1. Targeted Next‐Generation Sequencing Analysis of 1,000 Individuals with Intellectual Disability
- Author
-
Shoumo Bhattacharya, Olivera Spasic-Boskovic, Charles E. Schwartz, Catherine Cosgrove, Kathryn Friend, Keren J. Carss, F. Lucy Raymond, Roger E. Stevenson, Anna Hackett, Eric Haan, Zaamin B. Hussain, Matthew E. Hurles, Michael Field, Detelina Grozeva, James A B Floyd, Jozef Gecz, Maria-Isabel Tejada, Jamie Bentham, Mark A. Corbett, Bernard Keavney, Elizabeth Thompson, Marie Shaw, Alessandra Renieri, Cambridge Institute for Medical Research (CIMR), University of Cambridge [UK] (CAM), Department of Haematology, Hospital Universitario Cruces = Cruces University Hospital, University of Adelaide, Women’s and Children’s Hospital [Adelaide], Università degli Studi di Siena = University of Siena (UNISI), The Greenwood Genetic Center, 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, Charle, Floyd, James A. B., Bentham, Jamie, Cosgrove, Catherine, Keavney, Bernard, Bhattacharya, Shoumo, Hurles, Matthew, Raymond, F. Lucy, and Franco, Brunella
- Subjects
Male ,Proband ,Developmental delay ,Intellectual disability ,Mendelian disease ,Next-generation sequencing ,Genetics ,Genetics (clinical) ,Sequence analysis ,Alleles ,Cohort Studies ,Computational Biology ,Female ,Humans ,Inheritance Patterns ,Intellectual Disability ,Mutation ,Polymorphism, Single Nucleotide ,Genetic Association Studies ,High-Throughput Nucleotide Sequencing ,next‐generation sequencing ,Biology ,Bioinformatics ,DNA sequencing ,Genetic ,medicine ,Missense mutation ,Polymorphism ,Allele ,developmental delay ,intellectual disability ,next-generation sequencing ,Research Articles ,ATRX ,Single Nucleotide ,medicine.disease ,Settore MED/03 - Genetica Medica ,[SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics ,CUL4B ,Research Article - Abstract
International audience; 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 ß11% of the cases (113 variants in 107/986 individuals: ß8% of the individuals had a likely pathogenic loss-of-function [LoF] variant, whereas ß3% 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.
- Published
- 2015
- Full Text
- View/download PDF