyScreen+ newborn screening v0.1708 KCNJ11 Zornitza Stark Phenotypes for gene: KCNJ11 were changed from Hyperinsulinemic hypoglycemia, familial, MIM#601820 to Diabetes mellitus, transient neonatal, 3 610582; Diabetes, permanent neonatal, with or without neurologic features 606176; Hyperinsulinemic hypoglycemia, familial, 2 601820
BabyScreen+ newborn screening v0.1706 KCNJ11 Zornitza Stark reviewed gene: KCNJ11: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Diabetes mellitus, transient neonatal, 3 610582, Diabetes, permanent neonatal, with or without neurologic features 606176, Hyperinsulinemic hypoglycemia, familial, 2 601820; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
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 v0.1643 TH John Christodoulou reviewed gene: TH: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 20301610; Phenotypes: dystonia, Parkinsonism, dev delay, hypotonia, oculogyric crises; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1571 PLA2G6 Zornitza Stark Phenotypes for gene: PLA2G6 were changed from Infantile neuroaxonal dystrophy 1 to Infantile neuroaxonal dystrophy 1 MIM#256600; Neurodegeneration with brain iron accumulation 2B MIM#610217; Parkinson disease 14, autosomal recessive MIM#612953
BabyScreen+ newborn screening v0.1569 PLA2G6 Zornitza Stark reviewed gene: PLA2G6: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Infantile neuroaxonal dystrophy 1 MIM#256600, Neurodegeneration with brain iron accumulation 2B MIM#610217, Parkinson disease 14, autosomal recessive MIM#612953; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1560 PINK1 Zornitza Stark Phenotypes for gene: PINK1 were changed from Parkinson disease 6, early onset to Parkinson disease 6, early onset, MIM#605909
BabyScreen+ newborn screening v0.1557 PINK1 Zornitza Stark reviewed gene: PINK1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Parkinson disease 6, early onset, MIM#605909; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1545 TCOF1 Seb Lunke Phenotypes for gene: TCOF1 were changed from Treacher Collins syndrome 1 to Treacher Collins syndrome 1, MIM# 154500
BabyScreen+ newborn screening v0.1543 TCOF1 Seb Lunke reviewed gene: TCOF1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Treacher Collins syndrome 1, MIM# 154500; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
BabyScreen+ newborn screening v0.1501 PSAP Zornitza Stark Phenotypes for gene: PSAP were changed from Metachromatic leukodystrophy to Parkinson disease; Combined SAP deficiency, MIM# 611721; Encephalopathy due to prosaposin deficiency, MONDO:0012719; Krabbe disease, atypical, MIM# 611722; Metachromatic leukodystrophy due to SAP-b deficiency, MIM# 249900; Gaucher disease, atypical, MIM# 610539
BabyScreen+ newborn screening v0.1498 PSAP Zornitza Stark reviewed gene: PSAP: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Parkinson disease, Combined SAP deficiency, MIM# 611721, Encephalopathy due to prosaposin deficiency, MONDO:0012719, Krabbe disease, atypical, MIM# 611722, Metachromatic leukodystrophy due to SAP-b deficiency, MIM# 249900, Gaucher disease, atypical, MIM# 610539; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1456 REN Zornitza Stark changed review comment from: Established gene-disease association.

Presents as fetal anuria leading to perinatal death.

No specific treatment.; to: Established gene-disease association.

Bi-allelic LOF variants cause renal tubular dysgenesis, which presents as fetal anuria leading to perinatal death.. Mono-allelic variants, likely through a different mechanism (mostly missense) cause tubulointerstitial disease. More severe phenotype associated with variants that are located in the protein leader peptide and affecting its co-translational insertion in the endoplasmic reticulum (ER).

