Cystic fibrosis carrier screening using next generation sequencing: A cautionary tale

Cystic fibrosis carrier screening using next generation sequencing: A cautionary tale

VOLUME 114, ISSUE 3, P495-496


R. Matthew Coward, M.D., F.A.C.S., Elysia L. Davis, M.G.C., C.G.C., Steven L. Young, M.D., Ph.D.


Reflections on "Carriers of cystic fibrosis among sperm donors: complete CFTR gene analysis vs. CFTR genotyping" by Molina et al.

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Go to the profile of Marta Molina Romero
over 2 years ago

We read with interest your invited editorial on our paper. In our opinion, what is really alarming is the lack of consensus on the study of CFTR gene carriers and the considerable heterogeneity currently to be found in clinical practice and in the genotyping tests used in a given population.

All the variants reported in our study meet the criteria established for classification as ‘pathogenic’ or ‘probably pathogenic’ variants, according to the Standards and Guidelines for the Interpretation of Sequence Variants of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (1).

Due to the well-known clinical and genetic heterogeneity of cystic fibrosis (CF) and the incomplete penetrance of some of its variants, no clear genotype-phenotype relationship has yet been established. This circumstance underlies the present lack of consensus among scientific societies regarding the specific study of the CFTR gene. Furthermore, it has led to the existence of widely varying genotyping panels of the CFTR gene, with diverse residual risks. This scenario has created a situation of uncertainty among clinics and patients, which should not be ignored (2).

Advances in the genetics of CF have not only required changes in sperm donor screening, but have led to contradictory situations with regard to neonatal CF screening. In the latter case, situations have arisen that just a few years ago were unknown, such as CFTR-related metabolic syndrome (CRMS). In fact, in some neonatal screening programmes, more cases of CRMS than of classical CF are now being detected (3). It seems logical to assume that these advances will also impact on the screening of sperm donors.

In reproductive medicine, the information provided by NGS, in the case of a couple who have decided to perform genetic matching with their own gametes, should be treated in a different way from the situation of a woman who decides to use donor sperm. In the latter case, there is always the possibility of changing the donor, in order to reduce the reproductive risk. However, this possibility does not arise in the first situation. Accordingly, the two situations are ethically different, and this circumstance should be borne in mind (4)

In view of these considerations, we believe the protocols should be adapted to take into account the information provided by NGS, and that new strategies for consensus should be sought, rather than ignoring this new context and continuing to speak of reproductive risk in a generic way. Therefore, we would recommend that for sperm donors, the complete sequencing of the CFTR gene be performed, and the resulting information managed, for example, via the following strategies:

  • Donors carrying pathogenic CFTR variants clearly associated with a classical or severe phenotype --> Should not be accepted into the donation programme, thus reducing the risk of classical CF when donor sperm is used, with or without genetic matching. Justification: the use of sperm from a donor carrying a risky variant, even when the recipient is not a carrier of the CFTR gene, according to a genotyping panel, could be unsafe due to the limited ability of genotyping panels to detect pathogenic variants.
  • Donors carrying pathogenic variants in CFTR when there is no clear association with a classical or severe phenotype --> These donors should be accepted into the donation programme. CFTR variants will be considered in the designation of sperm donors, via recipient-donor genetic matching. Thus, when the recipient is a carrier of a pathogenic variant of CFTR, the donor assigned will not be a carrier of any pathogenic variant, according to the complete study of the CFTR gene, thus reducing the risk of CF being transmitted to the child, in the entire clinical spectrum. If the recipient is a non-carrier, according to the genotyping test, she may still be a carrier of a variant associated with a non-classical phenotype, and so the assignment of a donor carrying such a variant risks the birth of a child carrying two pathogenic variants of CFTR albeit with no obvious association with the classical phenotype, which in most cases is symptom-free. There is also a residual risk, that the recipient may be carrying a severe, but rare, pathogenic variant. Knowledge of these residual risks is dependent on the CFTR genotyping panel performed on the patient and it is very important that this information be reported.

We hope our article encourages scientific societies to agree upon which variants should be considered in the study of CFTR gene carriers in sperm donors, and which strategies should be applied to reduce the reproductive risks of CF in assisted reproduction treatments based on sperm donation.


  1. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015;17:405–424.
  2. Silver AJ, Larson JL, Silver MJ, Lim RM, Borroto C, Spurrier B et al. Carrier screening is a deficient strategy for determining sperm donor eligibility and reducing risk of disease in recipient children. Genet Test Mol Biomarkers 2016;20:276-84.
  3. Ren CL, Borowitz DS, Gonska T, et al. Cystic fibrosis transmembrane conductance regulator-related metabolic syndrome and cystic fibrosis screen positive, inconclusive diagnosis. J Pediatr 2017;181S:S45-S51.
  4. Dondorp W, De Wert G, Pennings G, et al. ESHRE Task Force on Ethics and Law 21: genetic screening of gamete donors: ethical issues. Hum Reprod 2014;29:1353-1359.

Marta Molina, M.Sc. a

José A. Castilla, M.D., Ph.D. a, b, c.

a Ceifer Biobanco – NextClinics, Granada, Spain; b U. Reproducción, UGC Obstetricia y Ginecología, HU Virgen de las Nieves, Granada, Spain; and c Instituto de Investigación Biosanitaria ibs.GRANADA, Granada, Spain.