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| Congenital Heart Defect v0.417 | BMP2 |
Ain Roesley gene: BMP2 was added gene: BMP2 was added to Congenital Heart Defect. Sources: Literature Mode of inheritance for gene: BMP2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: BMP2 were set to 29198724 Phenotypes for gene: BMP2 were set to Short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies 1, MIM# 617877 Review for gene: BMP2 was set to GREEN gene: BMP2 was marked as current diagnostic Added comment: 8 families with 12 affecteds 4 with CHD Transposition of the great arteries HP:0001669 Mild pulmonary valve stenosis HP:0001642 Ebstein's anomaly HP:0010316 Wolff-Parkinson-White syndrome HP:0001716, perimembranous VSD HP:0011682 Sources: Literature |
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| Congenital Heart Defect v0.395 | B3GAT3 | Zornitza Stark Phenotypes for gene: B3GAT3 were changed from to Multiple joint dislocations, short stature, craniofacial dysmorphism, with or without congenital heart defects -MIM#245600 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Congenital Heart Defect v0.392 | B3GAT3 | Zornitza Stark reviewed gene: B3GAT3: Rating: GREEN; Mode of pathogenicity: None; Publications: 26754439, 31988067, 26086840, 25893793, 21763480, 24668659; Phenotypes: Multiple joint dislocations, short stature, craniofacial dysmorphism, with or without congenital heart defects -MIM#245600; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Congenital Heart Defect v0.367 | KMT2B |
Violeta Velkoska-Ivanova changed review comment from: There is insufficient evidence in the published data to rate this gene as green in the context of congenital heart disease. The supporting evidence for rating this gene AMBER is as follows: No heart abnormalities were noted in the two KMT2B-associated disease phenotypes listed in OMIM ( both reviewed in 2022). The GenCC database( https://thegencc.org/) has summarised evidence from four reputable submitters: Genomic England Panel App, ClinGen, Ambry Genetics and Orphanet). Three classifications (two supportive, one strong) implicate KMT2B in two diseases: Dystonia,28, childhood-onset (MONDO:0015004; OMIM: 617284) and Complex Neurodevelopmental Disorder with Motor features (MONDO: 0100516) where the KMT2B variations are inherited in autosomal dominant mode. The ClinGen evaluation (The Clinical Genome Resource), with ten variants (missense, nonsense, and frameshift) being reported in 10 probands in 2 publications (PMIDs: 29276005, 33150406) and also in a non-human animal model (PMID: 23426673) provides definitive evidence for the KMT2B gene relationship with autosomal dominant, Complex Neurodevelopmental Disorder with Motor features (MONDO: 0100516). Regarding dosage sensitivity, there is sufficient evidence that this gene exhibits haploinsufficiency and is intolerant to LoF variation. The G2P database (https://www.ebi.ac.uk/gene2phenotype/) lists the KMT2B-associated complex early-onset dystonia in the Developmental Delay panel. Also, the KMT2B is absent from the Cardiac G2P, a publicly available resource designed for filtering and analysing genetic variants of inherited cardiac conditions (ICC)(PMID 37872640). The largest cohort with KMT2B variants (133 patients: 53 as the initial study cohort in addition to 80 published cases)(PMID:33150406) provides a detailed delineation of their clinical phenotype and molecular genetic features. Although this study emphasised that patients with chromosomal deletions and protein-truncating variants had a significantly higher burden of systemic disease (with earlier onset of dystonia) than those with missense variants, it reported on new disease features ( i.e. atypical patterns of dystonia evolution and a subgroup of patients with a non-dystonic neurodevelopmental phenotype). It also identified co-morbidities ( i.e. risk of status dystonicus, intrauterine growth retardation, and endocrinopathies); however, it failed to associate the KMT2B gene with congenital abnormalities of the heart. ; to: There is insufficient evidence in the published data to rate this gene as green in the context of congenital heart disease. The supporting evidence for rating this gene AMBER is as follows: No heart abnormalities were noted in the two KMT2B-associated disease phenotypes listed in OMIM ( both reviewed in 2022). The GenCC database( https://thegencc.org/) has summarised evidence from four reputable submitters: Genomic England Panel App, ClinGen, Ambry Genetics and Orphanet). Three classifications (two supportive, one strong) implicate KMT2B in two diseases: Dystonia,28, childhood-onset (MONDO:0015004; OMIM: 617284) and Complex Neurodevelopmental Disorder with Motor features (MONDO: 0100516) where the KMT2B variations are inherited in autosomal dominant mode. The ClinGen evaluation (The Clinical Genome Resource), with ten variants (missense, nonsense, and frameshift) being reported in 10 probands in 2 publications (PMIDs: 29276005, 33150406) and also in a non-human animal model (PMID: 23426673) provides definitive evidence for the KMT2B gene relationship with autosomal dominant, Complex Neurodevelopmental Disorder with Motor features (MONDO: 0100516). Regarding dosage sensitivity, there is sufficient evidence that this gene exhibits haploinsufficiency and is intolerant to LoF variation. The G2P database (https://www.ebi.ac.uk/gene2phenotype/) lists the KMT2B-associated complex early-onset dystonia in the Developmental Delay panel whose scope is" severe undiagnosed neurodevelopmental disorder and/or congenital anomalies, abnormal growth parameters, dysmorphic features and unusual behavioural phenotypes" and as such is part of the DD2P panel in Panel App England. Also, the KMT2B is absent from the Cardiac G2P, a publicly available resource designed for filtering and analysing genetic variants of inherited cardiac conditions (ICC)(PMID 37872640). The largest cohort of 133 patients with KMT2B variants (PMID:33150406) delineates their clinical phenotype and molecular genetic features. Although this study emphasised that patients with chromosomal deletions and protein-truncating variants had a significantly higher burden of systemic disease (with earlier onset of dystonia) than those with missense variants, it reported