No specific treatment for either.
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 v0.1367 INSR Zornitza Stark Marked gene: INSR as ready
BabyScreen+ newborn screening v0.1367 INSR Zornitza Stark Gene: insr has been classified as Red List (Low Evidence).
BabyScreen+ newborn screening v0.1367 INSR Zornitza Stark Phenotypes for gene: INSR were changed from Leprechaunism to Hyperinsulinemic hypoglycemia, familial, 5, MIM# 609968; Leprechaunism, MIM# 246200; Rabson-Mendenhall syndrome, MIM# 262190
BabyScreen+ newborn screening v0.1366 INSR Zornitza Stark Mode of inheritance for gene: INSR was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1365 INSR Zornitza Stark Classified gene: INSR as Red List (low evidence)
BabyScreen+ newborn screening v0.1365 INSR Zornitza Stark Gene: insr has been classified as Red List (Low Evidence).
BabyScreen+ newborn screening v0.1364 INSR Zornitza Stark reviewed gene: INSR: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Hyperinsulinemic hypoglycemia, familial, 5, MIM# 609968, Leprechaunism, MIM# 246200, Rabson-Mendenhall syndrome, MIM# 262190; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1347 INS Zornitza Stark Marked gene: INS as ready
BabyScreen+ newborn screening v0.1347 INS Zornitza Stark Gene: ins has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1347 INS Zornitza Stark Phenotypes for gene: INS were changed from Diabetes mellitus, permanent neonatal MIM# 618858Permanent neonatal diabetes mellitus-4 (PNDM4) is characterized by chronic hyperglycemia due to severe nonautoimmune insulin deficiency diagnosed in the first months of life to Diabetes mellitus, insulin-dependent, 2, MIM# 125852; Diabetes mellitus, permanent neonatal 4, MIM# 618858; Maturity-onset diabetes of the young, type 10, MIM# 613370
BabyScreen+ newborn screening v0.1346 INS Zornitza Stark Mode of inheritance for gene: INS was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1345 INS Zornitza Stark Tag for review tag was added to gene: INS.
Tag treatable tag was added to gene: INS.
Tag endocrine tag was added to gene: INS.
BabyScreen+ newborn screening v0.1345 INS Zornitza Stark edited their review of gene: INS: Changed rating: GREEN
BabyScreen+ newborn screening v0.1345 INS Zornitza Stark reviewed gene: INS: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Diabetes mellitus, insulin-dependent, 2, MIM# 125852, Diabetes mellitus, permanent neonatal 4, MIM# 618858, Maturity-onset diabetes of the young, type 10, MIM# 613370; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1294 HNF4A Zornitza Stark Phenotypes for gene: HNF4A were changed from Fanconi renotubular syndrome 4, with maturity-onset diabetes of the young, MIM# 616026; Hypoglycaemia, hyperinsulinaemic, MIM#125850 to Fanconi renotubular syndrome 4, with maturity-onset diabetes of the young, MIM# 616026; Hypoglycaemia, hyperinsulinaemic, MIM#125850; MODY, type I, OMIM # 125850
BabyScreen+ newborn screening v0.1272 HSD3B2 John Christodoulou reviewed gene: HSD3B2: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 26079780, PMID: 33757164; Phenotypes: adrenal insufficiency, hypspadias, pseudohermaphroditism in males, mild masculinization in females; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1230 HK1 Zornitza Stark Phenotypes for gene: HK1 were changed from Hemolytic anemia due to hexokinase deficiency; Haemolytic anaemia due to hexokinase deficiency , MIM#235700 to Hyperinsulinism MONDO:0002177, HK1-related
BabyScreen+ newborn screening v0.1227 HK1 Zornitza Stark reviewed gene: HK1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Hyperinsulinism MONDO:0002177, HK1-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
BabyScreen+ newborn screening v0.1193 GIF Zornitza Stark Phenotypes for gene: GIF were changed from Intrinsic factor deficiency, MIM# 261000; Intrinsic factor deficiency # 261000 to Intrinsic factor deficiency, MIM# 261000
