Genet Med. 2025 Sep 23:101588. doi: 10.1016/j.gim.2025.101588. Online ahead of print.
ABSTRACT
PURPOSE: In Friedreich ataxia (FRDA) the size of the smaller GAA expansion is a major determinant of disease severity; interruption motifs were identified after the discovery of the pathogenic expansions, but their impact only recently investigated.
METHODS: 164 FRDA patients with biallelic expansions, and 15 non-FRDA patients were analyzed for interruption(s) number, position, and motif. Expansion size and age at onset of ataxia (AAO) were determined for FRDA patients.
RESULTS: Three groups of FRDA patients were identified by the simultaneous analysis of the precise distance (“depth”) between the interruptions (mostly non-triplet) and the 3′ end of the expansion (P < 0.001), the smaller expansion size (P < 0.001), and AAO (P < 0.001). Classical FRDA corresponds to absence of interruption or interruption depth <8 repeats, with AAO often < 15 years (AUC = 0.90; 95% CI, 0.84-0.96); LOFA to interruption depth of 8-18 repeats (AUC = 0.97; 95% CI, 0.94-1), with AAO 15-34 years (AUC = 1; 95% CI, 1-1); vLOFA to interruption depth > 18 (AUC = 0.97; 95% CI, 0.92-1) and AAO >34 years. Multiple (>5) triplet interruptions hamper further expansion.
CONCLUSION: This study provides the molecular basis for a novel classification of FRDA that should be recommended for correct diagnosis.
PMID:41014100 | DOI:10.1016/j.gim.2025.101588