on new disease features ( i.e. atypical patterns of dystonia evolution and a subgroup of patients with a non-dystonic neurodevelopmental phenotype). It also identified co-morbidities ( i.e. risk of status dystonicus, intrauterine growth retardation, and endocrinopathies); however, it failed to associate the KMT2B gene with congenital abnormalities of the heart. However, the following evidence may be considered when upgrading the KMT2B gene to Green: KMT2B methyltransferase is a family of histone-modifying enzymes (KMTs) that catalyse the methylation of lysine 4 of the Histone 3 protein and regulate transcriptional activity at the chromatin level. As methylation is critical in transcriptional changes occurring during development, it is not unexpected that deregulated methylation marks are found in developmental disorders, human aging, and cancer. A range of neurodevelopmental disorders is caused by pathogenic variants in genes regulating chromatin function and structure that display abnormal DNA methylation patterns (episignatures) in peripheral blood. Similarly, deregulation of histone lysine methylation, essential during cardiac development, is associated with cardiac disease. ( 35506254) A recent review states that the known KMT2B paralogs (Gene Cards), KMT2A, KMT2C and KMT2D exhibit regulatory roles during heart development or disease (as defined by supporting data from multiple model systems and /or by disease association. (37504561). One such example is the KMT2D gene that confusingly shares the same alternate name as KMT2B- MLL2 despite the different genomic locations of both genes and other differences. Molecular rearrangements of KMT2D are associated with Kabuki Syndrome 1(KS) (OMIM: 147920) where, in addition to neurodevelopmental presentation, congenital heart defect, ventricular and atrial septal defect are also part of the phenotypic spectrum. Comparison of the methylation patterns in peripheral blood from patients with KMT2-dystonia, KMT2-Kabuki Syndrome and controls showed that most DNA regions with altered methylation patterns differ between these two disorders and controls with KMT2B being hypermethylated. The KMT2B is unique among ’chromatin neurodevelopmental disorders’ genes as its most prominent clinical feature is childhood-onset dystonia rather than developmental delay or congenital anomalies. (PMID:35506254). The KMT2B paralogs, KMT2A and KMT2D supported by patient phenotypic presentation and likely valid functional evidence in animal models have been investigated thus far as candidate genes in genomic sequencing studies of cardiac disease, including those for patients with congenital heart defect (PMID3378394;25972376;28884922). Thus far, the function of KMT2B in the context of congenital heart disease is yet to be phenotypically confirmed and recapitulated through further research. |
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| Congenital Heart Defect v0.358 | PIGV | Zornitza Stark Phenotypes for gene: PIGV were changed from mental retardation; seizures and hypotonia; hyperphosphatasia; facial dysmorphism; variable degrees of brachytelephalangy to Hyperphosphatasia with impaired intellectual development syndrome 1, MIM# 239300 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Congenital Heart Defect v0.315 | ARID1B | Michelle Wu reviewed gene: ARID1B: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: PMID: 35579625, 35445787, 29549119, 34324492; Phenotypes: Coffin-Siris syndrome 1, intellectual disability with or without nonspecific dysmorphic features; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Congenital Heart Defect v0.315 | NUP188 |
GORJANA ROBEVSKA gene: NUP188 was added gene: NUP188 was added to Congenital Heart Defect. Sources: Literature Mode of inheritance for gene: NUP188 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: NUP188 were set to PMID: 32021605; 32275884 Phenotypes for gene: NUP188 were set to Sandestig-Stefanova syndrome MIM 618804 Review for gene: NUP188 was set to GREEN Added comment: Sandestig et al 2020/19: two unrelated female infants from consanguineous families, each with homozygous nonsense gene variants of NUP188 (p.Tyr96* and p.Gln113*, respectively). Both patients showed close similarity and specificity of clinical features including the course of the disease and a poor prognosis. Muir et al 2020: Four unrelated families with six affected female infants with bi-allelic truncating variants in NUP188. all found to have very similar phenotypes Functional studies showed: 1. Nuclear import of proteins was decreased in affected individuals’ fibroblasts, supporting a possible disease mechanism. 2. CRISPR-mediated knockout of NUP188 in Drosophila revealed motor deficits and seizure susceptibility, partially recapitulating the neurological phenotype seen in affected individuals. 3. Removal of NUP188 also resulted in aberrant dendrite tiling, suggesting a potential role of NUP188 in dendritic development Key clinical features of Sandestig-Stefanova syndrome MIM 618804: - congenital cataracts - hypotonia, - prenatal-onset ventriculomegaly, - white-matter abnormalities, - hypoplastic corpus callosum, - congenital heart defects, and - central hypoventilation. Characteristic dysmorphic features include: - small palpebral fissures, - a wide nasal bridge and nose, - micrognathia, and - digital anomalies. Sources: Literature |
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| Congenital Heart Defect v0.315 | PIGV |
