Bader Ingrid, Decker E, Mayr J A, Lunzer V, Koch J, Boltshauser E, Sperl W, Pietsch P, Ertl-Wagner B, Bolz H, Bergmann C, Rittinger O
Clinical Genetics Unit, Children's Hospital, Paracelsus Medical University, Salzburg, Austria; kbo-Kinderzentrum, Technische Universität München, Germany.
Bioscientia, Center for Human Genetics, Ingelheim, Germany.
Eur J Med Genet. 2016 Aug;59(8):386-91. doi: 10.1016/j.ejmg.2016.06.007. Epub 2016 Jul 1.
Joubert syndrome (JS) is a clinically and genetically heterogeneous ciliopathy characterized by episodic hyperpnea and apnea, hypotonia, ataxia, cognitive impairment and ocular motor apraxia. The "molar tooth sign" is pathognomonic of this condition. Mutations in the MKS1 gene are a major cause of Meckel-Gruber syndrome (MKS), the most common form of syndromic neural tube defects, frequently resulting in perinatal lethality. We present the phenotype and genotype of a child with severe JS and agenesis of the corpus callosum (ACC). In our patient, a next generation sequencing (NGS) approach revealed the following two variants of the MKS1 gene: first, a novel missense variant [ c.240G > T (p.Trp80Cys)], which affects a residue that is evolutionarily highly conserved in mammals and ciliates; second, a 29 bp deletion in intron 15 [c.1408-35_1408-7del29], a founder mutation, which in a homozygous state constitutes the major cause of MKS in Finland. We review the MKS1-variants in all of the eleven JS patients reported to date and compare these patients to our case. To our knowledge, this is the first patient with Joubert syndrome and agenesis of the corpus callosum where a potentially causal genotype is provided.
乔伯特综合征（JS）是一种临床和遗传异质性的纤毛病，其特征为发作性呼吸急促和呼吸暂停、肌张力减退、共济失调、认知障碍和眼球运动失用。“磨牙症”是这种疾病的特征性表现。MKS1基因的突变是梅克尔-格鲁伯综合征（MKS）的主要病因，MKS是综合征性神经管缺陷最常见的形式，常导致围产期死亡。我们报告了一名患有严重JS和胼胝体发育不全（ACC）儿童的表型和基因型。在我们的患者中，下一代测序（NGS）方法揭示了MKS1基因的以下两个变异：第一，一个新的错义变异[c.240G>T（p.Trp80Cys）]，它影响了在哺乳动物和纤毛虫中进化上高度保守的一个残基；第二，内含子15中的一个29bp缺失[c.1408-35_1408-7del29]，这是一个奠基者突变，在纯合状态下是芬兰MKS的主要病因。我们回顾了迄今为止报道的所有11例JS患者中的MKS1变异，并将这些患者与我们的病例进行了比较。据我们所知，这是第一例有乔伯特综合征和胼胝体发育不全且提供了潜在致病基因型的患者。
