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 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.
Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, CB2 0XY, United Kingdom.
Detelina
D
Grozeva
The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SA, United Kingdom.|Department of Haematology, University of Cambridge, Cambridge, CB2 0PT, United Kingdom.
Keren
K
Carss
Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, CB2 0XY, United Kingdom.|East Anglian Medical Genetics Service, Addenbrooke's Hospital, Cambridge, CB2 0QQ, United Kingdom.
Olivera
O
Spasic-Boskovic
Molecular Genetics Laboratory, Genetics Service, Cruces University Hospital, BioCruces Health Research Institute, Barakaldo-Bizkaia, 48903, Spain.|Centre for Biomedical Research on Rare Diseases (CIBERER), Madrid, 28029, Spain.
Maria-Isabel
MI
Tejada
Department of Paediatrics and Robinson Research Institute, The University of Adelaide, Adelaide, South Australia, 5006, Australia.
Jozef
J
Gecz
Department of Paediatrics and Robinson Research Institute, The University of Adelaide, Adelaide, South Australia, 5006, Australia.
Marie
M
Shaw
Department of Paediatrics and Robinson Research Institute, The University of Adelaide, Adelaide, South Australia, 5006, Australia.
Mark
M
Corbett
Department of Paediatrics and Robinson Research Institute, The University of Adelaide, Adelaide, South Australia, 5006, Australia.
Eric
E
Haan
Department of Paediatrics and Robinson Research Institute, The University of Adelaide, Adelaide, South Australia, 5006, Australia.
Elizabeth
E
Thompson
SA Pathology, Women's and Children's Hospital, Adelaide, South Australia, 5006, Australia.
Kathryn
K
Friend
Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, CB2 0XY, United Kingdom.
Zaamin
Z
Hussain
Genetics of Learning Disability Service, Hunter Genetics, Waratah, New South Wales, 2298, Australia.
Anna
A
Hackett
Genetics of Learning Disability Service, Hunter Genetics, Waratah, New South Wales, 2298, Australia.
Michael
M
Field
Medical Genetics, University of Siena, Siena, 53100, Italy.|Genetica Medica, Azienda Ospedaliera Universitaria Senese, Siena, 53100, Italy.
Alessandra
A
Renieri
Greenwood Genetic Center, Greenwood, South Carolina, 29646.
Roger
R
Stevenson
Greenwood Genetic Center, Greenwood, South Carolina, 29646.
Charles
C
Schwartz
The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SA, United Kingdom.|The Genome Centre, John Vane Science Centre, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, United Kingdom.
James A B
JA
Floyd
Department of Cardiovascular Medicine, University of Oxford, Wellcome Trust Centre for Human Genetics, Oxford, OX3 7BN, United Kingdom.
Jamie
J
Bentham
Department of Cardiovascular Medicine, University of Oxford, Wellcome Trust Centre for Human Genetics, Oxford, OX3 7BN, United Kingdom.
Catherine
C
Cosgrove
Cardiovascular Research Group, Institute of Cardiovascular Sciences, University of Manchester, Manchester, M13 9NT, United Kingdom.
Bernard
B
Keavney
Department of Cardiovascular Medicine, University of Oxford, Wellcome Trust Centre for Human Genetics, Oxford, OX3 7BN, United Kingdom.
Shoumo
S
Bhattacharya
The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SA, United Kingdom.
Matthew
M
Hurles
Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, CB2 0XY, United Kingdom.
F Lucy
FL
Raymond
D000483:Alleles; D015331:Cohort Studies; D019295:Computational Biology / Q000379:methods; D005260:Female; D056726:Genetic Association Studies; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D040582:Inheritance Patterns; D008607:Intellectual Disability / Q000235:genetics*; D008297:Male; D009154:Mutation; D020641:Polymorphism, Single Nucleotide
Mendelian disease; developmental delay; intellectual disability; next-generation sequencing