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

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.

Personalized genetic counseling for Stargardt disease: Offspring risk estimates based on variant severity

“…Different combinations of CFTR variants, many of which result in residual CFTR function, have been associated with CFTR-related disorders (CFTR-RDs), the mildest of which is congenital absence of the vas deferens (CAVD [MIM: 277180]) in males with no evidence of lung disease. 4,5 For several CFTR variants, functional assays have demonstrated the resulting residual CFTR activity, [6][7][8] but for many missense variants, the functional effect is unknown. Finally, different combinations of ABCA4 variants (GenBank: NM_000350.2) can result in multiple retinal phenotypes, i.e., early-onset cone-rod dystrophy-sometimes diagnosed as retinitis pigmentosa (retinitis pigmentosa 19 [MIM: 601718])-panretinal cone-rod dystrophy (cone-rod dystrophy 3 [MIM: 604116]), due to the early degeneration of both cone and rod cells; classic Stargardt disease (STGD1); or late-onset macular degeneration (STGD1 [MIM: 248200]).…”

“…Existing guidelines for the interpretation of pathogenicity of variants are not tailored to assess variant severity. The commonly used 5-tier American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG-AMP) system addresses the likelihood of a variant's pathogenicity on a scale from benign (1) to pathogenic (5), which in no way relates to its severity. 37 For instance, the frequent mild ABCA4 variant c.5882G>A (p.Gly1961Glu) is considered ''likely pathogenic'' according to the ACMG-AMP guidelines, whereas variants classified as variants of uncertain significance by ACMG-AMP may well cause a severe phenotype.…”

­­Systematic estimation of cystic fibrosis prevalence in Chinese and genetic spectrum comparison to Caucasians

“…This nding is consistent with previous study. For example, the carrier frequency of I556V in Asia population is as high as 4.7% [17]. This uncovers the different allele frequency and incomplete penetrance among different populations.…”

“…Several studies have reported different founder variants of CFTR in various races. F508del was reported to account for 30-88% CFTR pathogenic variants in non-Chinese populations [17]. Besides, Pompei et al found that most variants were associated with the M470V allele in several European populations which can help to trace the origin of the V allele [19].…”

Current Status of Genetic Counselling for Rare Diseases in Spain

“…With the implementation of carrier screening tests [ 19 ], a gynaecologist can also evaluate the risk of a couple (or even gamete donors) of carrying genetic variants responsible for autosomal recessive or an X-linked genetic disease. Thus, they might be able to reduce the risks of having an affected child with diseases, such as cystic fibrosis [ 46 ] or X-fragile by the use of preimplantation genetic diagnosis (PGD) [ 47 ]. Also, prenatal genetic testing (either non-invasive as a screening method or invasive as a diagnostic tool) might allow early detection of genetic abnormalities.…”