Clinical, genetic and bioinformatic analysis of Saudi families with Joubert syndrome and related disorders

Joubert syndrome and related disorders (JSRD) are clinically and genetically heterogeneous ciliopathies caused by pathogenic variants in over 40 genes, mainly encoding ciliary proteins. However, data on JSRD in the Saudi population remain limited. This study aimed to identify novel and reported JSRD-causing variants in Saudi families and analyze their potential functional impact on protein structure using advanced computational tools. Patients with genetically or clinically confirmed/suspected JSRD were recruited according to ethical protocols. Clinical data were collected, and exome sequencing was performed, followed by Sanger validation of identified variant. Pathogenicity was assessed using bioinformatics tools, while conservation, expression and RNA structure analyses were conducted to evaluate the potential functional consequences. Homozygous variants were identified in three consanguineous Saudi families, including a novel stop-gain variant in KIF7 (c.2992 C > T; p.(Gln998Ter)), and novel splice-site variant in CEP104 (c.489 + 1G > A) and a previously reported splice-site variant in TMEM237 (c.869 + 1G > A). All variants were predicted to be pathogenic as per ACMG criteria and located in highly conserved regions, suggesting potential functional impact. RNA analysis suggested possible alterations in folding. This study identified three pathogenic variants in JSRD-related genes in Saudi families, including two novel variants. These findings expand the variant spectrum for JSRD, particularly in the Saudi population. Establishing a comprehensive regional variant database is essential for improving molecular diagnosis and genetic counseling in population with high consanguinity. Finally, these results highlight the need for further functional studies to validate their pathogenicity and elucidate their role in JSRD pathogenesis.