Jen Malcolm gene: PIGV was added gene: PIGV was added to Congenital Heart Defect. Sources: Other Mode of inheritance for gene: PIGV was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PIGV were set to PMID: 37372388; 24129430; 37390992; 20802478 Phenotypes for gene: PIGV were set to mental retardation; seizures and hypotonia; hyperphosphatasia; facial dysmorphism; variable degrees of brachytelephalangy Penetrance for gene: PIGV were set to unknown Mode of pathogenicity for gene: PIGV was set to Other Review for gene: PIGV was set to RED Added comment: Autosomal recessive. Multiple variants involved in Mabry syndrome (also known as Hyperphosphatasia)- intellectual disability, distinctive facial features, increased levels of an enzyme called alkaline phosphatase in the blood and other signs and symptoms. Literature: • Xue et al PMID: 27177984 2 Chinese infants with Mabry syndrome variants PIGV:c.615C>G (p.Asn205Lys) and c.854A>G (p.Tyr285Cys) • Thompson et al, PMID: 22315194 3 patients (2 sibs with compound heterozygotes for c.467G > A and c.494C > A (novel variant) in exon 3 of PIGV gene. 3rd unrelated individual compound heterozygote for the known c.1022C > A/c.1022C > T (p.Ala341Glu/p.Ala341Val) mutation) • Hutny et al PMID: 37372388, 6 Polish Patients all with homozygotic mutation (c.1022C>A; p.Ala341Glu) variant hyperphosphatasia with impaired intellectual development syndrome 1 (HPMRS1), distinct from other CDGs in terms of hyperphosphatemia related to abnormal ALP activity and brachytelephalangy. • Horn et al PMID: 24129430 16 individuals with Mabrys syndrome, most common variant c.1022C>A , and also novel variants (c. 176T>G, c.53G>A, c.905T>C, and c.1405C>T) detected PIGV mutations and demonstrate that the severe end of the clinical spectrum presents as a multiple congenital malformation syndrome with a high frequency of Hirschsprung disease, vesicoureteral, and renal anomalies as well as anorectal malformations. PIGV mutations are the major cause of HPMRS, which displays a broad clinical variability regarding associated malformations and growth patterns. Severe developmental delays, particular facial anomalies, brachytelephalangy, and hyperphosphatasia are consistently found in PIGV-positive individuals. No evidence of congenital heart defects found. Sources: Other |
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| Congenital Heart Defect v0.315 | TXNL4A |
LUCAS GARCIA ALVES FERREIRA gene: TXNL4A was added gene: TXNL4A was added to Congenital Heart Defect. Sources: Literature Mode of inheritance for gene: TXNL4A was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TXNL4A were set to 25434003; 28905882 Phenotypes for gene: TXNL4A were set to Burn-McKeown syndrome - MIM#608572 Penetrance for gene: TXNL4A were set to unknown Review for gene: TXNL4A was set to AMBER Added comment: Homozygous or compound heterozygous mutation in the TXNL4A gene are associated to Burn-McKeown syndrome (BMKS). BMKS is a rare disorder in which individuals with normal intellectual development exhibit the characteristic combination of choanal atresia, sensorineural deafness, cardiac defects, and typical craniofacial dysmorphism consisting of narrow palpebral fissures, coloboma of the lower eyelids, prominent nose with high nasal bridge, short philtrum, cleft lip and/or palate, and large and protruding ears (Wieczorek et al 2014 - PMID 25434003). Wieczorek et al (2014 - PMID: 25434003) report 9 families presenting individuals with BMKS and harboring biallelic variants in the TXNL4A gene. Four unrelated individuals presented cardiac defects. Goos et al (2017 - PMID: 28905882) report an individual with BMKS including asymptomatic atrial and ventricular septal defects, and harboring biallelic variants in the TXNL4A gene. Sources: Literature |
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| Congenital Heart Defect v0.315 | SMG9 |
Laura S edited their review of gene: SMG9: Added comment: Autosomal recessive inheritance Shaheen et al. in 2016 (27018474) published case reports about two consanguineous families in which a similar patter of congenital anomalies was found to be most likely caused by homozygous loss-of-function mutation in SMG9. This gene encodes an essential component of the SURF complex that generates phosphor-UPF1, the single most important step in nonsense-mediated decay (NMD). The authors generated a knock-out Smg9 mouse model using CRISPR/Cas9 and observed similar congenital anomaly syndrome to the one reported in humans. Additionally, human cells not expressing SMG9 had global transcriptional dysregulation, but not reduction of premature stop codon (PST)-containing transcripts. The affected family members in these two families showed to have phenotypic overlap between Dandy-Walker malformation and congenital heart disease. Due to the consanguineous nature in both families and the geographical proximity (both cases in Arabia) indicate the possibility of a homozygous pathogenic variants in the same gene. These variants are c.520_521delCC and c.701+4A>G, both affecting the gene SMG9. The indel in family 1 predicts a frameshift and premature truncation, p.Pro174Argfs*12. In family 2, a complete skipping of exon 6 was revealed by RT-PCR. The resulting aberrant transcript predicts frameshift and premature truncation (p.Tyr197Aspfs*10). In 2019, another case was reported by Lecoquierre et al. (31390136). The patient presented with a syndromic association of severe global developmental delay and diverse malformations. She carried a novel SMG9 homozygous variant NM_019108.3:c.1177C>T, p.(Gln393*), while her unaffected parents were both heterozygous and first-degree cousins. This absent variant in gnomaAD was predicted to result in a premature stop codon leading to nonsense-mediated decay within this single transcript gene. In 2020, Lemire et al. (32412169) reported a case of 7-year-old female with severe intellectual disability, multiple congenital anomalies, including cardiovascular anomalies, and facial dysmorphisms. No known consanguinity, the parents were heterozygous for the variant and she had an unaffected brother. She carried a homozygous missense variant in the SMG9 gene (c.1508G > C; p.Trp503Ser) identified as the likely etiology. In silico analysis predicted this change to impact protein structure/function. This missense change is rare, with only one allele count in gnomAD and no homozygotes. In 2021, Altuwaijri et al. (33609422) reported a new case in a research letter to the editor, in which a 25-month-old male had significant heart and brain malformations. Exome sequencing performed on the subject revealed the same homozygous splicing variant (NM_019108.4: exon7:c.701+4A>G) as their original report (Shaheen et al., 2016). Thus validating their previous findings.; Changed publications: 27018474 31390136 32412169 33609422; Changed phenotypes: Heart and brain malformation syndrome (HBMS) |
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| Congenital Heart Defect v0.315 | SMG9 |
