Genetic Characterization of Joubert Syndrome with COACH Features and in Silico Prediction of TMEM67 Gene Variants...

Joubert syndrome (JS) is an uncommon genetic condition presenting with diverse clinical manifestations involving the nervous system, liver, and eyes. A specific form of JS, known as cerebellar vermis hypoplasia, oligophrenia, ataxia, coloboma, and hepatic fibrosis (COACH) syndrome, is primarily associated with variants in the TMEM67 gene. This study aimed to identify the causative genetic variant in a patient with JS exhibiting the COACH phenotype and to investigate the spectrum and potential founder effects of TMEM67 gene variants within the Iranian population using the Iranome database.

This study reports an 8-year-old girl with a family history of developmental delay who shows clinical features typical of JS with the COACH phenotype. To verify the disease-causing nature of the genetic variant, whole exome sequencing along with in silico analysis was conducted. The variant's conservation across species highlighted its functional significance, and a co-segregation study confirmed its inheritance pattern. Moreover, we collected all TMEM67 gene variants identified in the Iranome project.

Our investigation revealed a homozygous missense variant in TMEM67 (c.725A>G; p.Asn242Ser) in the affected individual. Collective evidence from the Iranome database and previous studies demonstrates that this is a founder variant (c.725A>G) in the Iranian population.

This study highlights the intricate nature of JS and its genetic foundations, emphasizing the significance of founder variants in specific populations and the potential of national databases to enhance the precision of genetic diagnoses.