Genetic diagnosis and sperm retrieval outcomes for Chinese patients with congenital bilateral absence of vas deferens

Abstract

Background Congenital bilateral absence of the vas deferens (CBAVD) is a frequent cause of obstructive azoospermia. CBAVD is mainly caused by mutations in the CFTR (cystic fibrosis transmembrane conductance regulator) gene and is also related to the X‐linked ADGRG2 (adhesion G protein‐coupled receptor G2) gene. Genetic screening and counseling strategies for Chinese CBAVD populations remain controversial because the genetic background of CBAVD in Chinese population is largely unknown. Objectives In this study, we aimed to study the mutation spectrum of CFTR and ADGRG2 in a group of CBAVD patients and to evaluate sperm retrieval outcomes in a subset of CBAVD patients. Materials and methods Next‐generation targeted sequencing was used to identify mutations in the CFTR and ADGRG2 genes in 38 CBAVD patients. In addition, we followed and analyzed nine of the 38 patients who were undergoing sperm retrieval surgery. Results In total, 27 of 38 (71.05%) patients carried at least one likely pathogenic or pathogenic mutation in CFTR or ADGRG2. In addition to the IVS9‐5T allele, 15 CFTR and 1 ADGRG2 mutations were identified, including 4 novel mutations. CFTR hot‐spot mutations were not identified in our study. Spermatozoon was successfully obtained in all nine patients who underwent MESA or TESE surgery, but most patients had spermatozoa with relatively low motility and high abnormality rates. Discussion and conclusion Except for the IVS9‐5T allele, hot‐spot mutations of CFTR may not exist in Chinese CBAVD patients. Therefore, next‐generation targeted sequencing for whole CFTR and ADGRG2 gene may be the appropriate genetic testing method, and genetic counseling may be different from Caucasian populations. We observed a high success rate of sperm retrieval with relatively low motility and high abnormality rates in Chinese CBAVD patients. However, this is only a weak conclusion due to the small sample size.

Congenital absence of the vas deferens with hypospadias or without hypospadias: Phenotypic findings and genetic considerations

“…The 5T allele polymorphism varies considerably by geographic location and ethnicity, particularly among non-Caucasian populations ( Dork et al, 1997 ). In the current study, the frequency of the 5T allele was the most frequent variant, similar to other reports in Chinese cohorts ( Du et al, 2014 ; Gaikwad et al, 2018 ; Wang et al, 2020 ). No ADGRG2 variants were identified, suggesting ADGRG2 variants may not play a major role in these CAVD populations.…”

“…In this study, 29 out of 50 (58%) patients had at least one reportable CFTR variant. These results demonstrated that our CAVD population had a lower percentage than previous reports in which 70%-80% of CBAVD patients carried at least one CFTR mutation (Yu et al, 2012;Wang et al, 2020), which may be due to our small sample size. The variant c.1521_1523delCTT (F508del) is one of the most common variants in northern European CAVD populations, accounting for up to one-third of CAVD patients (Barratt et al, 2017;Bieth et al, 2021), whereas only two (2/50) are carriers in our CAVD patients.…”

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

“…Recent research reported that among 263 Chinese patients with CBAVD, 5 (1.9%) patients were detected for copy number variants in the region of the CFTR gene (four of them carried partial deletions and one carried partial duplication of CFTR ), 37 but other studies did not find copy number variations of CFTR in males with CBAVD. 38 , 39 A larger number of samples and more sensitive gene detection methods are essential for further research. Although a specific knock-in mouse model supported our findings, further investigations are needed to clarify the function of CFTR in spermatogenesis in animal models in vivo .…”

Fertility outcome of patients with CBAVD: a single-institution experience

“…This finding suggests the presence of a mixed pathology, with both obstructive damage and testicular failure. PESA outcomes justify these; both in terms of activity or vitality were low and abnormality rates were high [25].…”