GJA1 was first reported in relation to congenital heart disease in 1995 (Britz-Cunningham et al., PMID: 7715640). This gene-disease relationship in the literature reports both autosomal dominant and recessive cases and showed varying mechanisms of pathogenicity, so the mode of inheritance is currently undetermined. Three unique variants (missense) reported in three individuals with CHD (1 homozygous, 2 heterozygous) are included in this curation (PMID: 15978203, 19615768). There are more variants reported in other publications, however they were not included due to either unclear phenotype, high minor allele frequency (>0.00001) on gnomAD v.4, or unclear mode of inheritance with multiple variants reported in the proband (PMID: 7715640, 11470490, 19615768, 28991257, 32368696, 31564432, 31019026, 34670123). This gene-disease relationship is also supported by expression data in both mouse and human cardiac tissues (PMIDs: 12064615, 12881038). One mouse study showed that both heterozygous and homozygous GJA1 knock-in mice were long term viable with no heart defects (PMID: 22135478). Conversely, there are also several mouse studies showing heart defects in mice mutants, however none were scored due to inconsistent mechanisms of pathogenicity (PMIDs: 7892609, 9640330, 9486664, 9118799). In summary, there is limited evidence supporting the relationship between GJA1 and congenital heart disease. Although more evidence is needed to support a causal role, the contradictory evidence does not significantly outweigh the evidence that supports the gene-disease relationship either. This classification was approved by the ClinGen Congenital Heart Disease GCEP on the meeting date June 4th, 2024 (SOP Version 10).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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