Investigating the contribution of coding de novo mutations to orofacial clefts Open Access

Abstract

Orofacial clefts (OFCs), including cleft lip and cleft palate, are among the most common birth defects, occurring in approximately 1 in 1000 live births worldwide. OFCs have a strong genetic basis, with genetic variants of all types and frequencies increasing risk for an OFC. However,much of the genetic risk remains unaccounted for. Previous studies have highlighted a role for de novo mutations (DNMs) in contributing to OFC risk. Here, we analyzed coding DNMs found in whole genome sequence (WGS) data from 419 child-parent trios of Filipino ancestry with OFCsfrom the Gabriella Miller Kids First (GMKF) Research Program. We found a significant enrichment of predicted loss-of-function (pLOF) (p = 9.68 × 10-3) and protein-altering DNMs (p= 2.61 × 10-4). We also found a significant enrichment of pLOF DNMs in GRHL2 (p = 4.74 ×10-6), a gene intolerant to pLOF variants (LOEUF = 0.27, pLI = 1). We then combined the Filipino trios with three other previously studied GMKF cohorts with OFCs of Colombian, Taiwanese, and European ancestries, totaling 1,114 trios. In this combined cohort, we found a similar significant enrichment of pLOF (1.57 × 10-4) and protein-altering DNMs (p = 2.55 × 10-3). Genes with protein-altering DNMs were found to be enriched for pathways relevant to craniofacial development. We then analyzed de novo structural variants (SVs) in the cohort and identified additional SVs in multiple genes with protein-altering DNMs, including GRHL2. Overall, we have further demonstrated that DNMs contribute to OFC risk and identified several novel candidate genes such as GRHL2. Further investigations are required in order to interpret variants in these genes and their association with OFCs.

Table of Contents

Introduction ... 1

Methods ... 4

Results ... 8

Discussion ... 21

Reference List ... 25

Figures

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About this Honors Thesis

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School	Emory College
Department	Biology
Degree	B.S.
Submission	Honors Thesis
Language	English
Research Field	Biology, Genetics
Keyword	orofacial clefts OFC de novo mutations
Committee Chair / Thesis Advisor	Leslie, Elizabeth, Emory University
Committee Members	Epstein, Michael, Emory University Fritz, Andreas, Emory University

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