title: Microdeletions of ELP4 Are Associated with Language Impairment, Autism Spectrum Disorder, and Mental Retardation.
abstract: 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.
authors.affiliation: 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.
authors.forename: Laura
authors.initials: L
authors.lastname: Addis
authors.affiliation: Department of Cytogenetics, Guy's and St Thomas' NHS Foundation Trust, London, UK.
authors.forename: Joo Wook
authors.initials: JW
authors.lastname: Ahn
authors.affiliation: Department of Biostatistics and NIHR BRC for Mental Health, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
authors.forename: Richard
authors.initials: R
authors.lastname: Dobson
authors.affiliation: Department of Biostatistics and NIHR BRC for Mental Health, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
authors.forename: Abhishek
authors.initials: A
authors.lastname: Dixit
authors.affiliation: Department of Cytogenetics, Guy's and St Thomas' NHS Foundation Trust, London, UK.
authors.forename: Caroline M
authors.initials: CM
authors.lastname: Ogilvie
authors.affiliation: 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.
authors.forename: Dalila
authors.initials: D
authors.lastname: Pinto
authors.affiliation: The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Andrea K
authors.initials: AK
authors.lastname: Vaags
authors.affiliation: Department of Psychiatry, University of Utah School of Medicine, Salt Lake City, Utah.
authors.forename: Hilary
authors.initials: H
authors.lastname: Coon
authors.affiliation: Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: Pauline
authors.initials: P
authors.lastname: Chaste
authors.affiliation: 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.
authors.forename: Scott
authors.initials: S
authors.lastname: Wilson
authors.affiliation: Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Jeremy R
authors.initials: JR
authors.lastname: Parr
authors.affiliation: Institut de Génétique Médicale, Hopital Jeanne de Flandre, CHRU de Lille, France.
authors.forename: Joris
authors.initials: J
authors.lastname: Andrieux
authors.affiliation: Centre de Génétique Chromosomique, GHICL, Hôpital Saint Vincent de Paul, Lille, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Lenne
authors.affiliation: Applied Human Molecular Genetics, Kennedy Center, Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
authors.forename: Zeynep
authors.initials: Z
authors.lastname: Tumer
authors.affiliation: Department of Pediatrics, Child Neurology and Psychiatry, Sapienza Università di Roma, Rome, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Leuzzi
authors.affiliation: Institute of Human Genetics, Medical University of Graz, Graz, Austria.
authors.forename: Kristina
authors.initials: K
authors.lastname: Aubell
authors.affiliation: Department of Clinical Genetics, Helsinki University Hospital, Helsinki, Finland.
authors.forename: Hannele
authors.initials: H
authors.lastname: Koillinen
authors.affiliation: Department of Cytogenetics, Guy's and St Thomas' NHS Foundation Trust, London, UK.
authors.forename: Sarah
authors.initials: S
authors.lastname: Curran
authors.affiliation: The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada.|Department of Molecular Genetics, Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Christian R
authors.initials: CR
authors.lastname: Marshall
authors.affiliation: The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada.|McLaughlin Centre and Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Scherer
authors.affiliation: 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.
authors.forename: Lisa J
authors.initials: LJ
authors.lastname: Strug
authors.affiliation: Neuroscience Discovery Research, Eli Lilly and Company, Erl Wood, Surrey, UK.|Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
authors.forename: David A
authors.initials: DA
authors.lastname: Collier
authors.affiliation: Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
authors.forename: Deb K
authors.initials: DK
authors.lastname: Pal
mesh_terms: D000293:Adolescent; D000328:Adult; D000067877:Autism Spectrum Disorder / Q000235:genetics*; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D055028:Comparative Genomic Hybridization; D056915:DNA Copy Number Variations; D030541:Databases, Genetic; D066264:Datasets as Topic; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D007223:Infant; D040582:Inheritance Patterns; D008607:Intellectual Disability / Q000235:genetics*; D007806:Language Disorders / Q000235:genetics*; D008297:Male; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010641:Phenotype; D017384:Sequence Deletion; D055815:Young Adult
chemical_list: C456976:ELP4 protein, human; D009419:Nerve Tissue Proteins
keywords: CNV; copy number variation; developmental; epilepsy and seizures; neurology