Novel Protein-Altering Variants in Cleft Genes Transmitted in Families With NSCL±P

Pathogenic protein-altering variants play a role in the etiology of nonsyndromic cleft lip with or without palate (nsCL±P), one of the most common craniofacial anomalies. However, the genetic basis of many cases remains unclear, complicating risk prediction for affected families.

This study utilized whole-genome sequencing (WGS) of 150 case-families with nsCL±P from sub-Saharan Africa to identify pathogenic risk variants.

This study utilized whole-genome sequencing (WGS) of 150 case-families with nsCL±P from sub-Saharan Africa to identify risk variants.

Genetic variants.

Nonsyndromic cleft lip with or without palate (nsCL±P).

Genomes were sequenced at a mean ×30 coverage, and variants were prioritized using CADD (≥20), REVEL (≥0.5), and ACMG/AMP clinical significance criteria.

We identified pathogenic protein-altering variants in CHD7 (p.Arg1345His), LRP2 (p.Asp3245Asn), RYR1 (p.Arg2163Leu, p.Pro2903Thr), SHH (p.Met114Val), and WNT3 (p.Ser112Pro) highlighting the role of hedgehog signaling pathway (FDR=5.32e-12) in nsCL±P. These variants were inherited from unaffected parents suggesting an incomplete penetrance of the variant effect. Although mouse data showed that knockout of these genes produces cleft phenotypes, in vivo studies will help us better understand how the consequences of these variants differ from benign mutations. The presence of these protein-altering variants in unaffected parents-incomplete penetrance, provides additional evidence supporting the trait complexity.

This study identified rare, pathogenic protein-altering variants in genes involved in key developmental pathways in African families affected by nsCL±P. These findings highlight the critical role of the hedgehog signaling pathway and related networks in the etiology of nsCL±P. These findings underscore the importance of whole-genome sequencing in genetically diverse populations to uncover novel risk variants. These findings enhance our understanding of the genetic etiology of nsCL±P, particularly in under-represented African populations and support the multifactorial inheritance and the involvement of developmental pathways, such as hedgehog signaling in the etiology of clefting.