Speaker
Description
Introduction: Orofacial clefts (OFCs) are among the common congenital anomalies, presenting significant health, societal, and economic challenges. While extensive research has focused on single nucleotide variants and small insertions/deletions, these do not fully account for the genetic architecture of OFCs. Copy number variants (CNVs), especially in African populations, remain underexplored despite their known contribution to congenital anomalies. This study aimed to identify high-confidence CNVs contributing to the aetiology of syndromic OFCs in Ghanaian case-parent trios, and to investigate their functional and phenotypic relevance to craniofacial development. Methodology: Whole exome sequencing (WES) data at 100X from Ghanaian case-parent trios were processed through a five-phase pipeline. Following stringent quality control and preprocessing, CNVs were detected using four independent tools, namely, cn.MOPS, CODEX, ExomeDepth, and GATK-gCNV, and results were merged through a consensus-based approach, requiring support from at least two tools. AnnotSV was used to annotate and classify CNVs, while VarElect prioritised CNVs based on clinical phenotypes. High-confidence CNVs were mapped to patient phenotypes and interrogated for pathogenic potential. Finally, pathway enrichment analysis using g:Profiler revealed significant biological processes and phenotypes implicated in craniofacial development. Results: Several de novo and inherited CNVs were identified, including deletions and duplications involving key genes such as SHH, WBP11, and ADAMTS2, all of which are involved in craniofacial morphogenesis. In addition to known OFC-associated genes, the analysis revealed novel CNV regions encompassing genes not previously linked to OFCs, such as HYDIN, FLI1, ETS1, RSPH10B2, and CCZ1B. These were prioritised based on their expression patterns in mouse developmental models, suggesting potential functional relevance to OFC pathogenesis. Pathway enrichment analysis further identified significant biological processes associated with craniofacial, neurodevelopmental, and musculoskeletal development. Conclusion: The findings contribute to the understanding of the aetiology of syndromic OFCs and lay the groundwork for improved diagnostics, genetic counselling, and therapeutic strategies.