Microdeletions ofELP4Are Associated with Language Impairment, Autism Spectrum Disorder, and Mental Retardation

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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 theELP4-PAX6locus 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 withELP4deletions, and one with a partial duplication ofELP4andPAX6. 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 withELP4deletions, as well as another six (out of nine) with neurodevelopmental phenotypes from DECIPHER. CNVs atELP4were 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 thatELP4deletions 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.

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