BabyScreen+ newborn screening v0.1191 GIF Zornitza Stark reviewed gene: GIF: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Intrinsic factor deficiency MIM#261000; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1154 HADH John Christodoulou reviewed gene: HADH: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 16176262, PMID: 20936362; Phenotypes: hypoketotic hypoglycaemia, hyperinsulinism, fatty liver; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1132 HADH Zornitza Stark Phenotypes for gene: HADH were changed from Hyperinsulinemic hypoglycemia, familial, 4, MIM#609975 to 3-hydroxyacyl-CoA dehydrogenase deficiency, MIM# 231530
BabyScreen+ newborn screening v0.1094 SLC18A2 Seb Lunke reviewed gene: SLC18A2: Rating: GREEN; Mode of pathogenicity: None; Publications: 23363473; Phenotypes: Parkinsonism-dystonia, infantile, 2, MIM# 618049; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1003 FOXA2 Zornitza Stark Phenotypes for gene: FOXA2 were changed from Combined pituitary hormone deficiencies, genetic forms, ORPHA:95494; Congenital isolated hyperinsulinism, ORPHA:657 to Hyperinsulinism MONDO:0002177
BabyScreen+ newborn screening v0.1001 FOXA2 Zornitza Stark reviewed gene: FOXA2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Hyperinsulinism MONDO:0002177; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
BabyScreen+ newborn screening v0.997 FOXF1 Zornitza Stark Phenotypes for gene: FOXF1 were changed from Alveolar capillary dysplasia with misalignment of pulmonary veins to Alveolar capillary dysplasia with misalignment of pulmonary veins, MIM# 265380
BabyScreen+ newborn screening v0.995 FOXF1 Zornitza Stark reviewed gene: FOXF1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Alveolar capillary dysplasia with misalignment of pulmonary veins, MIM# 265380; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
BabyScreen+ newborn screening v0.950 GLUD1 John Christodoulou reviewed gene: GLUD1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 35752848; Phenotypes: hyperinsulinism; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
BabyScreen+ newborn screening v0.889 DNMT3B Zornitza Stark Phenotypes for gene: DNMT3B were changed from Immunodeficiency-centromeric instability-facial anomalies syndrome 1 to Immunodeficiency-centromeric instability-facial anomalies syndrome 1, MIM# 242860
BabyScreen+ newborn screening v0.888 DNMT3B Zornitza Stark reviewed gene: DNMT3B: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Immunodeficiency-centromeric instability-facial anomalies syndrome 1, MIM# 242860; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.864 LAMA2 Zornitza Stark changed review comment from: No specific treatment.; to: No specific treatment.
Succinylcholine in induction of anaesthesia because of risk of hyperkalaemia and cardiac conduction abnormalities; statins, cholesterol-lowering medications, because of the risk of muscle damage.
BabyScreen+ newborn screening v0.782 CREBBP Zornitza Stark Phenotypes for gene: CREBBP were changed from Rubinstein-Taybi syndrome to Rubinstein-Taybi syndrome 1, MIM# 180849; Menke-Hennekam syndrome 1, MIM# 618332
BabyScreen+ newborn screening v0.780 CREBBP Zornitza Stark reviewed gene: CREBBP: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Rubinstein-Taybi syndrome 1, MIM# 180849, Menke-Hennekam syndrome 1, MIM# 618332; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
BabyScreen+ newborn screening v0.719 MPI John Christodoulou reviewed gene: MPI: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 32266963, PMID: 19101627; Phenotypes: hyperinsulinism, hepatomegaly; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
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 v0.661 FLAD1 Zornitza Stark changed review comment from: Well established gene-disease association, more than 10 families reported.

