Institute of Human Genetics, University of Erlangen-Nuremberg, Germany.
Am J Hum Genet. 2012 Mar 9;90(3):565-72. doi: 10.1016/j.ajhg.2012.02.007.
Intellectual disability (ID) is a clinically and genetically heterogeneous common condition that remains etiologically unresolved in the majority of cases. Although several hundred diseased genes have been identified in X-linked, autosomal-recessive, or syndromic types of ID, the establishment of an etiological basis remains a difficult task in unspecific, sporadic cases. Just recently, de novo mutations in SYNGAP1, STXBP1, MEF2C, and GRIN2B were reported as relatively common causes of ID in such individuals. On the basis of a patient with severe ID and a 2.5 Mb microdeletion including ARID1B in chromosomal region 6q25, we performed mutational analysis in 887 unselected patients with unexplained ID. In this cohort, we found eight (0.9%) additional de novo nonsense or frameshift mutations predicted to cause haploinsufficiency. Our findings indicate that haploinsufficiency of ARID1B, a member of the SWI/SNF-A chromatin-remodeling complex, is a common cause of ID, and they add to the growing evidence that chromatin-remodeling defects are an important contributor to neurodevelopmental disorders.
智力障碍（ID）是一种临床和遗传上具有异质性的常见疾病，在大多数情况下其病因仍未得到解决。虽然已经在 X 连锁、常染色体隐性或综合征型 ID 中鉴定出几百种疾病基因，但在非特异性、散发性病例中建立病因基础仍然是一项艰巨的任务。最近，在这些个体中，SYNGAP1、STXBP1、MEF2C 和 GRIN2B 的新生突变被报道为 ID 的相对常见原因。基于一名患有严重 ID 的患者和一个包括 6q25 染色体区域内 ARID1B 的 2.5Mb 微缺失，我们对 887 名未明确原因的 ID 患者进行了突变分析。在该队列中，我们发现了另外 8 个（0.9%）新出现的无义或移码突变，预计会导致杂合性不足。我们的研究结果表明，SWI/SNF-A 染色质重塑复合物的成员 ARID1B 的杂合性不足是 ID 的一个常见原因，这进一步证明了染色质重塑缺陷是神经发育障碍的一个重要原因。
