Objective: To describe the genetic spectrum of (GAA)n-expansions in the FGF14 gene (size and structural repeats) associated with SCA27B in Slavic patients.

Background: The genetic basis of autosomal dominant SCA27B is caused by (GAA)n repeat expansions in the FGF14 gene with pathogenic thresholds of ∼250 (incomplete penetrance) and ≥300 GAA repeats (full penetrance). This region may also contain non-pathogenic hexameric expansions, such as (GAAGGA)n or (GAAGCA)n. Furthermore, the 5’ region flanking the repeats is quite variable and differs in expanded and non-expanded alleles.

Method: We evaluated 110 unrelated patients with late-onset cerebellar ataxia. All patients underwent preliminarily FXN, RFC1, ATXN1, ATXN2, ATXN3, CACNA1A, ATXN8/ATXN8OS and TBP gene expansions analysis. Screening for FGF14 repeat expansion was performed using flanking PCR and repeat-primed PCR. The analysis of the repeat structure and polymorphic 5’ region flanking the repeats was evaluated using Sanger sequencing (Nanophore 05, EZAN, Russia) and nanopore sequencing (Minion, Oxford Nanopore, UK).

Results: We identified 11 (10%) SCA27B patients carrying a pathogenic (GAA)n repeat expansion (≥ 300 repeats) in the FGF14 gene. Additionally, 5 (4,5%) individuals were identified carrying a (GAA)n expansion of ∼250 repeats, associated with incomplete penetrance. All patients had typical SCA27B clinical features: cerebellar ataxia, nystagmus and dysarthria with sensory neuropathy and vestibulopathy in some cases. Two patients carried a non‑pathogenic (GAAGGA)n repeat expansion with more than 300 repeats. We found that small the non-expanded alleles (9-40 repeats) in the polymorphic region contained an insertion (TAGTCATAGTACCCC), the expanded alleles with more than 40 triplet repeats do not have this insertion.

Conclusion: This study showed that SCA27B is a common cause of late-onset cerebellar ataxia. Accurate determination of repeat number is essential to distinguish between alleles associated with full (≥ 300 GAA repeats) and incomplete (∼250 GAA repeats) penetrance. Additionally, it is necessary to differentiate between pathogenic (GAA)n and non-pathogenic (GAAGGA)n expansions in molecular diagnostics of SCA27B. An insertion (TAGTCATAGTACCCC) in the 5′ region flanking the repeats is likely to stabilize the repeat tract, thereby preventing its expansion. The study was supported by RSF (project №24-15-00209).

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MDS Abstracts - https://www.mdsabstracts.org/abstract/genetic-spectrum-of-spinocerebellar-ataxia-type-27b-atx-fgf14-gaa-a-single-center-study/