FGF14 GAA Intronic Expansion in Unsolved Adult‐Onset Ataxia in the Care4Rare Canada Consortium
ABSTRACT Background and Objectives Spinocerebellar ataxias (SCA) represent a clinically and genetically heterogeneous group of progressive neurodegenerative diseases with prominent cerebellar atrophy. Recently, a novel pathogenic repeat expansion in intron 1 of FGF14 was identified, causing adult‐on...
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Wiley
2025-06-01
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| Series: | Annals of Clinical and Translational Neurology |
| Online Access: | https://doi.org/10.1002/acn3.70016 |
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| author | Alexanne Cuillerier Giulia F. Del Gobbo Layla Mackay Erika Wall Madeline Couse Laura M. McDonell Mireille Cloutier Matt C. Danzi Jodi Warman‐Chardon Pierre R. Bourque Oksana Suchowersky Alan Mears Luke Seldenthuis Wendy Mears Laura Larrigan Alexandre White‐Brown Gerald Pfeffer Dennis E. Bulman David Dyment Care4Rare Canada Consortium Kym M. Boycott |
| author_facet | Alexanne Cuillerier Giulia F. Del Gobbo Layla Mackay Erika Wall Madeline Couse Laura M. McDonell Mireille Cloutier Matt C. Danzi Jodi Warman‐Chardon Pierre R. Bourque Oksana Suchowersky Alan Mears Luke Seldenthuis Wendy Mears Laura Larrigan Alexandre White‐Brown Gerald Pfeffer Dennis E. Bulman David Dyment Care4Rare Canada Consortium Kym M. Boycott |
| author_sort | Alexanne Cuillerier |
| collection | DOAJ |
| description | ABSTRACT Background and Objectives Spinocerebellar ataxias (SCA) represent a clinically and genetically heterogeneous group of progressive neurodegenerative diseases with prominent cerebellar atrophy. Recently, a novel pathogenic repeat expansion in intron 1 of FGF14 was identified, causing adult‐onset SCA (SCA27B). We aimed to determine the proportion of our unsolved adult‐onset ataxia cohort harboring this expansion using several technologies, and to characterize the phenotypic presentation within our population. Methods Individuals presenting with adult‐onset ataxia (> 30 years old) and negative previous genetic testing were selected from the Care4Rare patient repository. Affected individuals were from all ethnicities, and 90% had a family history suggestive of dominant ataxia, representing 19 of the 23 families included. We used multiple tools (PCR, long‐read genome sequencing and optical genome mapping (OGM)) to identify the pathogenic GAA repeat in FGF14. Results Of the 23 families included in this study, 65.2% harbored a pathogenic GAA expansion in FGF14. Individuals of French‐Canadian descent (FC) represented most of our cohort and had a 64.7% diagnostic yield. Affected individuals presented with gaze‐evoked nystagmus, gait ataxia, cerebellar dysarthria, and early episodic features. The GAA expansion in FGF14 was visible by OGM in all individuals tested. Interpretation Our diagnostic yield demonstrates this expansion may be the most common cause of adult‐onset SCA in dominant families of FC ancestry. Our FC participants have a phenotype distinct from previously published FC patients, with gaze‐evoked nystagmus being the most common eye anomaly. From a diagnostic standpoint, the pathogenic GAA repeat can be identified by OGM, but additional tests are required to complement the interpretation. |
| format | Article |
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| institution | OA Journals |
| issn | 2328-9503 |
| language | English |
| publishDate | 2025-06-01 |
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| series | Annals of Clinical and Translational Neurology |
| spelling | doaj-art-3af4656d88bd46008f156fe2e750e89f2025-08-20T02:07:09ZengWileyAnnals of Clinical and Translational Neurology2328-95032025-06-011261118112510.1002/acn3.70016FGF14 GAA Intronic Expansion in Unsolved Adult‐Onset Ataxia in the Care4Rare Canada ConsortiumAlexanne Cuillerier0Giulia F. Del Gobbo1Layla Mackay2Erika Wall3Madeline Couse4Laura M. McDonell5Mireille Cloutier6Matt C. Danzi7Jodi Warman‐Chardon8Pierre R. Bourque9Oksana Suchowersky10Alan Mears11Luke Seldenthuis12Wendy Mears13Laura Larrigan14Alexandre White‐Brown15Gerald Pfeffer16Dennis E. Bulman17David Dyment18Care4Rare Canada Consortium19Kym M. Boycott20Children's Hospital of Eastern Ontario Research Institute Ottawa Ontario CanadaChildren's Hospital of Eastern Ontario Research Institute Ottawa Ontario CanadaChildren's Hospital of Eastern Ontario Research Institute Ottawa Ontario CanadaChildren's Hospital of Eastern Ontario Research Institute Ottawa Ontario CanadaCentre for Computational Medicine, the Hospital for Sick Children