Rare variants found in clinical gene panels illuminate the genetic and allelic architecture of orofacial clefting

Abstract

PurposeOrofacial clefts (OFCs) are common birth defects including cleft lip (CL), cleft lip and palate (CLP), and cleft palate (CP). OFCs have heterogeneous etiologies, complicating clinical diagnostics as it is not always apparent if the cause is Mendelian, environmental, or multifactorial. Sequencing is not currently performed for isolated or sporadic OFCs, so we estimated the diagnostic yield for 418 genes in 841 cases and 294 controls. MethodsWe evaluated 418 genes using genome sequencing and curated variants to assess their pathogenicity using American College of Medical Genetics criteria. Results9.04% of cases and 1.02% of controls had likely pathogenic (LP) variants (p<0.0001), which was almost exclusively driven by heterozygous variants in autosomal genes. CP (17.6%) and CLP (9.09%) cases had the highest yield while CL cases had a 2.80% yield. Out of 39 genes with LP variants, nine genes, including CTNND1 and IRF6, accounted for more than half of the yield (4.64% of cases). Most variants (61.8%) were variants of uncertain significance (VUSs), occurring more frequently in cases (p=0.004), but no individual gene showed a significant excess of VUSs. ConclusionThese results underscore the etiological heterogeneity of OFCs and suggest sequencing could reduce the diagnostic gap in OFCs.