Exome analyses unravel the genetic architecture of Mendelian dominant nonsyndromic orofacial clefts

Nonsyndromic orofacial clefts (NSOFC) represents a prevalent congenital anomalies, the etiology of which likely involves a complex interplay between genetic and environmental factors. To elucidate potential pathogenic variants, exome sequencing (ES) was conducted on 123 Chinese pedigrees demonstrating Mendelian dominant inheritance of NSOFC, including 251 patients and 130 unaffected relatives. This was followed by a standardized process of variant screening and filtering to identify novel variants within established candidate genes associated with clefting phenotypes. The study unveiled rare pathogenic variants in recognized genes with clefting across 101 pedigrees. These genes are implicated in essential biological processes such as primary ciliary function, bone formation and development, cell adhesion, and transcription regulation. Notably, the investigation into random X chromosome inactivation assay posited FLNA and GPC3 as factors contributing to NSOFC's incomplete dominance. Moreover, in vitro functional experiments targeting variants in two ciliary genes, TBC1D32 and SCLT1, elucidated their roles in NSOFC pathogenesis.