A Hidden Cystic Fibrosis Story in Refractory Asthma: Never Overlook a CFTR Intronic Variant

Pediatric patients who have recurrent asthma exacerbations and present with atypical clinical features in relation to their asthmatic status and treatment, such as poor weight gain or inadequate response to guideline-directed asthma therapy, pose a diagnostic challenge and often call for further evaluation. We present the cases of two pediatric patients who were evaluated for recurrent asthma exacerbations and poor weight gain that exhibited borderline sweat chloride levels and underwent cystic fibrosis transmembrane conductance regulator (CFTR) genetic testing. Despite the absence of pathogenic CFTR mutations, both patients were found to harbor intronic TG–poly(T) CFTR variants, including one case of homozygosity for c.1210-34TG[11]T[7]. These patient cases highlight the relevance of integrating genetic, clinical, and biochemical data into the evaluation of patients with suspected CFTR-related disorders and highlight the limitations of binary variant classification in clinical practice, particularly when borderline sweat chloride values do not meet established criteria for pulmonary disorders such as cystic fibrosis.