TBX1 mutation identified by exome sequencing in a Japanese family with 22q11.2 deletion syndrome-like craniofacial features and hypocalcemia.
TBX1 mutation identified by exome sequencing in a Japanese family with 22q11.2 deletion syndrome-like craniofacial features and hypocalcemia.
复制标题
DOI：
10.1371/journal.pone.0091598
复制
发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Matsubara Y
中科院分区：
文献类型：
--
作者：
Ogata T;Niihori T;Tanaka N;Kawai M;Nagashima T;Funayama R;Nakayama K;Nakashima S;Kato F;Fukami M;Aoki Y;Matsubara Y
尽管在 22q11.2 缺失综合征 (22q11.2DS) 样表型（包括特征性颅面特征、心血管异常、甲状旁腺功能减退和胸腺发育不全）患者中已发现 TBX1 突变，但在缺失阴性患者中 TBX1 突变的频率仍然很少。因此，对具有 22q11.2DS 样表型的缺失阴性患者进行全面的遗传分析是合理的。我们研究了三个具有颅面特征和低钙血症的受试者（第 1 组）、两个仅具有颅面特征的受试者（第 2 组）以及单个日本家庭中具有正常表型的三个受试者。荧光原位杂交分析排除了染色体 22q11.2 缺失，全基因组阵列比较基因组杂交分析显示第 1 组或第 1+2 组特异的拷贝数变化。然而，外显子组测序发现了 1+2 组特有的杂合 TBX1 移码突变 (c.1253delA、p.Y418fsX459)，以及 1+2 组特有的 6 个错义变体和两个框内微缺失，以及 1 组特有的两个错义变体。TBX1 突变位于外显子 9C，预计会产生非功能性突变。 截短的蛋白质缺少核定位信号和大部分反式激活结构域。 TBX1 突变可以很好地解释 1+2 组的临床特征，而其余变异的临床效果很大程度上未知。因此，结果证明了外显子组测序在鉴定家族性疾病致病突变方面的有用性。此外，结果与之前的数据相结合，表明 TBX1 亚型 C 是生物学上必需的变异体，并且 TBX1 突变与广泛的表型谱相关，包括大多数 22q11.2DS 表型。
Although TBX1 mutations have been identified in patients with 22q11.2 deletion syndrome (22q11.2DS)-like phenotypes including characteristic craniofacial features, cardiovascular anomalies, hypoparathyroidism, and thymic hypoplasia, the frequency of TBX1 mutations remains rare in deletion-negative patients. Thus, it would be reasonable to perform a comprehensive genetic analysis in deletion-negative patients with 22q11.2DS-like phenotypes. We studied three subjects with craniofacial features and hypocalcemia (group 1), two subjects with craniofacial features alone (group 2), and three subjects with normal phenotype within a single Japanese family. Fluorescence in situ hybridization analysis excluded chromosome 22q11.2 deletion, and genomewide array comparative genomic hybridization analysis revealed no copy number change specific to group 1 or groups 1+2. However, exome sequencing identified a heterozygous TBX1 frameshift mutation (c.1253delA, p.Y418fsX459) specific to groups 1+2, as well as six missense variants and two in-frame microdeletions specific to groups 1+2 and two missense variants specific to group 1. The TBX1 mutation resided at exon 9C and was predicted to produce a non-functional truncated protein missing the nuclear localization signal and most of the transactivation domain. Clinical features in groups 1+2 are well explained by the TBX1 mutation, while the clinical effects of the remaining variants are largely unknown. Thus, the results exemplify the usefulness of exome sequencing in the identification of disease-causing mutations in familial disorders. Furthermore, the results, in conjunction with the previous data, imply that TBX1 isoform C is the biologically essential variant and that TBX1 mutations are associated with a wide phenotypic spectrum, including most of 22q11.2DS phenotypes.
登录
查看更多内容
影响因子：
9.8
作者：
Zweier, Christiane;Sticht, Heinrich;Rauch, Anita
通讯作者：
Rauch, Anita
影响因子：
5.7
作者：
Griffin, Helen R.;Toepf, Ana;Goodship, Judith A.
通讯作者：
Goodship, Judith A.
DOI：
10.1073/pnas.0600206103
发表时间：
2006-05-16
影响因子：
11.1
作者：
Paylor, Richard;Glaser, Beate;Lindsay, Elizabeth
通讯作者：
Lindsay, Elizabeth
影响因子：
3.5
作者：
Stoller, JZ;Epstein, JA
通讯作者：
Epstein, JA
影响因子：
4
作者：
Rauch, Ralf;Hofbeck, Michael;Rauch, Anita
通讯作者：
Rauch, Anita