Compound heterozygous mutations in CFTR causing CBAVD in Chinese pedigrees

Area of Science:

• Genetics
• Reproductive Medicine
• Molecular Biology

Background:

• Congenital bilateral absence of the vas deferens (CBAVD) is a significant cause of obstructive azoospermia and male infertility.
• Mutations in the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) gene are responsible for most CBAVD cases, with ADGRG2 recently identified as another pathogenic gene.
• Previous genetic evidence primarily stemmed from sporadic cases, with limited identification of CFTR mutations.

Purpose of the Study:

• To investigate the genetic basis of CBAVD in familial cases.
• To identify causative mutations in two pedigrees with affected male siblings.

Main Methods:

• Whole exome sequencing was performed on individuals from two CBAVD pedigrees.
• Potential variants were validated using Sanger sequencing and direct sequencing.

Main Results:

• ADGRG2 variants were excluded.
• Compound heterozygous variants in the CFTR gene were identified in both families: c.1210-33_1210-6GT[13]T[5] (a known disease-causing variant) and c.4056G>C;p.Gln1352Cys in pedigree 1; c.592G>C;p.Ala198Pro and c.3717G>A;p.Arg1239= in pedigree 2.
• The identified variants were predicted to be deleterious or alter splicing patterns.

Conclusions:

• The findings provide familial evidence that only recessive variants (homozygous or compound heterozygous) in CFTR cause CBAVD.
• Whole exome sequencing is a valuable tool for mutation screening in genes associated with CBAVD.