| Date | Panel | Item | Activity | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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 |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Congenital Heart Defect v0.315 | WASHC5 |
Lucas Mitchell gene: WASHC5 was added gene: WASHC5 was added to Congenital Heart Defect. Sources: ClinGen,Literature Mode of inheritance for gene: WASHC5 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: WASHC5 were set to PMID: 24065355; 37840956; 30896870; 32349777; 32349777 Phenotypes for gene: WASHC5 were set to Ritscher-Schinzel syndrome - MIM#220210; Ventricular septal defect; Atrial septal defect; Tetralogy of Fallot; Double outlet right ventricle; Hypoplastic left heart; Aortic stenosis; Pulmonic stenosis Penetrance for gene: WASHC5 were set to unknown Review for gene: WASHC5 was set to AMBER Added comment: Homozygous/biallelic variants in WASHC5 (previous name KIAA0196) are associated with Ritscher-Schinzel syndrome (RSS) - A developmental malformation syndrome characterised by craniofacial abnormalities, congenital heart defects, and cerebellar brain malformations. Cardiac defects include septal defects and aortic stenosis, among others (OMIM: Leonardi et al., 2001; Elliott et al., 2013). Victor Chang CHD gene registry reports on WASHC5, also stating unknown penetrance. (https://chdgene.victorchang.edu.au/gene/9897) Literature (humans): Elliot et al, 2013 (24065355) 8 first nations patients, and 8 of their parents, and 5 unaffected people from same geographic region (northern Manitoba, Canada) underwent homozygosity mapping by SNP array and sanger sequencing. Variable phenotypic traits among affected members included atrial and ventricular septal defects. The only biallelic mutations identified occurred in KIAA0196 (WASHC5), where sequence analysis revealed homozygosity for three novel variants (c.3335+2T>A, c.3335 +4C>A and c.3335+8A>G) in each patient (figure 2A). All parents were heterozygous for the three sequence changes, and none of the five control subjects was homozygous for any of these changes. Comparison of normalised cycle threshold (Ct) values indicated a 6.98 to 8.72 (mean 7.85)-fold reduction in the relative amount of KIAA0196 transcript in the patient samples versus the control sample. Sanger sequencing of the cloned PCR product from a patient revealed that the primary product did not contain exon 27 (figure 2B). Suggesting altered KIAA0196 transcript produced by the patient might be targeted for nonsense mediated decay. Strumpellin, the product of KIAA0196, is a highly conserved glycoprotein from plants to humans, and ubiquitously expressed. Harvey et al, 2023 (37840956), reports 2 probands with WASHC5 variants and CHD phenotype. Not clear if probands related, or from same geographical area. Zygosity not clear. No information provided about probands, family testing/segregation. Landis 2023, (37681527) a cohort of 1362 with CHD, reports one with variant in WASHC5. No further information provided about variant, zygosity, or about participant in paper or supp data. Bu. 2020 et al, (30896870) Reports, 9mnth male in Changsha, China, with patent ductus arteriosus (PDA) - an opening between two blood vessels leading from the heart, patent foramen ovale (PFO) - hole between the left and right atria, and KIAA0196 (WASHC5) variant. No mention zygosity or biallelic. No supp data provided. Møller Nielsen, 2021(https://doi.org/10.1016/j.ijcchd.2021.100164), Danish cohort study with Atrial septal defects (ASD), 384 variants identified, three WASHC5 variants are considered pathogenic. Supplementary table 3 reports three WASHC5 variants, but no further information is provided about participants, zygosity of variants, or if blood-related. Limitations state only had singleton data and unable to clarify inheritance/de-novo. Supplementary table reported further info for the three WASHC5 variants, but no explicit mention if biallelic mutations. Excel column J reports 'reads (Ref:Alt)' and indicates participants are ?heterozygous variants which may conflict with RSS being a recessive/biallelic condition? Hseih, 2020, (32349777) Mentioned having two damaging germline and one mosaic mutations in their cohort that supports WASHC5 to be a candidate CHD gene. No further information about those variants or participants is provided. No supp data provided. Animal models: Mouse Genome Informatics MGI#2146110) : Homozygous knockout mice die well prior to E13.5 as no evidence of