The phenotype is extremely heterogeneous: some patients have a severe disorder with onset in infancy and cardiac and respiratory insufficiency resulting in early death, whereas others have a milder course with onset of muscle weakness in adulthood. Some patients show significant improvement with riboflavin treatment.

For discussion. Included as a treatable disorder in rx-genes.

Confirmatory non-genetic testing: Plasma acylcarnitine profile, Urine organic acid analysis,; to: Well established gene-disease association, more than 10 families reported.

The phenotype is extremely heterogeneous: some patients have a severe disorder with onset in infancy and cardiac and respiratory insufficiency resulting in early death, whereas others have a milder course with onset of muscle weakness in adulthood. Some patients show significant improvement with riboflavin treatment.

Included as a treatable disorder in rx-genes.

Confirmatory non-genetic testing: Plasma acylcarnitine profile, Urine organic acid analysis,
BabyScreen+ newborn screening v0.606 GATA4 Alison Yeung changed review comment from: Well-established gene-disease association for congenital heart defects and neonatal diabetes
Onset: infancy but variable expressivity and incomplete penetrance common for cardiac defects
Severity: variable defects. No syndromic features, no association with arrhythmias
Treatment: Echocardiogram and surgical repair for cardiac defects; Insulin for neonatal diabetes; to: Well-established gene-disease association for congenital heart defects and neonatal diabetes
Onset: infancy but variable expressivity and incomplete penetrance common for cardiac defects
Severity: variable defects. No syndromic features, no association with arrhythmias
Treatment: Echocardiogram and surgical repair for cardiac defects; Insulin for neonatal diabetes
BabyScreen+ newborn screening v0.606 GATA4 Alison Yeung changed review comment from: Well-established gene-disease association
Onset: infancy (congenital heart defects) but variable expressivity and incomplete penetrance common
Severity: variable defects. No syndromic features, no association with arrhythmias
Treatment: Echocardiogram and surgical repair; to: Well-established gene-disease association for congenital heart defects and neonatal diabetes
Onset: infancy but variable expressivity and incomplete penetrance common for cardiac defects
Severity: variable defects. No syndromic features, no association with arrhythmias
Treatment: Echocardiogram and surgical repair for cardiac defects; Insulin for neonatal diabetes
BabyScreen+ newborn screening v0.591 GCK Zornitza Stark reviewed gene: GCK: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Diabetes mellitus, noninsulin-dependent, late onset, AD (MIM#125853), Diabetes mellitus, permanent neonatal 1, AR (MIM#606176), Hyperinsulinemic hypoglycemia, familial, 3, AD (MIM#602485), MODY, type II, AD (MIM#125851); Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.583 FLAD1 John Christodoulou reviewed gene: FLAD1: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 30680745; Phenotypes: lactic acidosis, respiratory insufficiency, cardiomyopathy, skeletal myopathy, hypotonia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.529 CYP11A1 Zornitza Stark reviewed gene: CYP11A1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Adrenal insufficiency, congenital, with 46XY sex reversal, partial or complete, MIM# 613743; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.523 DDC John Christodoulou reviewed gene: DDC: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: hypotonia, oculogyric crises, temperature instability, ID, autonomic dysfunction, sleep disturbance, choreoathetosis; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.502 GAA Alison Yeung changed review comment from: Well establishes gene-disease association

Onset: Classic infantile form causes cardiomyopathy and severe hypotonia in infancy (<1 year); Late-onset form causes severe weakness and respiratory insufficiency with onset after 12 months; Adult form presents with progressive myopathy

Severity: Infantile form fatal in first year of life if untreated

Treatment: Enzyme replacement therapy with alglucosidase alfa prior to 6 months of age prolongs survival, reduces cardiac size and allows acquisition of motor skills; to: Well establishes gene-disease association

Onset: Classic infantile form causes cardiomyopathy and severe hypotonia in infancy (<1 year); Late-onset form causes severe weakness and respiratory insufficiency with onset after 12 months; Adult form presents with progressive myopathy

Severity: Infantile form fatal in first year of life if untreated

Treatment: Enzyme replacement therapy with alglucosidase alfa prior to 6 months of age prolongs survival, reduces cardiac size and allows acquisition of motor skills

