Congenital Bilateral Absence of Vas Deferens

Mendelian MONDO:0018801 Pathograph 16 Show in embeddings browser Male Infertility

Congenital bilateral absence of the vas deferens is obstructive azoospermia with intact spermatogenesis. The testis works; the conduit is missing. That separation is what makes the condition treatable - sperm can be recovered surgically from the epididymis or testis and used for ICSI - and it is also what makes it mechanistically interesting, because whatever destroys the vas deferens leaves the seminiferous epithelium alone. Most cases are a CFTR-related disorder. The genotypes involved are not the genotypes of cystic fibrosis: they retain enough residual CFTR function to spare lung and pancreas while still failing in the mesonephric duct derivatives, which appear to be the tissue with the least tolerance for reduced anion and fluid secretion. The commonest configuration is one severe and one mild allele in compound heterozygosity. A smaller group - about 2% of cases - is X-linked, caused by loss-of-function variants in ADGRG2, an adhesion GPCR specific to the epididymis and efferent ducts, and those men have no CFTR abnormality at all. The most useful distinction in this entry is not between those two genes but between two developmental timings. CAVD associated with a solitary kidney carries CFTR mutations at conspicuously low rates, and the coincidence of absent duct and absent kidney points to a failure of mesonephric duct organogenesis - an early, structural event. CFTR- and ADGRG2-related disease looks different: the duct forms and then involutes, progressively, later in fetal life and possibly beyond birth. This entry covers the second. The renal-anomaly group is a developmental field defect that happens to share a clinical endpoint.

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2
Inheritance
5
Pathophys.
5
Phenotypes
1
Gaps
16
Pathograph
3
Genes
4
Medical Actions
2
Subtypes
1
Differentials
4
Models
14
References
1
Deep Research
👪

Inheritance

2
Autosomal recessive HP:0000007
For the CFTR-related form. Two CFTR alleles are required, typically one severe and one mild in compound heterozygosity - the mild allele is what keeps the phenotype confined to the genital tract.
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:33000223 SUPPORT Human Clinical
"usually one severe and one mild, in compound heterozygosity"
The allele configuration underlying the recessive mode in this disease.
X-linked recessive HP:0001419
For the ADGRG2-related form. Hemizygous loss-of-function variants transmitted through carrier females, established from families with X-linked transmission of infertility.
X-linked recessive inheritance
Show evidence (1 reference)
PMID:32025909 SUPPORT Human Clinical
"Approximately 2% of the cases of CAVD are hemizygous for a loss-of-function mutation in the ADGRG2 gene that may cause a familial form of X-linked infertility."
Establishes both the X-linked mode and the share of cases it accounts for.
◆

Subtypes

2
?

Discussions and Knowledge Gaps

1
Is CAVD with a solitary kidney the same disease as CFTR-related CAVD, or a developmental field defect that shares an endpoint?
KNOWLEDGE GAP cbavd_two_developmental_timings
Attached to
pathophysiology#Progressive Involution of Mesonephric Duct Derivatives differential_diagnoses#Congenital unilateral absence of the vas deferens
Two lines of evidence say these are different processes. CAVD occurring with renal agenesis has a conspicuously low CFTR mutation rate - low enough that the reviewed literature describes CFTR mutations as absent in that group - and the co-occurrence of an absent duct with an absent kidney points at the mesonephric duct itself, from which both derive. Against that, CFTR- and ADGRG2-related disease shows a duct that formed and then degenerated, with fetal specimens at 12-18 weeks showing obstruction and denaturation by mucus that worsens as gestation proceeds. If that reading is right, then "CBAVD" as currently used names two mechanistically distinct conditions - an early organogenesis failure and a late progressive involution - that a clinician cannot separate without a renal ultrasound. It would explain the otherwise puzzling 10-20% of bilateral cases with no genetic diagnosis despite deep CFTR testing, and it would mean those men are not simply awaiting a better CFTR panel. What is missing is direct evidence. No study has compared duct histology across the two groups at matched gestational ages, and the renal-anomaly group has not been systematically exome-sequenced for developmental regulators of the mesonephric duct. Until it is, the distinction rests on an inference from mutation yield and a co-occurring anomaly.
Proposed experiments
Exome sequencing of CAVD stratified by renal ultrasound
cbavd_renal_anomaly_group_exome
Sequence CFTR-negative CAVD cohorts stratified by the presence or absence of a solitary kidney, testing whether the renal-anomaly group is enriched for variants in mesonephric duct developmental regulators rather than in ion transport genes.
Would support
pathophysiology#Progressive Involution of Mesonephric Duct Derivatives
Supporting outcome
  • The renal-anomaly group is enriched for developmental regulators and depleted of ion-transport variants, establishing two distinct genetic architectures behind one clinical endpoint.
Refuting outcome
  • Both groups converge on ion-transport and duct-maintenance genes, meaning the renal anomaly reflects severity along one mechanism rather than a separate one.
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Pathophysiology

