Joubert syndrome is a rare neurodevelopmental disorder characterized by clinical and genetic heterogeneity. The characteristic molar tooth sign, resulted from cerebellar vermis hypoplasia and midbrain anomalies, is expected to be the key diagnostic feature for this disease, but it is difficult to make a definite diagnosis in prenatal only based on the imageology due to its clinical heterogeneity.
We report on a fetus, who was detected cerebellum dysplasia and encephalocele by ultrasound at 19 and 23 weeks’ gestation, confirmed by MRI examination. The pregnancy was terminated at 23 weeks’ gestation. The induced fetus was identified postaxial polydactyly and deficient of occipital bone and skin.
The whole exome sequencing identified a novel compound heterozygous variation in the Joubert syndrome related CPLANE1 gene including a 2-bp insertion, NM_023073.3:c.1383_1384dup;p.(Gly462Glufs*3) and a non-classic splicing variation, NC_000005.10(NM_023073.3):c.7691-5_7691-4del. The pathogenicity of the non-classic splicing variation was further confirmed by cDNA level sequencing, which showed a exon 39 skipping that would introduce a premature termination. The novel compound heterozygous variation caused a completed function loss of CPLANE1 gene.
The cerebellum dysplasia fetus without obvious molar tooth sign was finally diagnosed as Joubert syndrome, combined with the results from genetic detecting and the postnatal clinical symptoms. We also highlight the clinical heterogeneity of encephalodysplasia in Joubert syndrome which increases the difficulty of clinical diagnosis especially for prenatal diagnosis. Our findings provides a new perspective for the prenatal diagnosis of Joubert syndrome with severe craniocerebral dysplasia and expanded the variation spectrum of CPLANE1 gene.

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