The improvement of the best practice guidelines for preimplantation genetic diagnosis of cystic fibrosis: toward an international consensus

Abstract

Cystic fibrosis (CF) is one of the most common indications for preimplantation genetic diagnosis (PGD) for single gene disorders, giving couples the opportunity to conceive unaffected children without having to consider termination of pregnancy. However, there are no available standardized protocols, so that each center has to develop its own diagnostic strategies and procedures. Furthermore, reproductive decisions are complicated by the diversity of disease-causing variants in the CFTR (cystic fibrosis transmembrane conductance regulator) gene and the complexity of correlations between genotypes and associated phenotypes, so that attitudes and practices toward the risks for future offspring can vary greatly between countries. On behalf of the EuroGentest Network, eighteen experts in PGD and/or molecular diagnosis of CF from seven countries attended a workshop held in Montpellier, France, on 14 December 2011. Building on the best practice guidelines for amplification-based PGD established by ESHRE (European Society of Human Reproduction and Embryology), the goal of this meeting was to formulate specific guidelines for CF-PGD in order to contribute to a better harmonization of practices across Europe. Different topics were covered including variant nomenclature, inclusion criteria, genetic counseling, PGD strategy and reporting of results. The recommendations are summarized here, and updated information on the clinical significance of CFTR variants and associated phenotypes is presented.

Recent Advances in Mitochondrial Disease

“…Preimplantation genetic diagnosis for mitochondrial disease is another reproductive option for couples at risk of transmitting nDNA or mtDNA mutations to their offspring (26,27,80,82). This technique involves genetic testing of cells removed from early embryos obtained during in vitro fertilization procedures and allows the selection of embryos with a reduced risk of mitochondrial disease for implantation.…”

“…The approach involves the elimination of mutant mtDNA from oocytes using nucleases engineered to bind and remove (through doublestrand breaks) specific mutant mtDNA sequences. These nucleases include mitochondrially targeted zinc-finger nucleases (mtZFNs) and mitochondrially targeted transcription activator-like effector nucleases (mitoTALENs), both of which selectively remove mutant mtDNA and reduce heteroplasmy levels in patient-derived transmitochondrial cybrid models (5,25,26,42,68). The same strategy has been applied to heteroplasmic mouse oocytes containing two different mtDNA genomes, revealing that nucleases can be used to prevent germline transmission of specific mtDNA sequences and reduce the level of pathogenic mtDNA mutations, as performed in heteroplasmic mouse oocytes generated by fusion with patient cells (79).…”

A Broad Test Based on Fluorescent-Multiplex PCR for Noninvasive Prenatal Diagnosis of Cystic Fibrosis

“…Our strategy was to base the diagnosis on an indirect approach, as the current practice in preimplantation genetic diagnosis [11,13] is characterization of the affected allele(s), using linked (intra-or extragenic) polymorphic markers, instead of detecting each specific mutation. It is especially relevant for CF since over 1,000 different mutations have been described ( [15]; CF mutation database, http://www.genet.sickkids.…”

Pros and cons of implementing a carrier genetic test in an infertility practice

“…Reproductive healthcare providers are acquainted with counselling on genetic disorders diagnosed in a targeted screening, although with single genes former Sanger sequencing still shows difficulties [15,16]. Concern exists in genetic professionals about the challenges to reproductive health providers arising with expanded CGT [17].…”