Molecular and clinical heterogeneity in an Iranian case series of Joubert syndrome

Joubert syndrome (JS) is a rare neurodevelopmental ciliopathy characterized by a distinctive midbrain-hindbrain malformation, manifested by hypotonia, ataxia, developmental delay, and variable multisystem involvement. The condition exhibits marked clinical and genetic heterogeneity, with over 40 genes implicated to date. However, the mutational spectrum and phenotypic presentation of JS in Middle Eastern populations, where consanguinity is prevalent, remain poorly characterized.

We retrospectively reviewed whole-exome sequencing (WES) data from patients referred to the Comprehensive Medical Genetics Center, Shiraz, Iran, between 2019 and 2024. Patients harboring variants in JS-related genes were identified, and their clinical records were analyzed to establish genotype-phenotype correlations.

A total of 21 cases with variants in JS-associated genes were identified. Neurological manifestations, including developmental delay/intellectual disability, speech defects, seizures, and motor impairment, were the most prevalent findings. Vision problems, renal involvement and polydactyly were also present. Molecular analysis revealed variants in 14 distinct genes, with AHI1 being the most frequently mutated (3 cases), followed by KIAA0586, CSPP1, KIAA0556, CC2D2A, and TMEM67. Eight cases carried pathogenic or likely pathogenic variants, while 12 cases had variants of uncertain significance (VUS), highlighting the diagnostic challenges in this genetically heterogeneous condition.

This study expands the mutational landscape of JS in the Iranian population and underscores the utility of WES as a first-tier diagnostic tool for JS and related ciliopathies. The high rate of consanguinity in this cohort likely contributes to the enrichment of autosomal recessive forms. Further functional studies are warranted to clarify the pathogenicity of the numerous VUS identified, which will improve genetic counseling and prenatal decision-making for affected families.