Genome-Wide Linkage, Epigenetic And Functional Role Of Growth Factors And Signalling Molecules In Orofacial Cleft Formation Among Malays
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Date
2017-02
Authors
Mohamad Shah, Nurul Syazana
Journal Title
Journal ISSN
Volume Title
Publisher
Universiti Sains Malaysia
Abstract
Orofacial cleft is one of the most common human birth defects worldwide that affects the lip and/or palate. The incidence of clefts varies among populations through ethnic, race or geographical differences. It is heterogenous with a multifactorial etiology, whereas both genetic and environmental factors contribute to the cleft formation. The focus on Malay non-syndromic cleft lip and/or palate (NSCLP) is because of a scarce report on genetic study in relation to this deformity in Malaysia. We were interested to discover both genetic and epigenetic factors to shed light on gene susceptibility that caused orofacial cleft formation. Genome-wide linkage and copy number variation analyses using microarray confirmed novel linkage evidence and significant low copy number of COL21A1 and TOX3 in NSCLP families. Several novel single nucleotide polymorphisms (SNPs) and frameshift mutations through exome sequencing was identified including PDE4DIP, PDE11A, LTBP4, ABCA10, MAPK81P2, Smad5, SLC38A3, MMP12, MMP28, COL6A5 and COL18A1. Novel partially methylated of FOXE1 and CLPTM1 in NSCLP patients provide an early understanding of methylation process in causing cleft. These outcomes would definitely shed light on known and novel genes that possibly susceptible to the cleft formation. The preliminary histopathology and morphology study on post-embryonic cleft lip (CL) tissue showed
apparent less dense and disoriented collagen fibers and orbicularis oris muscle. In molecular level, downregulation of Fibroblast growth factor 8 (FGF8) and Wingless-type 8a (Wnt8a) in CL tissue was found. The relation of both morphogenetic and molecular findings described the failure of lip fusion and migration process that caused cleft formation. Understanding the developmental processes at both morphogenetic and molecular level would direct us to tissue engineering approach for a better cleft treatment to the society in the future.
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Keywords
Gene susceptibility that caused , orofacial cleft formation.