Non-molecular confirmatory test: enzyme activity analysis
BabyScreen+ newborn screening v0.464 NTRK1 Zornitza Stark reviewed gene: NTRK1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Insensitivity to pain, congenital, with anhidrosis - MIM#256800; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.462 NR5A1 Zornitza Stark Phenotypes for gene: NR5A1 were changed from 46, XX sex reversal 4, MIM# 617480; 46XY sex reversal 3, MIM# 612965 to Adrenocortical insufficiency, (MIM#612964)
BabyScreen+ newborn screening v0.461 NR5A1 Zornitza Stark reviewed gene: NR5A1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Adrenocortical insufficiency, (MIM#612964); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
BabyScreen+ newborn screening v0.274 NTRK1 David Amor reviewed gene: NTRK1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Insensitivity to pain, congenital, with anhidrosis; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.274 NR5A1 David Amor reviewed gene: NR5A1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Adrenocortical insufficiency; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
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 v0.177 ATP1A2 Zornitza Stark Phenotypes for gene: ATP1A2 were changed from Hemiplegic migraine to Alternating hemiplegia of childhood 1, MIM#104290; Fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies, MIM# 619602; Developmental and epileptic encephalopathy 98, MIM# 619605
BabyScreen+ newborn screening v0.173 ATP1A2 Zornitza Stark reviewed gene: ATP1A2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Alternating hemiplegia of childhood 1, MIM#104290, Fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies, MIM# 619602, Developmental and epileptic encephalopathy 98, MIM# 619605; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
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 v0.121 AR Zornitza Stark Phenotypes for gene: AR were changed from Androgen insensitivity, MIM# 300068 to Hypospadias 1, X-linked MIM#30063; Androgen insensitivity MIM#300068; Androgen insensitivity, partial, with or without breast cancer MIM#312300
BabyScreen+ newborn screening v0.119 AR Zornitza Stark reviewed gene: AR: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Hypospadias 1, X-linked MIM#30063, Androgen insensitivity MIM#300068, Androgen insensitivity, partial, with or without breast cancer MIM#312300; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
BabyScreen+ newborn screening v0.118 AVP Zornitza Stark gene: AVP was added
gene: AVP was added to gNBS. Sources: Expert Review
treatable, clinical trial tags were added to gene: AVP.
Mode of inheritance for gene: AVP was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: AVP were set to 32052034; 31238300
Phenotypes for gene: AVP were set to Diabetes insipidus, neurohypophyseal MIM#125700
Review for gene: AVP was set to GREEN
Added comment: Well established gene-disease association.

Onset in childhood with polydipsia and polyuria. Can be life-threatening.

