Identification of Restless Legs Syndrome Genes by Mutational Load Analysis.
Journal
Annals of neurology
ISSN: 1531-8249
Titre abrégé: Ann Neurol
Pays: United States
ID NLM: 7707449
Informations de publication
Date de publication:
02 2020
02 2020
Historique:
received:
30
07
2019
revised:
28
11
2019
accepted:
29
11
2019
pubmed:
4
12
2019
medline:
19
5
2020
entrez:
3
12
2019
Statut:
ppublish
Résumé
Restless legs syndrome is a frequent neurological disorder with substantial burden on individual well-being and public health. Genetic risk loci have been identified, but the causatives genes at these loci are largely unknown, so that functional investigation and clinical translation of molecular research data are still inhibited. To identify putatively causative genes, we searched for highly significant mutational burden in candidate genes. We analyzed 84 candidate genes in 4,649 patients and 4,982 controls by next generation sequencing using molecular inversion probes that targeted mainly coding regions. The burden of low-frequency and rare variants was assessed, and in addition, an algorithm (binomial performance deviation analysis) was established to estimate independently the sequence variation in the probe binding regions from the variation in sequencing depth. Highly significant results (considering the number of genes in the genome) of the conventional burden test and the binomial performance deviation analysis overlapped significantly. Fourteen genes were highly significant by one method and confirmed with Bonferroni-corrected significance by the other to show a differential burden of low-frequency and rare variants in restless legs syndrome. Nine of them (AAGAB, ATP2C1, CNTN4, COL6A6, CRBN, GLO1, NTNG1, STEAP4, VAV3) resided in the vicinity of known restless legs syndrome loci, whereas 5 (BBS7, CADM1, CREB5, NRG3, SUN1) have not previously been associated with restless legs syndrome. Burden test and binomial performance deviation analysis also converged significantly in fine-mapping potentially causative domains within these genes. Differential burden with intragenic low-frequency variants reveals putatively causative genes in restless legs syndrome. ANN NEUROL 2020;87:184-193.
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
184-193Subventions
Organisme : German Research Foundation (DFG)
ID : 310572679
Pays : International
Organisme : German RLS Patient Organization
Pays : International
Organisme : Hertie Foundation
Pays : International
Organisme : Helmholtz Center Munich-German Research Center for Environmental Health
Pays : International
Organisme : German Federal Ministry of Education and Research and by the State of Bavaria
Pays : International
Organisme : Munich Center of Health Sciences, Ludwig Maximilian University
Pays : International
Commentaires et corrections
Type : CommentIn
Informations de copyright
© 2019 The Authors. Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Association.
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