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Rare Variants Analyses Suggest Novel Cleft Genes in the African Population

Article scientifique 2024 Anglais

Résumé

Abstract Non-syndromic orofacial clefts (NSOFCs) are common birth defects with a complex etiology. While over 60 common risk loci have been identified, they explain only a small proportion of the heritability for NSOFC. Rare variants have been implicated in the missing heritability. Thus, our study aimed to identify genes enriched with nonsynonymous rare coding variants associated with NSOFCs. Our sample included 814 non-syndromic cleft lip with or without palate (NSCL/P), 205 non-syndromic cleft palate only (NSCPO), and 2150 unrelated control children from Nigeria, Ghana, and Ethiopia. We conducted a gene-based analysis separately for each phenotype using three rare-variants collapsing models: (1) protein-altering (PA), (2) missense variants only (MO); and (3) loss of function variants only (LOFO). Subsequently, we utilized relevant transcriptomics data to evaluate associated gene expression and examined their mutation constraint using the gnomeAD database. In total, 13 genes showed suggestive associations (p = E-04). Among them, eight genes (ABCB1, ALKBH8, CENPF, CSAD, EXPH5, PDZD8, SLC16A9, and TTC28) were consistently expressed in relevant mouse and human craniofacial tissues during the formation of the face, and three genes (ABCB1, TTC28, and PDZD8) showed statistically significant mutation constraint. These findings underscore the role of rare variants in identifying candidate genes for NSOFCs. Main documents (excluding the methods section) word count: 2145

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Alade, A., Mossey, P., Awotoye, W., Busch, T., Oladayo, A., Aladenika, E., Olujitan, M., Gowans, J., Eshete, M., Adeyemo, W., Zeng, E., Otterloo, E., O’Rorke, M., Adeyemo, A., Murray, J., Cotney, J., Lachke, S., Romitti, P., Butali, A., Wentworth, E., Anand, D., Naicker, T. (2024). Rare Variants Analyses Suggest Novel Cleft Genes in the African Population. https://doi.org/10.21203/rs.3.rs-3921355/v1

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Auteur(s)

Azeez Alade Peter Anthony Mossey Waheed Awotoye Tamara Busch Abimbola Oladayo Emmanuel Aladenika Mojisola Olujitan Jephthah Gowans Mekonen Eshete Wasiu Lanre Adeyemo Erliang Zeng Eric Van Otterloo Michael A. O’Rorke Adebowale Adeyemo Jeffrey C. Murray Justin L. Cotney Salil A. Lachke Paul A. Romitti Azeez Butali Emma Wentworth Deepti Anand Thirona Naicker

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