Sifrim, AlejandroHitz, Marc-PhillipWilsdon, AnnaBreckpot, JeroenAl Turki, Saeed H.Thienpont, BernardMcRae, JeremyFitzgerald, Tomas WSingh, TarjinderSwaminathan, Ganesh JawaharPrigmore, ElenaRajan, DianaAbdul-Khaliq, HashimBanka, SiddharthBauer, Ulrike M. M.Bentham, JamieBerger, FelixBhattacharya, ShoumoBu'Lock, FrancesCanham, NatalieColgiu, Irina-GabrielaCosgrove, CatherineCox, HelenDaehnert, IngoDaly, AllanDanesh, JohnFryer, AlanGewillig, MarcHobson, EmmaHoff, KirstinHomfray, TessaKahlert, Anne-KarinKetley, AmiKramer, Hans-HeinerLachlan, KatherineLampe, Anne KatrinLouw, Jacoba J.Manickara, Ashok KumarManase, DorinMcCarthy, Karen P.Metcalfe, KayMoore, CarmelNewbury-Ecob, RuthOmer, Seham OsmanOuwehand, Willem H.Park, Soo-MiParker, Michael J.Pickardt, ThomasPollard, Martin O.Robert, LeemaRoberts, David J.Sambrook, JenniferSetchfield, KerryStiller, BrigitteThornborough, ChrisToka, OkanWatkins, HughWilliams, DeniseWright, MichaelMital, SeemaDaubeney, Piers E. F.Keavney, BernardGoodship, JudithAbu-Sulaiman, Riyadh MahdiKlaassen, SabineWright, Caroline F.Firth, Helen V.Barrett, Jeffrey C.Devriendt, KoenraadFitzPatrick, David R.Brook, J. DavidHurles, Matthew2018-07-252018Sifrim, A., M. Hitz, A. Wilsdon, J. Breckpot, S. H. Al Turki, B. Thienpont, J. McRae, et al. 2018. “Distinct genetic architectures for syndromic and nonsyndromic congenital heart defects identified by exome sequencing.” Nature genetics 48 (9): 1060-1065. doi:10.1038/ng.3627. http://dx.doi.org/10.1038/ng.3627.http://nrs.harvard.edu/urn-3:HUL.InstRepos:37298210Congenital Heart Defects (CHD) have a neonatal incidence of 0.8-1%1,2. Despite abundant examples of monogenic CHD in humans and mice, CHD has a low absolute sibling recurrence risk (~2.7%)3, suggesting a considerable role for de novo mutations (DNM), and/or incomplete penetrance4,5. De novo protein-truncating variants (PTVs) have been shown to be enriched among the 10% of ‘syndromic’ patients with extra-cardiac manifestations6,7. We exome sequenced 1,891 probands, including both syndromic (S-CHD, n=610) and non-syndromic cases (NS-CHD, n=1,281). In S-CHD, we confirmed a significant enrichment of de novo PTVs, but not inherited PTVs, in known CHD-associated genes, consistent with recent findings8. Conversely, in NS-CHD we observed significant enrichment of PTVs inherited from unaffected parents in CHD-associated genes. We identified three novel genome-wide significant S-CHD disorders caused by DNMs in CHD4, CDK13 and PRKD1. Our study reveals distinct genetic architectures underlying the low sibling recurrence risk in S-CHD and NS-CHD.en-USJournal Article2018-07-2510.1038/ng.3627