Treatment: DDAVP.
Clinical trials.
Sources: Expert Review
BabyScreen+ newborn screening v0.117 AVPR2 Zornitza Stark reviewed gene: AVPR2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Diabetes insipidus, nephrogenic, 1 304800; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
BabyScreen+ newborn screening v0.116 AQP2 Zornitza Stark reviewed gene: AQP2: Rating: GREEN; Mode of pathogenicity: None; Publications: 7537761, 11536078; Phenotypes: Diabetes insipidus, nephrogenic, MIM#125800; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.0 UCP2 Zornitza Stark Source Expert Review Red was added to UCP2.
Source BabySeq Category C gene was added to UCP2.
Added phenotypes Hyperinsulinism for gene: UCP2
Rating Changed from Green List (high evidence) to Red List (low evidence)
BabyScreen+ newborn screening v0.0 TRPM2 Zornitza Stark gene: TRPM2 was added
gene: TRPM2 was added to gNBS. Sources: Expert Review Red,BabySeq Category C gene
Mode of inheritance for gene: TRPM2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: TRPM2 were set to ALS and Parkinson's disease
BabyScreen+ newborn screening v0.0 PRKAG2 Zornitza Stark gene: PRKAG2 was added
gene: PRKAG2 was added to gNBS. Sources: BabySeq Category B gene,Expert Review Red,BabySeq Category A gene,BabySeq Category C gene
Mode of inheritance for gene: PRKAG2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: PRKAG2 were set to Cardiomyopathy, hypertrophic; Wolff-Parkinson-White syndrome; Glycogen storage disease of heart, lethal congenital
BabyScreen+ newborn screening v0.0 MAPT Zornitza Stark gene: MAPT was added
gene: MAPT was added to gNBS. Sources: Expert Review Red,BabySeq Category C gene
Mode of inheritance for gene: MAPT was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: MAPT were set to Dementia, frontotemporal, with or without parkinsonism
BabyScreen+ newborn screening v0.0 LRRK2 Zornitza Stark gene: LRRK2 was added
gene: LRRK2 was added to gNBS. Sources: Expert Review Red,BabySeq Category C gene
Mode of inheritance for gene: LRRK2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: LRRK2 were set to Parkinson disease
BabyScreen+ newborn screening v0.0 IRS1 Zornitza Stark gene: IRS1 was added
gene: IRS1 was added to gNBS. Sources: Expert Review Red,BabySeq Category C gene
Mode of inheritance for gene: IRS1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: IRS1 were set to Diabetes mellitus, noninsulin dependent
BabyScreen+ newborn screening v0.0 IGF1 Zornitza Stark gene: IGF1 was added
gene: IGF1 was added to gNBS. Sources: Expert Review Red,BabySeq Category C gene
Mode of inheritance for gene: IGF1 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: IGF1 were set to Insulin-like growth factor deficiency
BabyScreen+ newborn screening v0.0 HOXA1 Zornitza Stark gene: HOXA1 was added
gene: HOXA1 was added to gNBS. Sources: Expert Review Red,BabySeq Category C gene
Mode of inheritance for gene: HOXA1 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: HOXA1 were set to Athabaskan brainstem dysgenesis syndrome
BabyScreen+ newborn screening v0.0 COX4I2 Zornitza Stark gene: COX4I2 was added
gene: COX4I2 was added to gNBS. Sources: Expert Review Red,BabySeq Category C gene
Mode of inheritance for gene: COX4I2 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: COX4I2 were set to Exocrine pancreatic insufficiency, dyserythropoietic anemia, and calvarial hyperostosis
BabyScreen+ newborn screening v0.0 ATP1A3 Zornitza Stark gene: ATP1A3 was added
gene: ATP1A3 was added to gNBS. Sources: Expert Review Red,BabySeq Category C gene
Mode of inheritance for gene: ATP1A3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: ATP1A3 were set to Rapid-onset dystonia-parkinsonism
BabyScreen+ newborn screening v0.0 AKT2 Zornitza Stark gene: AKT2 was added
gene: AKT2 was added to gNBS. Sources: Expert Review Red,BabySeq Category C gene
Mode of inheritance for gene: AKT2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: AKT2 were set to Severe insulin resistance and diabetes mellitus
BabyScreen+ newborn screening v0.0 UCP2 Zornitza Stark gene: UCP2 was added
