Two novel B9D1 variants causing Joubert syndrome: Utility of mRNA and splicing studies

The primary cilium is an organelle which plays an important role in the transduction of signals in the Wnt and Sonic hedgehog pathways. Abnormal or absent primary cilia result in various neurodevelopmental, retinal, renal, hepatic and musculoskeletal abnormalities. Joubert syndrome (JS) is a ciliopathy with a prevalence estimated to be between 1:80 000 and 1:100 000. JS occurs due to bi-allelic mutations in one of the 34 identified genes, all of which encode for protein components of the primary cilia. The presentation of JS is highly variable, however a clinical diagnosis can be established by the presence of the molar tooth sign on axial brain MRI, hypotonia in infancy, and developmental delay. JS is less severe than Meckel syndrome (MKS), which is another recessive, and often lethal, ciliopathy. This report outlines an interesting case of JS, in which two novel mutations in B9D1 were identified. This gene is not commonly associated with JS, and is often implicated in MKS. Functional mRNA study was helpful in delineating the pathogenic role of novel variants in this case.