Departments of Pediatrics and Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
Am J Med Genet A. 2011 Nov;155A(11):2871-8. doi: 10.1002/ajmg.a.34286. Epub 2011 Oct 12.
The pontocerebellar hypoplasias (PCHs) are a group of clinically variable disorders characterized by abnormally small cerebellum and brainstem, generally inherited in an autosomal recessive pattern. While PCHs have been grouped into six subtypes, clinical diagnosis is equivocal until a genetic diagnosis is established. We report a patient with PCH, intrauterine growth restriction, ventricular septal defect, rib anomalies, midgut malrotation, and facial dysmorphic features. Using SNP analysis, we identified three de novo deletions of: 1.055 Mb at 6q24.3q25.1 (148174730-149229583); 169 kb at 16p13.2 (6565411-6733934); and 2.530 Mb at 19p13.11p13.12 (13857587-16387798), which were confirmed by FISH. 19p13 deletions are rare aberrations. Of patients previously described with overlapping 19p13.12 deletions and multiple anomalies, only one presented with PCH. Deleted in both that patient and the patient reported here, is DDX39, a DEAD-box RNA helicase. DDX39 is part of the homeostatic machinery that regulates the switch of cellular proliferation and differentiation. It is highly expressed in the developing central nervous system and optic cup of Xenopus laevis. The brain abnormalities in the patient reported here were more severe than the previously reported patient, which may be due to additional deletions or undetected point mutations in the nondeleted allele. Notably, the patient reported here also has a partial deletion of RBFOX1 (A2BP1), which lies within the autism susceptibility locus on 16p13.2. Our findings suggest chromosomal microarray analysis may be useful in determining etiology of syndromic PCH.
桥脑小脑发育不全症（PCHs）是一组临床表现多样的疾病，其特征为小脑和脑干异常小，通常呈常染色体隐性遗传模式。虽然 PCHs 已分为六个亚型，但在进行基因诊断之前，临床诊断仍存在不确定性。我们报告了一例 PCH 患者，其具有宫内生长受限、室间隔缺损、肋骨异常、中肠旋转不良和面部畸形特征。通过 SNP 分析，我们发现了三个新发的缺失：6q24.3q25.1 处的 1.055Mb（148174730-149229583）；16p13.2 处的 169kb（6565411-6733934）；以及 19p13.11p13.12 处的 2.530Mb（13857587-16387798），这些缺失通过 FISH 得到了证实。19p13 缺失是罕见的异常。先前有重叠 19p13.12 缺失和多种异常的患者中，只有一例表现为 PCH。在该患者和本报告中的患者中均缺失的是 DDX39，这是一种 DEAD-box RNA 解旋酶。DDX39 是调节细胞增殖和分化转换的稳态机制的一部分。它在发育中的中枢神经系统和非洲爪蟾的视杯中有高表达。本报告中患者的脑异常比先前报告的患者更严重，这可能是由于非缺失等位基因中存在额外缺失或未检测到的点突变。值得注意的是，本报告中的患者还存在 RBFOX1（A2BP1）的部分缺失，该缺失位于 16p13.2 的自闭症易感基因座内。我们的发现表明，染色体微阵列分析可能有助于确定综合征性 PCH 的病因。