5
Residual-Function CFTR Genotype
Mechanism confidence: Established
A CFTR genotype that reduces chloride and bicarbonate conductance without abolishing it. This is the defining feature of the disease and the reason it is not cystic fibrosis: the same gene, a different point on the residual- function axis. The threshold that matters is tissue-specific, and the mesonephric duct derivatives sit at the sensitive end of it - so a genotype that leaves lung and pancreas essentially normal still fails here.
genital tract epithelial cell CL:0000066 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves genital tract epithelial cell, annotated with epithelial cell (CL:0000066). CL:0000066 is a cell type from the Cell Ontology.
CFTR hgnc:1884 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves CFTR (hgnc:1884). hgnc:1884 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context CFTR hgnc:1884 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns CFTR (hgnc:1884). hgnc:1884 is a gene from the HUGO Gene Nomenclature Committee. functional_impact_category: PARTIAL_LOSS_OF_FUNCTION
chloride transmembrane transport GO:1902476 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased chloride transmembrane transport (GO:1902476). GO:1902476 is a biological process from the Gene Ontology.
chloride channel activity GO:0005254 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased chloride channel activity (GO:0005254). GO:0005254 is a molecular function from the Gene Ontology.
Downstream
Impaired Luminal Fluid and Anion Secretion
Show evidence (2 references)
PMID:33000223 SUPPORT Human Clinical
"Mutations in the CFTR gene impair the normal function of chloride channels and prevent them from regulating the flow of chloride ions and water across the cell membrane"
The molecular consequence of the CFTR genotype at this node.
PMID:33000223 SUPPORT Human Clinical
"a normal amount of functional CFTR protein may be required to ensure the normal development of the vas deferens"
States the dose-sensitivity of the vas deferens that this node describes as a tissue-specific threshold.
Impaired Luminal Fluid and Anion Secretion
Mechanism confidence: Established
CFTR in the apical membrane of genital tract epithelium drives anion and therefore water movement into the lumen. With reduced conductance the luminal secretion becomes scanty and viscous. Fluid secretion is required for normal mesonephric duct development, so this is the step at which an ion-transport defect becomes a developmental one.
epididymal epithelial cell CL:0000068 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves epididymal epithelial cell, annotated with duct epithelial cell (CL:0000068). CL:0000068 is a cell type from the Cell Ontology.
chloride transmembrane transport GO:1902476 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased chloride transmembrane transport (GO:1902476). GO:1902476 is a biological process from the Gene Ontology.
mesonephric duct UBERON:0003074 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in mesonephric duct (UBERON:0003074). UBERON:0003074 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Progressive Involution of Mesonephric Duct Derivatives
Show evidence (2 references)
PMID:33000223 SUPPORT Human Clinical
"It has also been demonstrated that fluid secretion is necessary for the normal development of the mesonephric duct"
The link from secretion to duct development that this node turns on.
PMID:33000223 SUPPORT Human Clinical
"resulting in the production of highly viscous mucus by epithelial cells of the male genital tract"
Describes the luminal consequence of the secretory defect.
Loss of ADGRG2 Signalling in Efferent Ducts
Mechanism confidence: Established
The alternative entry point. ADGRG2 is an adhesion GPCR expressed specifically in the epididymis and efferent ducts, where it is required for fluid reabsorption. Hemizygous truncating variants abolish it. That a receptor governing duct fluid handling and a channel governing duct fluid secretion both produce the same anatomical endpoint is the strongest argument that luminal fluid balance, rather than any one gene product, is what the mesonephric duct derivatives depend on.
ADGRG2 hgnc:4516 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves ADGRG2 (hgnc:4516). hgnc:4516 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context ADGRG2 hgnc:4516 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns ADGRG2 (hgnc:4516). hgnc:4516 is a gene from the HUGO Gene Nomenclature Committee. functional_impact_category: LOSS_OF_FUNCTION
epididymis UBERON:0001301 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in epididymis (UBERON:0001301). UBERON:0001301 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Progressive Involution of Mesonephric Duct Derivatives
Show evidence (2 references)
PMID:27476656 SUPPORT Human Clinical
"ADGRG2, encoding the epididymal- and efferent-ducts-specific adhesion G protein-coupled receptor G2"
Establishes the tissue-restricted expression that makes loss of this receptor produce an isolated genital phenotype.
PMID:27476656 SUPPORT Model Organism
"Previous studies have demonstrated that Adgrg2-knockout male mice develop obstructive infertility."
The model-organism support for ADGRG2 causing obstructive infertility, cited as prior work in the human discovery report.
