Joubert syndrome (JS) is a rare genetic disorder, which can be defined by brain stem malformation, cerebellar vermis hypoplasia, and consequent “molar tooth sign” (MTS). JS always shares variety of phenotypes in development defects. With the development of next-generation sequencing, dozens of causative genes have been identified to JS so far. Here, we investigated two male siblings with JS and uncovered a novel pathogenesis through combined methods. The siblings shared similar features of nystagmus, disorders of intellectual development, typical MTS, and abnormal morphology in fourth ventricle. Whole-exome sequencing (WES) and chromosome comparative genomic hybridization (CGH) were then performed on the proband. Strikingly, a maternal inherited nonsense variant (NM_025114.3: c.5953G>T [p.E1985*]) in CEP290 gene and a paternal inherited deletion in 12q21.32 including exons 1 to 10 of CEP290 gene were identified in the two affected siblings. We further confirmed the two variants by in vitro experiments: quantitative PCR and PCR sequencing. In this study, we first reported a novel causative mechanism of Joubert syndrome: a copy number variation (CNV) combined with a single-nucleotide variant in CEP290 gene, which can be helpful in the genetic diagnosis of this disease.

中文翻译：

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CEP290中的新型双等位基因功能丧失变异体在两个兄弟姐妹中引起了Joubert综合征。

Joubert综合征（JS）是一种罕见的遗传性疾病，可以通过脑干畸形，小脑ver部发育不全和随之而来的“磨牙迹象”（MTS）来定义。JS总是在开发缺陷中共享各种表型。迄今为止，随着下一代测序技术的发展，已经鉴定出数十种致病基因。在这里，我们调查了两个患有JS的男性同胞，并通过联合方法发现了一种新的发病机理。兄弟姐妹具有类似的眼球震颤，智力发育障碍，典型的MTS和第四脑室形态异常的特征。然后在先证者上进行全外显子测序（WES）和染色体比较基因组杂交（CGH）。令人惊讶的是，一个母体遗传的废话变体（NM_025114.3：c.5953G> T [p。在两个受影响的兄弟姐妹中鉴定出CEP290基因中的E1985 *]）和12q21.32中的父系遗传缺失，包括CEP290基因的外显子1至10。我们通过体外实验进一步证实了这两种变体：定量PCR和PCR测序。在这项研究中，我们首先报道了Joubert综合征的新型病因机制：CEP290基因中的拷贝数变异（CNV）与单核苷酸变异相结合，这可能有助于该疾病的遗传诊断。