Abstract
Many structural birth defect patients lack genetic diagnoses because there are many disease genes as yet to be discovered. We applied a gene burden test incorporating de novo predicted-loss-of-function (pLoF) and likely damaging missense variants together with inherited pLoF variants to a collection of congenital heart defect (CHD) and orofacial cleft (OC) parent-offspring trio cohorts (n = 3,835 and 1,844, respectively). We identified 17 novel candidate CHD genes and 10 novel candidate OC genes, of which many were known developmental disorder genes. Shorter genes were more powered in a "de novo only" analysis as compared to analysis including inherited pLoF variants. TFs were enriched among the significant genes; 14 and 8 transcription factor (TF) genes showed significant variant burden for CHD and OC, respectively. In total, 30 affected children had a de novo missense variant in a DNA binding domain of a known CHD, OC, and other developmental disorder TF genes. Our results suggest candidate pathogenic variants in CHD and OC and their potentially pleiotropic effects in other developmental disorders.