Clinical and Molecular Diagnosis of Joubert Syndrome and Related Disorders

Pediatr Neurol. 2020 May:106:43-49. doi: 10.1016/j.pediatrneurol.2020.01.012. Epub 2020 Feb 4.


Background: Joubert syndrome and related disorders are a group of ciliopathies characterized by mid-hindbrain malformation, developmental delay, hypotonia, oculomotor apraxia, and breathing abnormalities. Molar tooth sign in brain imaging is the hallmark for diagnosis. Joubert syndrome is a clinically and genetically heterogeneous disorder involving mutations in 35 ciliopathy-related genes. We present a large cohort of 59 patients with Joubert syndrome from 55 families. Molecular analysis was performed in 35 families (trio).

Methods: Clinical exome analysis was performed to identify causal mutations, and genotype-phenotype correlations were evaluated.

Results: All of the cases were stratified into pure Joubert syndrome (62.7%), Joubert syndrome with retinal disease (22.0%), polydactyly (8.5%), and liver (1.7%) and kidney (1.7%) involvement. Joubert syndrome-related disorders include Meckel-Gruber syndrome in 5.1% cases and Leber congenital amaurosis (1.7%). Of the 35 Joubert syndrome-related genes, 11 were identified in these patients, i.e., CEP290, C5ORF, TCTN1, CC2D2A, RPGRP1L, TCTN3, AHI1, INPP5E, TCTN2, NPHP1, and TMEM237. For the first time, we identified a ciliopathy gene, CCDC28B, as a causal gene in Joubert syndrome in one family. CEP290 accounted for 37.8% cases of pure Joubert syndrome, Joubert syndrome with retinal and renal disease, and Meckel-Gruber syndrome. The p.G1890∗ allele in CEP290 is highly recurrent. Of the six families with Joubert syndrome who had a prenatal diagnosis, one fetus was normal, two were carriers, and three were affected.

Conclusions: This is the largest study of Joubert syndrome from India. Although a high degree of locus and allelic heterogeneity was observed, CEP290 variants were the most common among these patients.

Keywords: CEP290; Ciliopathy; Joubert syndrome; Locus and allelic heterogeneity.

MeSH terms

  • Abnormalities, Multiple / diagnosis*
  • Abnormalities, Multiple / genetics*
  • Antigens, Neoplasm / genetics
  • Cell Cycle Proteins / genetics
  • Cerebellum / abnormalities*
  • Child
  • Child, Preschool
  • Ciliopathies / diagnosis*
  • Ciliopathies / genetics*
  • Cytoskeletal Proteins / genetics
  • Exome Sequencing
  • Eye Abnormalities / diagnosis*
  • Eye Abnormalities / genetics*
  • Female
  • Humans
  • India
  • Infant
  • Kidney Diseases, Cystic / diagnosis*
  • Kidney Diseases, Cystic / genetics*
  • Male
  • Pedigree
  • Phenotype
  • Prenatal Diagnosis
  • Retina / abnormalities*


  • Antigens, Neoplasm
  • Cell Cycle Proteins
  • Cep290 protein, human
  • Cytoskeletal Proteins

Supplementary concepts

  • Agenesis of Cerebellar Vermis