gene: UCP2 was added to gNBS. Sources: BeginNGS,Expert Review Green
Mode of inheritance for gene: UCP2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: UCP2 were set to Hyperinsulinism, ORPHA:276556
BabyScreen+ newborn screening v0.0 TCOF1 Zornitza Stark gene: TCOF1 was added
gene: TCOF1 was added to gNBS. Sources: BabySeq Category A gene,Expert Review Green
Mode of inheritance for gene: TCOF1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: TCOF1 were set to Treacher Collins syndrome 1
BabyScreen+ newborn screening v0.0 SLC18A2 Zornitza Stark gene: SLC18A2 was added
gene: SLC18A2 was added to gNBS. Sources: BeginNGS,Expert Review Green
Mode of inheritance for gene: SLC18A2 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: SLC18A2 were set to Parkinsonism-dystonia, infantile, 2, MIM# 618049
BabyScreen+ newborn screening v0.0 SLC16A1 Zornitza Stark gene: SLC16A1 was added
gene: SLC16A1 was added to gNBS. Sources: BeginNGS,Expert Review Green
Mode of inheritance for gene: SLC16A1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: SLC16A1 were set to Hyperinsulinemic hypoglycemia, familial, 7, MIM# 610021
BabyScreen+ newborn screening v0.0 PINK1 Zornitza Stark gene: PINK1 was added
gene: PINK1 was added to gNBS. Sources: BabySeq Category A gene,Expert Review Green
Mode of inheritance for gene: PINK1 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: PINK1 were set to Parkinson disease 6, early onset
BabyScreen+ newborn screening v0.0 NTRK1 Zornitza Stark gene: NTRK1 was added
gene: NTRK1 was added to gNBS. Sources: BabySeq Category A gene,Expert Review Green,BabySeq Category C gene
Mode of inheritance for gene: NTRK1 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: NTRK1 were set to Congenital insensitivity to pain with anhidrosis MIM#256800
BabyScreen+ newborn screening v0.0 KCNJ11 Zornitza Stark gene: KCNJ11 was added
gene: KCNJ11 was added to gNBS. Sources: BeginNGS,BabySeq Category A gene,Expert Review Green
Mode of inheritance for gene: KCNJ11 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: KCNJ11 were set to Hyperinsulinemic hypoglycemia, familial, MIM#601820
BabyScreen+ newborn screening v0.0 INSR Zornitza Stark gene: INSR was added
gene: INSR was added to gNBS. Sources: BabySeq Category A gene,Expert Review Green
Mode of inheritance for gene: INSR was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: INSR were set to Leprechaunism
BabyScreen+ newborn screening v0.0 INS Zornitza Stark gene: INS was added
gene: INS was added to gNBS. Sources: Expert list,BeginNGS,Expert Review Green
Mode of inheritance for gene: INS was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: INS were set to Diabetes mellitus, permanent neonatal MIM# 618858Permanent neonatal diabetes mellitus-4 (PNDM4) is characterized by chronic hyperglycemia due to severe nonautoimmune insulin deficiency diagnosed in the first months of life
BabyScreen+ newborn screening v0.0 HPD Zornitza Stark gene: HPD was added
gene: HPD was added to gNBS. Sources: BeginNGS,Expert Review Green
Mode of inheritance for gene: HPD was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Phenotypes for gene: HPD were set to Hawkinsinuria , MIM#140350; Tyrosinaemia, type III 276710
BabyScreen+ newborn screening v0.0 HNF4A Zornitza Stark gene: HNF4A was added
gene: HNF4A was added to gNBS. Sources: BeginNGS,Expert Review Green,BabySeq Category C gene
Mode of inheritance for gene: HNF4A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: HNF4A were set to Fanconi renotubular syndrome 4, with maturity-onset diabetes of the young, MIM# 616026; Hypoglycaemia, hyperinsulinaemic, MIM#125850
BabyScreen+ newborn screening v0.0 HADH Zornitza Stark gene: HADH was added
gene: HADH was added to gNBS. Sources: BeginNGS,BabySeq Category A gene,Expert Review Green,BabySeq Category C gene
Mode of inheritance for gene: HADH was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: HADH were set to Hyperinsulinemic hypoglycemia, familial, 4, MIM#609975
BabyScreen+ newborn screening v0.0 GLUD1 Zornitza Stark gene: GLUD1 was added
