Joubert Syndrome and the AHI1 p.Gln981Glu Variant: A Molecular and Clinical Study

Abstract

Joubert syndrome (JS) is a rare autosomal recessive ciliopathy characterized by a distinctive molar tooth sign (MTS) on brain imaging and with variable multisystem involvement, including developmental delay, ataxia, and oculomotor abnormalities. The AHI1 gene plays a critical role in ciliary function and neurodevelopment, with pathogenic variants implicated in JS and related ciliopathies. A 3-year-old boy underwent comprehensive clinical evaluation, including developmental assessments, neurological and ophthalmological examinations, and systemic investigations. Magnetic resonance imaging (MRI) of the brain was performed to confirm the diagnosis. Genomic DNA was extracted, and exome-sequencing was employed to identify pathogenic variants, which was followed by in silico analyses, structural modeling, and protein-protein interaction (PPI) studies. Variant validation and segregation analysis were conducted using polymerase chain reaction (PCR) and Sanger sequencing. Evolutionary conservation of the variant residue was evaluated using comparative genomics. The proband exhibited hallmark JS features, including generalized hypotonia, ataxia, developmental delay, and the MTS on MRI. Systemic evaluations revealed no extracerebral organ involvement. Exome-sequencing identified a novel AHI1 variant, c.2941C>G; p.Gln981Glu, absent in public population databases. In silico prediction tools supported pathogenicity, with high conservation of the mutated residue across species. Structural modeling and PPI analysis revealed conformational changes and disrupted interactions in ciliary function-related pathways. Sanger sequencing confirmed autosomal recessive inheritance, with the proband homozygous for the variant, while both parents were heterozygous carriers. This study expands the mutational spectrum of AHI1 and demonstrates the clinical utility of exome-sequencing in diagnosing JS, especially in consanguineous populations. Findings emphasize the importance of genetic counseling, risk assessment, and advanced reproductive technologies to reduce the risk of recurrence in affected families. The integration of clinical, genetic, and computational analyses enhances our understanding of JS pathogenesis and supports personalized care for affected families.