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Clinical and genetic analyses of a Swedish patient series diagnosed with ataxia

Gorcenco, Sorina LU ; Kafantari, Efthymia LU ; Wallenius, Joel LU orcid ; Karremo, Christin LU ; Alinder, Erik ; Dobloug, Sigurd LU ; Landqvist Waldö, Maria LU ; Englund, Elisabet LU orcid ; Ehrencrona, Hans LU orcid and Wictorin, Klas LU , et al. (2024) In Journal of Neurology 271(1). p.526-542
Abstract

Hereditary ataxia is a heterogeneous group of complex neurological disorders. Next-generation sequencing methods have become a great help in clinical diagnostics, but it may remain challenging to determine if a genetic variant is the cause of the patient’s disease. We compiled a consecutive single-center series of 87 patients from 76 families with progressive ataxia of known or unknown etiology. We investigated them clinically and genetically using whole exome or whole genome sequencing. Test methods were selected depending on family history, clinical phenotype, and availability. Genetic results were interpreted based on the American College of Medical Genetics criteria. For high-suspicion variants of uncertain significance, renewed... (More)

Hereditary ataxia is a heterogeneous group of complex neurological disorders. Next-generation sequencing methods have become a great help in clinical diagnostics, but it may remain challenging to determine if a genetic variant is the cause of the patient’s disease. We compiled a consecutive single-center series of 87 patients from 76 families with progressive ataxia of known or unknown etiology. We investigated them clinically and genetically using whole exome or whole genome sequencing. Test methods were selected depending on family history, clinical phenotype, and availability. Genetic results were interpreted based on the American College of Medical Genetics criteria. For high-suspicion variants of uncertain significance, renewed bioinformatical and clinical evaluation was performed to assess the level of pathogenicity. Thirty (39.5%) of the 76 families had received a genetic diagnosis at the end of our study. We present the predominant etiologies of hereditary ataxia in a Swedish patient series. In two families, we established a clinical diagnosis, although the genetic variant was classified as “of uncertain significance” only, and in an additional three families, results are pending. We found a pathogenic variant in one family, but we suspect that it does not explain the complete clinical picture. We conclude that correctly interpreting genetic variants in complex neurogenetic diseases requires genetics and clinical expertise. The neurologist’s careful phenotyping remains essential to confirm or reject a diagnosis, also by reassessing clinical findings after a candidate genetic variant is suggested. Collaboration between neurology and clinical genetics and combining clinical and research approaches optimizes diagnostic yield.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Hereditary ataxia, Next-generation sequencing, Post-NGS phenotyping
in
Journal of Neurology
volume
271
issue
1
pages
526 - 542
publisher
Springer
external identifiers
  • pmid:37787810
  • scopus:85173119632
ISSN
0340-5354
DOI
10.1007/s00415-023-11990-x
language
English
LU publication?
yes
id
5f7c34a2-8f70-4bbf-bcd9-493601e2b778
date added to LUP
2023-12-20 10:40:32
date last changed
2024-04-18 20:19:35
@article{5f7c34a2-8f70-4bbf-bcd9-493601e2b778,
  abstract     = {{<p>Hereditary ataxia is a heterogeneous group of complex neurological disorders. Next-generation sequencing methods have become a great help in clinical diagnostics, but it may remain challenging to determine if a genetic variant is the cause of the patient’s disease. We compiled a consecutive single-center series of 87 patients from 76 families with progressive ataxia of known or unknown etiology. We investigated them clinically and genetically using whole exome or whole genome sequencing. Test methods were selected depending on family history, clinical phenotype, and availability. Genetic results were interpreted based on the American College of Medical Genetics criteria. For high-suspicion variants of uncertain significance, renewed bioinformatical and clinical evaluation was performed to assess the level of pathogenicity. Thirty (39.5%) of the 76 families had received a genetic diagnosis at the end of our study. We present the predominant etiologies of hereditary ataxia in a Swedish patient series. In two families, we established a clinical diagnosis, although the genetic variant was classified as “of uncertain significance” only, and in an additional three families, results are pending. We found a pathogenic variant in one family, but we suspect that it does not explain the complete clinical picture. We conclude that correctly interpreting genetic variants in complex neurogenetic diseases requires genetics and clinical expertise. The neurologist’s careful phenotyping remains essential to confirm or reject a diagnosis, also by reassessing clinical findings after a candidate genetic variant is suggested. Collaboration between neurology and clinical genetics and combining clinical and research approaches optimizes diagnostic yield.</p>}},
  author       = {{Gorcenco, Sorina and Kafantari, Efthymia and Wallenius, Joel and Karremo, Christin and Alinder, Erik and Dobloug, Sigurd and Landqvist Waldö, Maria and Englund, Elisabet and Ehrencrona, Hans and Wictorin, Klas and Karrman, Kristina and Puschmann, Andreas}},
  issn         = {{0340-5354}},
  keywords     = {{Hereditary ataxia; Next-generation sequencing; Post-NGS phenotyping}},
  language     = {{eng}},
  number       = {{1}},
  pages        = {{526--542}},
  publisher    = {{Springer}},
  series       = {{Journal of Neurology}},
  title        = {{Clinical and genetic analyses of a Swedish patient series diagnosed with ataxia}},
  url          = {{http://dx.doi.org/10.1007/s00415-023-11990-x}},
  doi          = {{10.1007/s00415-023-11990-x}},
  volume       = {{271}},
  year         = {{2024}},
}