Cerebellar and posterior fossa malformations in patients with autism-associated chromosome 22q13 terminal deletion
Cerebellar and posterior fossa malformations in patients with autism-associated chromosome 22q13 terminal deletion
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DOI：
10.1002/ajmg.a.35700
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发表时间：
2013-01-01
影响因子：
2
通讯作者：
Dobyns, William B.
中科院分区：
文献类型：
--
作者：
Aldinger, Kimberly A.;Kogan, Jillene;Dobyns, William B.
22q13.3 缺失会导致神经发育综合征，也称为 Phelan-McDermid 综合征 (MIM #606232)，其特征是发育迟缓和严重迟缓或缺乏表达性言语。当脑影像学研究显示小脑蚓部发育不全 (CBVH) 时，两名 22q13.3 半合子染色体端粒缺失患者被转诊至我们。为了确定小脑发育异常是否是 22q13.3 缺失综合征的一致特征，我们检查了 10 名不相关的 22q13 末端缺失受试者的脑成像研究。在 DNA 和阵列技术允许的情况下，我们使用单核苷酸多态性 (SNP) 微阵列的比较强度分析来绘制缺失边界的七种情况。另外三个病例的大致删除边界来自临床或已发表的分子数据。我们还检查了一名患有基因内 SHANK3 突变的患者的脑成像研究。我们报告的第一个脑成像数据显示，一些 22q13 缺失的患者患有严重的后部 CBVH，而一个具有 SHANK3 突变的个体具有正常的小脑。这项基因型表型研究表明，22q13 缺失表型包括异常的后颅窝结构，不太可能归因于 SHANK3 破坏。该区域的其他基因，包括 PLXNB2 和 MAPK8IP2，显示出对小脑正常发育至关重要的大脑表达模式和小鼠突变表型。未来对这些基因的研究可能会阐明它们与 22q13.3 缺失表型的关系。 (c) 2012 年 Wiley 期刊公司。
The 22q13.3 deletion causes a neurodevelopmental syndrome, also known as Phelan-McDermid syndrome (MIM #606232), characterized by developmental delay and severe delay or absence of expressive speech. Two patients with hemizygous chromosome 22q13.3 telomeric deletion were referred to us when brain-imaging studies revealed cerebellar vermis hypoplasia (CBVH). To determine whether developmental abnormalities of the cerebellum are a consistent feature of the 22q13.3 deletion syndrome, we examined brain-imaging studies for 10 unrelated subjects with 22q13 terminal deletion. In seven cases where the availability of DNA and array technology allowed, we mapped deletion boundaries using comparative intensity analysis with single nucleotide polymorphism (SNP) microarrays. Approximate deletion boundaries for three additional cases were derived from clinical or published molecular data. We also examined brain-imaging studies for a patient with an intragenic SHANK3 mutation. We report the first brain-imaging data showing that some patients with 22q13 deletions have severe posterior CBVH, and one individual with a SHANK3 mutation has a normal cerebellum. This genotypephenotype study suggests that the 22q13 deletion phenotype includes abnormal posterior fossa structures that are unlikely to be attributed to SHANK3 disruption. Other genes in the region, including PLXNB2 and MAPK8IP2, display brain expression patterns and mouse mutant phenotypes critical for proper cerebellar development. Future studies of these genes may elucidate their relationship to 22q13.3 deletion phenotypes. (c) 2012 Wiley Periodicals, Inc.