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ABSTRACT
Background: Orofacial clefts (OFCs), including cleft lip and/or palate, are among the most prevalent congenital anomalies, affecting approximately 1 in 700 births worldwide. However, there is significant variation in incidence based on human ancestry, suggesting the existence of ancestry-specific and enriched genetic risk factors. These conditions result from incomplete fusion of facial structures during embryogenesis and are driven by complex genetic and environmental factors. This study aimed to investigate the genetic basis of OFCs in multiplex families from Ghanaians.
Method: The study involved 25 Ghanaian multiplex families recruited from the National Cleft Care Center, Komfo Anokye Teaching Hospital. Saliva/cheek swab samples and clinical data were collected from participants. Whole exome sequencing (WES) was performed on DNA from participants at 100X read depth using the Illumina HiSeq platform. Variants were annotated with Ensembl Variant Effect Predictor (VEP), and those with a minor allele frequency (MAF) <0.01 were filtered out. The pathogenicity of variants was ascertained using 11 tools built in dbNSFP and other tools like spliceAI. Variant prioritisation employed the American College of Medical Genetics and Genomics (ACMG) guidelines, inheritance patterns, tissue-specific expression, and OFC-related pathways.
Results: Likely causative variants were identified in genes such as GRHL3 (p.Arg520Gln), CTNND1 (p.Thr113Pro), IRF6 (p.Arg400Trp), STAB2 (p.Pro257Gln), ZFYVE21 (p.Arg139Cys) and NOTCH4 (p.Arg1924Trp). Pathway enrichment analysis highlighted disrupted cell-cell adhesion as a key mechanism, consistent with the roles of these genes in epithelial integrity, neural crest cell migration, and tissue fusion during embryogenesis.
Conclusion: In essence, we found novel and known genetic variants associated with OFCs in multiplex families, reinforcing the critical role of cell-cell adhesion biological pathways in craniofacial development. These findings enhance our understanding of the molecular pathophysiology of OFCs and pave the way for targeted genetic screening and molecular therapeutics in affected families.