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Hum Mutat. 2015 Sep;36(9):842-50. doi: 10.1002/humu.22816. Epub 2015 Jun 30.

Microdeletions of ELP4 Are Associated with Language Impairment, Autism Spectrum Disorder, and Mental Retardation.

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Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
Neuroscience Discovery Research, Eli Lilly and Company, Erl Wood, Surrey, UK.
Department of Cytogenetics, Guy's and St Thomas' NHS Foundation Trust, London, UK.
Department of Biostatistics and NIHR BRC for Mental Health, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
Departments of Psychiatry, and Genetics and Genomic Sciences, Seaver Autism Center, The Mindich Child Health & Development Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada.
Department of Psychiatry, University of Utah School of Medicine, Salt Lake City, Utah.
Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Perth, Western Australia, Australia.
School of Medicine and Pharmacology, University of Western Australia, Nedlands, Western Australia, Australia.
Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK.
Institut de Génétique Médicale, Hopital Jeanne de Flandre, CHRU de Lille, France.
Centre de Génétique Chromosomique, GHICL, Hôpital Saint Vincent de Paul, Lille, France.
Applied Human Molecular Genetics, Kennedy Center, Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
Department of Pediatrics, Child Neurology and Psychiatry, Sapienza Università di Roma, Rome, Italy.
Institute of Human Genetics, Medical University of Graz, Graz, Austria.
Department of Clinical Genetics, Helsinki University Hospital, Helsinki, Finland.
Department of Molecular Genetics, Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada.
McLaughlin Centre and Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
Program in Genetics and Genome Biology, The Hospital for Sick Children, Division of Biostatistics, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada.


Copy-number variations (CNVs) are important in the aetiology of neurodevelopmental disorders and show broad phenotypic manifestations. We compared the presence of small CNVs disrupting the ELP4-PAX6 locus in 4,092 UK individuals with a range of neurodevelopmental conditions, clinically referred for array comparative genomic hybridization, with WTCCC controls (n = 4,783). The phenotypic analysis was then extended using the DECIPHER database. We followed up association using an autism patient cohort (n = 3,143) compared with six additional control groups (n = 6,469). In the clinical discovery series, we identified eight cases with ELP4 deletions, and one with a partial duplication of ELP4 and PAX6. These cases were referred for neurological phenotypes including language impairment, developmental delay, autism, and epilepsy. Six further cases with a primary diagnosis of autism spectrum disorder (ASD) and similar secondary phenotypes were identified with ELP4 deletions, as well as another six (out of nine) with neurodevelopmental phenotypes from DECIPHER. CNVs at ELP4 were only present in 1/11,252 controls. We found a significant excess of CNVs in discovery cases compared with controls, P = 7.5 × 10(-3) , as well as for autism, P = 2.7 × 10(-3) . Our results suggest that ELP4 deletions are highly likely to be pathogenic, predisposing to a range of neurodevelopmental phenotypes from ASD to language impairment and epilepsy.


CNV; copy number variation; developmental; epilepsy and seizures; neurology

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