Enrichment of Repeat Expansions in FGF14 Associated with Amyotrophic Lateral Sclerosis

Intronic GAA repeat expansion in FGF14, with expanded pure GAA alleles predicted to form triplex (H-DNA) structures and the repeat-containing isoform 1B being the predominant transcript in motor neurons.

Intronic GAA repeat expansions in FGF14 cause spinocerebellar ataxia type 27B (SCA27B), whose spectrum extends beyond cerebellar ataxia and frequently includes pyramidal signs. Hypothesising a contribution to amyotrophic lateral sclerosis and to corticospinal tract degeneration, the authors screened 62 individuals with ALS by PacBio HiFi long-read whole-genome sequencing against 256 healthy controls from the Human Pangenome Reference Consortium, with confirmation by flanking and repeat-primed PCR. Pathogenic-range GAA expansions (≥250 repeats, the established SCA27B threshold) were found in 3 of 62 ALS cases (4.8%) and in no control. Expansions of ≥200 repeats were enriched in ALS compared with controls (8.1% vs 0.4%; p = 0.0013), whereas GAAGGA expansions were not significantly associated. Expanded pure GAA alleles were predicted to form triplex (H-DNA) structures, with the repeat-containing isoform 1B the predominant FGF14 transcript in motor neurons.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

This non-peer-reviewed medRxiv preprint rests on 62 cases: three carriers of a pathogenic-range expansion are enough to produce a significant difference but not to establish causation, all the more so as the controls come from a reference resource rather than a matched population. Replication in ALS cohorts of several hundred patients, with detailed cerebellar and pyramidal phenotyping, is needed to separate a genuine contribution from co-occurrence or from SCA27B as a differential diagnosis. As things stand, there is no case for routinely testing for an FGF14 expansion in ALS outside a research protocol.

Analysis by Dr Thibaut Benquey