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RFC1 Repeat Expansion in Chronic Cough: Findings From the Korean Chronic Cough Registry
Kyung Eun Park1, Jiwon Lee2, Jun-Pyo Choi3
1University of Ulsan College of Medicine, Ulsan, Korea.
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.
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