WS23.5 Clinical importance of homozygous R117C (c.349C>T) CFTR mutation

Abstract

Objectives: The CFTR2 Database considers the class IV CFTR mutation R117C (c.349C>T) to be a disease causing mutation. However, the clinical importance is difficult to determine due to its rareness. This report describes the first case of R117C homozygosity, by maternal uniparental isodisomy (UPD) causing cystic fibrosis (CF) and Silver–Russell syndrome. Methods: Clinical description, genetic diagnosis, nasal potential difference (NPD). Results: A 17 months old boy was referred to our CF Centre as a part of the investigation of failure to thrive. Height and weight was within normal variation at birth but decreased to −4SD. The history revealed recurrent upper respiratory tract infections, but no pneumonias, normal stools. Exams showed: Sweat Cl− (Gibson): 54 and 64mmol/L, chest radiogram: bronchial thickening, pulmonary function test: Vmax FRC 275 (+0.2 SD), anti-S. aureus and P. aeruginosa: negative, F-chymotrypsine and -elastase: normal. DNA sequence analysis showed that the mother was a carrier of R117C (IVS-8 7T). No sequence change could be detected in the father. Microsatellites covering chromosome 7 showed maternal UPD of chromosome 7. NPD showed borderline pathology. Patient outcome up to 6 years of age: Sweat Cl−: 92 and 75mmol/L. Chest radiogram: bronchial thickening w/o bronchiectasis. Pulmonary function test: Vmax FRC 335 (−0.3 SD) at 3 yrs and FEV1 0.61 L (58%) at 6 yrs. Occasional cultures of Haemophilus influenzae and Moraxella catarrhalis. Anti-S. aureus and P. aeruginosa: negative. F-elastase: normal. The patient has intermittent need of inhalation therapy. Conclusion: The clinical manifestations and the NPD result for mutation R117C are non classical. WS23.6 Ivacaftor treatment in patients with cystic fibrosis who have an R117H-CFTR mutation, the KONDUCT study R.B. Moss1, P.A. Flume2, J.S. Elborn3, J. Cooke4, S.M. Rowe5, S.A. McColley6, R.C. Rubenstein7, M. Higgins4, on behalf of the VX11–770-110 (KONDUCT) Study Group. 1Stanford University School of Medicine, Palo Alto, United States; 2Medical University of South Carolina, Charleston, United States; 3Queen’s University Belfast, Belfast, United Kingdom; 4Vertex Pharmaceuticals Incorporated, Boston, United States; 5University of Alabama at Birmingham, Birmingham, United States; 6Northwestern University Feinberg School of Medicine, Chicago, United States; 7The Children’s Hospital of Philadelphia, Philadelphia, United States