Rare variants analyses suggest novel cleft genes in the African population

Azeez Alade (Lead / Corresponding author), Peter Mossey, Waheed Awotoye, Tamara Busch, Abimbola M. Oladayo, Emmanuel Aladenika, Mojisola Olujitan, Emma Wentworth, Deepti Anand, Thirona Naicker, Lord J.J. Gowans, Mekonen A. Eshete, Wasiu L. Adeyemo, Erliang Zeng, Eric Van Otterloo, Michael O’Rorke, Adebowale Adeyemo, Jeffrey C. Murray, Justin Cotney, Salil A. LachkePaul Romitti, Azeez Butali (Lead / Corresponding author)

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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 NSOFCs. 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.

Original languageEnglish
Article number14279
Number of pages10
JournalScientific Reports
Volume14
Issue number1
Early online date20 Jun 2024
DOIs
Publication statusE-pub ahead of print - 20 Jun 2024

Keywords

  • Craniofacial
  • Genetics
  • Nonsyndromic
  • Orofacial clefts
  • Rare variants
  • Transcriptomics

ASJC Scopus subject areas

  • General

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