NKX2.5 was first reported in relation to autosomal dominant NKX2.5-related congenital, conduction and myopathic heart disease in 1998 (Schott et al., PMID:9651244) including congenital heart disease entities: Atrial septal defect 7, with or without AV conduction defects (OMIM:108900), Conotruncal heart malformations, variable (OMIM:217095), Hypoplastic left heart syndrome 2 (OMIM:614435), Tetralogy of Fallot (OMIM:187500), Ventricular septal defect 3 (OMIM:614432). Since then, more than 26 unique variants (missense, nonsense, frameshift, deletions) across 18 papers have reported cases of a similar phenotype including congenital heart disease (predominantly ASD), AV block and later onset dilated cardiomyopathy and/or hypertrabeculation with predisposition to atrial and ventricular arrhythmias (PMIDs 38670870, 36609421, 34277740, 33082984, 31654754, 30471092, 30479953, 30354339, 28690296, 26679770, 27855642, 25503402, 24880466, 23661673, 20456451, 15810002, 14607454, 10587520 ). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanisms or inheritance pattern and these phenotypes have been lumped. Phenotype is variable within families and individuals may have only some of these features. Variants causing this phenotype appear to be either truncating or missense within the homeodomain. The relevance of non-truncating variants outside of the homeodomain is unclear. This gene-disease relationship is supported by three mouse models, functional alteration data, and protein interaction data (PMIDs: 28352650, 18689573, 7628699, 26146939, 27154817). In summary, NKX2.5 is definitively associated with autosomal dominant NKX2.5-related congenital, conduction and myopathic heart disease. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Congenital Heart Disease GCEP on the meeting date 3/7/2023 (SOP Version 9), and the summary was updated by the ClinGen Hereditary Cardiovascular Disease GCEP after meeting on 11/7/2024 to expand detail on the cardiomyopathy and arrhythmia aspects of the phenotype. .
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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