Ben-Salem Salma, Sobreira Nara, Akawi Nadia A, Al-Shamsi Aisha M, John Anne, Pramathan Thachillath, Valle David, Ali Bassam R, Al-Gazali Lihadh
Department of Pathology, College of Medicine and Heath Sciences, United Arab Emirates University, Al-Ain, United Arab Emirates.
Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Am J Med Genet A. 2016 Jan;170A(1):156-61. doi: 10.1002/ajmg.a.37405. Epub 2015 Sep 23.
The gene encoding the AT-rich interaction domain-containing protein 1B (ARID1B) has recently been shown to be one of the most frequently mutated genes in patients with intellectual disability (ID). The phenotypic spectrums associated with variants in this gene vary widely ranging for mild to severe non-specific ID to Coffin-Siris syndrome. In this study, we evaluated three children from a consanguineous Emirati family affected with ID and dysmorphic features. Genomic DNA from all affected siblings was analyzed using CGH array and whole-exome sequencing (WES). Based on a recessive mode of inheritance, homozygous or compound heterozygous variants shared among all three affected children could not be identified. However, further analysis revealed a heterozygous variant (c.4318C>T; p.Q1440*) in the three affected children in an autosomal dominant ID causing gene, ARID1B. This variant was absent in peripheral blood samples obtained from both parents and unaffected siblings. Therefore, we propose that the most likely explanation for this situation is that one of the parents is a gonadal mosaic for the variant. To the best of our knowledge, this is the first report of a gonadal mosaicism inheritance of an ARID1B variant leading to familial ID recurrence.
编码富含AT互作结构域蛋白1B（ARID1B）的基因最近被证明是智力障碍（ID）患者中最常发生突变的基因之一。该基因变异相关的表型谱差异很大，从轻度到重度非特异性ID，再到科芬-西里斯综合征。在本研究中，我们评估了一个近亲阿联酋家庭中三名患有ID和畸形特征的儿童。使用比较基因组杂交阵列（CGH array）和全外显子测序（WES）对所有患病兄弟姐妹的基因组DNA进行了分析。基于隐性遗传模式，未在所有三名患病儿童中鉴定出共同的纯合或复合杂合变异。然而，进一步分析发现，在一个常染色体显性ID致病基因ARID1B中，三名患病儿童存在一个杂合变异（c.4318C>T；p.Q1440*）。从父母和未患病的兄弟姐妹采集的外周血样本中不存在该变异。因此，我们认为这种情况最可能的解释是父母一方是该变异的生殖腺嵌合体。据我们所知，这是关于导致家族性ID复发的ARID1B变异的生殖腺嵌合体遗传的首次报告。
