Dissertation
Contribution of genetic variants to orofacial clefts in African populations
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Spring 2022
DOI: 10.25820/etd.006558
Abstract
Orofacial clefts (OFCs) are the most common craniofacial birth defect and epidemiological studies report their huge burden on public health. Genetic risk factors contributions to the OFCs etiopathogenesis have long been investigated in other populations but the African population is understudied. Findings from these studies could only explain 25% OFCs genetic risk factors. Risk loci which have been associated with OFCs are population specific and the high genetic variation within the African genome provide opportunity for novel discovery. In order to identify new genetic risk factors in OFCs developmental pathogenesis we employed novel analytical approaches. First, using the African nonsyndromic OFCs (nsOFCs) common polymorphisms data we conducted a genome-wide association studies testing the effect of Gene-by-sex (GxSex) interaction on the risk of nsOFCs. We identified a novel risk locus on chromosome 8p22 which is in topologically associating domain (TAD) with craniofacially expressed and enriched genes during embryonic development. Whole-exome sequencing analysis found pathogenic variants of some of these genes in nsOFCs cohort providing further evidence of these genes in cleft pathogenesis.
Secondly, we conducted whole-genome sequencing analysis of nsCL/P African case-parent trios in order to identify novel pathogenic mutations. We identified pathogenic de-novo mutations (DNMs) in genes with evidence of their roles in craniofacial development and OFCs pathogenesis. Some of these genes are enriched in neural crest migration, lip, and palate developmental process.
In addition to these DNMs, we identified pathogenic mutations in a novel cleft candidate gene, AFDN. Computational analyses suggest that the mutations in Afadin affect its interactions with cleft candidate gene products, notable among them being nectins. Perturbations of these interactions have been reported in syndromic cleft.
In summary, we employed several approaches to investigate the African genome for genetic risks to nsOFCs pathogenesis and found novel risk factors and plausible mechanism involved which could serve as bedrock for effective therapeutic intervention targeted at prevention. Additionally, these findings provide further evidence supporting the need to increase genetic studies in the African population.
Details
- Title: Subtitle
- Contribution of genetic variants to orofacial clefts in African populations
- Creators
- Waheed O Awotoye
- Contributors
- Azeez Butali (Advisor)Jeffrey A. Banas (Committee Member)Robert Cornell (Committee Member)Jacob J. Michaelson (Committee Member)Shankar Rengasamy Venugopalan (Committee Member)Erliang Zeng (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Oral Science
- Date degree season
- Spring 2022
- DOI
- 10.25820/etd.006558
- Publisher
- University of Iowa
- Number of pages
- xv, 179 pages
- Copyright
- Copyright 2022 Waheed O Awotoye
- Language
- English
- Description illustrations
- color illustrations
- Description bibliographic
- Includes bibliographical references.
- Public Abstract (ETD)
Orofacial Clefts are the most common birth defect of the head and neck region and pose a huge burden on public health. Disease-causing alterations in the genes have been implicated in the development of these birth defects. Despite the number of research aimed at identifying these disease-causing alterations, majority of these alterations are yet to be identified. Many of these research were conducted in non-African population. We therefore conducted research studies aimed at identifying those alterations in an understudied population.
Our first analysis identified a new region in the African genome where disease-causing alterations will potentially result in clefts. Surrounding this region are genes involved in the development of the head and neck. Additionally, we identified individuals with these defects harboring disease-causing changes in some of these genes.
Secondly, we identified disease-causing genetic changes in the genome of affected African families. Each family consisted of a child with the birth defect and the unaffected parents. In this study, we discovered disease-causing changes present only in the affected children but not present in the unaffected parents. Further analysis and evidence from prior studies support the role of these changes in the development of clefts.
Some disease-causing genetic changes have been reported not to manifest in these defects. Thus, we identified disease-causing changes in AFDN, a gene that produces Afadin and interact with known risk genes. Analysis showed that these changes result in the defect in the child but not in the parents. These discoveries show the opportunity of studying the African genome.
- Academic Unit
- Oral Pathology, Radiology and Medicine; Craniofacial Anomalies Research Center
- Record Identifier
- 9984271155702771
Metrics
3 File views/ downloads
101 Record Views