Li Chen, Wang Xingwang, Li Fake, Ding Hongke, Liu Ling, Xiong Ying, Yang Chaoxiang, Zhang Yan, Wu Jing, Yin Aihua
Medical Genetic Center, Guangdong Women and Children Hospital, Guangzhou, China.
Medical Imaging Department, Guangdong Women and Children Hospital, Guangzhou, China.
Front Genet. 2023 Jan 10;13:1064762. doi: 10.3389/fgene.2022.1064762. eCollection 2022.
Joubert syndrome (JBS) is a rare neurodevelopmental disorder associated with progressive renal, liver, and retinal involvement that exhibits heterogeneity in both clinical manifestations and genetic etiology. Therefore, it is difficult to make a definite prenatal diagnosis. Whole-exome sequencing and Sanger sequencing were performed to screen the causative gene variants in a suspected JBS family. RNA-seq and protein model prediction were performed to clarify the potential pathogenic mechanism. A more comprehensive review of previously reported cases with variants is presented and may help to establish a genotype-phenotype. We identified a novel non-sense variant in the gene, (NM_003611.3): c.2848A>T (p.Lys950Ter). Sanger sequencing confirmed cosegregation among this family. RNA-seq confirmed that partial degradation of mutant transcripts, which was predicted to be caused by the non-sense-mediated mRNA decay (NMD) mechanism, may explain the reduction in the proportion of mutant transcripts. Protein structure prediction of the non-sense variant transcript revealed that this variant may lead to a change in the protein structure. The genetic variation spectrum of JBS10 caused by was broadened. The novel variants further deepened our insight into the molecular mechanism of the disease.
乔伯特综合征（JBS）是一种罕见的神经发育障碍，与进行性肾脏、肝脏和视网膜受累有关，在临床表现和遗传病因上均表现出异质性。因此，很难做出明确的产前诊断。对一个疑似JBS家庭进行了全外显子组测序和桑格测序，以筛查致病基因变异。进行了RNA测序和蛋白质模型预测，以阐明潜在的致病机制。对先前报道的有变异的病例进行了更全面的综述，这可能有助于建立基因型-表型关系。我们在该基因（NM_003611.3）中鉴定出一个新的无义变异：c.2848A>T（p.Lys950Ter）。桑格测序证实了该变异在这个家族中的共分离。RNA测序证实，突变转录本的部分降解，预计是由无义介导的mRNA衰变（NMD）机制引起的，这可能解释了突变转录本比例的降低。对无义变异转录本的蛋白质结构预测表明，该变异可能导致蛋白质结构发生变化。由该基因导致的JBS10遗传变异谱得到了拓宽。这些新变异进一步加深了我们对该疾病分子机制的认识。
