Molecular Spectrum and Deep Phenotyping of a Turkish Joubert Syndrome Cohort, Including a Potential Candidate Gene,...

Joubert syndrome (JS) is a rare neurodevelopmental ciliopathy defined by the molar tooth sign (MTS) on brain magnetic resonance imaging accompanied by hypotonia, oculomotor apraxia (OMA), developmental delay, and multisystem involvement. With over 40 genes implicated, JS displays genetic and phenotypic heterogeneity. This study aimed to define the clinical and molecular spectrum of JS in a Turkish cohort.

This study included 31 JS patients from 28 unrelated families, followed for 7.4 years. Genetic variants were identified using whole exome sequencing and confirmed by Sanger sequencing.

Genetic diagnosis was established in 23 families in 13 JS-related genes, with AHI1 (17.9%) and CEP290 (14.3%) most frequently affected. Thirteen novel variants were identified, including a variant of uncertain significance in NPHP4 in a patient with OMA, retinal involvement, MTS, and grade-III vesicoureteral reflux (VUR). The MTS was absent in 2 AHI1 and atypical in 1 TMEM107 patient; others exhibited typical MTS. Ptosis occurred in all MKS1 and TCTN2 patients. Retinopathy and vision impairment were most common in AHI1 and CEP290. Cognitive outcomes varied; normal cognitive function was seen in 1 AHI1 and 1 CEP290 case. Renal/hepatic involvement was generally mild; kidney hypoplasia occurred in 1 AHI1, VUR in 1 NPHP4, and transient transaminase elevation in 1 TCTN2 patient. One patient without a genetic diagnosis had situs inversus totalis. Intra-familial variability occurred among siblings carrying an AHI1 variant.

This study highlights the genotypic and phenotypic diversity of JS, identifying 13 novel variants and suggesting NPHP4 as a potential JS-associated gene.