Laura S changed review comment from: Autosomal recessive inheritance Shaheen et al. in 2016 (27018474) published case reports about two consanguineous families in which a similar patter of congenital anomalies was found to be most likely caused by homozygous loss-of-function mutation in SMG9. This gene encodes an essential component of the SURF complex that generates phosphor-UPF1, the single most important step in nonsense-mediated decay (NMD). The authors generated a knock-out Smg9 mouse model using CRISPR/Cas9 and observed similar congenital anomaly syndrome to the one reported in humans. Additionally, human cells not expressing SMG9 had global transcriptional dysregulation, but not reduction of premature stop codon (PST)-containing transcripts. The affected family members in these two families showed to have phenotypic overlap between Dandy-Walker malformation and congenital heart disease. Due to the consanguineous nature in both families and the geographical proximity (both cases in Arabia) indicate the possibility of a homozygous pathogenic variants in the same gene. These variants are c.520_521delCC and c.701+4A>G, both affecting the gene SMG9. The indel in family 1 predicts a frameshift and premature truncation, p.Pro174Argfs*12. In family 2, a complete skipping of exon 6 was revealed by RT-PCR. The resulting aberrant transcript predicts frameshift and premature truncation (p.Tyr197Aspfs*10). In 2019, another case was reported by Lecoquierre et al. (31390136). The patient presented with a syndromic association of severe global developmental delay and diverse malformations. She carried a novel SMG9 homozygous variant NM_019108.3:c.1177C>T, p.(Gln393*), while her unaffected parents were both heterozygous and first-degree cousins. This absent variant in gnomaAD was predicted to result in a premature stop codon leading to nonsense-mediated decay within this single transcript gene. In 2020, Lemire et al. (32412169) reported a case of 7-year-old female with severe intellectual disability, multiple congenital anomalies, including cardiovascular anomalies, and facial dysmorphisms. No known consanguinity, the parents were heterozygous for the variant and she had an unaffected brother. She carried a homozygous missense variant in the SMG9 gene (c.1508G > C; p.Trp503Ser) identified as the likely etiology. In silico analysis predicted this change to impact protein structure/function. This missense change is rare, with only one allele count in gnomAD and no homozygotes. In 2021, Altuwaijri et al. (33609422) reported a new case in a research letter to the editor, in which a 25-month-old male had significant heart and brain malformations. Exome sequencing performed on the subject revealed the same homozygous splicing variant (NM_019108.4: exon7:c.701+4A>G) as their original report (Shaheen et al., 2016). Thus validating their previous findings. Sources: Literature; to: Autosomal recessive inheritance Shaheen et al. in 2016 (27018474) published case reports about two consanguineous families in which a similar patter of congenital anomalies was found to be most likely caused by homozygous loss-of-function mutation in SMG9. This gene encodes an essential component of the SURF complex that generates phosphor-UPF1, the single most important step in nonsense-mediated decay (NMD). The authors generated a knock-out Smg9 mouse model using CRISPR/Cas9 and observed similar congenital anomaly syndrome to the one reported in humans. Additionally, human cells not expressing SMG9 had global transcriptional dysregulation, but not reduction of premature stop codon (PST)-containing transcripts. The affected family members in these two families showed to have phenotypic overlap between Dandy-Walker malformation and congenital heart disease. Due to the consanguineous nature in both families and the geographical proximity (both cases in Arabia) indicate the possibility of a homozygous pathogenic variants in the same gene. These variants are c.520_521delCC and c.701+4A>G, both affecting the gene SMG9. The indel in family 1 predicts a frameshift and premature truncation, p.Pro174Argfs*12. In family 2, a complete skipping of exon 6 was revealed by RT-PCR. The resulting aberrant transcript predicts frameshift and premature truncation (p.Tyr197Aspfs*10). In 2019, another case was reported by Lecoquierre et al. (31390136). The patient presented with a syndromic association of severe global developmental delay and diverse malformations. She carried a novel SMG9 homozygous variant NM_019108.3:c.1177C>T, p.(Gln393*), while her unaffected parents were both heterozygous and first-degree cousins. This absent variant in gnomaAD was predicted to result in a premature stop codon leading to nonsense-mediated decay within this single transcript gene. In 2020, Lemire et al. (32412169) reported a case of 7-year-old female with severe intellectual disability, multiple congenital anomalies, including cardiovascular anomalies, and facial dysmorphisms. No known consanguinity, the parents were heterozygous for the variant and she had an unaffected brother. She carried a homozygous missense variant in the SMG9 gene (c.1508G > C; p.Trp503Ser) identified as the likely etiology. In silico analysis predicted this change to impact protein structure/function. This missense change is rare, with only one allele count in gnomAD and no homozygotes. In 2021, Altuwaijri et al. (33609422) reported a new case in a research letter to the editor, in which a 25-month-old male had significant heart and brain malformations. Exome sequencing performed on the subject revealed the same homozygous splicing variant (NM_019108.4: exon7:c.701+4A>G) as their original report (Shaheen et al., 2016). Thus validating their previous findings. Sources: Literature |
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| Congenital Heart Defect v0.315 | SMG9 |
