Genomic analysis of 11,555 probands identifies 60 dominant congenital heart disease genes

• DOI: 10.1073/pnas.2420343122
• Publication Date: 2025-03-24T19:13:45Z
• Authors: Michael C. Sierant; Sheng Chih Jin; Kaya Bilguvar; Sarah U. Morton; Weilai Dong; Wei Jiang; Ziyu Lu; Boyang Li; Francesc López-Gi...; Irina Tikhonova; Xue Zeng; Qiongshi Lu; Jungmin Choi; Junhui Zhang; Carol Nelson-Will...; James R. Knight; Hongyu Zhao; Junyue Cao; Shrikant Mane; Stanley C. Sedore; Peter J. Gruber; Monkol Lek; Elizabeth Goldmuntz; John Deanfield; Alessandro Giardini; Seema Mital; Mark Russell; J. William Gaynor; Eileen King; Michael Wagner; Deepak Srivastava; Yufeng Shen; Daniel Bernstein; George A. Porter; Jane W. Newburger; Jonathan G. Seidman; Amy E. Roberts; Mark Yandell; H. Joseph Yost; Martin Tristani-F...; Richard Kim; Wendy K. Chung; Bruce D. Gelb; Christine E. Seidman; Martina Brueckner; Richard P. Lifton
• Keywords: Proband; Penetrance; Loss function

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 11,555 CHD probands. The results identified 60 with significant burden heterozygous variants. Variants these accounted for 10.1% probands similar contributions from transmitted parent–offspring trios that showed incomplete penetrance. DNMs 58% the signal DNMs. Thirty-three were linked to single subtype while 12 associated 2 4 subtypes. Seven only isolated CHD, 37 1 or more extracardiac abnormalities. Genes selectively expressed cardiomyocyte lineage those widely brain also neurodevelopmental delay (NDD). Missense introducing removing cysteines epidermal growth factor (EGF)-like domains NOTCH1 enriched tetralogy Fallot conotruncal defects, unlike broader spectrum seen loss function Transmitted missense MYH6 multiple phenotypes account ~1% all Probands characteristic causing syndromic frequently not diagnosed clinically, often due missing cardinal phenotypes. positively negatively development NDD suggest clinical value genetic testing. These findings expand understanding genetics support use molecular diagnostics CHD.