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Diagnosis of an imprinted-gene syndrome by a novel bioinformatics analysis of whole-genome sequences from a family trio

Whole-genome sequencing and whole-exome sequencing are becoming more widely applied in clinical medicine to help diagnose rare genetic diseases. Identification of the underlying causative mutations by genome-wide sequencing is greatly facilitated by concurrent analysis of multiple family members, mo...

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Autores principales: Bodian, Dale L, Solomon, Benjamin D, Khromykh, Alina, Thach, Dzung C, Iyer, Ramaswamy K, Link, Kathleen, Baker, Robin L, Baveja, Rajiv, Vockley, Joseph G, Niederhuber, John E
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BlackWell Publishing Ltd 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4303223/
https://www.ncbi.nlm.nih.gov/pubmed/25614875
http://dx.doi.org/10.1002/mgg3.107
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author Bodian, Dale L
Solomon, Benjamin D
Khromykh, Alina
Thach, Dzung C
Iyer, Ramaswamy K
Link, Kathleen
Baker, Robin L
Baveja, Rajiv
Vockley, Joseph G
Niederhuber, John E
author_facet Bodian, Dale L
Solomon, Benjamin D
Khromykh, Alina
Thach, Dzung C
Iyer, Ramaswamy K
Link, Kathleen
Baker, Robin L
Baveja, Rajiv
Vockley, Joseph G
Niederhuber, John E
author_sort Bodian, Dale L
collection PubMed
description Whole-genome sequencing and whole-exome sequencing are becoming more widely applied in clinical medicine to help diagnose rare genetic diseases. Identification of the underlying causative mutations by genome-wide sequencing is greatly facilitated by concurrent analysis of multiple family members, most often the mother–father–proband trio, using bioinformatics pipelines that filter genetic variants by mode of inheritance. However, current pipelines are limited to Mendelian inheritance patterns and do not specifically address disorders caused by mutations in imprinted genes, such as forms of Angelman syndrome and Beckwith–Wiedemann syndrome. Using publicly available tools, we implemented a genetic inheritance search mode to identify imprinted-gene mutations. Application of this search mode to whole-genome sequences from a family trio led to a diagnosis for a proband for whom extensive clinical testing and Mendelian inheritance-based sequence analysis were nondiagnostic. The condition in this patient, IMAGe syndrome, is likely caused by the heterozygous mutation c.832A>G (p.Lys278Glu) in the imprinted gene CDKN1C. The genotypes and disease status of six members of the family are consistent with maternal expression of the gene, and allele-biased expression was confirmed by RNA-Seq for the heterozygotes. This analysis demonstrates that an imprinted-gene search mode is a valuable addition to genome sequence analysis pipelines for identifying disease-causative variants.
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spelling pubmed-43032232015-01-22 Diagnosis of an imprinted-gene syndrome by a novel bioinformatics analysis of whole-genome sequences from a family trio Bodian, Dale L Solomon, Benjamin D Khromykh, Alina Thach, Dzung C Iyer, Ramaswamy K Link, Kathleen Baker, Robin L Baveja, Rajiv Vockley, Joseph G Niederhuber, John E Mol Genet Genomic Med Original Articles Whole-genome sequencing and whole-exome sequencing are becoming more widely applied in clinical medicine to help diagnose rare genetic diseases. Identification of the underlying causative mutations by genome-wide sequencing is greatly facilitated by concurrent analysis of multiple family members, most often the mother–father–proband trio, using bioinformatics pipelines that filter genetic variants by mode of inheritance. However, current pipelines are limited to Mendelian inheritance patterns and do not specifically address disorders caused by mutations in imprinted genes, such as forms of Angelman syndrome and Beckwith–Wiedemann syndrome. Using publicly available tools, we implemented a genetic inheritance search mode to identify imprinted-gene mutations. Application of this search mode to whole-genome sequences from a family trio led to a diagnosis for a proband for whom extensive clinical testing and Mendelian inheritance-based sequence analysis were nondiagnostic. The condition in this patient, IMAGe syndrome, is likely caused by the heterozygous mutation c.832A>G (p.Lys278Glu) in the imprinted gene CDKN1C. The genotypes and disease status of six members of the family are consistent with maternal expression of the gene, and allele-biased expression was confirmed by RNA-Seq for the heterozygotes. This analysis demonstrates that an imprinted-gene search mode is a valuable addition to genome sequence analysis pipelines for identifying disease-causative variants. BlackWell Publishing Ltd 2014-11 2014-08-26 /pmc/articles/PMC4303223/ /pubmed/25614875 http://dx.doi.org/10.1002/mgg3.107 Text en © 2014 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc. http://creativecommons.org/licenses/by/3.0/ This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Articles
Bodian, Dale L
Solomon, Benjamin D
Khromykh, Alina
Thach, Dzung C
Iyer, Ramaswamy K
Link, Kathleen
Baker, Robin L
Baveja, Rajiv
Vockley, Joseph G
Niederhuber, John E
Diagnosis of an imprinted-gene syndrome by a novel bioinformatics analysis of whole-genome sequences from a family trio
title Diagnosis of an imprinted-gene syndrome by a novel bioinformatics analysis of whole-genome sequences from a family trio
title_full Diagnosis of an imprinted-gene syndrome by a novel bioinformatics analysis of whole-genome sequences from a family trio
title_fullStr Diagnosis of an imprinted-gene syndrome by a novel bioinformatics analysis of whole-genome sequences from a family trio
title_full_unstemmed Diagnosis of an imprinted-gene syndrome by a novel bioinformatics analysis of whole-genome sequences from a family trio
title_short Diagnosis of an imprinted-gene syndrome by a novel bioinformatics analysis of whole-genome sequences from a family trio
title_sort diagnosis of an imprinted-gene syndrome by a novel bioinformatics analysis of whole-genome sequences from a family trio
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4303223/
https://www.ncbi.nlm.nih.gov/pubmed/25614875
http://dx.doi.org/10.1002/mgg3.107
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