Abstract
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.
Highlights
Joubert syndrome (JBTS) is characterized by cerebellar vermian, mid-hindbrain dysgenesis, cerebellar ataxia, developmental delay, oculomotor apraxia, and abnormalities in breathing patterns [1]
G-banding analysis showed that the karyotype of the index fetus was 46, XY
We report a nonconsanguineous healthy Chinese couple with three male fetuses, all of whom were suspected to suffer from DandyWalker variant (DWV) by prenatal ultrasound screening
Summary
Joubert syndrome (JBTS) is characterized by cerebellar vermian, mid-hindbrain dysgenesis, cerebellar ataxia, developmental delay, oculomotor apraxia, and abnormalities in breathing patterns [1]. JBTS is a clinically and genetically heterogeneous group of ciliary diseases. 34 subtypes of JBTS have been classified due to different causative genes or extra clinical features. Most of JBTS are autosomal recessive, while only the subtype 10 (JBTS10) is X-linked recessive disorder caused by OFD mutations. The variants of OFD have been known to cause several genetic disorders. The most common is orofaciodigital syndrome I (OFD1 syndrome, MIM 311200), which is a male-lethal X-linked dominant disease [4]. Three other rare recessive X-linked disorders include Joubert syndrome 10 (JBTS10, MIM 300804) [5,6,7], Simpson-Golabi-Behmel syndrome, type 2 (SGBS2, MIM 300209) [8], and a severe retinitis pigmentosa (RP32, MIM 300424) [9]. It is still hard to gain a comprehensive understanding for such a very rare disease
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