A novel cystic fibrosis mutation “delS1255” in a male diagnosed at birth

Abstract

Cystic fibrosis (CF) is an autosomal recessive disorder caused by pathogenic variants in the CFTR gene. Over 2000 CFTR variants have been identified, and ongoing genetic characterization remains critical for guiding eligibility for CFTR modulator therapies and contributing to variant databases that support diagnosis and research. We describe a 20-year-old Caucasian male who is a compound heterozygous for the common F508del mutation and a novel variant, p.Ser1255del (c.3763_3765delTCA; delS1255). He was diagnosed with CF in the neonatal period following meconium ileus, confirmed by elevated sweat chloride testing. His clinical course included pancreatic insufficiency, chronic Staphylococcus aureus colonization, and sinus disease with nasal polyps, but no evidence of CF-related diabetes or liver disease. Molecular diagnostic testing conducted at Stanford Clinical Laboratory using PCR and bidirectional Sanger sequencing confirmed the F508del mutation and identified the previously unreported delS1255 variant, an in-frame deletion of a serine residue at position 1255. This variant is absent from population databases and a missense mutation at the same codon has previously been associated with severe CF phenotypes, supporting its likely pathogenicity. The patient was initiated on elexacaftor-tezacaftor-ivacaftor (ETI) therapy in 2021, based on the presence of the F508del allele. Since starting ETI, he has experienced substantial clinical improvement, including improved spirometry, radiology, and a marked reduction in sweat chloride concentration. The response is presumed to be driven by the F508del variant, while the effect of delS1255 on modulator responsiveness remains unknown. This case adds to the growing spectrum of CFTR variants with clinical relevance.