Cargando…
Targeted Next‐Generation Sequencing Analysis of 1,000 Individuals with Intellectual Disability
To identify genetic causes of intellectual disability (ID), we screened a cohort of 986 individuals with moderate to severe ID for variants in 565 known or candidate ID‐associated genes using targeted next‐generation sequencing. Likely pathogenic rare variants were found in ∼11% of the cases (113 va...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2015
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4833192/ https://www.ncbi.nlm.nih.gov/pubmed/26350204 http://dx.doi.org/10.1002/humu.22901 |
_version_ | 1782427327635914752 |
---|---|
author | Grozeva, Detelina Carss, Keren Spasic‐Boskovic, Olivera Tejada, Maria‐Isabel Gecz, Jozef Shaw, Marie Corbett, Mark Haan, Eric Thompson, Elizabeth Friend, Kathryn Hussain, Zaamin Hackett, Anna Field, Michael Renieri, Alessandra Stevenson, Roger Schwartz, Charles Floyd, James A.B. Bentham, Jamie Cosgrove, Catherine Keavney, Bernard Bhattacharya, Shoumo Hurles, Matthew Raymond, F. Lucy |
author_facet | Grozeva, Detelina Carss, Keren Spasic‐Boskovic, Olivera Tejada, Maria‐Isabel Gecz, Jozef Shaw, Marie Corbett, Mark Haan, Eric Thompson, Elizabeth Friend, Kathryn Hussain, Zaamin Hackett, Anna Field, Michael Renieri, Alessandra Stevenson, Roger Schwartz, Charles Floyd, James A.B. Bentham, Jamie Cosgrove, Catherine Keavney, Bernard Bhattacharya, Shoumo Hurles, Matthew Raymond, F. Lucy |
author_sort | Grozeva, Detelina |
collection | PubMed |
description | To identify genetic causes of intellectual disability (ID), we screened a cohort of 986 individuals with moderate to severe ID for variants in 565 known or candidate ID‐associated genes using targeted next‐generation sequencing. Likely pathogenic rare variants were found in ∼11% of the cases (113 variants in 107/986 individuals: ∼8% of the individuals had a likely pathogenic loss‐of‐function [LoF] variant, whereas ∼3% had a known pathogenic missense variant). Variants in SETD5, ATRX, CUL4B, MECP2, and ARID1B were the most common causes of ID. This study assessed the value of sequencing a cohort of probands to provide a molecular diagnosis of ID, without the availability of DNA from both parents for de novo sequence analysis. This modeling is clinically relevant as 28% of all UK families with dependent children are single parent households. In conclusion, to diagnose patients with ID in the absence of parental DNA, we recommend investigation of all LoF variants in known genes that cause ID and assessment of a limited list of proven pathogenic missense variants in these genes. This will provide 11% additional diagnostic yield beyond the 10%–15% yield from array CGH alone. |
format | Online Article Text |
id | pubmed-4833192 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-48331922016-06-24 Targeted Next‐Generation Sequencing Analysis of 1,000 Individuals with Intellectual Disability Grozeva, Detelina Carss, Keren Spasic‐Boskovic, Olivera Tejada, Maria‐Isabel Gecz, Jozef Shaw, Marie Corbett, Mark Haan, Eric Thompson, Elizabeth Friend, Kathryn Hussain, Zaamin Hackett, Anna Field, Michael Renieri, Alessandra Stevenson, Roger Schwartz, Charles Floyd, James A.B. Bentham, Jamie Cosgrove, Catherine Keavney, Bernard Bhattacharya, Shoumo Hurles, Matthew Raymond, F. Lucy Hum Mutat Research Articles To identify genetic causes of intellectual disability (ID), we screened a cohort of 986 individuals with moderate to severe ID for variants in 565 known or candidate ID‐associated genes using targeted next‐generation sequencing. Likely pathogenic rare variants were found in ∼11% of the cases (113 variants in 107/986 individuals: ∼8% of the individuals had a likely pathogenic loss‐of‐function [LoF] variant, whereas ∼3% had a known pathogenic missense variant). Variants in SETD5, ATRX, CUL4B, MECP2, and ARID1B were the most common causes of ID. This study assessed the value of sequencing a cohort of probands to provide a molecular diagnosis of ID, without the availability of DNA from both parents for de novo sequence analysis. This modeling is clinically relevant as 28% of all UK families with dependent children are single parent households. In conclusion, to diagnose patients with ID in the absence of parental DNA, we recommend investigation of all LoF variants in known genes that cause ID and assessment of a limited list of proven pathogenic