Laura S gene: SMG9 was added gene: SMG9 was added to Congenital Heart Defect. Sources: Literature Mode of inheritance for gene: SMG9 was set to Other Publications for gene: SMG9 were set to 27018474 Review for gene: SMG9 was set to RED Added comment: Autosomal recessive inheritance Shaheen et al. in 2016 (27018474) published case reports about two consanguineous families in which a similar patter of congenital anomalies was found to be most likely caused by homozygous loss-of-function mutation in SMG9. This gene encodes an essential component of the SURF complex that generates phosphor-UPF1, the single most important step in nonsense-mediated decay (NMD). The authors generated a knock-out Smg9 mouse model using CRISPR/Cas9 and observed similar congenital anomaly syndrome to the one reported in humans. Additionally, human cells not expressing SMG9 had global transcriptional dysregulation, but not reduction of premature stop codon (PST)-containing transcripts. The affected family members in these two families showed to have phenotypic overlap between Dandy-Walker malformation and congenital heart disease. Due to the consanguineous nature in both families and the geographical proximity (both cases in Arabia) indicate the possibility of a homozygous pathogenic variants in the same gene. These variants are c.520_521delCC and c.701+4A>G, both affecting the gene SMG9. The indel in family 1 predicts a frameshift and premature truncation, p.Pro174Argfs*12. In family 2, a complete skipping of exon 6 was revealed by RT-PCR. The resulting aberrant transcript predicts frameshift and premature truncation (p.Tyr197Aspfs*10). In 2019, another case was reported by Lecoquierre et al. (31390136). The patient presented with a syndromic association of severe global developmental delay and diverse malformations. She carried a novel SMG9 homozygous variant NM_019108.3:c.1177C>T, p.(Gln393*), while her unaffected parents were both heterozygous and first-degree cousins. This absent variant in gnomaAD was predicted to result in a premature stop codon leading to nonsense-mediated decay within this single transcript gene. In 2020, Lemire et al. (32412169) reported a case of 7-year-old female with severe intellectual disability, multiple congenital anomalies, including cardiovascular anomalies, and facial dysmorphisms. No known consanguinity, the parents were heterozygous for the variant and she had an unaffected brother. She carried a homozygous missense variant in the SMG9 gene (c.1508G > C; p.Trp503Ser) identified as the likely etiology. In silico analysis predicted this change to impact protein structure/function. This missense change is rare, with only one allele count in gnomAD and no homozygotes. In 2021, Altuwaijri et al. (33609422) reported a new case in a research letter to the editor, in which a 25-month-old male had significant heart and brain malformations. Exome sequencing performed on the subject revealed the same homozygous splicing variant (NM_019108.4: exon7:c.701+4A>G) as their original report (Shaheen et al., 2016). Thus validating their previous findings. Sources: Literature |
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| Congenital Heart Defect v0.282 | MAP4K4 |
Zornitza Stark gene: MAP4K4 was added gene: MAP4K4 was added to Congenital Heart Defect. Sources: Literature Mode of inheritance for gene: MAP4K4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: MAP4K4 were set to 37126546 Phenotypes for gene: MAP4K4 were set to RASopathy, MONDO:0021060, MAP4K4-related Review for gene: MAP4K4 was set to GREEN Added comment: 26 individuals from 21 families reported with Rasopathy-like phenotype, comprising ID/DD, dysmorphic features and congenital anomalies. Sources: Literature |
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| Congenital Heart Defect v0.269 | AMOTL1 |
Lucy Spencer gene: AMOTL1 was added gene: AMOTL1 was added to Congenital Heart Defect. Sources: Literature Mode of inheritance for gene: AMOTL1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: AMOTL1 were set to 36751037 Phenotypes for gene: AMOTL1 were set to Orofacial clefting syndrome, MONDO:0015335, AMOTL1-related Review for gene: AMOTL1 was set to GREEN Added comment: PMID: 36751037- 16 individuals from 12 families with orofacial clefting syndrome and het variants in AMOTL1. Many in 1 hotspot: 5 individuals from 3 families have R157C, 6 individuals from another 4 families have R157H, 1 has P160L, and another has Q161R. Out of this hostpaot- 1 with P368A, 1 with E507K, 1 with E579K. 7 are de novo. All but 2 have clefting, 7 are dysmorphic, 5 have hearing loss, 9 have CHD, 7 have tall stature, 6 have dev delay. Other features include liver disease, myopia, scoliosis and immune involvement. Another 2 families have been previously reported (described in the panelapp review below) with variants in this hotspot 1 has 2 individuals with R157C, the other has 1 individual with P160L. All hotspot are absent from gnomad v2. Sources: Literature |
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| Congenital Heart Defect v0.262 | ALDH1A2 | Zornitza Stark Phenotypes for gene: ALDH1A2 were changed from Congenital heart defects; diaphragmatic eventration; pulmonary hypoplasia; dysmorphic features to Diaphragmatic hernia 4, with cardiovascular defects, MIM# 620025 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Congenital Heart Defect v0.213 | MAPKAPK5 | Zornitza Stark Phenotypes for gene: MAPKAPK5 were changed from Developmental delay, variable brain anomalies, congenital heart defects, dysmorphic to Neurocardiofaciodigital syndrome, MIM# 619869 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Congenital Heart Defect v0.199 | NAA15 |
Krithika Murali edited their review of gene: NAA15: Added comment: Monoallelic variants associated with syndromic ID. At least 47 individuals from 42 unrelated families in the published literature. Phenotypic features reported include: - ID (all) - Mild dysmorphic features (20/30) - ASD/ADHD/behavioural issues (30/33) - Skeletal and connective tissue anomalies (10/22) - Congenital heart defects (4/19) - Hypertrophic cardiomyopathy (paediatric onset) - 2 unrelated individuals (PMID: 33103328) In addition: PMID 33557580 - WES of 4511 patients with CHD identified 4 subjects with a rare LoF variant (allele frequency <0.00005) in the NAA15 gene, resulting in NAA15 haploinsufficiency. Parental analyses indicated that 3 of these LoF variants (p.Ser761*, p.Lys336Lys fs*6, and p.Arg470*) arose de novo in the probands. The inheritance of the p.Ala718fs variant is uncertain, as parental samples were unavailable. The authors also reference their previous studies identifying 2 other patients with CHD and LoF NAA15 heterozygous variants.; Changed phenotypes: Intellectual developmental disorder, autosomal dominant 50, with behavioral abnormalities - MIM#617787, congenital heart defect |
