Genotypes and phenotypes of Joubert syndrome and related disorders

Joubert syndrome is an autosomal recessive condition characterized by hypotonia, ataxia, psychomotor delay and variable occurrence of oculomotor apraxia and neonatal breathing abnormalities. The neuroradiological hallmark of JS is a complex midbrain–hindbrain malformation known as the “molar tooth sign” (MTS), originating from the association of cerebellar vermis hypo-/aplasia, horizontally-oriented and thickened superior cerebellar peduncles and a deepened interpeduncular fossa. A group of pleiotropic conditions, termed “Joubert syndrome related disorders” (JSRDs), present the pathognomonic clinical and neuroradiological features of JS associated with the variable involvement of other organs and systems, mainly the eyes and kidneys. Genetic heterogeneity mirrors the clinical heterogeneity of JSRDs, with several genes identified over the last few years. By reviewing all molecular screenings of JSRD patients published so far and evaluating genotype–phenotype correlates, we propose an algorithm for molecular diagnosis of these conditions. We also discuss the emerging clinical and genetic overlap between JSRDs and a growing number of distinct syndromes that share a common pathogenetic mechanism that is the loss of normal function of the primary cilium and its apparatus.