Infantile-Onset Syndromic Cerebellar Ataxia and CACNA1G Mutations
Infantile-Onset Syndromic Cerebellar Ataxia and CACNA1G Mutations
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DOI：
10.1016/j.pediatrneurol.2019.09.005
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发表时间：
2020-03-01
影响因子：
3.8
通讯作者：
Tartaglia, Marco
中科院分区：
文献类型：
--
作者：
Barresi, Sabina;Dentici, Maria Lisa;Tartaglia, Marco
背景：与小脑萎缩相关的先天性共济失调是一种临床异质性疾病，其发病年龄和分子基础各不相同。基因组测序的无假设方法导致了与这些疾病有关的新基因的发现，并确定了意想不到的基因-表型相关性。虽然CACNA1G中一个重复的杂合突变(p.Arg1715His)被认为是导致成人起病的脊髓小脑性共济失调42(SCA42*616795)的原因，但最近通过全外显子组测序(WES)在四名患有小脑萎缩和共济失调、精神运动迟缓和其他可变特征的儿童中发现了该基因的功能获得突变。方法：我们描述了四名来自无血缘关系的家庭的儿童，他们在磁共振成像上有小脑异常(小脑棘萎缩或发育不良)、强直症、精神运动和语言发育迟缓、严重的智能障碍、眼科特征和特殊的变形特征。所有患者都接受了基于TRIO的WES分析。结果：在这些患者中发现了两个先前报道的CACNA1G新基因突变(c.2881G>；A，p.Ala961Thr和c.4591A>；G，p.Met1531Val)，为这些变异的特定影响提供了进一步的证据。所有四名患者都表现出与先前报道的患者重叠的独特的变形和外胚层特征，这使得我们能够定义这种与CACNA1G功能上调相关的同质性神经发育综合征的主要特征。结论：我们的发现证实了CACNA1G窄谱错义突变与一种新的婴儿起病小脑性共济失调综合征之间的特定关联，并为这一新的神经发育特征提供了一种形态异常的描绘。(C)2019 Elsevier Inc.保留所有权利。
Background: Congenital ataxias associated with cerebellar atrophy are clinically heterogeneous conditions with a variable age of onset and a diverse molecular basis. The hypothesis-free approach of genomic sequencing has led to the discovery of new genes implicated in these disorders and the identification of unexpected genotype-phenotype correlations. Although a recurrent heterozygous mutation (p.Arg1715His) in CACNA1G is known to cause adult-onset spinocerebellar ataxia 42 (SCA42*616795), gain-of-function mutations in this gene have recently been identified by whole exome sequencing (WES) in four children with cerebellar atrophy and ataxia, psychomotor delay, and other variable features.Methods: We describe four children from unrelated families with cerebellar anomalies on magnetic resonance imaging (atrophy or hypoplasia of the cerebellar vermis), hypertonia, psychomotor and speech delay, severe intellectual disability, ophthalmologic features and peculiar dysmorphic traits. All patients underwent a trio-based WES analysis. Clinical records were used to characterize the clinical profile of this newly recognized disorder.Results: Two previously reported de novo disease-causing mutations in CACNA1G (c.2881G>A, p.Ala961Thr and c.4591A>G, p.Met1531Val) were identified in these patients, providing further evidence of the specific impact of these variants. All four patients exhibit distinctive dysmorphic and ectodermal features which overlap those of the previously reported patients, allowing us to define the major features characterizing this homogeneous neurodevelopmental syndromic disorder associated with upregulated CACNA1G function.Conclusion: Our findings confirm the specific association between a narrow spectrum of missense mutations in CACNA1G and a novel syndrome with infantile-onset cerebellar ataxiaand provide a dysmorphologic delineation of this novel neurodevelopmental trait. (C) 2019 Elsevier Inc. All rights reserved.