Recurrent, founder and hypomorphic variants contribute to the genetic landscape of Joubert syndrome.
Cerebellar Diseases
Founder Effect
Gene Frequency
Genetic Carrier Screening
Genotype
Journal
Journal of medical genetics
ISSN: 1468-6244
Titre abrégé: J Med Genet
Pays: England
ID NLM: 2985087R
Informations de publication
Date de publication:
09 2023
09 2023
Historique:
received:
24
05
2022
accepted:
08
01
2023
medline:
23
8
2023
pubmed:
15
2
2023
entrez:
14
2
2023
Statut:
ppublish
Résumé
Joubert syndrome (JS) is a neurodevelopmental ciliopathy characterised by a distinctive mid-hindbrain malformation, the 'molar tooth sign'. Over 40 JS-associated genes are known, accounting for two-thirds of cases. While most variants are novel or extremely rare, we report on 11 recurring variants in seven genes, including three known 'founder variants' in the Ashkenazi Jewish, Hutterite and Finnish populations. We evaluated variant frequencies in ~550 European patients with JS and compared them with controls (>15 000 Italian plus gnomAD), and with an independent cohort of ~600 JS probands from the USA. All variants were markedly enriched in the European JS cohort compared with controls. When comparing allele frequencies in the two JS cohorts, the Ashkenazim founder variant ( This study contributes to understand the complex genetic landscape of JS, explain its variable prevalence in distinct geographical areas and characterise two recurrent hypomorphic variants.
Sections du résumé
BACKGROUND
Joubert syndrome (JS) is a neurodevelopmental ciliopathy characterised by a distinctive mid-hindbrain malformation, the 'molar tooth sign'. Over 40 JS-associated genes are known, accounting for two-thirds of cases.
METHODS
While most variants are novel or extremely rare, we report on 11 recurring variants in seven genes, including three known 'founder variants' in the Ashkenazi Jewish, Hutterite and Finnish populations. We evaluated variant frequencies in ~550 European patients with JS and compared them with controls (>15 000 Italian plus gnomAD), and with an independent cohort of ~600 JS probands from the USA.
RESULTS
All variants were markedly enriched in the European JS cohort compared with controls. When comparing allele frequencies in the two JS cohorts, the Ashkenazim founder variant (
CONCLUSION
This study contributes to understand the complex genetic landscape of JS, explain its variable prevalence in distinct geographical areas and characterise two recurrent hypomorphic variants.
Identifiants
pubmed: 36788019
pii: jmg-2022-108725
doi: 10.1136/jmg-2022-108725
pmc: PMC10447400
doi:
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
885-893Subventions
Organisme : NICHD NIH HHS
ID : P50 HD103524
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS064077
Pays : United States
Organisme : NICHD NIH HHS
ID : U54 HD083091
Pays : United States
Organisme : NICHD NIH HHS
ID : R01 HD100730
Pays : United States
Informations de copyright
© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
Déclaration de conflit d'intérêts
Competing interests: None declared.
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