Prevalence of CBAVD in azoospermic men carrying pathogenic <i>CFTR</i> mutations ‐ Evaluated in a cohort of 639 non‐vasectomized azoospermic men

Fedder, Jens; Jørgensen, Mette W; Engvad, Birte

doi:10.1111/andr.12925

Cited by 14 publications

(19 citation statements)

References 42 publications

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“…Several reports include description of the diagnoses of CF during adulthood in patients suffering from CF-like symptoms, such as bronchiectasis or azoospermia [6][7][8][9][10][11].…”

Section: Introductionmentioning

confidence: 99%

The Diagnosis of Cystic Fibrosis in Adult Age. Data from the Italian Registry

et al. 2021

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Cystic Fibrosis (CF) registries are an essential resource of epidemiological and clinical data. Although the median age at diagnosis is usually reported in the first months of life, a minority of individuals is diagnosed during adulthood. The aim of this study was to describe demographic, genetic, and clinical characteristics of this subgroup of the Italian CF population by using data from the Italian CF Registry (ICFR). Patients ≥18 years at diagnosis were selected and clinical data at diagnosis were analyzed from the 2012–2018 ICFR data (Cohort A). Subjects with diagnosis ≥18 years were selected from 2018 ICFR dataset (Cohort B) to describe their clinical status. In 2012–18 the incidence of late diagnosis was 18.2%, whereas, in 2018, the prevalence of patients diagnosed > 18 years was 12.54%. The median age of late diagnosis was 36.2 years, ranging from 19.0 to 68.3. The male patients were diagnosed because of infertility in the 45.9% of cases. Median sweat chloride value (SCL) was 69 mmol/L (range 9–150). F508del mutation accounted for 28.3% of alleles. A wide variability in respiratory function was present with a median percent predicted Forced Expiratory Volume in the first second (ppFEV1) of 90.8% (range 20–147%). Low prevalence of pancreatic insufficiency (25%) and of Pseudomonas aeruginosa (Pa) infection (17%) suggest a mild CF phenotype in the majority of patients. The assessment of the clinical status in the 2018 dataset and the comparison between genders showed a greater nutritional and respiratory impairment in females. Further studies are needed to clarify the importance of a true diagnostic delay or of late onset of CF symptoms.

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“…Several reports include description of the diagnoses of CF during adulthood in patients suffering from CF-like symptoms, such as bronchiectasis or azoospermia [6][7][8][9][10][11].…”

Section: Introductionmentioning

confidence: 99%

The Diagnosis of Cystic Fibrosis in Adult Age. Data from the Italian Registry

et al. 2021

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“… 7 Therefore, some researchers propose that CFTR mutations may affect male fertility through mechanisms other than reproductive tract obstruction. 18 In contrast, other investigators have not found a significant relationship between NOA and CFTR mutations. 19 – 21 We previously found that CFTR is expressed on human sperm and that it plays critical roles in sperm capacitation and fertilizing capability by regulating ion transport.…”

Section: Introductionmentioning

confidence: 90%

Loss-of-function CFTR p.G970D missense mutation might cause congenital bilateral absence of the vas deferens and be associated with impaired spermatogenesis

Hou

Wang

et al. 2022

Asian Journal of Andrology

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Congenital bilateral absence of the vas deferens (CBAVD) is observed in 1%–2% of males presenting with infertility and is clearly associated with cystic fibrosis transmembrane conductance regulator ( CFTR ) mutations. CFTR is one of the most well-known genes related to male fertility. The frequency of CFTR mutations or impaired CFTR expression is increased in men with nonobstructive azoospermia (NOA). CFTR mutations are highly polymorphic and have established ethnic specificity. Compared with F508Del in Caucasians, the p.G970D mutation is reported to be the most frequent CFTR mutation in Chinese patients with cystic fibrosis. However, whether p.G970D participates in male infertility remains unknown. Herein, a loss-of-function CFTR p.G970D missense mutation was identified in a patient with CBAVD and NOA. Subsequent retrospective analysis of 122 Chinese patients with CBAVD showed that the mutation is a common pathogenic mutation (4.1%, 5/122), excluding polymorphic sites. Furthermore, we generated model cell lines derived from mouse testes harboring the homozygous Cftr p.G965D mutation equivalent to the CFTR variant in patients. The Cftr p.G965D mutation may be lethal in spermatogonial stem cells and spermatogonia and affect the proliferation of spermatocytes and Sertoli cells. In spermatocyte GC-2(spd)ts (GC2) Cftr p.G965D cells, RNA splicing variants were detected and CFTR expression decreased, which may contribute to the phenotypes associated with impaired spermatogenesis. Thus, this study indicated that the CFTR p.G970D missense mutation might be a pathogenic mutation for CBAVD in Chinese males and associated with impaired spermatogenesis by affecting the proliferation of germ cells.

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“…In a meta-analysis study, 78% of men with CBAVD carried one or two (a severe and a mild or two mild) CFTR variants 7 . CBAVD was found in ~ 44% of a relatively unselected population of azoospermic men with p.Phe508del/ p.Arg117His variants 8 . The variant frequency and hot spots of CFTR gene in Caucasians were demonstrated to be significantly higher than that in individuals of Asian descent.…”

Section: Introductionmentioning

confidence: 99%

Correlation between CFTR variants and outcomes of ART in patients with CAVD in Central China

Cui

et al. 2023

Sci Rep

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Biallelic variants in Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) are the main pathogenic factor of congenital absence of the vas deferens (CAVD), including congenital bilateral absence of the vas deferens (CBAVD) and congenital unilateral absence of the vas deferens (CUAVD). However, there are few reports about the correlation between CFTR variant and outcomes of assisted reproductive technology (ART) in CAVD patients of China. In this study, 104 patients with CAVD were recruited in Central China, and provided gene detection by the whole-exome sequencing, among them 69% (72/104) carried at least one variant in CFTR and one carried adhesion G protein-coupled receptor G2 (ADGRG2) variant. A total of 81 CAVD patients were treated with ART, of which 21 and 60 carried none or at least one variant in CFTR, respectively. The fertilization rate, cleavage rate, effective embryo rate, implantation rate, clinical pregnancy rate and live birth rate per fresh embryo transfer were compared between patients with and without CFTR variants. It was found that the ART outcomes had no significant difference whether the patients carried the CFTR variant or not. In addition, all of the offspring were healthy after follow-up. In conclusion, rare CFTR variants may play a major role in patients with CAVD in Central China, which were greatly different from other descent. There was no significant difference in ART outcomes in CAVD patients with or without CFTR variants. The limitations of this study were that there was no statistical analysis of the sperm quality through TESA and conclusions were relatively limited due to the small sample size of the study.

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Prevalence of CBAVD in azoospermic men carrying pathogenic CFTR mutations ‐ Evaluated in a cohort of 639 non‐vasectomized azoospermic men

Cited by 14 publications

References 42 publications

The Diagnosis of Cystic Fibrosis in Adult Age. Data from the Italian Registry

The Diagnosis of Cystic Fibrosis in Adult Age. Data from the Italian Registry

Loss-of-function CFTR p.G970D missense mutation might cause congenital bilateral absence of the vas deferens and be associated with impaired spermatogenesis

Correlation between CFTR variants and outcomes of ART in patients with CAVD in Central China

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