CFTR – Congenital Bilateral Absence of Vas Deferens

CFTR-related congenital bilateral absence of vas deferens (CBAVD) is an autosomal recessive disorder characterized by obstructive azoospermia and male infertility (HP:0011962, HP:0012873). CBAVD represents the mildest phenotypic expression of CFTR dysfunction, often manifesting without pulmonary or pancreatic disease. Genetic testing in CBAVD cohorts has revealed biallelic CFTR mutations in a majority of patients, underscoring the gene’s critical role in Wolffian duct development.

Large case series have identified CFTR variants in CBAVD patients across multiple ethnicities. In 23 Italian CBAVD men, comprehensive screening (reverse dot-blot, MLPA, DHPLC) detected a second CFTR mutation in 6 probands, raising the detection rate to 60.8% (PMID:20657600). Copy number variant analysis in 263 Chinese CBAVD patients revealed CFTR exon deletions or duplications in 5 individuals (1.9%) (PMID:32951344). Targeted sequencing of 80 Indian CBAVD men uncovered 20 CFTR variants, including eight novel missense and two novel splice-site mutations, with a significant association versus controls (P<0.0001) (PMID:34145097). A cohort of 639 azoospermic men found that 44% of those with ΔF508/R117H mutations exhibited CBAVD (PMID:33095972).

Segregation data for CFTR in CBAVD are limited due to use of sporadic case series, though compound heterozygosity for CFTR mutations in affected individuals across unrelated families supports autosomal recessive inheritance with full penetrance of the genital phenotype. No extended pedigrees with multiple affected relatives have been reported in CBAVD cohorts, consistent with the sporadic referral pattern for assisted reproduction.

The CFTR variant spectrum in CBAVD includes missense (e.g., c.313A>C (p.Ile105Leu)), splice-site (e.g., IVS8-5T), small indels, and CNVs. Recurrent alleles such as the 5T-12TG haplotype show population-specific enrichment in CBAVD patients (PMID:17234733). Large rearrangements account for a minority of cases yet warrant routine MLPA analysis in mutation-negative patients.

Functional studies demonstrate that CBAVD-associated CFTR alleles impair mRNA splicing, protein maturation, or chloride conductance without causing full CF. RFLP-PCR of the M469I variant confirmed complete absence in controls and specific detection in obstructive azoospermia patients (PMID:25246892). In vitro CNV assays verify genomic rearrangements, and haplotype analyses elucidate TG-polyT interactions that modulate exon 9 skipping.

Integration of genetic and functional data yields a Definitive gene–disease association. Comprehensive CFTR testing, including full coding sequencing, intron 8 poly-T/TG haplotyping, and CNV analysis, is clinically indispensable for CBAVD diagnosis, genetic counseling, and reproductive planning.

Key Take-home: Full CFTR analysis—beyond standard mutation panels—is required in CBAVD patients to detect biallelic variants, guide ICSI counseling, and prevent transmission of classic cystic fibrosis.

References

• Asian journal of andrology • 2010 • Identification of the second CFTR mutation in patients with congenital bilateral absence of vas deferens undergoing ART protocols. PMID:20657600
• Molecular genetics & genomic medicine • 2020 • Analysis of CNVs of CFTR gene in Chinese Han population with CBAVD. PMID:32951344
• Iranian journal of reproductive medicine • 2012 • Exon 10 CFTR gene mutation in male infertility. PMID:25246892
• Clinical chemistry • 2007 • Simple method for haplotyping the poly(TG) repeat in individuals carrying the IVS8 5T allele in the CFTR gene. PMID:17234733
• Andrology • 2021 • Prevalence of CBAVD in azoospermic men carrying pathogenic CFTR mutations - Evaluated in a cohort of 639 non-vasectomized azoospermic men. PMID:33095972

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