Repeat-associated ataxias in a German patient cohort analysed by targeted parallel long-read sequencing

Hereditary adult-onset ataxias are a heterogeneous group of phenotypically overlapping conditions, often caused by pathogenic expansions of short tandem repeats. Currently, 18 repeat disorders with a core phenotype of adult-onset ataxia are known. Diagnosis typically relies on sequential PCR-based methods, which are labour-intensive and lack precision. Long-read sequencing (LRS) has the potential to overcome these limitations and is currently implemented and validated in clinical genetics. Using clinical nanopore Cas9-targeted sequencing (Clin-CATS) for parallel in-depth repeat analysis, we evaluated a diagnostic cohort of 513 adult-onset ataxia patients, determining frequencies of all known repeat-associated ataxias except Spinocerebellar ataxia 4 (SCA4), as well as the carrier frequencies for autosomal-recessive disorders, RFC1 spectrum disorder and Friedreich's ataxia (FRDA). Additionally, phenotypes of patients with established genetic diagnoses were characterized, especially those of patients living with RFC1 spectrum disorder and SCA27B. Repeat-associated ataxias were confirmed in 33.3% of cases, including rare ataxias, such as SCA10, SCA36 and SCA37, alongside as the most prevalent conditions SCA27B and RFC1 spectrum disorder. Potentially pathogenic expansions in FGF14 were identified in an additional 4.7% of patients. Testing of another 347 patients for ZFHX3 expansions linked to SCA4 did not identify any cases. Dual diagnoses were frequent, occurring in 6.4% of patients with repeat-associated ataxia. We confirmed a high RFC1 spectrum disorder carrier frequency (7.2%) and reclassified certain FXN expansions as likely non-pathogenic, resulting in a lower than estimated carrier frequency for FRDA of 0.8%. We also identified novel repeat configurations in several loci and illustrated the high heterogeneity of repeat expansions in RFC1, highlighting it as a potential source of false results when using PCR-based methods. This study underscores the diagnostic advantages of LRS for comprehensive repeat analysis and recommends its adoption as a standard in clinical genetics, replacing Southern blot and PCR-based approaches. Furthermore, based on our findings in a large patient cohort a re-evaluation of existing phenotype-genotype correlations is recommended as well as evaluating additional parameters alongside the repeat length to improve diagnostic precision of repeat analysis.

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Journal
Brain
Published
2025-09-01
DOI
https://doi.org/10.1093/brain/awaf318
Citations
1
Primary Topic
Genetic Neurodegenerative Diseases
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article
Field-Weighted Citation Impact
0.91

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article

Repeat-associated ataxias in a German patient cohort analysed by targeted parallel long-read sequencing

Alexander Jäck, Elsa Leitão, Veronika Scholz, Sibylle Wilfling et al.
1 citations
Brain
Genetic Neurodegenerative Diseases
0.91
article

Repeat-associated ataxias in a German patient cohort analysed by targeted parallel long-read sequencing

Alexander Jäck, Elsa Leitão, Veronika Scholz, Sibylle Wilfling, Dávid Brenner, Christine Schneider, Christiane Schneider‐Gold, Gilbert Wunderlich, Christine Dineiger, Filip Thiessen, Isolde Schreyer, Teresa Neuhann, Simone Zittel, Marius Näher, Sabine Kaya, Inga Van Buren, Franziska Schnabel, Christel Depienne, Rosanna Krakowsky, Konstanze Dunker, Johannes Gerb, Tessa Huchtemann, Yorck Hellenbroich, Johannes Levin, Kerstin Becker, Christina Bjørk Petersen, Ken Möhwald, Hannes Erdmann, Denis Grabova, Elke Holinski‐Feder, Anna Benet‐Pagès, Karoline Steinmetz, Günter U. Höglinger, Doreen Huppert, Annalisa Schaub, Morghan C. Lucas, Mayra Sauer, Fabian Kilpert, Andreas Zwergal, Isabell Cordts, Sandra Becker‐Bense, Inga Claus, Filipp Filippopulos, Khalid Akbari, Thomas Klopstock, Michael Strupp, Florian Schöberl, Eva Breithausen, Lena Fabritius, Larissa Mämecke, Kirsten Muhle
article en
1 citations

