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Review
. 2020 Jun 4;11(6):619.
doi: 10.3390/genes11060619.

Molecular Diagnosis and Genetic Counseling of Cystic Fibrosis and Related Disorders: New Challenges

Thierry Bienvenu  1 , Maureen Lopez  1 , Emmanuelle Girodon  1
Affiliations
Review

Molecular Diagnosis and Genetic Counseling of Cystic Fibrosis and Related Disorders: New Challenges

Thierry Bienvenu et al. Genes (Basel). .

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.

Keywords: CFTR; CFTR variants; CFTR-related disorders; Next Generation Sequencing (NGS); cystic fibrosis; disease liability; genotype-guided therapy; interpretation; molecular diagnosis; penetrance.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Molecular investigation for the diagnosis of cystic fibrosis (CF) and cystic fibrosis transmembrane conductance regulator related disorders (CFTR-RD) in three steps. Sensitivity refers to variant detection rate in patients with CF.
Figure 2
Figure 2
Links between health care professionals for carrying out appropriate CFTR studies and accurate interpretation of CFTR genetic test results. NPD: nasal potential difference; ICM: intestinal chloride measurement; SCT: sweat chloride testing.
Figure 3
Figure 3
Penetrance of phenotypes in individuals who are compound heterozygous for c.[350G>A;1210-12T[7]];[1521_1523del] (R117H;T7/F508del) from Thauvin et al. [67].
Figure 4
Figure 4
Genetic counseling situations (in orange), with potential identification of CF carriers, according to variable practices of molecular analysis (in blue). The number of variants tested is indicated in brackets. CFTR-RD: CFTR-related disorder; NBS: newborn screening; NIPD: non-invasive prenatal diagnosis; PND: prenatal diagnosis; PGD: preimplantation genetic diagnosis. Hatched lines: expected practice in the near future.
See this image and copyright information in PMC

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