An intronic GAA repeat expansion in FGF14 causes the autosomal-dominant adult-onset ataxia SCA50/ATX-FGF14

Haloom Rafehi; Justin Read; David J Szmulewicz; Kayli C Davies; Penny Snell; Liam G Fearnley; Liam Scott; Mirja Thomsen; Greta Gillies; Kate Pope; Mark F Bennett; Jacob E Munro; Kathie J Ngo; Luke Chen; Mathew J Wallis; Ernest G Butler; Kishore R Kumar; Kathy Hc Wu; Susan E Tomlinson; Stephen Tisch; Abhishek Malhotra; Matthew Lee-Archer; Egor Dolzhenko; Michael A Eberle; Leslie J Roberts; Brent L Fogel; Norbert Brüggemann; Katja Lohmann; Martin B Delatycki; Melanie Bahlo; Paul J Lockhart

doi:10.1016/j.ajhg.2022.11.015

An intronic GAA repeat expansion in FGF14 causes the autosomal-dominant adult-onset ataxia SCA50/ATX-FGF14

Am J Hum Genet. 2023 Jan 5;110(1):105-119. doi: 10.1016/j.ajhg.2022.11.015. Epub 2022 Dec 8.

Authors

Haloom Rafehi¹, Justin Read², David J Szmulewicz³, Kayli C Davies², Penny Snell⁴, Liam G Fearnley⁵, Liam Scott⁶, Mirja Thomsen⁷, Greta Gillies⁴, Kate Pope⁴, Mark F Bennett⁸, Jacob E Munro¹, Kathie J Ngo⁹, Luke Chen¹⁰, Mathew J Wallis¹¹, Ernest G Butler¹², Kishore R Kumar¹³, Kathy Hc Wu¹⁴, Susan E Tomlinson¹⁵, Stephen Tisch¹⁶, Abhishek Malhotra¹⁷, Matthew Lee-Archer¹⁸, Egor Dolzhenko¹⁹, Michael A Eberle¹⁹, Leslie J Roberts²⁰, Brent L Fogel²¹, Norbert Brüggemann²², Katja Lohmann⁷, Martin B Delatycki²³, Melanie Bahlo²⁴, Paul J Lockhart²⁵

Affiliations

¹ Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia.
² Bruce Lefroy Centre, Murdoch Children's Research Institute, Parkville, VIC 3052, Australia; Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Parkville, VIC, Australia.
³ Cerebellar Ataxia Clinic, Eye and Ear Hospital, Melbourne, VIC, Australia; The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, VIC, Australia.
⁴ Bruce Lefroy Centre, Murdoch Children's Research Institute, Parkville, VIC 3052, Australia.
⁵ Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia; Bruce Lefroy Centre, Murdoch Children's Research Institute, Parkville, VIC 3052, Australia.
⁶ Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.
⁷ Institute of Neurogenetics, University of Lübeck, Lübeck, Germany.
⁸ Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia; Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Heidelberg, VIC, Australia.
⁹ Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA, USA.
¹⁰ Alfred Hospital, Department of Neurology, Melbourne, VIC, Australia.
¹¹ Clinical Genetics Service, Austin Health, Melbourne, VIC, Australia; Department of Medicine, University of Melbourne, Austin Health, Melbourne, VIC, Australia; School of Medicine and Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS, Australia.
¹² Peninsula Health, Melbourne, VIC, Australia.
¹³ Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia; Molecular Medicine Laboratory and Department of Neurology, Concord Repatriation General Hospital, Concord, NSW, Australia; Garvan Institute of Medical Research, Sydney, NSW, Australia.
¹⁴ School of Medicine, University of New South Wales, Sydney, NSW, Australia; Clinical Genomics, St Vincent's Hospital, Darlinghurst, NSW, Australia; Discipline of Genomic Medicine, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia; School of Medicine, University of Notre Dame, Sydney, NSW, Australia.
¹⁵ School of Medicine, University of Notre Dame, Sydney, NSW, Australia; Department of Neurology, St Vincent's Hospital, Darlinghurst, NSW, Australia.
¹⁶ School of Medicine, University of New South Wales, Sydney, NSW, Australia; Department of Neurology, St Vincent's Hospital, Darlinghurst, NSW, Australia.
¹⁷ Department of Neuroscience, University Hospital Geelong, Geelong, VIC, Australia.
¹⁸ Launceston General Hospital, Tasmanian Health Service, Launceston, TAS, Australia.
¹⁹ Illumina Inc, San Diego, CA, USA.
²⁰ Department of Neurology and Neurological Research, St. Vincent's Hospital, Melbourne, VIC, Australia.
²¹ Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA, USA; Departments of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA, USA.
²² Institute of Neurogenetics, University of Lübeck, Lübeck, Germany; Department of Neurology, University Medical Center Schleswig-Holstein, Campus Lübeck, Germany.
²³ Bruce Lefroy Centre, Murdoch Children's Research Institute, Parkville, VIC 3052, Australia; Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Parkville, VIC, Australia; Victorian Clinical Genetics Services, Melbourne, VIC, Australia.
²⁴ Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia. Electronic address: bahlo@wehi.edu.au.
²⁵ Bruce Lefroy Centre, Murdoch Children's Research Institute, Parkville, VIC 3052, Australia; Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Parkville, VIC, Australia. Electronic address: paul.lockhart@mcri.edu.au.

Abstract

Adult-onset cerebellar ataxias are a group of neurodegenerative conditions that challenge both genetic discovery and molecular diagnosis. In this study, we identified an intronic (GAA) repeat expansion in fibroblast growth factor 14 (FGF14). Genetic analysis of 95 Australian individuals with adult-onset ataxia identified four (4.2%) with (GAA)_>300 and a further nine individuals with (GAA)_>250. PCR and long-read sequence analysis revealed these were pure (GAA) repeats. In comparison, no control subjects had (GAA)_>300 and only 2/311 control individuals (0.6%) had a pure (GAA)_>250. In a German validation cohort, 9/104 (8.7%) of affected individuals had (GAA)_>335 and a further six had (GAA)_>250, whereas 10/190 (5.3%) control subjects had (GAA)_>250 but none were (GAA)_>335. The combined data suggest (GAA)_>335 are disease causing and fully penetrant (p = 6.0 × 10^-8, OR = 72 [95% CI = 4.3-1,227]), while (GAA)_>250 is likely pathogenic with reduced penetrance. Affected individuals had an adult-onset, slowly progressive cerebellar ataxia with variable features including vestibular impairment, hyper-reflexia, and autonomic dysfunction. A negative correlation between age at onset and repeat length was observed (R² = 0.44, p = 0.00045, slope = -0.12) and identification of a shared haplotype in a minority of individuals suggests that the expansion can be inherited or generated de novo during meiotic division. This study demonstrates the power of genome sequencing and advanced bioinformatic tools to identify novel repeat expansions via model-free, genome-wide analysis and identifies SCA50/ATX-FGF14 as a frequent cause of adult-onset ataxia.

Keywords: ataxia; bilateral vestibulopathy; cerebellar ataxia; repeat expansions; short tandem repeats; whole-genome sequencing.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Ataxia / genetics
Australia
Cerebellar Ataxia* / genetics
Fibroblast Growth Factors*
Friedreich Ataxia* / genetics
Humans
Trinucleotide Repeat Expansion* / genetics

Substances

fibroblast growth factor 14
Fibroblast Growth Factors