Abstract
Identification of the cystic fibrosis transmembrane conductance regulator (CFTR) gene and its numerous variants opened the way to fantastic breakthroughs in diagnosis, research and treatment of cystic fibrosis (CF). The current and future challenges of molecular diagnosis of CF and CFTR-related disorders and of genetic counseling are here reviewed. Technological advances have enabled to make a diagnosis of CF with a sensitivity of 99% by using next generation sequencing in a single step. The detection of heretofore unidentified variants and ethnic-specific variants remains challenging, especially for newborn screening (NBS), CF carrier testing and genotype-guided therapy. Among the criteria for assessing the impact of variants, population genetics data are insufficiently taken into account and the penetrance of CF associated with CFTR variants remains poorly known. The huge diversity of diagnostic and genetic counseling indications for CFTR studies makes assessment of variant disease-liability critical. This is especially discussed in the perspective of wide genome analyses for NBS and CF carrier screening in the general population, as future challenges.
Highlights
Cystic fibrosis (CF) is one of the most frequent life-limiting autosomal recessive diseases, characterized in its classical form by chronic pulmonary obstruction and infections, pancreatic insufficiency, male infertility, sweat chloride concentrations ≥60 mmol/L and two loss-of-function variants in the cystic fibrosis transmembrane conductance regulator (CFTR) gene (NM_000492.4; LRG_663t1) [1]
Technical milestones have led to identify a huge number of CFTR gene variants and a variety of molecular mechanisms responsible for CF [3], which contribute to the wide phenotype variability, and to achieve one of the highest sensitivities in the diagnosis of a hereditary disease, more than 99% of CF-causing variants being identified in newborns with CF [4]
We review the current and future challenges of molecular diagnosis and genetic counseling
Summary
Cystic fibrosis (CF) is one of the most frequent life-limiting autosomal recessive diseases, characterized in its classical form by chronic pulmonary obstruction and infections, pancreatic insufficiency, male infertility, sweat chloride concentrations ≥60 mmol/L and two loss-of-function variants in the cystic fibrosis transmembrane conductance regulator (CFTR) gene (NM_000492.4; LRG_663t1) [1]. Technical milestones have led to identify a huge number of CFTR gene variants and a variety of molecular mechanisms responsible for CF [3], which contribute to the wide phenotype variability, and to achieve one of the highest sensitivities in the diagnosis of a hereditary disease, more than 99% of CF-causing variants being identified in newborns with CF [4]. The contribution of CFTR variants varies from one condition to another, and may act in a multifactorial context, with other genes being potentially involved, such as ADGRG2 in male infertility by the absence of vas deferens [10] or PRSS1, SPINK1 and CTRC in pancreatitis [11]. We will emphasize on the importance to consider population genetics and penetrance data in the process to evaluate the impact of variants These data will eventually be discussed in the perspective of implementation of wide genome analyses for NBS and preconception. CF carrier screening in the general population in an increasing number of countries
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