Clinical and Molecular Diagnosis of Joubert Syndrome and Related Disorders

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).

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

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.

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.