Novel Candidate Genes Identified in Men with Congenital Absence of Vas Deferens without CFTR Gene Abnormalities

Area of Science:

• Genetics
• Reproductive Medicine
• Human Molecular Genetics

Background:

• Congenital absence of the vas deferens (CAVD) has unknown genetic causes in a significant percentage of cases, particularly when CFTR pathogenic variants are absent.
• Investigating the genetic underpinnings of CAVD, with and without renal anomalies, is crucial for understanding its etiology and improving diagnostic approaches.

Purpose of the Study:

• To identify the genetic etiology of congenital bilateral absence of the vas deferens (CBAVD) and congenital unilateral absence of the vas deferens (CUAVD) in individuals negative for CFTR pathogenic variants.
• To explore genetic causes in CAVD cases, considering the presence or absence of renal anomalies.

Main Methods:

• Whole-exome sequencing (WES) was performed on 16 men with CAVD.
• Targeted resequencing was conducted on a total of 19 CAVD cases, including those who underwent WES and additional CBAVD cases without renal anomalies.
• Analysis focused on individuals with CAVD who were negative for CFTR variants via Sanger sequencing.

Main Results:

• A novel hemizygous ADGRG2 pathogenic variant was identified in two men with CBAVD without renal anomalies.
• Pathogenic variants in AR, NCKPAL1, FSHR, and SLC26A4 genes were detected in CBAVD cases without renal anomalies.
• Variants in FREM1, WNT2B, and TBX6 genes were found in CBAVD men with renal abnormalities; no variants were detected in CUAVD with renal anomalies.

Conclusions:

• ADGRG2, AR, NCKPAL1, FSHR, and SLC26A4 represent novel candidate genes for CBAVD in CFTR-negative individuals.
• Genetic testing for ADGRG2 is recommended for genetic counseling in CFTR-negative CBAVD due to its X-linked transmission.
• Whole-exome sequencing for CFTR, ADGRG2, and other candidate genes is advised for genetic screening prior to Intracytoplasmic sperm injection (ICSI).