Identification and characterisation of pathogenic and non-pathogenic FGF14 repeat expansions

Area of Science:

• Genetics
• Neurology
• Molecular Biology

Background:

• Autosomal dominant late-onset cerebellar ataxia (SCA27B) is caused by repeat expansions in the FGF14 gene.
• Current understanding of pathogenic thresholds for FGF14 expansions is based primarily on repeat size, with limited exploration of sequence variations.

Purpose of the Study:

• To investigate the sequence of pathogenic and non-pathogenic FGF14 expansions.
• To compare FGF14 expansion alleles, including interruptions and flanking regions, in patients and controls.
• To refine diagnostic criteria and thresholds for SCA27B.

Main Methods:

• Utilized STRling and ExpansionHunter for short-read genome data analysis.
• Employed long-range PCR and nanopore sequencing for comprehensive analysis of FGF14 expansions.
• Compared expansion alleles, interruptions, and flanking sequences in 169 ataxia patients and 802 controls.

Main Results:

• Accurate detection of FGF14 expansions using outlier approaches in genome data.
• Uninterrupted AAG expansions showed enrichment in ataxia patients at lower repeat counts (180-200) than previously established.
• AAGGAG hexameric expansions were equally prevalent in patients and controls, suggesting they are non-pathogenic.
• Distinct secondary structures were observed between pure AAG (pathogenic) and AAGGAG (non-pathogenic) repeats.
• SCA27B presents as a distinct clinical entity with episodic ataxia and downbeat nystagmus.

Conclusions:

• SCA27B is a significant, often overlooked, cause of adult-onset ataxia, potentially explaining 23-31% of unsolved cases.
• Pathogenic thresholds for FGF14 expansions require re-evaluation, considering repeat sequence and structure.
• Integrating expansion sequencing into molecular diagnostics is crucial for accurate SCA27B diagnosis.