University of Toronto Toronto Ontario CanadaChildren's Hospital of Eastern Ontario Research Institute Ottawa Ontario CanadaDepartment of Genetics Children's Hospital of Eastern Ontario Ottawa Ontario CanadaDr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics University of Miami Miller School of Medicine Miami Florida USAChildren's Hospital of Eastern Ontario Research Institute Ottawa Ontario CanadaUniversity of Ottawa Ottawa Ontario CanadaFaculty of Medicine, Department of Neurology, Pediatrics, Psychiatry and Medical University of Alberta Edmonton Alberta CanadaNewborn Screening Ontario Ottawa Ontario CanadaChildren's Hospital of Eastern Ontario Research Institute Ottawa Ontario CanadaChildren's Hospital of Eastern Ontario Research Institute Ottawa Ontario CanadaChildren's Hospital of Eastern Ontario Research Institute Ottawa Ontario CanadaChildren's Hospital of Eastern Ontario Research Institute Ottawa Ontario CanadaAlberta Child and Health Research Institute, Department of Medical Genetics, Cumming School of Medicine University of Calgary Calgary Alberta CanadaAlberta Child and Health Research Institute, Department of Medical Genetics, Cumming School of Medicine University of Calgary Calgary Alberta CanadaChildren's Hospital of Eastern Ontario Research Institute Ottawa Ontario CanadaChildren's Hospital of Eastern Ontario Research Institute Ottawa Ontario CanadaChildren's Hospital of Eastern Ontario Research Institute Ottawa Ontario CanadaABSTRACT Background and Objectives Spinocerebellar ataxias (SCA) represent a clinically and genetically heterogeneous group of progressive neurodegenerative diseases with prominent cerebellar atrophy. Recently, a novel pathogenic repeat expansion in intron 1 of FGF14 was identified, causing adult‐onset SCA (SCA27B). We aimed to determine the proportion of our unsolved adult‐onset ataxia cohort harboring this expansion using several technologies, and to characterize the phenotypic presentation within our population. Methods Individuals presenting with adult‐onset ataxia (> 30 years old) and negative previous genetic testing were selected from the Care4Rare patient repository. Affected individuals were from all ethnicities, and 90% had a family history suggestive of dominant ataxia, representing 19 of the 23 families included. We used multiple tools (PCR, long‐read genome sequencing and optical genome mapping (OGM)) to identify the pathogenic GAA repeat in FGF14. Results Of the 23 families included in this study, 65.2% harbored a pathogenic GAA expansion in FGF14. Individuals of French‐Canadian descent (FC) represented most of our cohort and had a 64.7% diagnostic yield. Affected individuals presented with gaze‐evoked nystagmus, gait ataxia, cerebellar dysarthria, and early episodic features. The GAA expansion in FGF14 was visible by OGM in all individuals tested. Interpretation Our diagnostic yield demonstrates this expansion may be the most common cause of adult‐onset SCA in dominant families of FC ancestry. Our FC participants have a phenotype distinct from previously published FC patients, with gaze‐evoked nystagmus being the most common eye anomaly. From a diagnostic standpoint, the pathogenic GAA repeat can be identified by OGM, but additional tests are required to complement the interpretation.https://doi.org/10.1002/acn3.70016 |
| spellingShingle | Alexanne Cuillerier Giulia F. Del Gobbo Layla Mackay Erika Wall Madeline Couse Laura M. McDonell Mireille Cloutier Matt C. Danzi Jodi Warman‐Chardon Pierre R. Bourque Oksana Suchowersky Alan Mears Luke Seldenthuis Wendy Mears Laura Larrigan Alexandre White‐Brown Gerald Pfeffer Dennis E. Bulman David Dyment Care4Rare Canada Consortium Kym M. Boycott FGF14 GAA Intronic Expansion in Unsolved Adult‐Onset Ataxia in the Care4Rare Canada Consortium Annals of Clinical and Translational Neurology |
| title | FGF14 GAA Intronic Expansion in Unsolved Adult‐Onset Ataxia in the Care4Rare Canada Consortium |
| title_full | FGF14 GAA Intronic Expansion in Unsolved Adult‐Onset Ataxia in the Care4Rare Canada Consortium |
| title_fullStr | FGF14 GAA Intronic Expansion in Unsolved Adult‐Onset Ataxia in the Care4Rare Canada Consortium |
| title_full_unstemmed | FGF14 GAA Intronic Expansion in Unsolved Adult‐Onset Ataxia in the Care4Rare Canada Consortium |
| title_short | FGF14 GAA Intronic Expansion in Unsolved Adult‐Onset Ataxia in the Care4Rare Canada Consortium |
| title_sort | fgf14 gaa intronic expansion in unsolved adult onset ataxia in the care4rare canada consortium |
| url | https://doi.org/10.1002/acn3.70016 |
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