Abstract

Hereditary adult-onset ataxias are a heterogeneous group of phenotypically overlapping conditions, often caused by pathogenic expansions of short tandem repeats. Currently, 18 repeat disorders with a core phenotype of adult-onset ataxia are known. Diagnosis typically relies on sequential PCR-based methods, which are labour-intensive and lack precision. Long-read sequencing (LRS) has the potential to overcome these limitations and is currently implemented and validated in clinical genetics. Using clinical nanopore Cas9-targeted sequencing (Clin-CATS) for parallel in-depth repeat analysis, we evaluated a diagnostic cohort of 513 adult-onset ataxia patients, determining frequencies of all known repeat-associated ataxias except Spinocerebellar ataxia 4 (SCA4), as well as the carrier frequencies for autosomal-recessive disorders, RFC1 spectrum disorder and Friedreich's ataxia (FRDA). Additionally, phenotypes of patients with established genetic diagnoses were characterized, especially those of patients living with RFC1 spectrum disorder and SCA27B. Repeat-associated ataxias were confirmed in 33.3% of cases, including rare ataxias, such as SCA10, SCA36 and SCA37, alongside as the most prevalent conditions SCA27B and RFC1 spectrum disorder. Potentially pathogenic expansions in FGF14 were identified in an additional 4.7% of patients. Testing of another 347 patients for ZFHX3 expansions linked to SCA4 did not identify any cases. Dual diagnoses were frequent, occurring in 6.4% of patients with repeat-associated ataxia. We confirmed a high RFC1 spectrum disorder carrier frequency (7.2%) and reclassified certain FXN expansions as likely non-pathogenic, resulting in a lower than estimated carrier frequency for FRDA of 0.8%. We also identified novel repeat configurations in several loci and illustrated the high heterogeneity of repeat expansions in RFC1, highlighting it as a potential source of false results when using PCR-based methods. This study underscores the diagnostic advantages of LRS for comprehensive repeat analysis and recommends its adoption as a standard in clinical genetics, replacing Southern blot and PCR-based approaches. Furthermore, based on our findings in a large patient cohort a re-evaluation of existing phenotype-genotype correlations is recommended as well as evaluating additional parameters alongside the repeat length to improve diagnostic precision of repeat analysis.

BrainVol. 149(3)
OTH Regensburg (DE), Universität Hamburg (DE), Hochschule Bremen (DE), University of Augsburg (DE), Universität Ulm (DE), German Center for Neurodegenerative Diseases (DE), University Hospital Augsburg (DE), TUM Klinikum (DE), Helmholtz Zentrum München (DE), University Hospital Münster (DE), University Medical Center Hamburg-Eppendorf (DE), University Hospital Schleswig-Holstein (DE), Munich Cluster for Systems Neurology (DE), Medical Genetics Center (DE), Institute of Human Genetics (PL), Essen University Hospital (DE), German Center for Lung Research (DE), Friedrich Baur Stiftung (DE), Praxis für Humangenetik (DE), St. Josef-Hospital (DE), Mayo Clinic in Florida (US), University Hospital Cologne (DE), University Hospital Ulm (DE), Technische Hochschule Ulm (DE), University of Regensburg (DE), University of Duisburg-Essen (DE), Ludwig-Maximilians-Universität München (DE), Leipzig University (DE), University of Lübeck (DE)
E-Rare, European Commission, Bundesministerium für Bildung und Forschung
Openalex Percentile: Top 23%
Genetic Neurodegenerative Diseases
0.91
DOIOpen Access PDFOpenAlex
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