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

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

doi:10.1016/j.ajhg.2022.11.015

Title

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

Publication Date

2023-01-05

Author(s)

Rafehi, Haloom

Read, Justin

Szmulewicz, David J

Davies, Kayli C

Snell, Penny

Fearnley, Liam G

Scott, Liam

Thomsen, Mirja

Gillies, Greta

Pope, Kate

Bennett, Mark F

Munro, Jacob E

Ngo, Kathie J

Chen, Luke

Wallis, Mathew J

Butler, Ernest G

Kumar, Kishore R

Wu, Kathy Hc

Tomlinson, Susan E

Tisch, Stephen

Malhotra, Abhishek

Lee-Archer, Matthew

Dolzhenko, Egor

Eberle, Michael A

Roberts, Leslie J

Fogel, Brent L

Brüggemann, Norbert

Lohmann, Katja

Delatycki, Martin B

Bahlo, Melanie

Lockhart, Paul J

Subject

ataxia

bilateral vestibulopathy

cerebellar ataxia

repeat expansions

short tandem repeats

whole-genome sequencing

Type of document

Journal Article

OrcId

#PLACEHOLDER_PARENT_METADATA_VALUE#

DOI

10.1016/j.ajhg.2022.11.015

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.

Link

link

Citation

American Journal of Human Genetics 2023; 110(1)

Jornal Title

American Journal of Human Genetics

ISSN

1537-6605

Austin Health

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