Rare variants in embryonic development and cell signalling genes in syndromic and non-syndromic orofacial clefts: evidence from a Colombian Caribbean cohort

Abstract Orofacial clefts (OFCs) are common craniofacial malformations broadly classified as syndromic or non-syndromic. While syndromic OFCs are often caused by rare, high-impact variants, non-syndromic OFCs are typically associated with multiple low-impact common variants. However, growing evidence suggests that rare variants may also contribute to non-syndromic OFCs. To explore this, we performed exome sequencing in 45 individuals from 20 Colombian families, predominantly from the Caribbean region, a genetically distinct and underrepresented population. Our goal was to identify rare variants potentially contributing to both syndromic and non-syndromic OFCs. We identified 15 rare protein-altering variants in 11 families that showed strong phenotype-genotype concordance. Four probands carried a previously reported common ACSS2 variant (c.1487 T > C), with two probands also harbouring variants in Pleckstrin Homology Domain Containing (PLEKH ) genes. Five variants were previously reported in ClinVar (two with conflicting interpretations, one pathogenic, and two of uncertain significance), while ten were novel. Variants were found in known OFC-associated genes ( MID1, FLNA, FGF10 ) and emerging candidates ( ZFHX4, PLEKHA5, PLEKHA7 ). These findings provide further evidence that rare variants in developmental and signalling pathways contribute to both syndromic and non-syndromic OFCs, reinforcing previous studies and expanding the catalogue of candidate genes in underrepresented populations.