A diagnostic ceiling for exome sequencing in cerebellar ataxia and related neurological disorders.
ataxia
cerebellar ataxia
cerebellum
diagnostic testing
exome
gait disorders
genetics
genomics
neurogenetics
spastic paraparesis
spastic paraplegia
spinocerebellar ataxia
Journal
Human mutation
ISSN: 1098-1004
Titre abrégé: Hum Mutat
Pays: United States
ID NLM: 9215429
Informations de publication
Date de publication:
02 2020
02 2020
Historique:
received:
14
05
2019
revised:
25
10
2019
accepted:
01
11
2019
pubmed:
7
11
2019
medline:
23
7
2021
entrez:
7
11
2019
Statut:
ppublish
Résumé
Genetic ataxias are associated with mutations in hundreds of genes with high phenotypic overlap complicating the clinical diagnosis. Whole-exome sequencing (WES) has increased the overall diagnostic rate considerably. However, the upper limit of this method remains ill-defined, hindering efforts to address the remaining diagnostic gap. To further assess the role of rare coding variation in ataxic disorders, we reanalyzed our previously published exome cohort of 76 predominantly adult and sporadic-onset patients, expanded the total number of cases to 260, and introduced analyses for copy number variation and repeat expansion in a representative subset. For new cases (n = 184), our resulting clinically relevant detection rate remained stable at 47% with 24% classified as pathogenic. Reanalysis of the previously sequenced 76 patients modestly improved the pathogenic rate by 7%. For the combined cohort (n = 260), the total observed clinical detection rate was 52% with 25% classified as pathogenic. Published studies of similar neurological phenotypes report comparable rates. This consistency across multiple cohorts suggests that, despite continued technical and analytical advancements, an approximately 50% diagnostic rate marks a relative ceiling for current WES-based methods and a more comprehensive genome-wide assessment is needed to identify the missing causative genetic etiologies for cerebellar ataxia and related neurodegenerative diseases.
Identifiants
pubmed: 31692161
doi: 10.1002/humu.23946
pmc: PMC7182470
mid: NIHMS1565462
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
487-501Subventions
Organisme : NHGRI NIH HHS
ID : U54HG003273
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS082094
Pays : United States
Organisme : NINDS NIH HHS
ID : R25 NS065723
Pays : United States
Organisme : NHGRI NIH HHS
ID : U54 HG006542
Pays : United States
Organisme : NINDS NIH HHS
ID : R35 NS105078
Pays : United States
Organisme : NHGRI NIH HHS
ID : K08 HG008986
Pays : United States
Organisme : NINDS NIH HHS
ID : R01NS058529
Pays : United States
Organisme : NINDS NIH HHS
ID : K08 NS105916
Pays : United States
Organisme : NIA NIH HHS
ID : RF1 AG061351
Pays : United States
Organisme : NINDS NIH HHS
ID : R25NS065723
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR001881
Pays : United States
Organisme : NHGRI NIH HHS
ID : UM1 HG006542
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR000124
Pays : United States
Organisme : NHGRI NIH HHS
ID : U54 HG003273
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS058529
Pays : United States
Organisme : Wellcome Trust
Pays : United Kingdom
Informations de copyright
© 2019 Wiley Periodicals, Inc.
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