The genetic landscape and phenotypic spectrum of GAA-FGF14 ataxia in China: a large cohort studyResearch in context
Riwei Ouyang,
Linlin Wan,
David Pellerin,
Zhe Long,
Jian Hu,
Qian Jiang,
Chunrong Wang,
Linliu Peng,
Huirong Peng,
Lang He,
Rong Qiu,
Junling Wang,
Jifeng Guo,
Lu Shen,
Bernard Brais,
Matt C. Danzi,
Stephan Zuchner,
Beisha Tang,
Zhao Chen,
Hong Jiang
Affiliations
Riwei Ouyang
Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
Linlin Wan
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
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
Department of Neurology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China
Jian Hu
Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
Qian Jiang
Key Laboratory of Hunan Province in Neurodegenerative Disorders, Central South University, Changsha, Hunan, 410008, China
Chunrong Wang
Department of Pathology, Xiangya Hospital, Central South University, Changsha, Hunan, China
Linliu Peng
Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
Huirong Peng
Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
Lang He
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
School of Computer Science and Engineering, Central South University, Changsha, Hunan, 410083, China
Junling Wang
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
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
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
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
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
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
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
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; Corresponding author. Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, China.
Hong Jiang
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; Corresponding author. Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, China.
Summary: 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: 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: 17 GAA-FGF14 positive patients with a (GAA)≥250 expansion (12 patients with a GAA-pure expansion, five patients with a (GAA)≥250-[(GAA)n (GCA)m]z expansion) and two possible patients with biallelic (GAA)202/222 alleles were identified. The clinical phenotypes of the 19 positive and possible positive cases covered LOCA phenotype, EOCA phenotype and MSA-c phenotype. Five of six patients with EOCA phenotype were found to have another genetic disorder. The NfL levels of patients with EOCA and MSA-c phenotypes were significantly higher than patients with LOCA phenotype and age-matched controls (p < 0.001). NfL levels of pre-ataxic GAA-FGF14 positive individuals were lower than pre-ataxic SCA3 (p < 0.001) and similar to controls. Interpretation: The frequency of GAA-FGF14 expansion in a large Chinese LOCA cohort was low (1.3%). Biallelic (GAA)202/222 alleles and co-occurrence with other acquired or hereditary diseases may contribute to phenotypic variation and different progression. Funding: 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).
