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Whole genome sequencing of orofacial cleft trios from the Gabriella Miller Kids First Pediatric Research Consortium identifies a new locus on chromosome 21

Orofacial clefts (OFCs) are among the most prevalent craniofacial birth defects worldwide and create a significant public health burden. The majority of OFCs are non-syndromic, and the genetic etiology of non-syndromic OFCs is only partially determined. Here, we analyze whole genome sequence (WGS) d...

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Autores principales: Mukhopadhyay, Nandita, Bishop, Madison, Mortillo, Michael, Chopra, Pankaj, Hetmanski, Jacqueline B., Taub, Margaret A., Moreno, Lina M., Valencia-Ramirez, Luz Consuelo, Restrepo, Claudia, Wehby, George L., Hecht, Jacqueline T., Deleyiannis, Frederic, Butali, Azeez, Weinberg, Seth M., Beaty, Terri H., Murray, Jeffrey C., Leslie, Elizabeth J., Feingold, Eleanor, Marazita, Mary L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Berlin Heidelberg 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6981325/
https://www.ncbi.nlm.nih.gov/pubmed/31848685
http://dx.doi.org/10.1007/s00439-019-02099-1
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author Mukhopadhyay, Nandita
Bishop, Madison
Mortillo, Michael
Chopra, Pankaj
Hetmanski, Jacqueline B.
Taub, Margaret A.
Moreno, Lina M.
Valencia-Ramirez, Luz Consuelo
Restrepo, Claudia
Wehby, George L.
Hecht, Jacqueline T.
Deleyiannis, Frederic
Butali, Azeez
Weinberg, Seth M.
Beaty, Terri H.
Murray, Jeffrey C.
Leslie, Elizabeth J.
Feingold, Eleanor
Marazita, Mary L.
author_facet Mukhopadhyay, Nandita
Bishop, Madison
Mortillo, Michael
Chopra, Pankaj
Hetmanski, Jacqueline B.
Taub, Margaret A.
Moreno, Lina M.
Valencia-Ramirez, Luz Consuelo
Restrepo, Claudia
Wehby, George L.
Hecht, Jacqueline T.
Deleyiannis, Frederic
Butali, Azeez
Weinberg, Seth M.
Beaty, Terri H.
Murray, Jeffrey C.
Leslie, Elizabeth J.
Feingold, Eleanor
Marazita, Mary L.
author_sort Mukhopadhyay, Nandita
collection PubMed
description Orofacial clefts (OFCs) are among the most prevalent craniofacial birth defects worldwide and create a significant public health burden. The majority of OFCs are non-syndromic, and the genetic etiology of non-syndromic OFCs is only partially determined. Here, we analyze whole genome sequence (WGS) data for association with risk of OFCs in European and Colombian families selected from a multicenter family-based OFC study. This is the first large-scale WGS study of OFC in parent–offspring trios, and a part of the Gabriella Miller Kids First Pediatric Research Program created for the study of childhood cancers and structural birth defects. WGS provides deeper and more specific genetic data than using imputation on present-day single nucleotide polymorphic (SNP) marker panels. Genotypes of case–parent trios at single nucleotide variants (SNV) and short insertions and deletions (indels) spanning the entire genome were called from their sequences using human GRCh38 genome assembly, and analyzed for association using the transmission disequilibrium test. Among genome-wide significant associations, we identified a new locus on chromosome 21 in Colombian families, not previously observed in other larger OFC samples of Latin American ancestry. This locus is situated within a region known to be expressed during craniofacial development. Based on deeper investigation of this locus, we concluded that it contributed risk for OFCs exclusively in the Colombians. This study reinforces the ancestry differences seen in the genetic etiology of OFCs, and underscores the need for larger samples when studying for OFCs and other birth defects in populations with diverse ancestry. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s00439-019-02099-1) contains supplementary material, which is available to authorized users.