Progressive Involution of Mesonephric Duct Derivatives
Mechanism confidence: Provisional
The duct is formed and then lost. Fetal studies report the vas deferens obstructed and degenerating by mucus at 12-18 weeks, with the process worsening as gestation continues - so this is involution of a structure that developed, not failure to develop one. The timing is the load-bearing point of this entry: it distinguishes CFTR- and ADGRG2-related disease from the CAVD that accompanies renal agenesis, where the duct appears never to have formed properly at all.
chloride transmembrane transport GO:1902476 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased chloride transmembrane transport (GO:1902476). GO:1902476 is a biological process from the Gene Ontology.
vas deferens UBERON:0001000 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in vas deferens (UBERON:0001000). UBERON:0001000 is an anatomical location from the Uberon multi-species anatomy ontology. epididymis UBERON:0001301 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in epididymis (UBERON:0001301). UBERON:0001301 is an anatomical location from the Uberon multi-species anatomy ontology. seminal vesicle UBERON:0000998 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in seminal vesicle (UBERON:0000998). UBERON:0000998 is an anatomical location from the Uberon multi-species anatomy ontology.
Animal models
Slc9a3 knockout mouse (obstructive azoospermia via CFTR loss) Mouse recapitulates Loss of Slc9a3 destabilizes CFTR protein in the epididymis and vas deferens, producing the same progressive luminal obstruction and duct compromise seen with direct CFTR or ADGRG2 loss - support for this entry's claim that ductal fluid handling, not any one gene product, is the shared dependency of the mesonephric duct derivatives.
Adgrg2 (He6/Gpr64) knockout mouse (efferent duct fluid dysregulation) Mouse partially recapitulates An isolated fluid-reabsorption defect in the efferent ductules causing duct dilation, spermatozoal obstruction, and testicular fluid backup - the same class of duct-fluid-handling failure this entry attributes to human ADGRG2 loss, from the mouse ortholog of the same receptor. Partial rather than full recapitulation: the lesion sits in a different duct segment and the duct is not lost.
CFTR-knockout rat (bilateral vasal absence and epididymal hypoplasia) Rat recapitulates Loss of Cftr in the rat reproduces the defining endpoint of this node - bilateral loss of the vas deferens with an underdeveloped epididymis - in the gene that accounts for most human cases.
CFTR knock-in and partial-knockout mouse (fertile, no vasal phenotype) Mouse fails to recapitulate Residual-function Cftr alleles in the mouse leave fertility intact, so these models do not reproduce the progressive duct involution this node describes.
Downstream
Obstructive Azoospermia with Preserved Spermatogenesis
Show evidence (2 references)
PMID:32025909 SUPPORT Human Clinical
"unlike CAVDs related to CFTR or ADGRG2 mutations, which might be the result of progressive degeneration that begins later in fetal life and probably continues after birth"
States the progressive-involution model and explicitly contrasts it with the early-organogenesis group, which is the distinction this node records.
PMID:33000223 SUPPORT Human Clinical
"In 12-18 week-old abortive fetuses with CFTR gene mutations, the vas deferens is obstructed and denatured by mucus, and the vas deferens may be further aggravated in embryonic development"
The fetal observation that dates the involution and shows it worsening across gestation.
Obstructive Azoospermia with Preserved Spermatogenesis
Mechanism confidence: Established
The clinical endpoint. Spermatozoa are produced normally in the testis but have no route out, so the ejaculate is azoospermic, low in volume, acidic and depleted of the seminal vesicle contribution - fructose in particular. Testis size and FSH are normal or near-normal, which is what separates this biochemically from non-obstructive azoospermia and is why surgical retrieval works.
vas deferens UBERON:0001000 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in vas deferens (UBERON:0001000). UBERON:0001000 is an anatomical location from the Uberon multi-species anatomy ontology.
Show evidence (3 references)
PMID:29216686 SUPPORT Human Clinical
"Diagnosis of CBAVD is generally based on these criteria: presence of normal to slightly small sized testicles, non-palpable vas deferens, normal plasma levels of FSH (Follicle-Stimulating Hormone), and reduced ejaculate volume"
The clinical picture of preserved testicular function with an absent conduit.
PMID:33000223 SUPPORT Human Clinical
"The hallmarks of CBAVD include azoospermia, reduced semen volume (<1 ml), pH value (≤7.0) and seminal fructose, as well as decreased production of spermatozoa in the testicles."
The semen findings recorded at this node.
PMID:20301428 SUPPORT Other
"male infertility due to hypoplasia or aplasia of the vas deferens"
The GeneReviews statement of the mechanism, listed among the morbidities of CFTR dysfunction.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Congenital Bilateral Absence of Vas Deferens Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