missense variants in these genes. This will provide 11% additional diagnostic yield beyond the 10%–15% yield from array CGH alone. John Wiley and Sons Inc. 2015-09-30 2015-12 /pmc/articles/PMC4833192/ /pubmed/26350204 http://dx.doi.org/10.1002/humu.22901 Text en © 2015 The Authors. **Human Mutation published by Wiley Periodicals, Inc. This is an open access article under the terms of the Creative Commons Attribution (http://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Articles Grozeva, Detelina Carss, Keren Spasic‐Boskovic, Olivera Tejada, Maria‐Isabel Gecz, Jozef Shaw, Marie Corbett, Mark Haan, Eric Thompson, Elizabeth Friend, Kathryn Hussain, Zaamin Hackett, Anna Field, Michael Renieri, Alessandra Stevenson, Roger Schwartz, Charles Floyd, James A.B. Bentham, Jamie Cosgrove, Catherine Keavney, Bernard Bhattacharya, Shoumo Hurles, Matthew Raymond, F. Lucy Targeted Next‐Generation Sequencing Analysis of 1,000 Individuals with Intellectual Disability |
title | Targeted Next‐Generation Sequencing Analysis of 1,000 Individuals with Intellectual Disability |
title_full | Targeted Next‐Generation Sequencing Analysis of 1,000 Individuals with Intellectual Disability |
title_fullStr | Targeted Next‐Generation Sequencing Analysis of 1,000 Individuals with Intellectual Disability |
title_full_unstemmed | Targeted Next‐Generation Sequencing Analysis of 1,000 Individuals with Intellectual Disability |
title_short | Targeted Next‐Generation Sequencing Analysis of 1,000 Individuals with Intellectual Disability |
title_sort | targeted next‐generation sequencing analysis of 1,000 individuals with intellectual disability |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4833192/ https://www.ncbi.nlm.nih.gov/pubmed/26350204 http://dx.doi.org/10.1002/humu.22901 |
work_keys_str_mv | AT grozevadetelina targetednextgenerationsequencinganalysisof1000individualswithintellectualdisability AT carsskeren targetednextgenerationsequencinganalysisof1000individualswithintellectualdisability AT spasicboskovicolivera targetednextgenerationsequencinganalysisof1000individualswithintellectualdisability AT tejadamariaisabel targetednextgenerationsequencinganalysisof1000individualswithintellectualdisability AT geczjozef targetednextgenerationsequencinganalysisof1000individualswithintellectualdisability AT shawmarie targetednextgenerationsequencinganalysisof1000individualswithintellectualdisability AT corbettmark targetednextgenerationsequencinganalysisof1000individualswithintellectualdisability AT haaneric targetednextgenerationsequencinganalysisof1000individualswithintellectualdisability AT thompsonelizabeth targetednextgenerationsequencinganalysisof1000individualswithintellectualdisability AT friendkathryn targetednextgenerationsequencinganalysisof1000individualswithintellectualdisability AT hussainzaamin targetednextgenerationsequencinganalysisof1000individualswithintellectualdisability AT hackettanna targetednextgenerationsequencinganalysisof1000individualswithintellectualdisability AT fieldmichael targetednextgenerationsequencinganalysisof1000individualswithintellectualdisability AT renierialessandra targetednextgenerationsequencinganalysisof1000individualswithintellectualdisability AT stevensonroger targetednextgenerationsequencinganalysisof1000individualswithintellectualdisability AT schwartzcharles targetednextgenerationsequencinganalysisof1000individualswithintellectualdisability AT floydjamesab targetednextgenerationsequencinganalysisof1000individualswithintellectualdisability AT benthamjamie targetednextgenerationsequencinganalysisof1000individualswithintellectualdisability AT cosgrovecatherine targetednextgenerationsequencinganalysisof1000individualswithintellectualdisability AT keavneybernard targetednextgenerationsequencinganalysisof1000individualswithintellectualdisability AT bhattacharyashoumo targetednextgenerationsequencinganalysisof1000individualswithintellectualdisability AT targetednextgenerationsequencinganalysisof1000individualswithintellectualdisability AT targetednextgenerationsequencinganalysisof1000individualswithintellectualdisability AT targetednextgenerationsequencinganalysisof1000individualswithintellectualdisability AT hurlesmatthew targetednextgenerationsequencinganalysisof1000individualswithintellectualdisability AT raymondflucy targetednextgenerationsequencinganalysisof1000individualswithintellectualdisability |