Assessment of the Clinical Interactions of GAA Repeat Expansions in FGF14 and FXN

Brandon J Gerhart; David Pellerin; Matt C Danzi; Stephan Zuchner; Bernard Brais; Gabriel Matos-Rodrigues; Andre Nussenzweig; Karen Usdin; Courtney C Park; Jill S Napierala; David R Lynch; Marek Napierala

doi:10.1212/NXG.0000000000200210

Assessment of the Clinical Interactions of GAA Repeat Expansions in FGF14 and FXN

Neurol Genet. 2024 Nov 20;10(6):e200210. doi: 10.1212/NXG.0000000000200210. eCollection 2024 Dec.

Affiliation

¹ From the Department of Neurology (B.J.G., J.S.N., M.N.), O'Donnell Brain Institute, University of Texas Southwestern Medical Center, Dallas; Department of Neurology and Neurosurgery (D.P., B.B.), Montreal Neurological Hospital and Institute, McGill University, Montreal, Quebec, Canada; Department of Neuromuscular Diseases (D.P.), UCL Queen Square Institute of Neurology and The National Hospital for Neurology and Neurosurgery, University College London, United Kingdom; Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics (M.C.D., S.Z.), University of Miami Miller School of Medicine, FL; Department of Human Genetics (B.B.), McGill University, Montreal, Quebec, Canada; Laboratory of Genome Integrity (G.M.-R., A.N.), National Cancer Institute, NIH; Laboratory of Cell and Molecular Biology (K.U.), National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD; and Department of Pediatrics and Neurology (C.C.P., D.R.L.), The Children's Hospital of Philadelphia, PA.

Abstract

Background and objectives: The number of GAA repeats in the FXN gene is a major but not sole determinant of the clinical presentation of Friedreich ataxia (FRDA). The objective of this study was to establish whether the length of the GAA repeat tract in the FGF14 gene, which is associated with another neurodegenerative disorder (SCA27B), affects the clinical presentation (age at onset, mFARS score) of patients with FRDA.

Methods: The number of GAA repeats in the FXN and FGF14 genes was determined using PCR in a cohort of 221 patients with FRDA. Next, we compared absolute lengths of the FGF14 GAAs with FXN GAAs, followed by correlative analyses to determine potential effects of FGF14 GAA length on age at onset and clinical presentation (mFARS) of FRDA.

Results: We found no significant correlation between the size of the GAA repeats in FXN and FGF14 loci in our FRDA cohort. Moreover, the number of GAAs in FGF14 did not affect the clinical presentation of FRDA even in a small number of cases where a long FGF14 allele was present.

Discussion: Despite both molecular and clinical similarities between FRDA and SCA27B, the length of the GAA repeats in the FGF14 gene, including potentially pathogenic alleles, did not influence the clinical presentation of FRDA.