5
Obstructive Azoospermia VERY_FREQUENT Reproductive HP:0000027 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Azoospermia (HP:0000027). HP:0000027 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33000223 SUPPORT Human Clinical
"The hallmarks of CBAVD include azoospermia, reduced semen volume (<1 ml), pH value (≤7.0) and seminal fructose"
Names azoospermia first among the hallmark findings.
Absent Vas Deferens VERY_FREQUENT Reproductive HP:0012873 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Absent vas deferens (HP:0012873). HP:0012873 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29216686 SUPPORT Human Clinical
"Diagnosis of CBAVD is generally based on these criteria: presence of normal to slightly small sized testicles, non-palpable vas deferens, normal plasma levels of FSH (Follicle-Stimulating Hormone), and reduced ejaculate volume"
Places bilaterally non-palpable vasa deferentia among the diagnostic criteria, alongside the preserved testicular size and normal FSH that mark the obstruction as the lesion.
Male Infertility VERY_FREQUENT Reproductive HP:0003251 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Male infertility (HP:0003251). HP:0003251 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33000223 SUPPORT Human Clinical
"Congenital bilateral absence of the vas deferens (CBAVD) accounts for 2-6% of male infertility cases and up to 25% of cases of obstructive azoospermia"
Quantifies the contribution to male infertility and to obstructive azoospermia.
Seminal Vesicle Abnormality FREQUENT Reproductive HP:6000190 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal seminal vesicle morphology (HP:6000190). HP:6000190 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:33000223 SUPPORT Human Clinical
"atrophy or absence of seminal vesicle and cauda epididymis"
Documents seminal vesicle involvement alongside the epididymis.
PMID:41255074 SUPPORT Human Clinical
"Only 2 out of 51 patients (3.9%) had a standard SV."
Quantifies how nearly universal seminal vesicle abnormality is on MRI in this population.
Epididymal Abnormality FREQUENT Reproductive HP:0009714 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal epididymis morphology (HP:0009714). HP:0009714 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33000223 SUPPORT Human Clinical
"atrophy or absence of seminal vesicle and cauda epididymis"
Documents cauda epididymis involvement.
🧬

