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Ultra-Rare Variants Identify Biological Pathways and Candidate Genes in the Pathobiology of Non-Syndromic Cleft Palate Only Publisher



Iovino E1 ; Scapoli L2 ; Palmieri A2 ; Sgarzani R2 ; Nouri N3 ; Pellati A4 ; Carinci F4 ; Seri M1, 5 ; Pippucci T5 ; Martinelli M2
Authors
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Authors Affiliations
  1. 1. Department of Medical and Surgical Sciences, University of Bologna, Bologna, 40138, Italy
  2. 2. Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, 40138, Italy
  3. 3. Craniofacial and Cleft Research Center, Isfahan University of Medical Sciences, Isfahan, 81745-319, Iran
  4. 4. Department of Translational Medicine, University of Ferrara, Ferrara, 44121, Italy
  5. 5. Medical Genetics Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, 40138, Italy

Source: Biomolecules Published:2023


Abstract

In recent decades, many efforts have been made to elucidate the genetic causes of non-syndromic cleft palate (nsCPO), a complex congenital disease caused by the interaction of several genetic and environmental factors. Since genome-wide association studies have evidenced a minor contribution of common polymorphisms in nsCPO inheritance, we used whole exome sequencing data to explore the role of ultra-rare variants in this study. In a cohort of 35 nsCPO cases and 38 controls, we performed a gene set enrichment analysis (GSEA) and a hypergeometric test for assessing significant overlap between genes implicated in nsCPO pathobiology and genes enriched in ultra-rare variants in our cohort. GSEA highlighted an enrichment of ultra-rare variants in genes principally belonging to cytoskeletal protein binding pathway (Probability Density Function corrected p-value = 1.57 × 10−4); protein-containing complex binding pathway (p-value = 1.06 × 10−2); cell adhesion molecule binding pathway (p-value = 1.24 × 10−2); ECM-receptor interaction pathway (p-value = 1.69 × 10−2); and in the Integrin signaling pathway (p-value = 1.28 × 10−2). Two genes implicated in nsCPO pathobiology, namely COL2A1 and GLI3, ranked among the genes (n = 34) with nominal enrichment in the ultra-rare variant collapsing analysis (Fisher’s exact test p-value < 0.05). These genes were also part of an independent list of genes highly relevant to nsCPO biology (n = 25). Significant overlap between the two sets of genes (hypergeometric test p-value = 5.86 × 10−3) indicated that enriched genes are likely to be implicated in physiological palate development and/or the pathological processes of oral clefting. In conclusion, ultra-rare variants collectively impinge on biological pathways crucial to nsCPO pathobiology and point to candidate genes that may contribute to the individual risk of disease. Sequencing can be an effective approach to identify candidate genes and pathways for nsCPO. © 2023 by the authors.
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