Molecular Genetics of Joubert Syndrome

Abstract

Abstract Joubert syndrome (JS) is an autosomal recessive or X‐linked congenital cerebellar ataxia characterised by a peculiar hindbrain–midbrain malformation, the ‘molar tooth sign’ (MTS). JS is characterised by neonatal hypotonia which later evolves into ataxia, developmental delay, abnormal eye movements, breathing abnormalities and intellectual disability. This neurological presentation can be variably complicated by the involvement of multiple organs such as the kidneys, retina, liver and skeleton. JS is genetically heterogeneous, with 26 causative genes identified to date. All genes encode for proteins of the primary cilium, a nearly ubiquitous subcellular organelle that plays essential roles in embryonic development and cell functioning. Indeed, JS is part of ciliopathies, an expanding group of disorders that share many clinical and genetic determinants. The marked clinical and genetic heterogeneity of JS and ciliopathies may be explained by oligogenic inheritance and the existence of genetic modifiers. Key Concepts: Joubert syndrome (JS) is a congenital ataxia with autosomal or X‐linked recessive inheritance. The diagnostic hallmark of JS is a peculiar cerebellar and brainstem malformation, the so‐called ‘molar tooth sign’ recognisable on brain imaging. Neurological features of JS include hypotonia, ataxia, developmental delay, intellectual impairment, oculomotor abnormalities and alterations of the breathing pattern in neonatal age. JS may present with variable involvement of the eyes, kidneys, liver, polydactyly and oral‐facial defects. JS is genetically heterogeneous, with 26 genes identified to date, that are overall responsible of about half cases. JS pathogenesis is related to the dysfunction of the primary cilium, making JS part of the expanding group of ‘ciliopathies’. The primary cilium is an immotile organelle, located of the surface of nearly every cell type, that plays key roles in cellular functioning and embryonic development. Ciliopathies are characterised by wide clinical and genetic heterogeneity, and present significant clinical and genetic overlap among distinct conditions. Such complexity has been partly explained by showing oligogenic inheritance and the existence of genetic modifiers of the phenotype.