Genetic Associations

3
CFTR
Gene: CFTR hgnc:1884 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is CFTR (hgnc:1884). hgnc:1884 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (6 references)
PMID:29216686 SUPPORT Human Clinical
"Some mutations in the gene encoding cystic fibrosis transmembrane conductance regulator (CFTR) can lead to CBAVD as a monosymptomatic form of CF."
States the relationship between the CBAVD genotype and cystic fibrosis.
PMID:35119551 SUPPORT Human Clinical
"There are no obvious hotspot CFTR mutations in Chinese CBAVD patients besides the IVS9-5 T allele."
Establishes the 5T tract as the one recurrent allele in that population, and the absence of other hotspots.
PMID:35119551 SUPPORT Human Clinical
"In total, 35 of 46 (76.09%) patients carried at least one variation in CFTR, but no copy number variants or ADGRG2 variations were found."
The CFTR-positive rate and the absence of ADGRG2 variants in this cohort.
+ 3 more references
ADGRG2
Gene: ADGRG2 hgnc:4516 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is ADGRG2 (hgnc:4516). hgnc:4516 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (2 references)
PMID:32025909 SUPPORT Human Clinical
"Approximately 2% of the cases of CAVD are hemizygous for a loss-of-function mutation in the ADGRG2 gene"
The share of cases attributable to ADGRG2.
PMID:37273165 SUPPORT Human Clinical
"This mutation was also unexpectedly found in a male member with normal reproductive capability."
The incomplete-penetrance observation that qualifies ADGRG2 counselling.
SLC9A3
Gene: SLC9A3 hgnc:11073 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is SLC9A3 (hgnc:11073). hgnc:11073 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: SUSCEPTIBILITY
Show evidence (4 references)
PMID:28384194 SUPPORT Model Organism
"we found that CFTR expression was dramatically decreased in the epididymis and vas deferens of Slc9a3 knockout mice"
The mechanistic link from SLC9A3 loss to reduced CFTR in exactly the tissues this disease affects.
PMID:28384194 SUPPORT Model Organism
"Slc9a3-/- mice developed obstructive azoospermia because of abnormal abundant secretions and calcification in the lumen of the reproductive tract"
The phenotype, which is this disease's endpoint reached through a third gene.
PMID:28384194 SUPPORT Human Clinical
"Some patients have a single copy deletion of the solute carrier family 9 isoform 3 (SLC9A3) gene."
The human genetic observation that motivated the mouse work.
+ 1 more reference
💊