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| Congenital Heart Defect v0.199 | NAA15 |
Krithika Murali gene: NAA15 was added gene: NAA15 was added to Congenital Heart Defect. Sources: Literature Mode of inheritance for gene: NAA15 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: NAA15 were set to 33103328; 29656860; 31127942; 28191889; 33557580; 28990276 Phenotypes for gene: NAA15 were set to Intellectual developmental disorder, autosomal dominant 50, with behavioral abnormalities - MIM#617787 Review for gene: NAA15 was set to GREEN Added comment: Monoallelic variants associated with syndromic ID. At least 47 individuals from 42 unrelated families in the published literature. Phenotypic features reported include: - ID (all) - Mild dysmorphic features (20/30) - ASD/ADHD/behavioural issues (30/33) - Skeletal and connective tissue anomalies (10/22) - Congenital heart defects (4/19) - Hypertrophic cardiomyopathy (paediatric onset) - 2 unrelated individuals (PMID: 33103328) In addition: PMID 33557580 - WES of 4511 patients with CHD identified 4 subjects with a rare LoF variant (allele frequency <0.00005) in the NAA15 gene, resulting in NAA15 haploinsufficiency. Parental analyses indicated that 3 of these LoF variants (p.Ser761*, p.Lys336Lys fs*6, and p.Arg470*) arose de novo in the probands. The inheritance of the p.Ala718fs variant is uncertain, as parental samples were unavailable. The authors also reference their previous studies identifying 2 other patients with CHD and LoF NAA15 heterozygous variants. Sources: Literature |
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| Congenital Heart Defect v0.189 | SEMA3A |
Krithika Murali gene: SEMA3A was added gene: SEMA3A was added to Congenital Heart Defect. Sources: Literature Mode of inheritance for gene: SEMA3A was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal Publications for gene: SEMA3A were set to 28075028; 33369061; 20301509; 21059704; 24124006; 22927827 Phenotypes for gene: SEMA3A were set to {Hypogonadotropic hypogonadism 16 with or without anosmia - MIM#614897; congenital heart disease; short stature Review for gene: SEMA3A was set to GREEN Added comment: Heterozygous variants associated with isolated GnRH deficiency with or without anosmia (Kallman syndrome like). More severe phenotype with biallelic SEMA3A variants including postnatal short stature and congenital heart defects in 3/3 published, unrelated individuals. PMID 33369061 Gileta et al 2021 - report x1 patient. Female proband was compound heterozygote for a nonsense variant and a multiexonic deletion of SEMA3A. Presents with postnatal short stature, congenital cardiac anomalies, dysmorphic features, hypogonadotrophic hypogonadism and anosmia. PMID 28075028 Baumann et al 2017 - report x1 patient. Homozygous LoF variants identified in a proband from a consanguineous Turkish family. Noted at birth to have a high-positioned scapulae, deformed ribs and a lateral clavicular hook. The patient also had upper/lower limb contractures and aberrant right subclavian artery. Mild facial dysmorphism, micropenis and hypogonadotrophic hypogonadism also noted in the first week of life. Postnatal short stature (length 50cm at term birth) PMID 24124006 Hofmann et al 2013 - first reported biallelic variants in a proband with postnatal short stature, skeletal anomalies of the thorax, congenital heart defect and camptodactyly Sources: Literature |
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| Congenital Heart Defect v0.163 | MIB1 |
Zornitza Stark changed review comment from: Established congenital cardiac disease gene. PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio study from the Deciphering Developmental Disorders study. 11 de novo variants (1 frameshift, 2 missense, 2 splice acceptor, 1 splice donor, 5 stopgain) identified in ~10,000 cases with developmental disorders (no other phenotype info provided). Sources: Expert Review; to: Li 2018 (PMID: 30322850): - in 4 CHD patients: p.Q237H (gv2v3 absent), p.W271G (gv2v3 absent), p.S520R (v2 5 hets) and p.T312Kfs*55 (NMD-pred, absent but many comparables in gnomAD). - HEK293T cells transfection studies showed: T312Kfs*55 and W271G strongly impaired MIB1 function on substrate ubiquitination, while Q237H and S520R had slight or no obvious changes. Interaction between MIB1 and JAG1 is severely interrupted by p.T312Kfs*55 and p.W271G, but not really in the other 2 missense. - Overexpression of wt or mutant in zebrafish all resulted in dysmorphic pheno, therefore not informative. PMID: 33057194 - Has been identified as a gene with significant de novo enrichment in a large trio study from the Deciphering Developmental Disorders study. 11 de novo variants (1 frameshift, 2 missense, 2 splice acceptor, 1 splice donor, 5 stopgain) identified in ~10,000 cases with developmental disorders (no other phenotype info provided). Sources: Expert Review |
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| Congenital Heart Defect v0.149 | MAPKAPK5 |
Zornitza Stark gene: MAPKAPK5 was added gene: MAPKAPK5 was added to Congenital Heart Defect. Sources: Expert Review Mode of inheritance for gene: MAPKAPK5 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MAPKAPK5 were set to 33442026 Phenotypes for gene: MAPKAPK5 were set to Developmental delay, variable brain anomalies, congenital heart defects, dysmorphic Review for gene: MAPKAPK5 was set to GREEN Added comment: 3 individuals from 2 families with severe developmental delay, variable brain anomalies, congenital heart defects, dysmorphic facial features, and a distinctive type of synpolydactyly with an additional hypoplastic digit between the fourth and fifth digits of hands and/or feet. Exome sequencing identified different homozygous truncating variants in MAPKAPK5 in both families, segregating with disease and unaffected parents as carriers. Patient-derived cells showed no expression of MAPKAPK5 protein isoforms and reduced levels of the MAPKAPK5-interacting protein ERK3. F-actin recovery after latrunculin B treatment was found to be less efficient in patient-derived fibroblasts than in control cells, supporting a role of MAPKAPK5 in F-actin polymerization. Sources: Expert Review |