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spelling pubmed-69813252020-02-06 Whole genome sequencing of orofacial cleft trios from the Gabriella Miller Kids First Pediatric Research Consortium identifies a new locus on chromosome 21 Mukhopadhyay, Nandita Bishop, Madison Mortillo, Michael Chopra, Pankaj Hetmanski, Jacqueline B. Taub, Margaret A. Moreno, Lina M. Valencia-Ramirez, Luz Consuelo Restrepo, Claudia Wehby, George L. Hecht, Jacqueline T. Deleyiannis, Frederic Butali, Azeez Weinberg, Seth M. Beaty, Terri H. Murray, Jeffrey C. Leslie, Elizabeth J. Feingold, Eleanor Marazita, Mary L. Hum Genet Original Investigation Orofacial clefts (OFCs) are among the most prevalent craniofacial birth defects worldwide and create a significant public health burden. The majority of OFCs are non-syndromic, and the genetic etiology of non-syndromic OFCs is only partially determined. Here, we analyze whole genome sequence (WGS) data for association with risk of OFCs in European and Colombian families selected from a multicenter family-based OFC study. This is the first large-scale WGS study of OFC in parent–offspring trios, and a part of the Gabriella Miller Kids First Pediatric Research Program created for the study of childhood cancers and structural birth defects. WGS provides deeper and more specific genetic data than using imputation on present-day single nucleotide polymorphic (SNP) marker panels. Genotypes of case–parent trios at single nucleotide variants (SNV) and short insertions and deletions (indels) spanning the entire genome were called from their sequences using human GRCh38 genome assembly, and analyzed for association using the transmission disequilibrium test. Among genome-wide significant associations, we identified a new locus on chromosome 21 in Colombian families, not previously observed in other larger OFC samples of Latin American ancestry. This locus is situated within a region known to be expressed during craniofacial development. Based on deeper investigation of this locus, we concluded that it contributed risk for OFCs exclusively in the Colombians. This study reinforces the ancestry differences seen in the genetic etiology of OFCs, and underscores the need for larger samples when studying for OFCs and other birth defects in populations with diverse ancestry. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s00439-019-02099-1) contains supplementary material, which is available to authorized users. Springer Berlin Heidelberg 2019-12-17 2020 /pmc/articles/PMC6981325/ /pubmed/31848685 http://dx.doi.org/10.1007/s00439-019-02099-1 Text en © The Author(s) 2019 Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Original Investigation
Mukhopadhyay, Nandita
Bishop, Madison
Mortillo, Michael
Chopra, Pankaj
Hetmanski, Jacqueline B.
Taub, Margaret A.
Moreno, Lina M.
Valencia-Ramirez, Luz Consuelo
Restrepo, Claudia
Wehby, George L.
Hecht, Jacqueline T.
Deleyiannis, Frederic
Butali, Azeez
Weinberg, Seth M.
Beaty, Terri H.
Murray, Jeffrey C.
Leslie, Elizabeth J.
Feingold, Eleanor
Marazita, Mary L.
Whole genome sequencing of orofacial cleft trios from the Gabriella Miller Kids First Pediatric Research Consortium identifies a new locus on chromosome 21
title Whole genome sequencing of orofacial cleft trios from the Gabriella Miller Kids First Pediatric Research Consortium identifies a new locus on chromosome 21
title_full Whole genome sequencing of orofacial cleft trios from the Gabriella Miller Kids First Pediatric Research Consortium identifies a new locus on chromosome 21
title_fullStr Whole genome sequencing of orofacial cleft trios from the Gabriella Miller Kids First Pediatric Research Consortium identifies a new locus on chromosome 21
title_full_unstemmed Whole genome sequencing of orofacial cleft trios from the Gabriella Miller Kids First Pediatric Research Consortium identifies a new locus on chromosome 21
title_short Whole genome sequencing of orofacial cleft trios from the Gabriella Miller Kids First Pediatric Research Consortium identifies a new locus on chromosome 21
title_sort whole genome sequencing of orofacial cleft trios from the gabriella miller kids first pediatric research consortium identifies a new locus on chromosome 21
topic Original Investigation
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6981325/
https://www.ncbi.nlm.nih.gov/pubmed/31848685
http://dx.doi.org/10.1007/s00439-019-02099-1
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