Distinct genetic architectures for syndromic and nonsyndromic congenital heart defects identified by exome sequencing.
Alejandro SifrimMarc-Phillip HitzAnna WilsdonJeroen BreckpotSaeed H Al TurkiBernard ThienpontJeremy McRaeTomas W FitzgeraldTarjinder SinghGanesh Jawahar SwaminathanElena PrigmoreDiana RajanHashim Abdul-KhaliqSiddharth BankaUlrike M M BauerJamie BenthamFelix BergerShoumo BhattacharyaFrances Bu'LockNatalie CanhamIrina-Gabriela ColgiuCatherine CosgroveHelen CoxIngo DaehnertAllan DalyJohn DaneshAlan FryerMarc GewilligEmma HobsonKirstin HoffTessa Homfraynull nullAnne-Karin KahlertAmi KetleyHans-Heiner KramerKatherine LachlanAnne Katrin LampeJacoba J LouwAshok Kumar ManickaraDorin ManaseKaren P McCarthyKay MetcalfeCarmel MooreRuth Newbury-EcobSeham Osman OmerWillem H OuwehandSoo-Mi ParkMichael J ParkerThomas PickardtMartin O PollardLeema RobertDavid J RobertsJennifer SambrookKerry SetchfieldBrigitte StillerChris ThornboroughOkan TokaHugh WatkinsDenise WilliamsMichael WrightSeema MitalPiers E F DaubeneyBernard D KeavneyJudith Goodshipnull nullRiyadh Mahdi Abu-SulaimanSabine KlaassenCaroline F WrightHelen V FirthJeffrey C BarrettKoenraad DevriendtDavid R FitzPatrickJ David Brooknull nullMatthew E HurlesPublished in: Nature genetics (2016)
Congenital heart defects (CHDs) have a neonatal incidence of 0.8-1% (refs. 1,2). Despite abundant examples of monogenic CHD in humans and mice, CHD has a low absolute sibling recurrence risk (∼2.7%), suggesting a considerable role for de novo mutations (DNMs) and/or incomplete penetrance. De novo protein-truncating variants (PTVs) have been shown to be enriched among the 10% of 'syndromic' patients with extra-cardiac manifestations. We exome sequenced 1,891 probands, including both syndromic CHD (S-CHD, n = 610) and nonsyndromic CHD (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 findings. Conversely, in NS-CHD we observed significant enrichment of PTVs inherited from unaffected parents in CHD-associated genes. We identified three genome-wide significant S-CHD disorders caused by DNMs in CHD4, CDK13 and PRKD1. Our study finds evidence for distinct genetic architectures underlying the low sibling recurrence risk in S-CHD and NS-CHD.