Deletion 17q12 Is a Recurrent Copy Number Variant that Confers High Risk of Autism and Schizophrenia
Deletion 17q12 Is a Recurrent Copy Number Variant that Confers High Risk of Autism and Schizophrenia
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DOI：
10.1016/j.ajhg.2010.10.004
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发表时间：
2010-11-12
影响因子：
9.8
通讯作者：
Ledbetter, David H.
中科院分区：
文献类型：
--
作者：
Moreno-De-Luca, Daniel;Mulle, Jennifer G.;Ledbetter, David H.
孤独症谱系障碍（ASD）和精神分裂症是神经发育障碍，最近的证据表明罕见拷贝数变异（CNV）在其病因学中起重要作用，并提示了共同的遗传机制。我们在临床测试的神经发育障碍患者的发现样本中进行了细胞基因组阵列分析。我们检测到17 q12处的复发性1 4 Mb缺失，其携带HNF 1B，在15，749名患者中有18名（包括几名ASD患者）患有肾囊肿和糖尿病综合征（RCAD），但在4，519名对照患者中没有发现该基因。我们在9名可用于临床评估的患者中鉴定了其他共同的表型特征，包括大头畸形特征性面部特征肾异常，和神经认知障碍在一个大的随访样本中，在2/1,182名ASD/神经认知障碍和4/6340名精神分裂症患者中鉴定出相同的缺失，但在0/47929对照中，（校正后p = 7.37 × 10（-5））这些数据表明17 q12缺失是一种复发性，致病性CNV，其赋予ASD和精神分裂症非常高的风险，并显示缺失的间隔中的15个基因中的一个或多个是剂量敏感的，并且对于正常的脑发育是必需的，此外，CNV患者的表型特征与仅由HNF 1B突变引起的RCAD以外的连续基因综合征一致
Autism spectrum disorders (ASD) and schizophrenia are neurodevelopmental disorders for which recent evidence indicates an important etiologic role for rare copy number variants (CNVs) and suggests common genetic mechanisms We performed cytogenomic array analysis in a discovery sample of patients with neurodevelopmental disorders referred for clinical testing We detected a recurrent 1 4 Mb deletion at 17q12 which harbors HNF1B, the gene responsible for renal cysts and diabetes syndrome (RCAD), in 18/15,749 patients including several with ASD, but 0/4 519 controls We identified additional shared phenotypic features among nine patients available for clinical assessment including macrocephaly characteristic facial features renal anomalies, and neurocognitive impairments In a large follow up sample the same deletion was identified in 2/1,182 ASD/neurocognitive impairment and in 4/6 340 schizophrenia patients, but in 0/47 929 controls (corrected p = 7 37 x 10(-5)) These data demonstrate that deletion 17q12 is a recurrent, pathogenic CNV that confers a very high risk for ASD and schizophrenia and show that one or more of the 15 genes in the deleted Interval is dosage sensitive and essential for normal brain development and function In addition the phenotypic features of patients with this CNV are consistent with a contiguous gene syndrome that extends beyond RCAD which is caused by HNF1B mutations only