• PMID: 31672438
• Gene Name: CFTR
• Condition: Congenital bilateral absence of vas deferens (CBAVD)
• Association: Associated
• Mutation: p.(Arg117Cys), p.(Arg1158*), p.(Asp110His), p.(Ser945Leu), p.(Arg248Thr), p.(Phe508Cys), p.(Gly463Ser), p.(Phe508del), p.(Arg117His)
• Population size: 1112
• Population details: 1112 idiopathic infertile men with azoospermia or severe oligozoospermia. Pre-screening exclusion criteria were CBAVD by clinical examination with positive CFTR sequence analysis as part of routine fertility workup
• Sex: Male
• Infertility type: Male infertility
• Associated genes: NGS

Improved detection of CFTR variants by targeted next-generation sequencing in male infertility: a case series

Smits RM, Oud MS, Vissers LELM, Lugtenberg D, Braat DDM, Fleischer K, Ramos L, D'Hauwers KWM.

RESEARCH QUESTION: Congenital bilateral absence of vas deferens (CBAVD) is characterized by 'obstructive azoospermia' in male patients with primary infertility. In the routine clinical workup of infertile men, patients with an absence of vas deferens are screened for CFTR variants. However, current genetic testing panels do not cover all variants, missing some CBAVD cases. Here, CFTR testing was explored by targeted next-generation sequencing (NGS) to improve variant detection. DESIGN: Five individuals with heterozygous pathogenic CFTR variants were identified using targeted NGS in a cohort of 1112 idiopathic infertile men with azoospermia or severe oligozoospermia. Pre-screening exclusion criteria were CBAVD by clinical examination with positive CFTR sequence analysis as part of routine fertility workup. RESULTS: Cases 1, 2 and 3 presented with CBAVD after which CFTR screening by mutation panel analysis was negative. Case 4 presented with congenital unilateral absence of vas deferens, after which CFTR panel analysis identified a heterozygous p.(Phe508del) variant. Case 5 presented with a palpable vas deferens so CFTR panel analysis was not offered. In all five men, targeted NGS revealed additional pathogenic variants: p.(Arg117Cys) and p.(Arg1158*) (case 1); p.(Asp110His) and p.(Ser945Leu) (case 2); p.(Arg248Thr) and p.(Phe508Cys) (case 3); p.(Gly463Ser) (case 4); p.(Phe508del) (case 4 and 5); and p.(Arg117His) (case 5). CONCLUSIONS: Targeted NGS led to the detection of five infertile men with CFTR variants who would otherwise have remained undiagnosed after routine genetic screening during the fertility workup for azoospermia or severe oligozoospermia. Given the wide availability of affordable targeted NGS, the data suggest that full gene analysis, and not mutation panels, should be considered to screen CFTR in azoospermic men. CI - Copyright © 2019 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved. FAU - Smits, Roos M AU - Smits RM AD - Department of Obstetrics and Gynaecology, Radboud University Medical Centre, Nijmegen, The Netherlands. Electronic address: roos.smits@radboudumc.nl. FAU - Oud, Manon S AU - Oud MS AD - Department of Human Genetics, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Centre, Nijmegen, The Netherlands. FAU - Vissers, Lisenka E L M AU - Vissers LELM AD - Department of Human Genetics, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Centre, Nijmegen, The Netherlands. FAU - Lugtenberg, Dorien AU - Lugtenberg D AD - Department of Human Genetics, Radboud University Medical Centre, Nijmegen, The Netherlands. FAU - Braat, Didi D M AU - Braat DDM AD - Department of Obstetrics and Gynaecology, Radboud University Medical Centre, Nijmegen, The Netherlands. FAU - Fleischer, Kathrin AU - Fleischer K AD - Department of Obstetrics and Gynaecology, Radboud University Medical Centre, Nijmegen, The Netherlands. FAU - Ramos, Liliana AU - Ramos L AD - Department of Obstetrics and Gynaecology, Radboud University Medical Centre, Nijmegen, The Netherlands.