Diagnosis of Joubert Syndrome 10 in a Fetus with Suspected Dandy-Walker Variant by WES: A Novel Splicing Mutation in OFD1
Diagnosis of Joubert Syndrome 10 in a Fetus with Suspected Dandy-Walker Variant by WES: A Novel Splicing Mutation in OFD1
复制标题
DOI：
10.1155/2018/4032543
复制
发表时间：
2018-11
影响因子：
--
通讯作者：
S. Linpeng;Jing Liu;J. Pan;Yingxi Cao;Y. Teng;D. Liang;Zhuo Li;Lingqian Wu
中科院分区：
文献类型：
--
作者：
S. Linpeng;Jing Liu;J. Pan;Yingxi Cao;Y. Teng;D. Liang;Zhuo Li;Lingqian Wu
Joubert综合征(JBTS)是一组临床和遗传异质性的睫状体疾病。到目前为止，已根据不同的致病基因或额外的临床特征对34种JBTS亚型进行了分类。大多数为常染色体隐性遗传，仅有10亚型(JBTS10)是一种罕见的由OFD1突变引起的X连锁隐性遗传病，报道较少。本研究利用全外显子测序技术，在1例疑似Dandy-Walker变异(DWV)并并指畸形的男性胎儿中发现了一种新的OFD1剪接突变(C.2488+2T>；C)，并排除了异常核型和致病CNV。这种突变是从母亲那里遗传来的，她之前经历过两次类似的怀孕。RT-PCR和测序证实OFD1基因第18外显子异常跳跃。定量RT-PCR结果还显示，指标胎儿的总OFD1基因表达水平显著低于对照组。结合基因检测结果和基因-表型相关性分析，OFD1中的新突变c.2488+2T>；C被认为是胎儿发病的遗传原因。因此，诊断应是JBTS10，而不是DWV的主要临床诊断。我们报告了中国人群中第一例JBTS10产前病例，这不仅有助于家庭预测未来妊娠的复发风险，也为了解这种罕见疾病提供了更多的信息。提示WES是Joubert综合征胎儿产前诊断的有效方法。
Joubert syndrome (JBTS) is a clinically and genetically heterogeneous group of ciliary diseases. To date, 34 subtypes of JBTS have been classified due to different causative genes or extra clinical features. Most of them are autosomal recessive, while only the subtype 10 (JBTS10) is a quite rare X-linked recessive disorder caused by OFD1 mutations with few reports. In this study, by using whole exome sequencing (WES), a novel OFD1 splicing mutation (c.2488+2T>C) was identified in a male fetus with suspected Dandy-Walker variant (DWV) and syndactyly, for whom abnormal karyotype and pathogenic CNV have been excluded. This mutation was inherited from the mother who has experienced two similar pregnancies before. An abnormal skipping of exon 18 in OFD1 mRNA was confirmed by RT-PCR and sequencing. Result from quantitative RT-PCR also showed that total OFD1 mRNA in the index fetus was significantly lower than the control. After a combined analysis of genetic testing results and genotype-phenotype correlations, the novel mutation c.2488+2T>C in OFD1 was considered to be the genetic cause for the affected fetus. Thus the diagnosis should be JBTS10 rather than the primary clinical diagnosis of DWV. We report the first prenatal case of JBTS10 in Chinese population, which not only helps the family to predict recurrence risks for future pregnancies but also provides more information for understanding such a rare disease. The results also present evidence that WES is an effective method in prenatal diagnosis for those fetuses with Joubert syndrome.