Differential methylation is associated with non-syndromic cleft lip and palate and contributes to penetrance effects

Abstract Non-syndromic cleft lip and/or palate (NSCLP) is a common congenital malformation with a multifactorial model of inheritance. Although several at-risk alleles have been identified, they do not completely explain the high heritability. We postulate that epigenetic factors as DNA methylation...

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Autores principales:	Lucas Alvizi, Xiayi Ke, Luciano Abreu Brito, Rimante Seselgyte, Gudrun E. Moore, Philip Stanier, Maria Rita Passos-Bueno
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/e5bb70625e764a11be2c07ab251f41fb
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spelling	oai:doaj.org-article:e5bb70625e764a11be2c07ab251f41fb2021-12-02T16:06:12ZDifferential methylation is associated with non-syndromic cleft lip and palate and contributes to penetrance effects10.1038/s41598-017-02721-02045-2322https://doaj.org/article/e5bb70625e764a11be2c07ab251f41fb2017-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-02721-0https://doaj.org/toc/2045-2322Abstract Non-syndromic cleft lip and/or palate (NSCLP) is a common congenital malformation with a multifactorial model of inheritance. Although several at-risk alleles have been identified, they do not completely explain the high heritability. We postulate that epigenetic factors as DNA methylation might contribute to this missing heritability. Using a Methylome-wide association study in a Brazilian cohort (67 NSCLP, 59 controls), we found 578 methylation variable positions (MVPs) that were significantly associated with NSCLP. MVPs were enriched in regulatory and active regions of the genome and in pathways already implicated in craniofacial development. In an independent UK cohort (171 NSCLP, 177 controls), we replicated 4 out of 11 tested MVPs. We demonstrated a significant positive correlation between blood and lip tissue DNA methylation, indicating blood as a suitable tissue for NSCLP methylation studies. Next, we quantified CDH1 promoter methylation levels in CDH1 mutation-positive families, including penetrants, non-penetrants or non-carriers for NSCLP. We found methylation levels to be significantly higher in the penetrant individuals. Taken together, our results demonstrated the association of methylation at specific genomic locations as contributing factors to both non-familial and familial NSCLP and altered DNA methylation may be a second hit contributing to penetrance.Lucas AlviziXiayi KeLuciano Abreu BritoRimante SeselgyteGudrun E. MoorePhilip StanierMaria Rita Passos-BuenoNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-8 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Lucas Alvizi Xiayi Ke Luciano Abreu Brito Rimante Seselgyte Gudrun E. Moore Philip Stanier Maria Rita Passos-Bueno Differential methylation is associated with non-syndromic cleft lip and palate and contributes to penetrance effects
description	Abstract Non-syndromic cleft lip and/or palate (NSCLP) is a common congenital malformation with a multifactorial model of inheritance. Although several at-risk alleles have been identified, they do not completely explain the high heritability. We postulate that epigenetic factors as DNA methylation might contribute to this missing heritability. Using a Methylome-wide association study in a Brazilian cohort (67 NSCLP, 59 controls), we found 578 methylation variable positions (MVPs) that were significantly associated with NSCLP. MVPs were enriched in regulatory and active regions of the genome and in pathways already implicated in craniofacial development. In an independent UK cohort (171 NSCLP, 177 controls), we replicated 4 out of 11 tested MVPs. We demonstrated a significant positive correlation between blood and lip tissue DNA methylation, indicating blood as a suitable tissue for NSCLP methylation studies. Next, we quantified CDH1 promoter methylation levels in CDH1 mutation-positive families, including penetrants, non-penetrants or non-carriers for NSCLP. We found methylation levels to be significantly higher in the penetrant individuals. Taken together, our results demonstrated the association of methylation at specific genomic locations as contributing factors to both non-familial and familial NSCLP and altered DNA methylation may be a second hit contributing to penetrance.
format	article
author	Lucas Alvizi Xiayi Ke Luciano Abreu Brito Rimante Seselgyte Gudrun E. Moore Philip Stanier Maria Rita Passos-Bueno
author_facet	Lucas Alvizi Xiayi Ke Luciano Abreu Brito Rimante Seselgyte Gudrun E. Moore Philip Stanier Maria Rita Passos-Bueno
author_sort	Lucas Alvizi
title	Differential methylation is associated with non-syndromic cleft lip and palate and contributes to penetrance effects
title_short	Differential methylation is associated with non-syndromic cleft lip and palate and contributes to penetrance effects
title_full	Differential methylation is associated with non-syndromic cleft lip and palate and contributes to penetrance effects
title_fullStr	Differential methylation is associated with non-syndromic cleft lip and palate and contributes to penetrance effects
title_full_unstemmed	Differential methylation is associated with non-syndromic cleft lip and palate and contributes to penetrance effects
title_sort	differential methylation is associated with non-syndromic cleft lip and palate and contributes to penetrance effects
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/e5bb70625e764a11be2c07ab251f41fb
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Differential methylation is associated with non-syndromic cleft lip and palate and contributes to penetrance effects

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