BACKGROUND Joubert syndrome (JBTS) is a genetically heterogeneous group of neurodevelopmental syndromes caused by primary cilia dysfunction. Usually the neurological presentation starts with abnormal neonatal breathing followed by muscular hypotonia, psychomotor delay, and cerebellar ataxia. Cerebral MRI shows mid- and hindbrain anomalies including the molar tooth sign. We report a male patient with atypical presentation of Joubert syndrome type 23, thus expanding the phenotype. CASE PRESENTATION Clinical features were consistent with JBTS already from infancy, yet the syndrome was not suspected before cerebral MRI later in childhood showed the characteristic molar tooth sign and ectopic neurohypophysis. From age 11 years seizures developed and after few years became increasingly difficult to treat, also related to inadequate compliance to therapy. He died at 23 years of sudden unexpected death in epilepsy (SUDEP). The genetic diagnosis remained elusive for many years, despite extensive genetic testing. We reached the genetic diagnosis by performing whole genome sequencing of the family trio and analyzing the data with the combination of one analysis pipeline for single nucleotide variants (SNVs)/indels and one for structural variants (SVs). This lead to the identification of the most common variant detected in patients with JBTS23 (OMIM# 616490), rs534542684, in compound heterozygosity with a 8.3 kb deletion in KIAA0586, not previously reported. CONCLUSIONS We describe for the first time ectopic neurohypophysis and SUDEP in JBTS23, expanding the phenotype of this condition and raising the attention on the possible severity of the epilepsy in this disease. We also highlight the diagnostic power of WGS, which efficiently detects SNVs/indels and in addition allows the identification of SVs.

中文翻译：

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在WGS数据上使用SNV / indels和结构变异管道诊断出的Joubert综合征23癫痫和异位神经垂体突然死亡。

背景技术乔伯特综合症（JBTS）是由原发性纤毛功能障碍引起的神经发育综合症的遗传异质性组。通常，神经系统表现始于新生儿呼吸异常，然后是肌张力减退，精神运动迟缓和小脑性共济失调。脑MRI显示中脑和后脑异常，包括磨牙迹象。我们报告了一名非典型表现为23型Joubert综合征的男性患者，从而扩大了表型。病例表现临床特征与婴儿期的JBTS一致，但在儿童后来的MRI表现出特征性磨牙特征和异位神经垂体之前，并未怀疑该综合征。从11岁开始癫痫发作，几年后变得越来越难以治疗，也与对治疗的依从性不足有关。他死于癫痫病（SUDEP）意外猝死23年。尽管进行了广泛的基因测试，但基因诊断仍然遥遥无期。我们通过对家族三者进行全基因组测序并结合一种分析管道（针对单核苷酸变体（SNV）/ indels和一种针对结构变体（SV））进行数据分析，从而实现了基因诊断。这导致鉴定出在JBTS23（OMIM＃616490）的患者中检测到的最常见的变体rs534542684，其复合杂合性在KIAA0586中缺失8.3 kb，以前没有报道。结论我们首次描述了JBTS23中的异位神经垂体和SUDEP，扩大这种病的表型，并引起人们对该病癫痫病严重程度的关注。我们还将重点介绍WGS的诊断功能，该功能可以有效地检测SNV / indels，此外还可以识别SV。