Medical Actions

4
Surgical Sperm Retrieval with ICSI
Action: sperm retrievalNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is sperm retrieval (NCIT:C94427). NCIT:C94427 is a clinical intervention from the NCI Thesaurus. Ontology label: Sperm Retrieval NCIT:C94427
Platform: Surgery
The definitive management, and it works because the lesion is obstructive. Sperm are recovered from the epididymis or testis and used for intracytoplasmic sperm injection. Outcomes in isolated CBAVD are notably better than in men with full cystic fibrosis: in a two-centre comparison the CF group had lower retrieved sperm concentration and motile count, needed rescue testicular extraction far more often, and had roughly half the fertilisation rate. That gradient is evidence that CFTR affects sperm function itself and not only the conduit - which qualifies the tidy "obstruction only" account this entry otherwise gives.
Mechanism Target:
MODULATES Obstructive Azoospermia with Preserved Spermatogenesis — Bypasses the missing conduit rather than restoring it. No postnatal treatment reaches the duct involution - but see the prenatal CFTR modulator entry, which reports the one setting in which something appears to.
Show evidence (2 references)
PMID:32930103 SUPPORT Human Clinical
"The CF group also demonstrated a significantly higher rate of rescue testicular sperm extraction (70.0% vs 27.6%, P < 0.03) and lower fertilization rate with ICSI (32.5% vs 68.9%, P < 0.01)."
The comparative outcome data distinguishing isolated CBAVD from full cystic fibrosis.
PMID:32930103 SUPPORT Human Clinical
"those with CF demonstrated lower sperm quality, greater difficulty with sperm retrieval, and worse ICSI outcomes compared with CBAVD-only patients"
The study's conclusion, which supports treating retrieval success in isolated CBAVD as the favourable case.
Partner CFTR Screening and Genetic Counselling
Action: genetic counselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is genetic counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. Ontology label: Genetic Counseling NCIT:C15240
Platform: Other
Not optional. Because the man carries at least one cystic fibrosis-causing allele, a carrier partner puts the couple at risk of a child with classic cystic fibrosis - a far more serious disease than the father's. Partner screening and, where indicated, preimplantation genetic testing are what convert a treatable infertility into a safe one.
Show evidence (3 references)
PMID:29216686 SUPPORT Human Clinical
"genetic counseling should be offered to couples undergoing ART to discuss the probability of having offspring that carry CFTR gene mutations"
The counselling recommendation this entry records.
PMID:33000223 SUPPORT Human Clinical
"With the use of pre-implantation genetic diagnosis, testicular or epididymal sperm aspiration, intracytoplasmic sperm injection and in vitro fertilization, patients affected by CBAVD are able to have children who do not carry CFTR gene mutations, thereby preventing disease."
Establishes preimplantation genetic testing as the route to avoiding transmission.
PMID:20301428 SUPPORT Other
"Once the CFTR pathogenic variants have been identified in an affected family member, targeted heterozygote testing for at-risk relatives and prenatal/preimplantation genetic testing for CF are possible."
The GeneReviews genetic-counselling position, which is the baseline this entry's counselling treatment follows.
Intracytoplasmic Sperm Injection
Action: intracytoplasmic sperm injectionNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is intracytoplasmic sperm injection (NCIT:C185482). NCIT:C185482 is a clinical intervention from the NCI Thesaurus. Ontology label: Intracytoplasmic Sperm Injection NCIT:C185482
Platform: Other
Fertilisation of the partner's oocytes with the retrieved spermatozoa. Recorded separately from retrieval because the two steps have different determinants: retrieval success depends on residual CFTR activity, while cumulative ICSI success in the same Lille cohort did not differ between cystic fibrosis and CFTR-related disorder groups. Once usable sperm are in hand, the CFTR genotype stops mattering as much.
Mechanism Target:
MODULATES Obstructive Azoospermia with Preserved Spermatogenesis — Achieves fertilisation without the conduit.
Show evidence (2 references)
PMID:40850271 SUPPORT Human Clinical
"Cumulative success rates of ICSI did not differ significantly across groups."
The result that separates ICSI outcome from retrieval outcome in this population.
PMID:35119551 SUPPORT Human Clinical
"Spermatozoa were successfully retrachieved in 46 patients, and 39 of the patients had their own offspring through ICSI."
The paternity rate achieved through retrieval plus ICSI in a consecutive CBAVD series. Quoted verbatim including the source's typo 'retrachieved' for 'retrieved'.
Prenatal CFTR Modulator Therapy
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Platform: Small molecule
The one intervention that appears to reach the mechanism rather than bypass it, and it is a single case. A male fetus with cystic fibrosis whose heterozygous carrier mother began elexacaftor/tezacaftor/ivacaftor at 27+4 weeks had bilateral vasa deferentia demonstrable on ultrasound at 8 weeks of age - a structure absent in nearly all males with cystic fibrosis at birth. The timing is what makes it mechanistically informative rather than merely encouraging. Men already born and taking modulators show no improvement in infertility. A structure that can be preserved at 27 weeks and not recovered afterwards is a structure that is being lost during gestation, which is independent evidence for the progressive-involution model this entry is built on and against fixed early agenesis. n=1, uncontrolled, and the ethical position for a heterozygous fetus - who would not develop the disease - is unresolved. Recorded because of what it establishes about the mechanism, not as a management recommendation.
Mechanism Target:
INHIBITS Progressive Involution of Mesonephric Duct Derivatives — Restores CFTR function during the window in which the duct is still present, apparently arresting the involution.
Show evidence (3 references)
PMID:41654435 SUPPORT Human Clinical
"Remarkably, ultrasound at 8 weeks demonstrated bilateral vas deferens, a structure typically absent in nearly all male patients with CF at birth."
The observation itself, and the reason it is remarkable.
PMID:41654435 SUPPORT Human Clinical
"These findings suggest that prenatal CFTR modulation - even when initiated late in gestation - may alter the trajectory of CF-related organ manifestations, including male reproductive development."
The authors' own hedged interpretation, which this entry does not strengthen.
PMID:39288989 SUPPORT Human Clinical
"At present male patients taking CFTR modulators have not shown improvement in infertility."
The postnatal complement: modulators given after birth do not restore fertility, which is what makes the prenatal timing the load-bearing variable.
🔬

