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, nonsyndromic 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 phenotypegenotype concordance. Four probands carried a previously reported common ACSS2 variant (c.1487T>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, two likely pathogenic/pathogenic, and one 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.

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Identifiers

ORCID for Carolina Jaramillo Oquendo: orcid.org/0000-0002-9875-0998

ORCID for Andrew Collins: orcid.org/0000-0001-7108-0771

ORCID for Sarah Ennis: orcid.org/0000-0003-2648-0869

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