Targeted Next‐Generation Sequencing Analysis of 1,000 Individuals with Intellectual Disability |
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| 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 Matthew Hurles F. Lucy Raymond |
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| Affiliation: | 1. Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom;2. The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, United Kingdom;3. Department of Haematology, University of Cambridge, Cambridge, United Kingdom;4. East Anglian Medical Genetics Service, Addenbrooke's Hospital, Cambridge, CB2 0QQ, United Kingdom;5. Molecular Genetics Laboratory, Genetics Service, Cruces University Hospital, Barakaldo‐Bizkaia, Spain;6. Centre for Biomedical Research on Rare Diseases (CIBERER), Madrid, Spain;7. Department of Paediatrics and Robinson Research Institute, The University of Adelaide, Adelaide, South Australia, Australia;8. SA Pathology, Women's and Children's Hospital, Adelaide, South Australia, Australia;9. Genetics of Learning Disability Service, Hunter Genetics, Waratah, New South Wales, Australia;10. Medical Genetics, University of Siena, Siena, Italy;11. Genetica Medica, Azienda Ospedaliera Universitaria Senese, Siena, Italy;12. Greenwood Genetic Center, Greenwood, South Carolina;13. The Genome Centre, John Vane Science Centre, Queen Mary University of London, London, United Kingdom;14. Department of Cardiovascular Medicine, University of Oxford, Oxford, United Kingdom;15. Cardiovascular Research Group, Institute of Cardiovascular Sciences, University of Manchester, Manchester, M13 9NT, United Kingdom |
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| 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. |
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| Keywords: | intellectual disability next‐generation sequencing Mendelian disease developmental delay |
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