Carrier screening for cystic fibrosis in the new era of medications that restore CFTR function

Abstract

2 and has been established in the USA, Australia, and parts of Europe. 3 Carrier screening has been shown to reduce the pro- portion of livebirths with cystic fi brosis by 50% in two US states, 50% in Edinburgh, and 75% in northeastern Italy. 4-7 In these series, most of the remaining cystic fi brosis births have resulted from couples choosing to continue aff ected pregnancies to term, rather than from aff ected fetuses missed by screening. The widespread introduction of carrier screening for cystic fi brosis has been limited by several issues for health-care providers and policy makers, including variable phenotype of patients with the same genotype, the numerous muta- tions associated with cystic fi brosis, low public awareness of the disease, infrastructure for preconception and pre- natal care, genetic counselling resources, and health economic considerations. 3,8 Resolution of these issues has been slow. Furthermore, a new issue has emerged— namely, the development of CFTR restorative therapy that challenges the idea that cystic fi brosis is not curable. We discuss the implications of CFTR restorative therapy on carrier screening for cystic fi brosis. After decades of solely supportive therapies, several therapeutic advances have been made targeting the basic CFTR defect. 9,10 These developments include a CFTR suppressor that promotes ribosomal read-through for patients with nonsense (stop-codon) class I mutations (atarulen, PTC124; PTC Therapeutics, South Plainfi eld, NJ, USA), a CFTR potentiator that promotes chloride- channel gating (ivacaftor; Vertex Pharmaceuticals, Cambridge, MA, USA) for patients with class III-V mutations, and two CFTR correctors that promote traffi cking through the cytosol to the epithelial apical membrane for patients with the class II mutation Phe508del (lumacaftor and VX-661; Vertex Pharma- ceuticals). 9