Expanding the phenotypic and genetic spectrum of Chinese patients with congenital absence of vas deferens bearing CFTR and ADGRG2 alleles

Abstract

BackgroundCongenital absence of vas deferens (CAVD) is a major cause of obstructive azoospermia. Mutations in CFTR and ADGRG2 are responsible for this disease. However, until now the genetic spectrum of the CFTR and ADGRG2 genes in Chinese population and the reasons of the differences from Caucasian cohorts were not clear.Objectives(i) To study the characteristic and functional consequences of CFTR and ADGRG2 mutations in Chinese CAVD patients. (ii) To describe the genetic spectrum of Chinese CAVD patients and explain the reasons of the differences from Caucasian cohorts and Chinese cystic fibrosis (CF) patients.Materials and MethodsPatients were screened for mutations in CFTR by Sanger sequencing. Patients with only one or no mutations were further investigated by multiplex ligation‐dependent probe amplification analysis and direct sequencing of ADGRG2 gene. Bioinformatic analysis and structural modeling of proteins were performed.ResultsA total of 28 mutations in CFTR were identified in 72 patients, of which five mutations were novel. Fifty‐five patients (76.39%) had CFTR mutations but no indels, among which 80.00% CBAVD patients have at least one CFTR mutation and 66.67% CUAVD have at least one CFTR mutation. Two novel mutations (p.Lys818* and p.Arg1008Gln) in ADGRG2 were detected. These novel mutations were predicted to be damaging by bioinformatics and were absent or extremely low frequency among our controls and databases. The genetic spectrum of Chinese CAVD patients revealed that the most common mutations were c.1210‐12T[5], p.Ile556Val and p.Gln1352His, the last two of which were predicted to reduce the domains’ contacts and weaken adenosine triphosphate binding.Discussion and ConclusionThis study illustrates the significance of all exon sequencing in CFTR and ADGRG2. A picture of the genetic spectrum of Chinese CAVD patients and the most common mutations can be described, which are different from Caucasian cohorts and Chinese CF patients.

Genetics of the congenital absence of the vas deferens

“…The establishment of the causal role of these mutations in the iCBAVD phenotype was based on a set of arguments: (i) male ADGRG2 knockout (KO) mice develop OA without any other significant abnormality (Davies et al 2004), (ii) histological examination of an epididymal biopsy of one of the four individuals showed a lack of expression of ADGRG2 in the epithelium of efferent ductules that were abnormally dilated, (iii) one of the truncated mutations was identified in two infertile individuals related by a maternal link (a nephew and a maternal uncle). Since then, three publications (Yang et al 2017;Yuan et al 2019; Khan et al 2018) have reported the identification of five new rare variations of ADGRG2 in six iCBAVD patients of Asian origin with no pathogenic CFTR mutation: two nonsense mutations classified as pathogenic, including one in two infertile brothers of Pakistani origin (Khan et al 2018) and three missense mutations, including one affecting the GPS region which was classified as pathogenic (Yang et al 2017). These six patients had no renal abnormalities.…”

“…The determinism of URA-CAVDs is probably complex depending on genetic, epigenetic, and environmental factors. It is perplexing that URA-CAVD is more rarely reported in studies of non-European populations that are actually well documented (Yang et al 2015;Radpour et al 2008;Sharma et al 2014;Wu et al 2004;Yuan et al 2019). New studies using integrative multi-omics approaches will probably make it possible to specify the share of determinism linked to genetic mutations and to identify possible epigenetic causes of URA-CAVDs in distinct ethnic populations of origin.…”

High‐resolution imaging of the actin cytoskeleton and epithelial sodium channel, CFTR, and aquaporin‐9 localization in the vas deferens

“…Extending these earlier findings, we suggest that ENaC has a role in the function of vas deferens smooth muscle cells that remain to be defined. (de Souza et al, 2018;Yuan et al, 2019). Yet, the molecular mechanisms by which the CFTR mutations lead to problems of organogenesis remain ununderstood.…”

The X chromosome and male infertility

“…By exome sequencing of CFTR-negative CBAVD patients, LoF mutations were recently identified in the X-linked ADGRG2 gene (Patat et al 2016), which encodes an adhesion G protein-coupled receptor that is specifically expressed in the epididymis and efferent ducts (Obermann et al 2003). Subsequently, further truncating and missense variants in ADGRG2 have been described Yuan et al 2019;Pagin et al 2019). In accordance with human data, previous studies have already demonstrated that Adgrg2-knock-out male mice develop obstructive infertility (Davies et al 2004).…”