biostudies-literatureSierant MCNICHD NIH HHSNCATS NIH HHSAmerican Heart Association (AHA)NHLBI NIH HHSChildren's Discovery Institute (CDI)HHS | NIH | National Human Genome Research Institute (NHGRI)HHS | NIH | National Heart, Lung, and Blood Institute (NHLBI)HHS | NIH | National Center for Advancing Translational Sciences (NCATS)HHS | NIH | Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)NHGRI NIH HHSHHMI (HHMI)e2420343122https://www.ebi.ac.uk/biostudies/studies/S-EPMC12002227biostudies-literatureUnknown122(13)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 selectivelProceedings of the National Academy of Sciences of the United States of AmericaGenomic analysis of 11,555 probands identifies 60 dominant congenital heart disease genes.PMC12002227U01 HL098162R03 HD1008835U54HG006504K08 HL1576531UG1HL135680-01CDI-FR-2021-926RM1HG011014T32 HD007149UO1 HL153009U54 HG006504UO1 HL098147U01 HL15300919PRE3438084UO1 HL098162NIH R03HD100883-A1UG1 HL135680R00HL143036-02U01 HL098147U01 HL098153UL1TR000003RM1 HG011014UL1 TR000003UO1 HL131003U01 HL128711R00 HL143036HL157653U01 HL131003HHMIUO1 HL128711Morton SULek MDong WSrivastava DDeanfield JYandell MZhang JBrueckner MCao JLu ZTikhonova IRoberts AEChoi JGruber PJChung WKSedore SCSierant MCNelson-Williams CYost HJJiang WSeidman CETristani-Firouzi MLi BShen YZhao HGaynor JWJin SCBernstein DWagner MBilguvar KZeng XKing EMital SPorter GARussell MMane SSeidman JGKim RKnight JRLopez-Giraldez FGiardini AGelb BDLifton RPGoldmuntz ELu QNewburger JWfalseGenomic analysis of 11,555 probands identifies 60 dominant congenital heart disease genes.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 selectivel2025-01-01T00:00:00Z2025 Apr2026-06-01T10:21:56.05Z2026-04-08T11:21:24.2ZS-EPMC120022274012727610.1073/pnas.2420343122