Microdeletions of ELP4 Are Associated with Language Impairment, Autism Spectrum Disorder, and Mental Retardation
Microdeletions of ELP4 Are Associated with Language Impairment, Autism Spectrum Disorder, and Mental Retardation
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DOI：
10.1002/humu.22816
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发表时间：
2015-09-01
期刊：
影响因子：
3.9
通讯作者：
Pal, Deb K.
中科院分区：
文献类型：
--
作者：
Addis, Laura;Ahn, Joo Wook;Pal, Deb K.
拷贝数变异（CNVs）在神经发育障碍的病因学中是重要的，并显示出广泛的表型表现。我们比较了4，092名具有一系列神经发育状况的英国个体中破坏ELP 4-PAX 6基因座的小CNV的存在，临床上称为阵列比较基因组杂交，WTCCC对照（n = 4，783）。然后使用DECIPHER数据库扩展表型分析。我们使用自闭症患者队列（n = 3，143）与另外六个对照组（n = 6，469）进行了随访。在临床发现系列中，我们发现了8例ELP 4缺失病例，1例ELP 4和PAX 6部分重复。这些病例因神经系统表型（包括语言障碍、发育迟缓、自闭症和癫痫）而转诊。另外6例初步诊断为自闭症谱系障碍（ASD）和类似的次要表型的病例被鉴定为ELP 4缺失，另外6例（共9例）被鉴定为DECIPHER的神经发育表型。ELP 4处的CNV仅存在于1/11，252个对照中。我们发现，与对照组相比，发现病例中的CNVs显著过量，P = 7.5 x 10（-3），自闭症也是如此，P = 2.7 x 10（-3）。我们的研究结果表明，ELP 4缺失极有可能是致病性的，易诱发从ASD到语言障碍和癫痫的一系列神经发育表型。(C)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 x 10(-3), as well as for autism, P = 2.7 x 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. (C) 2015 Wiley Periodicals, Inc.