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<p>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 <i>ACSS2</i> variant (c.1487 T &gt; C), with two probands also harbouring variants in Pleckstrin Homology Domain Containing <i>(PLEKH</i>) genes. Five variants were previously reported in ClinVar (two with conflicting interpretations, one&#xa0;pathogenic, and two of uncertain significance), while ten were novel. Variants were found in known OFC-associated genes (<i>MID1, FLNA, FGF10</i>) and emerging candidates (<i>ZFHX4, PLEKHA5, PLEKHA7</i>). 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月30日

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  • Alejandro Silva,
  • Carolina Jaramillo Oquendo,
  • Jaime E. Bernal,
  • Julio Cesar Martinez,
  • Andrew Collins,
  • Ignacio Briceño,
  • Escilda Benavides,
  • Zulieth López Arrieta,
  • Sarah Ennis

摘要

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.