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

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...

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Autor principal: Parisi, Melissa A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: IOS Press 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6864416/
https://www.ncbi.nlm.nih.gov/pubmed/31763177
http://dx.doi.org/10.3233/TRD-190041
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author Parisi, Melissa A.
author_facet Parisi, Melissa A.
author_sort Parisi, Melissa A.
collection PubMed
description 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 genotype-phenotype 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.
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spelling pubmed-68644162019-11-21 The molecular genetics of Joubert syndrome and related ciliopathies: The challenges of genetic and phenotypic heterogeneity Parisi, Melissa A. Transl Sci Rare Dis Research Article 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 genotype-phenotype 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. IOS Press 2019-07-04 /pmc/articles/PMC6864416/ /pubmed/31763177 http://dx.doi.org/10.3233/TRD-190041 Text en © 2019 – IOS Press and the authors. All rights reserved https://creativecommons.org/licenses/by-nc/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution Non-Commercial (CC BY-NC 4.0) License (https://creativecommons.org/licenses/by-nc/4.0/) , which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Article
Parisi, Melissa A.
The molecular genetics of Joubert syndrome and related ciliopathies: The challenges of genetic and phenotypic heterogeneity
title The molecular genetics of Joubert syndrome and related ciliopathies: The challenges of genetic and phenotypic heterogeneity
title_full The molecular genetics of Joubert syndrome and related ciliopathies: The challenges of genetic and phenotypic heterogeneity
title_fullStr The molecular genetics of Joubert syndrome and related ciliopathies: The challenges of genetic and phenotypic heterogeneity
title_full_unstemmed The molecular genetics of Joubert syndrome and related ciliopathies: The challenges of genetic and phenotypic heterogeneity
title_short The molecular genetics of Joubert syndrome and related ciliopathies: The challenges of genetic and phenotypic heterogeneity
title_sort molecular genetics of joubert syndrome and related ciliopathies: the challenges of genetic and phenotypic heterogeneity
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6864416/
https://www.ncbi.nlm.nih.gov/pubmed/31763177
http://dx.doi.org/10.3233/TRD-190041
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