Microdeletions of ELP4 are associated with language impairment, autism spectrum disorder and epilepsy

Copy number variations (CNV) 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 U.K. individuals with a range of neurodevelopmental conditions, clinically referred for array comparative genomic hybridisation (aCGH), 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 ASD and similar secondary phenotypes were identified with ELP4 deletions, as well as another six (out of 9) 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=7.5x10-3; as well as for autism, p=2.7x10-3. Our results suggest ELP4 deletions are highly likely to be pathogenic, predisposing to a range of neurodevelopmental phenotypes from ASD to language impairment and epilepsy.