PMC6000882_01
Clinical features of the fetus. (a) The sagittal ultrasound image shows hypoplasia of the cerebellar vermis and a triangular shaped fourth ventricle. (b) The axial ultrasound image shows a 'bat-wing'-shaped superior fourth ventricle. (c) The sagittal MRI image shows vermian agenesis and hypoplastic superior cerebellar peduncle. The axial T2-weighted (d) and diffusion-weighted (e) MRI images show prominent interpeduncular fossa and a deep cleft between thickened cerebellar peduncles comprising the molar tooth sign, as indicated by the arrows. After artificial abortion, polydactyly of both feet (f) and left hand (g) was noted, and the brain autopsy revealed the molar tooth sign (h, i). CV: cerebellar vermis, BS: brainstem, FV: fourth ventricle, CSP: cavum septi pellucidi.
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Routine mid-trimester fetal ultrasound scan at 23+4 weeks of gestation suggested agenesis of cerebellar vermis, which was confirmed by a follow-up ultrasound scan at 29+3 weeks of gestation (Figures 1(a) and 1(b)). And fetal brain MRI performed at 29+3 weeks showed deep interpeduncular fossa and thick, elongated cerebellar peduncles, consistent with the MTS, as well as hypoplastic cerebellar vermis (Figures 1(c)-1(e)). The fetus displayed polydactyly of left hand and both feet, and the brain autopsy revealed the molar tooth sign, which confirmed the diagnosis of Joubert syndrome with oral-facial-digital features (JS-OFD) (Figures 1(f)-1(i)).
Genetic analysis of the family. (a) The pedigree of the family. Individuals marked with a question mark (?) were not genotyped for the C5orf42 variants. (b) Sequencing chromatographs of C5orf42 gene revealed variants in the proband, the parents, and the sister. Variants were indicated by black arrows. (c) Sequence alignment of C5orf42 protein and its orthologs in different species. The amino acid in position 1286 is highlighted by a blue box.
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Direct sanger sequencing results confirmed the compound variants in the fetus and revealed that the father was heterozygous for the c.3857G>A variant, and the mother and sister were both heterozygous for the c.3599C>T variant (Figure 2(b)). A pedigree of this family was shown in Figure 2(a). Sequence alignment of the C5orf42 protein sequence in different species revealed that the arginine residue (R1286 in the human protein) is highly conserved among species (Figure 2(c)).