conceptus. In heterozygous knockout mice no cardiovascular defect recorded. Bu, 2020 (32417190) Mouse and zebrafish studies show potential evidence for WASHC5 biallelic variants cause CHD/. However CliniGen Commented "neither provide evidence to support the gene-disease relationship (Bu et al., PMID:32417190)" In summary, Elliot et al provides detailed evidence, however looking further at recent literature, studies mention or report on WASHC5 variants and possible associations with CHD, but do not report enough detail to be confident and satisfy ClinGene/PanelApp criteria. Sources: ClinGen, Literature |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Congenital Heart Defect v0.212 | SON | Zornitza Stark Marked gene: SON as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Congenital Heart Defect v0.212 | SON | Zornitza Stark Gene: son has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Congenital Heart Defect v0.212 | SON | Zornitza Stark Phenotypes for gene: SON were changed from to ZTTK syndrome, MIM# 617140 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Congenital Heart Defect v0.211 | SON | Zornitza Stark Publications for gene: SON were set to | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Congenital Heart Defect v0.210 | SON | Zornitza Stark Mode of inheritance for gene: SON was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Congenital Heart Defect v0.209 | SON | Zornitza Stark reviewed gene: SON: Rating: GREEN; Mode of pathogenicity: None; Publications: 27545680, 27545676, 31005274; Phenotypes: ZTTK syndrome, MIM# 617140; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Congenital Heart Defect v0.120 | UBR1 | Zornitza Stark Phenotypes for gene: UBR1 were changed from to Johanson-Blizzard syndrome (MIM#243800) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Congenital Heart Defect v0.117 | UBR1 | Zornitza Stark reviewed gene: UBR1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Johanson-Blizzard syndrome (MIM#243800); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Congenital Heart Defect v0.117 | UBR1 | Teresa Zhao reviewed gene: UBR1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 24599544; Phenotypes: Johanson-Blizzard syndrome (MIM#243800); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Congenital Heart Defect v0.112 | ZEB2 | Zornitza Stark Phenotypes for gene: ZEB2 were changed from to Mowat-Wilson syndrome, MIM# 235730; MONDO:0009341 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Congenital Heart Defect v0.109 | ZEB2 | Zornitza Stark reviewed gene: ZEB2: Rating: GREEN; Mode of pathogenicity: None; Publications: 29300384, 27831545, 24715670, 19215041, 17958891; Phenotypes: Mowat-Wilson syndrome, MIM# 235730, MONDO:0009341; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Congenital Heart Defect v0.75 | TAF1 | Zornitza Stark Phenotypes for gene: TAF1 were changed from Dystonia-Parkinsonism, X-linked 314250; Mental retardation, X-linked, syndromic 33 300966; congenital cardiac disease and global developmental delay to Mental retardation, X-linked, syndromic 33 300966; congenital cardiac disease and global developmental delay | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Congenital Heart Defect v0.73 | TAF1 |
Elena Savva gene: TAF1 was added gene: TAF1 was added to Congenital Heart Defect. Sources: Literature Mode of inheritance for gene: TAF1 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females Publications for gene: TAF1 were set to PMID: 32396742; 31646703; 26637982; 31341187 Phenotypes for gene: TAF1 were set to Dystonia-Parkinsonism, X-linked 314250; Mental retardation, X-linked, syndromic 33 300966; congenital cardiac disease and global developmental delay Review for gene: TAF1 was set to AMBER Added comment: -Carrier females consistently shown to be asymptomatic with skewed X-inactivation -While no PTCs have been reported, the lack of representation in population databases strongly suggests these mutations are not compatible with life (Gudmundsson, S. et al. (2019)) Two patients with hemizygous missense variants, with congenital cardiac disease and global developmental delay Sources: Literature |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Congenital Heart Defect v0.0 | SON |
Zornitza Stark gene: SON was added gene: SON was added to Congenital Heart Defect_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services Mode of inheritance for gene: SON was set to Unknown |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||