RFC1 Repeat Expansion in Chronic Cough: Findings From the Korean Chronic Cough Registry.

PURPOSE: Biallelic repeat expansions in the Replication Factor C Subunit 1 (RFC1) gene are associated with cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS). Recent studies have shown that chronic cough often precedes neurological symptoms in CANVAS by 10-20 years, suggesting a potential link between RFC1 repeat expansion and chronic cough. However, the prevalence and clinical relevance of RFC1 expansions in chronic cough, particularly in non-Caucasian populations, remain unknown.

METHODS

We analyzed 128 consecutive patients with chronic cough who were enrolled in the Korean Chronic Cough Registry at 2 tertiary clinics. All patients underwent a comprehensive clinical evaluation and were followed up for at least 6 months to assess treatment response and to identify the diagnosis of refractory chronic cough (RCC). RFC1 repeat expansions, including both biallelic and monoallelic variants, were assessed using flanking and repeat-primed polymerase chain reactions. Whole genome sequencing (WGS) was performed in selected cases to explore additional genetic variants.

RESULTS

RFC1 repeat expansions were identified in 12 patients with chronic cough, comprising 3 biallelic (2.3%), and 9 monoallelic (7.0%) carriers. RCC was diagnosed in 55 of the 109 subjects who completed follow-up. The percentage of RFC1 expansions was significantly higher in RCC than in non-RCC (18.2% vs. 1.9%, P = 0.005), comprising 5.5% biallelic and 12.7% monoallelic expansions in the RCC group. Carriers had longer cough duration (11.0 vs. 4.0 years, P = 0.048) and poorer cough-specific quality of life (Leicester Cough Questionnaire score: 8.5 ± 2.2 vs. 10.5 ± 3.4; P = 0.027). All of the biallelic carriers were diagnosed with RCC and showed poor response to antitussive therapies. WGS identified no additional pathogenic variants in most cases.

CONCLUSIONS

This is the first study to evaluate RFC1 repeat expansions in non-Caucasian patients with chronic cough. The findings suggest that RFC1 expansions may define a distinct, treatment-refractory phenotype of chronic cough.