The genetic landscape and phenotypic spectrum of GAA-FGF14 ataxia in China: a large cohort study.

Biallelic (GAA)(n) allele Co-occurrence GAA-FGF14 ataxia GAA-impure expansion Long-read sequencing

Journal

EBioMedicine
ISSN: 2352-3964
Titre abrégé: EBioMedicine
Pays: Netherlands
ID NLM: 101647039

Informations de publication

Date de publication:
20 Mar 2024
Historique:
received: 25 10 2023
revised: 06 03 2024
accepted: 07 03 2024
medline: 22 3 2024
pubmed: 22 3 2024
entrez: 21 3 2024
Statut: aheadofprint

Résumé

An intronic GAA repeat expansion in FGF14 was recently identified as a cause of GAA-FGF14 ataxia. We aimed to characterise the frequency and phenotypic profile of GAA-FGF14 ataxia in a large Chinese ataxia cohort. A total of 1216 patients that included 399 typical late-onset cerebellar ataxia (LOCA), 290 early-onset cerebellar ataxia (EOCA), and 527 multiple system atrophy with predominant cerebellar ataxia (MSA-c) were enrolled. Long-range and repeat-primed PCR were performed to screen for GAA expansions in FGF14. Targeted long-read and whole-genome sequencing were performed to determine repeat size and sequence configuration. A multi-modal study including clinical assessment, MRI, and neurofilament light chain was conducted for disease assessment. 17 GAA-FGF14 positive patients with a (GAA) The frequency of GAA-FGF14 expansion in a large Chinese LOCA cohort was low (1.3%). Biallelic (GAA) This study was funded by the National Key R&D Program of China (2021YFA0805200 to H.J.), the National Natural Science Foundation of China (81974176 and 82171254 to H.J.; 82371272 to Z.C.; 82301628 to L.W.; 82301438 to Z.L.; 82201411 to L.H.), the Innovation Research Group Project of Natural Science Foundation of Hunan Province (2020JJ1008 to H.J.), the Key Research and Development Program of Hunan Province (2020SK2064 to H.J.), the Innovative Research and Development Program of Development and Reform Commission of Hunan Province to H.J., the Natural Science Foundation of Hunan Province (2024JJ3050 to H.J.; 2022JJ20094 and 2021JJ40974 to Z.C.; 2022JJ40783 to L.H.; 2022JJ40703 to Z.L.), the Project Program of National Clinical Research Center for Geriatric Disorders (Xiangya Hospital, 2020LNJJ12 to H.J.), the Central South University Research Programme of Advanced Interdisciplinary Study (2023QYJC010 to H.J.) and the Science and Technology Innovation Program of Hunan Province (2022RC1027 to Z.C.). D.P. holds a Fellowship award from the Canadian Institutes of Health Research (CIHR).

Sections du résumé

BACKGROUND BACKGROUND
An intronic GAA repeat expansion in FGF14 was recently identified as a cause of GAA-FGF14 ataxia. We aimed to characterise the frequency and phenotypic profile of GAA-FGF14 ataxia in a large Chinese ataxia cohort.
METHODS METHODS
A total of 1216 patients that included 399 typical late-onset cerebellar ataxia (LOCA), 290 early-onset cerebellar ataxia (EOCA), and 527 multiple system atrophy with predominant cerebellar ataxia (MSA-c) were enrolled. Long-range and repeat-primed PCR were performed to screen for GAA expansions in FGF14. Targeted long-read and whole-genome sequencing were performed to determine repeat size and sequence configuration. A multi-modal study including clinical assessment, MRI, and neurofilament light chain was conducted for disease assessment.
FINDINGS RESULTS
17 GAA-FGF14 positive patients with a (GAA)
INTERPRETATION CONCLUSIONS
The frequency of GAA-FGF14 expansion in a large Chinese LOCA cohort was low (1.3%). Biallelic (GAA)
FUNDING BACKGROUND
This study was funded by the National Key R&D Program of China (2021YFA0805200 to H.J.), the National Natural Science Foundation of China (81974176 and 82171254 to H.J.; 82371272 to Z.C.; 82301628 to L.W.; 82301438 to Z.L.; 82201411 to L.H.), the Innovation Research Group Project of Natural Science Foundation of Hunan Province (2020JJ1008 to H.J.), the Key Research and Development Program of Hunan Province (2020SK2064 to H.J.), the Innovative Research and Development Program of Development and Reform Commission of Hunan Province to H.J., the Natural Science Foundation of Hunan Province (2024JJ3050 to H.J.; 2022JJ20094 and 2021JJ40974 to Z.C.; 2022JJ40783 to L.H.; 2022JJ40703 to Z.L.), the Project Program of National Clinical Research Center for Geriatric Disorders (Xiangya Hospital, 2020LNJJ12 to H.J.), the Central South University Research Programme of Advanced Interdisciplinary Study (2023QYJC010 to H.J.) and the Science and Technology Innovation Program of Hunan Province (2022RC1027 to Z.C.). D.P. holds a Fellowship award from the Canadian Institutes of Health Research (CIHR).