gene: GLUD1 was added to gNBS. Sources: BeginNGS,BabySeq Category A gene,Expert Review Green
Mode of inheritance for gene: GLUD1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: GLUD1 were set to Hyperinsulinism, MIM#606762
BabyScreen+ newborn screening v0.0 GIF Zornitza Stark Source Expert list was added to GIF.
Added phenotypes Intrinsic factor deficiency # 261000 for gene: GIF
BabyScreen+ newborn screening v0.0 GCK Zornitza Stark gene: GCK was added
gene: GCK was added to gNBS. Sources: BeginNGS,BabySeq Category A gene,Expert Review Green
Mode of inheritance for gene: GCK was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: GCK were set to Hyperinsulinemic hypoglycemia, familial, MIM#602485
BabyScreen+ newborn screening v0.0 FOXF1 Zornitza Stark gene: FOXF1 was added
gene: FOXF1 was added to gNBS. Sources: BabySeq Category A gene,Expert Review Green
Mode of inheritance for gene: FOXF1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: FOXF1 were set to Alveolar capillary dysplasia with misalignment of pulmonary veins
BabyScreen+ newborn screening v0.0 FOXA2 Zornitza Stark gene: FOXA2 was added
gene: FOXA2 was added to gNBS. Sources: BeginNGS,Expert Review Green
Mode of inheritance for gene: FOXA2 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Phenotypes for gene: FOXA2 were set to Combined pituitary hormone deficiencies, genetic forms, ORPHA:95494; Congenital isolated hyperinsulinism, ORPHA:657
BabyScreen+ newborn screening v0.0 DNMT3B Zornitza Stark gene: DNMT3B was added
gene: DNMT3B was added to gNBS. Sources: BabySeq Category A gene,Expert Review Green
Mode of inheritance for gene: DNMT3B was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: DNMT3B were set to Immunodeficiency-centromeric instability-facial anomalies syndrome 1
BabyScreen+ newborn screening v0.0 CYP11A1 Zornitza Stark gene: CYP11A1 was added
gene: CYP11A1 was added to gNBS. Sources: BeginNGS,BabySeq Category A gene,Expert Review Green
Mode of inheritance for gene: CYP11A1 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: CYP11A1 were set to Adrenal insufficiency, congenital, with 46XY sex reversal, partial or complete, MIM#613743
BabyScreen+ newborn screening v0.0 CREBBP Zornitza Stark gene: CREBBP was added
gene: CREBBP was added to gNBS. Sources: BabySeq Category A gene,Expert Review Green
Mode of inheritance for gene: CREBBP was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: CREBBP were set to Rubinstein-Taybi syndrome
BabyScreen+ newborn screening v0.0 GIF Zornitza Stark gene: GIF was added
gene: GIF was added to gNBS. Sources: BeginNGS,Expert Review Green
Mode of inheritance for gene: GIF was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: GIF were set to Intrinsic factor deficiency, MIM# 261000
BabyScreen+ newborn screening v0.0 AVPR2 Zornitza Stark gene: AVPR2 was added
gene: AVPR2 was added to gNBS. Sources: BeginNGS,BabySeq Category A gene,Expert Review Green
Mode of inheritance for gene: AVPR2 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Phenotypes for gene: AVPR2 were set to Diabetes insipidus, nephrogenic, MIM#304800
BabyScreen+ newborn screening v0.0 AR Zornitza Stark gene: AR was added
gene: AR was added to gNBS. Sources: BabySeq Category A gene,Expert Review Green,BabySeq Category C gene
Mode of inheritance for gene: AR was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Phenotypes for gene: AR were set to Androgen insensitivity, MIM# 300068
BabyScreen+ newborn screening v0.0 AQP2 Zornitza Stark gene: AQP2 was added
gene: AQP2 was added to gNBS. Sources: BeginNGS,Expert Review Green
Mode of inheritance for gene: AQP2 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Phenotypes for gene: AQP2 were set to Diabetes insipidus, nephrogenic, 2, MIM#125800
BabyScreen+ newborn screening v0.0 ABCC8 Zornitza Stark gene: ABCC8 was added
gene: ABCC8 was added to gNBS. Sources: BeginNGS,BabySeq Category A gene,Expert Review Green
Mode of inheritance for gene: ABCC8 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Phenotypes for gene: ABCC8 were set to Hyperinsulinemic hypoglycemia, familial, MIM#256450