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| Congenital Heart Defect v0.130 | WLS |
Teresa Zhao gene: WLS was added gene: WLS was added to Congenital Heart Defect. Sources: Literature Mode of inheritance for gene: WLS was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: WLS were set to PMID: 34587386 Phenotypes for gene: WLS were set to Syndromic structural birth defects Review for gene: WLS was set to GREEN Added comment: - Homozygous mutations in 10 affected persons from 5 unrelated families. - Patients had multiorgan defects, including microcephal, facial dysmorphism, foot syndactyly, renal agenesis, alopecia, iris coloboma, and heart defects. - The mutations affected WLS protein stability and Wnt signaling. Knock-in mice showed tissue and cell vulnerability consistent with Wnt-signaling intensity and individual and collective functions of Wnts in embryogenesis. Sources: Literature |
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| Congenital Heart Defect v0.129 | SPEN |
Elena Savva gene: SPEN was added gene: SPEN was added to Congenital Heart Defect. Sources: Literature Mode of inheritance for gene: SPEN was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: SPEN were set to PMID: 33596411 Phenotypes for gene: SPEN were set to Radio-Tartaglia syndrome MIM#619312 Review for gene: SPEN was set to GREEN gene: SPEN was marked as current diagnostic Added comment: PMID: 33596411 - 34 individuals with truncating variants in SPEN reported, most are de novo variants. - Clinical profile includes developmental delay/intellectual disability, autism spectrum disorder, anxiety, aggressive behavior, attention deficit disorder, hypotonia, brain and spine anomalies, congenital heart defects, high/narrow palate, facial dysmorphisms, and obesity/increased BMI, especially in females. - Authors showed haploinsufficiency of SPEN is associated with a distinctive DNA methylation episignature of the X chromosome in affected females. Sources: Literature |
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| Congenital Heart Defect v0.128 | ZMYM2 |
Zornitza Stark gene: ZMYM2 was added gene: ZMYM2 was added to Congenital Heart Defect. Sources: Expert Review Mode of inheritance for gene: ZMYM2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: ZMYM2 were set to 32891193 Phenotypes for gene: ZMYM2 were set to Neurodevelopmental-craniofacial syndrome with variable renal and cardiac abnormalities, MIM# 619522 Review for gene: ZMYM2 was set to GREEN Added comment: Connaughton et al (2020 - PMID: 32891193) report on 19 individuals (from 15 unrelated families) with heterozygous pathogenic ZMYM2 variants. Affected individuals from 7 families presented with CAKUT while all of them displayed extra-renal features. Neurological manifestations were reported in 16 individuals from 14 families (data not available for 1 fam), among others hypotonia (3/14 fam), speech delay (4/14 fam), global DD (9/14 fam), ID (4/14 fam), microcephaly (4/14 fam). ASD was reported in 4 fam (4 indiv). Seizures were reported in 2 fam (2 indiv). Variable other features included cardiac defects, facial dysmorphisms, small hands and feet with dys-/hypo-plastic nails and clinodactyly. 14 pLoF variants were identified, in most cases as de novo events (8 fam). In 2 families the variant was inherited from an affected parent. Germline mosaicism occurred in 1 family. The human disease features were recapitulated in a X. tropicalis morpholino knockdown, with expression of truncating variants failing to rescue renal and craniofacial defects. Heterozygous Zmym2-deficient mice also recapitulated the features of CAKUT. ZMYM2 (previously ZNF198) encodes a nuclear zinc finger protein localizing to the nucleus (and PML nuclear body). It has previously been identified as transcriptional corepressor interacting with nuclear receptors and the LSD1-CoREST-HDAC1 complex. It has also been shown to interact with FOXP transcription factors. The authors provide evidence for loss of interaction of the truncated ZMYM2 with FOXP1 (mutations in the latter having recently been reported in syndromic CAKUT). Sources: Expert Review |
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| Congenital Heart Defect v0.126 | ZNF699 |
Zornitza Stark gene: ZNF699 was added gene: ZNF699 was added to Congenital Heart Defect. Sources: Literature Mode of inheritance for gene: ZNF699 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ZNF699 were set to 33875846 Phenotypes for gene: ZNF699 were set to DEGCAGS syndrome, MIM# 619488 Review for gene: ZNF699 was set to GREEN Added comment: DEGCAGS syndrome is a neurodevelopmental disorder characterized by global developmental delay, coarse and dysmorphic facial features, and poor growth and feeding apparent from infancy. Affected individuals have variable systemic manifestations often with significant structural defects of the cardiovascular, genitourinary, gastrointestinal, and/or skeletal systems. Additional features may include sensorineural hearing loss, hypotonia, anaemia or pancytopaenia, and immunodeficiency with recurrent infections. 12 unrelated families reported, 5 different homozygous frameshift variants. Sources: Literature |
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| Congenital Heart Defect v0.99 | ALDH1A2 |
Bryony Thompson gene: ALDH1A2 was added gene: ALDH1A2 was added to Congenital Heart Defect. Sources: Literature Mode of inheritance for gene: ALDH1A2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ALDH1A2 were set to 33565183; 10192400 Phenotypes for gene: ALDH1A2 were set to Congenital heart defects; diaphragmatic eventration; pulmonary hypoplasia; dysmorphic features Review for gene: ALDH1A2 was set to GREEN Added comment: Two families, an Australian family with segregation of biallelic variants and an unrelated Italian proband with biallelic variants with similar phenotypes. Functional assays suggest the variants in the 2 families are hypomorphic. Knockout mouse model is embryonic lethal due utero defects in early heart morphogenesis. Sources: Literature |
