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© 2015 WILEY PERIODICALS, INC.. 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. We have identified a significant excess (p = 7.5 × 10-3) of small deletions (shown as red lines on the figure) at the PAX6-ELP4 locus, 11p13, in three cohorts of patients with neurodevelopmental disorders. The deletions predispose to a range of phenotypes including autism spectrum disorder, language impairment, mental retardation and epilepsy, and likely disrupt the functions of the Elongator protein complex and/or the transcription factor PAX6.
Author(s): Addis L, Ahn JW, Dobson R, Dixit A, Ogilvie CM, Pinto D, Vaags AK, Coon H, Chaste P, Wilson S, Parr JR, Andrieux J, Lenne B, Tumer Z, Leuzzi V, Aubell K, Koillinen H, Curran S, Marshall CR, Scherer SW, Strug LJ, Collier DA, Pal DK
Publication type: Article
Publication status: Published
Journal: Human Mutation
Year: 2015
Volume: 36
Issue: 9
Pages: 842-850
Online publication date: 23/05/2015
Acceptance date: 15/05/2015
ISSN (print): 1059-7794
ISSN (electronic): 1098-1004
Publisher: John Wiley and Sons Inc.
URL: http://doi.org/10.1002/humu.22816
DOI: 10.1002/humu.22816
PubMed id: 26010655
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