A rare mutant of OFD1 gene responsible for Joubert syndrome with significant phenotype variation

Mol Genet Genomics. 2021 Jan;296(1):33-40. doi: 10.1007/s00438-020-01726-1. Epub 2020 Sep 18.


Joubert syndrome (JBTS), a rare genetic disorder resulted from primary cilium defects or basal-body dysfunction, is characterized by agenesis of cerebellar vermis and abnormal brain stem. Both genotypes and phenotypes of JBTS are highly heterogeneous. The identification of pathogenic gene variation is essential for making a definite diagnosis on JBTS. Here, we found that hypoplasia of cerebellar vermis occurred in three male members in a Chinese family. Then, we performed whole exome sequencing to identify a novel missense mutation c.599T > C (p. L200P) in the OFD1 gene which is the candidate gene of X-linked JBTS (JBST10). The following analysis showed that the variant was absent in the 1000 Genomes, ExAC and the 200 female controls; the position 200 Leucine residue was highly conserved across species; the missense variant was predicted to be deleterious using PolyPhen-2, PROVEAN, SIFT and Mutation Taster. The OFD1 expression was heavily lower in the proband and an induced male fetus compared with a healthy male with a wild-type OFD1 gene. The in vitro expression analysis of transiently transfecting c.599T or c.599C plasmids into HEK-293T cells confirmed that the missense mutation caused OFD1 reduction at the protein level. And further the mutated OFD1 decreased the level of Gli1 protein, a read-out of Sonic hedgehog (SHH) signaling essential for development of central neural system. A known pathogenic variant c.515T > C (p. L172P) showed the similar results. All of these observations suggested that the missense mutation causes the loss function of OFD1, resulting in SHH signaling impairs and brain development abnormality. In addition, the three patients have Dandy-Walker malformation, macrogyria and tetralogy of Fallot, respectively, the latter two of which are firstly found in JBTS10 patients. In conclusion, our findings expand the context of genotype and phenotype in the JBTS10 patients.

Keywords: Joubert syndrome; Macrogyria; OFD1; Tetralogy of Fallot; c.599T > C.

Publication types

  • Case Reports

MeSH terms

  • Abnormalities, Multiple / diagnostic imaging
  • Abnormalities, Multiple / genetics*
  • Abnormalities, Multiple / metabolism
  • Abnormalities, Multiple / pathology
  • Amino Acid Sequence
  • Brain Stem / abnormalities
  • Brain Stem / diagnostic imaging
  • Brain Stem / metabolism
  • Cerebellar Vermis / abnormalities
  • Cerebellar Vermis / diagnostic imaging
  • Cerebellar Vermis / metabolism
  • Cerebellum / abnormalities*
  • Cerebellum / diagnostic imaging
  • Cerebellum / metabolism
  • Cerebellum / pathology
  • Child, Preschool
  • Dandy-Walker Syndrome / diagnostic imaging
  • Dandy-Walker Syndrome / genetics*
  • Dandy-Walker Syndrome / metabolism
  • Dandy-Walker Syndrome / pathology
  • Eye Abnormalities / diagnostic imaging
  • Eye Abnormalities / genetics*
  • Eye Abnormalities / metabolism
  • Eye Abnormalities / pathology
  • Family
  • Female
  • Gene Expression
  • Genotype
  • HEK293 Cells
  • Hedgehog Proteins / deficiency
  • Hedgehog Proteins / genetics
  • Humans
  • Kidney Diseases, Cystic / diagnostic imaging
  • Kidney Diseases, Cystic / genetics*
  • Kidney Diseases, Cystic / metabolism
  • Kidney Diseases, Cystic / pathology
  • Lissencephaly / diagnostic imaging
  • Lissencephaly / genetics*
  • Lissencephaly / metabolism
  • Lissencephaly / pathology
  • Male
  • Mutation, Missense*
  • Pedigree
  • Phenotype
  • Proteins / genetics*
  • Proteins / metabolism
  • Retina / abnormalities*
  • Retina / diagnostic imaging
  • Retina / metabolism
  • Retina / pathology
  • Sequence Alignment
  • Sequence Homology, Amino Acid
  • Sex Factors
  • Signal Transduction
  • Tetralogy of Fallot / diagnostic imaging
  • Tetralogy of Fallot / genetics*
  • Tetralogy of Fallot / metabolism
  • Tetralogy of Fallot / pathology
  • Zinc Finger Protein GLI1 / deficiency
  • Zinc Finger Protein GLI1 / genetics


  • GLI1 protein, human
  • Hedgehog Proteins
  • OFD1 protein, human
  • Proteins
  • SHH protein, human
  • Zinc Finger Protein GLI1

Supplementary concepts

  • Agenesis of Cerebellar Vermis