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| Congenital Heart Defect v0.88 | UBR7 | Zornitza Stark Phenotypes for gene: UBR7 were changed from Intellectual disability; epilepsy; hypothyroidism; congenital anomalies; dysmorphic features to Li-Campeau syndrome, MIM# 619189; Intellectual disability; epilepsy; hypothyroidism; congenital anomalies; dysmorphic features | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Congenital Heart Defect v0.87 | UBR7 | Zornitza Stark edited their review of gene: UBR7: Changed phenotypes: Li-Campeau syndrome, MIM# 619189, Intellectual disability, epilepsy, hypothyroidism, congenital anomalies, dysmorphic features | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Congenital Heart Defect v0.85 | UBR7 |
Zornitza Stark gene: UBR7 was added gene: UBR7 was added to Congenital Heart Defect. Sources: Literature Mode of inheritance for gene: UBR7 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: UBR7 were set to 33340455 Phenotypes for gene: UBR7 were set to Intellectual disability; epilepsy; hypothyroidism; congenital anomalies; dysmorphic features Review for gene: UBR7 was set to GREEN Added comment: Seven individuals from 6 unrelated families. All had developmental delay, and all males had urogenital anomalies, namely cryptorchidism in 5/6 and small penis in 1/6. Six individuals had seizures and hypotonia. Hypothyroidism was present in 4/7 individuals, and ptosis was noted in 6/7 individuals. Five individuals exhibited cardiac abnormalities: two had ventricular septal defect, one had atrial septal defect, one had a patent ductus arteriosus requiring surgery, and the other had a patent ductus arteriosus and a patent foramen ovale that both closed spontaneously. Five individuals had short stature (height < 3rd percentile). Physical examination revealed various dysmorphic features, including prominent forehead (3/7), hypertelorism (4/7), telecanthus (1/7), epicanthus(1/7), downslanting palpebral fissures (3/7), thick eyebrow (1/7), low-set ears (3/7), long philtrum (2/7), unilateral single transverse palmar crease (1/7), and hypertrichosis (1/7). Sources: Literature |
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| Congenital Heart Defect v0.56 | SMO | Zornitza Stark Phenotypes for gene: SMO were changed from Microcephaly, congenital heart disease, polydactyly, aganglionosis to Microcephaly, congenital heart disease, polydactyly, aganglionosis; Pallister-Hall-like syndrome , MIM#241800 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Congenital Heart Defect v0.55 | SMO | Zornitza Stark edited their review of gene: SMO: Changed phenotypes: Microcephaly, congenital heart disease, polydactyly, aganglionosis, Pallister-Hall-like syndrome , MIM#241800 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Congenital Heart Defect v0.51 | TMEM94 |
Zornitza Stark gene: TMEM94 was added gene: TMEM94 was added to Congenital Heart Defect. Sources: Expert list Mode of inheritance for gene: TMEM94 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TMEM94 were set to Intellectual developmental disorder with cardiac defects and dysmorphic facies Phenotypes for gene: TMEM94 were set to 30526868 Review for gene: TMEM94 was set to GREEN Added comment: Ten individuals from 6 unrelated families reported, variety of congenital heart defects in addition to ID (ASD, VSD, Tetralogy of Fallot). Sources: Expert list |
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| Congenital Heart Defect v0.48 | ABL1 |
Ain Roesley gene: ABL1 was added gene: ABL1 was added to Congenital Heart Defect. Sources: Literature Mode of inheritance for gene: ABL1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: ABL1 were set to PMID: 28288113 Phenotypes for gene: ABL1 were set to Congenital heart defects and skeletal malformations syndrome (MIM# 617602) Penetrance for gene: ABL1 were set to unknown Review for gene: ABL1 was set to GREEN Added comment: PMID: 28288113: six affected individuals from 4 unrelated families who shared similar clinical features including dysmorphic facial features (6/6), congenital heart disease (CHD, 6/6), skeletal abnormalities (6/6), joint problems (5/6), failure to thrive (5/6), gastrointestinal problems (5/6), and male genital/sexual abnormalities (3/4). Missense variants with 3 families sharing the same variant (Tyr245Cys). Authors also noted similar congenital malformations observed in fetuses exposed to the selective tyrosine kinase inhibitor imatinib, and patients with constitutional ABL1 variants Sources: Literature |
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| Congenital Heart Defect v0.48 | SMO | Zornitza Stark Marked gene: SMO as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Congenital Heart Defect v0.48 | SMO | Zornitza Stark Gene: smo has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Congenital Heart Defect v0.48 | SMO | Zornitza Stark Classified gene: SMO as Green List (high evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Congenital Heart Defect v0.48 | SMO | Zornitza Stark Gene: smo has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Congenital Heart Defect v0.47 | SMO |
Zornitza Stark gene: SMO was added gene: SMO was added to Congenital Heart Defect. Sources: Literature Mode of inheritance for gene: SMO was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SMO were set to 32413283 Phenotypes for gene: SMO were set to Microcephaly, congenital heart disease, polydactyly, aganglionosis Review for gene: SMO was set to GREEN Added comment: Bi-allelic loss-of-function variations in SMO reported in seven individuals from five independent families. Wide phenotypic spectrum of developmental anomalies affecting the brain (hypothalamic hamartoma and microcephaly), heart (atrioventricular septal defect), skeleton (postaxial polydactyly, narrow chest, and shortening of long bones), and enteric nervous system (aganglionosis). Sources: Literature |
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| Congenital Heart Defect v0.25 | CDK13 | Zornitza Stark Phenotypes for gene: CDK13 were changed from to Congenital heart defects, dysmorphic facial features, and intellectual developmental disorder, 617360 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Congenital Heart Defect v0.22 | CDK13 | Kristin Rigbye reviewed gene: CDK13: Rating: GREEN; Mode of pathogenicity: None; Publications: 29021403, 29393965, 30904094; Phenotypes: Congenital heart defects, dysmorphic facial features, and intellectual developmental disorder, 617360; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||