Background

Joubert syndrome and related disorders are a group of ciliopathies characterized by mid-hindbrain malformation, developmental delay, hypotonia, oculomotor apraxia, and breathing abnormalities. Molar tooth sign in brain imaging is the hallmark for diagnosis. Joubert syndrome is a clinically and genetically heterogeneous disorder involving mutations in 35 ciliopathy-related genes. We present a large cohort of 59 patients with Joubert syndrome from 55 families. Molecular analysis was performed in 35 families (trio).

Methods

Clinical exome analysis was performed to identify causal mutations, and genotype-phenotype correlations were evaluated.

Results

All of the cases were stratified into pure Joubert syndrome (62.7%), Joubert syndrome with retinal disease (22.0%), polydactyly (8.5%), and liver (1.7%) and kidney (1.7%) involvement. Joubert syndrome-related disorders include Meckel-Gruber syndrome in 5.1% cases and Leber congenital amaurosis (1.7%). Of the 35 Joubert syndrome-related genes, 11 were identified in these patients, i.e., CEP290, C5ORF, TCTN1, CC2D2A, RPGRP1L, TCTN3, AHI1, INPP5E, TCTN2, NPHP1, and TMEM237. For the first time, we identified a ciliopathy gene, CCDC28B, as a causal gene in Joubert syndrome in one family. CEP290 accounted for 37.8% cases of pure Joubert syndrome, Joubert syndrome with retinal and renal disease, and Meckel-Gruber syndrome. The p.G1890∗ allele in CEP290 is highly recurrent. Of the six families with Joubert syndrome who had a prenatal diagnosis, one fetus was normal, two were carriers, and three were affected.

Conclusions

This is the largest study of Joubert syndrome from India. Although a high degree of locus and allelic heterogeneity was observed, CEP290 variants were the most common among these patients.

中文翻译：

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Joubert综合征和相关疾病的临床和分子诊断。

背景

乔伯特综合症和相关疾病是一组以中枢神经畸形，发育迟缓，肌张力低下，动眼性运动失用和呼吸异常为特征的纤毛病。脑成像中的磨牙迹象是诊断的标志。Joubert综合征是一种临床和遗传异质性疾病，涉及35种与睫状体病相关基因的突变。我们目前来自55个家庭的59名Joubert综合征患者的大队列研究。在35个家庭（三人）中进行了分子分析。

方法

进行临床外显子组分析以鉴定因果突变，并评估基因型与表型的相关性。

结果

所有病例均分为纯Joubert综合征（62.7％），患有视网膜疾病的Joubert综合征（22.0％），多指（8.5％）以及肝脏（1.7％）和肾脏（1.7％）受累。Joubert综合征相关疾病包括5.1％的Meckel-Gruber综合征和Leber先天性黑度（1.7％）。在这35个Joubert综合征相关基因中，在这些患者中鉴定出11个基因，即CEP290，C5ORF，TCTN1，CC2D2A，RPGRP1L，TCTN3，AHI1，INPP5E，TCTN2，NPHP1和TMEM237。我们首次鉴定出睫状体疾病基因CCDC28B，作为一个家庭的乔伯特综合征的病因基因。CEP290占纯Joubert综合征，患有视网膜和肾脏疾病的Joubert综合征以及Meckel-Gruber综合征的37.8％。在p.G1890 *等位基因CEP290是极易复发。在有产前诊断的六个患有Joubert综合征的家庭中，一名胎儿是正常的，两名是携带者，三名受到了影响。

结论

这是印度有关乔伯特综合症的最大研究。尽管观察到高度的基因座和等位基因异质性，但在这些患者中，CEP290变异体最为常见。