Identifiants

DOI: 10.1016/j.ebiom.2024.105077 PMID: 38513302
pubmed: 38513302
pii: S2352-3964(24)00112-9
doi: 10.1016/j.ebiom.2024.105077
pii:
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

105077

Informations de copyright

Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests S.Z. has received consultancy honoraria from Neurogene, Aeglea BioTherapeutics, Applied Therapeutics, and is an unpaid officer of the TGP foundation, all unrelated to the present manuscript. The other authors report no conflicts of interest.

Auteurs

Riwei Ouyang (R)

Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.

Linlin Wan (L)

Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China; Key Laboratory of Hunan Province in Neurodegenerative Disorders, Central South University, Changsha, Hunan, 410008, China; Bioinformatics Center & National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China; Department of Radiology, Xiangya Hospital, Central South University, Changsha, Hunan, China; National International Collaborative Research Center for Medical Metabolomics, Central South University, Changsha, Hunan, China.

David Pellerin (D)

Department of Neurology and Neurosurgery, Montreal Neurological Hospital and Institute, McGill University, Montreal, QC, Canada; Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology and the National Hospital for Neurology and Neurosurgery, University College London, London, United Kingdom.

Zhe Long (Z)

Department of Neurology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China.

Jian Hu (J)

Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.

Qian Jiang (Q)

Key Laboratory of Hunan Province in Neurodegenerative Disorders, Central South University, Changsha, Hunan, 410008, China.

Chunrong Wang (C)

Department of Pathology, Xiangya Hospital, Central South University, Changsha, Hunan, China.

Linliu Peng (L)

Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.

Huirong Peng (H)

Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.

Lang He (L)

Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China; Department of Pathology, Xiangya Hospital, Central South University, Changsha, Hunan, China.

Rong Qiu (R)

School of Computer Science and Engineering, Central South University, Changsha, Hunan, 410083, China.

Junling Wang (J)

Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China; Key Laboratory of Hunan Province in Neurodegenerative Disorders, Central South University, Changsha, Hunan, 410008, China; Bioinformatics Center & National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China; Hunan International Scientific and Technological Cooperation Base of Neurodegenerative and Neurogenetic Diseases, Changsha, China.

Jifeng Guo (J)

Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China; Key Laboratory of Hunan Province in Neurodegenerative Disorders, Central South University, Changsha, Hunan, 410008, China; Bioinformatics Center & National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China; Hunan International Scientific and Technological Cooperation Base of Neurodegenerative and Neurogenetic Diseases, Changsha, China.

Lu Shen (L)

Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China; Key Laboratory of Hunan Province in Neurodegenerative Disorders, Central South University, Changsha, Hunan, 410008, China; Bioinformatics Center & National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China; Hunan International Scientific and Technological Cooperation Base of Neurodegenerative and Neurogenetic Diseases, Changsha, China.

Bernard Brais (B)

Department of Neurology and Neurosurgery, Montreal Neurological Hospital and Institute, McGill University, Montreal, QC, Canada; Department of Human Genetics, McGill University, Montreal, QC, Canada.

Matt C Danzi (MC)

Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA.

Stephan Zuchner (S)

Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA.

Beisha Tang (B)

Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China; Key Laboratory of Hunan Province in Neurodegenerative Disorders, Central South University, Changsha, Hunan, 410008, China; Bioinformatics Center & National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China; Hunan International Scientific and Technological Cooperation Base of Neurodegenerative and Neurogenetic Diseases, Changsha, China.

Zhao Chen (Z)

Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China; Key Laboratory of Hunan Province in Neurodegenerative Disorders, Central South University, Changsha, Hunan, 410008, China; Bioinformatics Center & National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China; Hunan International Scientific and Technological Cooperation Base of Neurodegenerative and Neurogenetic Diseases, Changsha, China. Electronic address: czcf98@csu.edu.cn.

Hong Jiang (H)

Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China; Department of Neurology, The Third Xiangya Hospital of Central South University, Changsha, Hunan, 410008, China; Key Laboratory of Hunan Province in Neurodegenerative Disorders, Central South University, Changsha, Hunan, 410008, China; Bioinformatics Center & National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China; Hunan International Scientific and Technological Cooperation Base of Neurodegenerative and Neurogenetic Diseases, Changsha, China; National International Collaborative Research Center for Medical Metabolomics, Central South University, Changsha, Hunan, China; Furong Laboratory, Central South University, Changsha, Hunan, 410008, China; Brain Research Center, Central South University, Changsha, Hunan, 410008, China. Electronic address: jianghong73868@csu.edu.cn.

Classifications MeSH