2025-03-25 ロックフェラー大学
<関連情報>
- https://www.rockefeller.edu/news/37519-study-implicates-60-genes-in-congenital-heart-disease-including-some-that-that-also-contribute-to-related-to-disorders-such-as-autism/
- https://www.pnas.org/doi/10.1073/pnas.2420343122
11,555人のプロバンドを対象としたゲノム解析により、60の優性先天性心疾患遺伝子が同定される Genomic analysis of 11,555 probands identifies 60 dominant congenital heart disease genes
Michael C. Sierant, Sheng Chih Jin, Kaya Bilguvar, +42 , and Richard P. Lifton
Proceedings of the National Academy of Sciences Published:March 24, 2025
DOI:https://doi.org/10.1073/pnas.2420343122
Significance
We identified 60 genes with significant burden of monoallelic damaging variants, accounting for 10.1% of probands, with equal contributions from de novo and transmitted variants. Mutations often produced variable congenital heart disease (CHD) and extracardiac (EC) phenotypes. Mutation frequency was variable and not explained by mutability. Probands with mutations associated with syndromic CHD were frequently not clinically diagnosed, often due to the absence of characteristic phenotypes. Genes with predominantly transmitted variants were enriched for isolated CHD and depleted for extracardiac features including neurodevelopmental disorders (NDD). There was wide variation in risk of NDD (e.g., 4% for MYH6 mutation vs. 95% for CHD7). Results support increased use of molecular diagnosis to assess risk and allow early intervention to potentially improve outcomes.
Abstract
Congenital heart disease (CHD) is a leading cause of infant mortality. We analyzed de novo mutations (DNMs) and very rare transmitted/unphased damaging variants in 248 prespecified genes in 11,555 CHD probands. The results identified 60 genes with a significant burden of heterozygous damaging variants. Variants in these genes accounted for CHD in 10.1% of probands with similar contributions from de novo and transmitted variants in parent–offspring trios that showed incomplete penetrance. DNMs in these genes accounted for 58% of the signal from DNMs. Thirty-three genes were linked to a single CHD subtype while 12 genes were associated with 2 to 4 subtypes. Seven genes were only associated with isolated CHD, while 37 were associated with 1 or more extracardiac abnormalities. Genes selectively expressed in the cardiomyocyte lineage were associated with isolated CHD, while those widely expressed in the brain were also associated with neurodevelopmental delay (NDD). Missense variants introducing or removing cysteines in epidermal growth factor (EGF)-like domains of NOTCH1 were enriched in tetralogy of Fallot and conotruncal defects, unlike the broader CHD spectrum seen with loss of function variants. Transmitted damaging missense variants in MYH6 were enriched in multiple CHD phenotypes and account for ~1% of all probands. Probands with characteristic mutations causing syndromic CHD were frequently not diagnosed clinically, often due to missing cardinal phenotypes. CHD genes that were positively or negatively associated with development of NDD suggest clinical value of genetic testing. These findings expand the understanding of CHD genetics and support the use of molecular diagnostics in CHD.
