Meta-analysis reveals transcription factors and DNA binding domain variants associated with congenital heart defect and orofacial cleft

Many congenital anomaly 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 (OFC) parent-offspring trio cohorts (n = 3835 and 1844, respectively). We identified 17 novel candidate CHD genes and 8 novel candidate OFC genes, of which many were known developmental disorder genes. TFs were enriched among the significant genes; 14 and 8 transcription factor (TF) genes showed significant variant burden for CHD and OFC, respectively. In total, 30 affected children had a de novo missense variant in a DNA binding domain of a known CHD, OFC, and other developmental disorder TF genes. Our results suggest candidate pathogenic variants in CHD and OFC and their potentially pleiotropic effects in other developmental disorders.