Whole-genome sequencing analyses of Africans with clefts 2.0-insights gained

Background: Harmful genetic mutations are known to contribute to the risk of the most common craniofacial anomaly, orofacial clefts (OFCs). However, even within families known to carry these mutations, the resulting manifestations can vary from no overt clefting to the presence of different cleft types that vary in severity and laterality. To unravel the genetic etiology of OFCs, which will inform diagnosis and genetic counseling, we conducted the second whole-genome sequencing (WGS) analysis on a large cohort of families with nonsyndromic cleft lip with or without cleft palate (nsCL/P) from Africa, the most genetically diverse human population.Methods: We sequenced the genomes of 148 case-parent trios, each including a child affected by nsCL/P. We investigated pathogenic protein-altering variants with CADD scores ≥ 20 and REVEL scores ≥ 0.5 as well as computed their clinical significance using criteria from the American College of Medical Genetics and Genomics / American Association of Molecular Pathology (ACMG/AMP). Genotype-phenotype analyses were performed using mouse gene expression and human genomics databases to link those pathogenic variants with cleft pathogenesis.