Targeted Next‐Generation Sequencing Analysis of 1,000 Individuals with Intellectual Disability
Year: 2015
Type: article
Study design: Observational Study
Abstract: 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.
Source: Human Mutation
DOI: 10.1002/humu.22901
Authors: Detelina Grozeva, Keren Carss, Olivera Spasic‐Boskovic, Maria‐Isabel Tejada, Jozef Gecz, Marie Shaw, Mark Corbett, Eric Haan, Elizabeth Thompson, Kathryn Friend, Zaamin Hussain, Anna Hackett, Michael Field, Alessandra Renieri, Roger Stevenson, Charles Schwartz, James A.B. Floyd, Jamie Bentham, Catherine Cosgrove, Bernard Keavney, Shoumo Bhattacharya, Italian X‐linked Mental Retardation Project, Matthew Hurles, F. Lucy Raymond
Institutions: University of Cambridge, Wellcome Sanger Institute, Addenbrooke's Hospital, BioCruces Health research Institute, Centre for Biomedical Network Research on Rare Diseases, Hospital de Cruces, The University of Adelaide, South Australia Pathology, Women's and Children's Hospital, Hunter Genetics, University of Siena, Azienda Ospedaliera Universitaria Senese, Greenwood Genetic Center, Queen Mary University of London, Centre for Human Genetics, University of Oxford, University of Manchester
Language: English
Topic: Genomics and Rare Diseases
Subfield: Genetics
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $2,740
OpenAlex ID: W1810362853