The molecular genetics of Joubert syndrome and related ciliopathies: The challenges of genetic and phenotypic heterogeneity

Abstract

Joubert syndrome (JS; MIM PS213300) is a rare, typically autosomal recessive disorder characterized by cerebellar vermis hypoplasia and a distinctive malformation of the cerebellum and brainstem identified as the "molar tooth sign" on brain MRI. Other universal features include hypotonia with later ataxia and intellectual disability/developmental delay, with additional features consisting of oculomotor apraxia and abnormal respiratory pattern. Notably, other, more variable features include renal cystic disease, typically nephronophthisis, retinal dystrophy, and congenital hepatic fibrosis; skeletal changes such as polydactyly and findings consistent with short-rib skeletal dysplasias are also seen in many subjects. These pleiotropic features are typical of a number of disorders of the primary cilium, and make the identification of causal genes challenging given the significant overlap between JS and other ciliopathy conditions such as nephronophthisis and Meckel, Bardet-Biedl, and COACH syndromes. This review will describe the features of JS, characterize the 35 known genes associated with the condition, and describe some of the genetic conundrums of JS, such as the heterogeneity of founder effects, lack of genotypephenotype correlations, and role of genetic modifiers. Finally, aspects of JS and related ciliopathies that may pave the way for development of therapeutic interventions, including gene therapy, will be described.

Ciliary Genes in Renal Cystic Diseases

“…Joubert syndrome (JBTS) is characterized by hypoplasia of the cerebellar vermis with the characteristic 'molar tooth sign', developmental delay, neonatal breathing abnormalities, muscular hypotonia, ataxia and cyst formation in the kidneys. The syndrome affects 1 in 80,000-100,000 newborns and is associated with mutations in 35 ciliary genes [85]. Defects in genes associated with Joubert syndrome are often the main causes of other ciliopathies such as Nephronophthisis or Meckel-Gruber syndrome.…”

Linear and whorled nevoid hypermelanosis and Joubert syndrome: a novel association: A case report and literature review

“…Those symptoms were compatible with Joubert syndrome, an autosomal recessive disorder caused by mutations related to cell structures called primary cilia. 3,4 Comparative genomic hybridization carried out on blood sample had failed to show differences in DNA sequence and number.…”

Update of genetic variants in CEP120 and CC2D2A -- with an emphasis on genotype-phenotype correlations, tissue specific transcripts and exploring mutation specific exon skipping therapies

“…As well as the high level of phenotypic complexity and overlap of clinical phenotypes, mutations within the same gene can give rise to distinct ciliopathy syndromes, known as genetic pleiotropy (Coppieters, Lefever, Leroy, & De Baere, 2010;Roosing et al, 2016;Shaheen et al, 2016;Shamseldin et al, 2020). In addition, mutations in different genes can cause the same ciliopathy syndrome (genetic heterogeneity) such as it is the case of JBTS, with more than 35 genes associated ( Figure S1 ) (Braun & Hildebrandt, 2017;Mitchison & Valente, 2017;Parisi, 2019). In addition, we have recently shown that differences in phenotypic presentation in patients with the same mutations, is in part due to the presence of genetic modifiers (Ramsbottom et al, 2020).…”

“…In addition, we have recently shown that differences in phenotypic presentation in patients with the same mutations, is in part due to the presence of genetic modifiers (Ramsbottom et al, 2020). JBTS represents the least severe end in the spectrum of neuronal ciliopathies (Parisi, 2019;Radha Rama Devi, Naushad, & Lingappa, 2020). The cerebellar and brainstem malformation, described as the "molar tooth sign" (MTS), is the hallmark for the diagnosis (Romani, Micalizzi, & Valente, 2013).…”