Biochemical Markers

1
Seminal Fructose (Decreased)
Context: Fructose is contributed to the ejaculate almost entirely by the seminal vesicles, so an undetectable or low level is the biochemical correlate of the seminal-vesicle atrophy this entry already models, alongside the low volume and acidic pH that come from the same missing contribution.
Pathograph Readouts
Readout Of Seminal Vesicle Abnormality Threshold Dependent Diagnostic
Undetectable or low seminal fructose is the semen-analysis correlate of seminal vesicle involvement, used alongside low volume and acidic pH to build the CBAVD semen picture.
Show evidence (1 reference)
PMID:29216686 SUPPORT Human Clinical
"azoospermic, acidic pH, undetectable or low fructose concentrations (normal: >25 μM)"
Names low/undetectable seminal fructose as one of the semen-analysis hallmarks, alongside the normal reference threshold.
Show evidence (1 reference)
PMID:29216686 SUPPORT Human Clinical
"azoospermic, acidic pH, undetectable or low fructose concentrations (normal: >25 μM)"
Establishes the biochemical finding and its normal reference threshold in this population.
🔬

Diagnosis

3
Clinical and Semen Assessment
Bilaterally non-palpable vasa on scrotal examination, with a semen profile of azoospermia, low volume, acidic pH and low fructose, against normal FSH and normal or near-normal testicular size. That combination separates obstructive from non-obstructive azoospermia before any genetic test is sent.
physical examination NCIT:C20989 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:29216686 SUPPORT Human Clinical
"Diagnosis of CBAVD is generally based on these criteria: presence of normal to slightly small sized testicles, non-palpable vas deferens, normal plasma levels of FSH (Follicle-Stimulating Hormone), and reduced ejaculate volume"
The diagnostic criteria this entry describes.
CFTR and ADGRG2 Testing with Renal Ultrasound
CFTR testing is indicated in essentially every case, both to establish the diagnosis and because the result determines whether the partner needs carrier screening. ADGRG2 is the next test in CFTR-negative men. Renal ultrasound belongs in the same workup for a different reason: a solitary kidney marks the developmental-field group, in which CFTR mutations are conspicuously uncommon and a negative CFTR result is therefore expected rather than surprising.
genetic testing NCIT:C15709 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:32025909 SUPPORT Human Clinical
"The majority of subjects with CAVD carry at least one cystic fibrosis-causing mutation that warrants CFTR testing and in case of a positive result, genetic counseling prior to conception."
Establishes CFTR testing and the counselling that follows a positive result.
PMID:32025909 SUPPORT Human Clinical
"An important proportion of these unexplained CAVDs coexist with a solitary kidney suggesting an early organogenesis disorder (Wolffian duct)"
The reason renal imaging belongs in the workup - it identifies a group with a different developmental mechanism and a different expected genetic yield.
Scrotal Ultrasound and Pelvic MRI
Imaging confirms the absent vasa and characterises the seminal vesicles, which are abnormal in nearly every patient. MRI adds the intra-abdominal segment, which scrotal ultrasound cannot reach - and a dilated intra-abdominal vas deferens, seen in bilateral but not unilateral disease, is a positive imaging argument for acquired involution rather than primary agenesis. That makes imaging evidence for this entry's central mechanism and not only a diagnostic step.
magnetic resonance imaging procedure NCIT:C16809 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:41255074 SUPPORT Human Clinical
"The intra-abdominal part of the VD dilatation is a new finding in CAVD and was not found in patients with CUAVD."
The imaging finding specific to bilateral disease.
PMID:41255074 SUPPORT Human Clinical
"Preliminary findings in this study are consistent with the theory of acquired vasal agenesis in CBAVD."
An independent line of support for the progressive-involution model this entry is built on.
📈

Progression

1
Fetal and early postnatal
The window in which the disease happens. The duct forms, is obstructed and degraded by mucus by 12-18 weeks, and the process worsens as gestation proceeds and probably continues after birth. After that it is static: there is no adult progression, and the clinical course is a fixed obstructive azoospermia. The therapeutic corollary is in the prenatal CFTR modulator entry - restoration during this window preserved the duct in one reported case, while postnatal modulators do not restore fertility.
Show evidence (1 reference)
PMID:32025909 SUPPORT Human Clinical
"unlike CAVDs related to CFTR or ADGRG2 mutations, which might be the result of progressive degeneration that begins later in fetal life and probably continues after birth"
The timing of the process, which is what makes this a progression record with a closing window rather than an ongoing course.
📊

Prevalence

1
Men, worldwide
Point Prevalence 100.0 per 100,000 >1 in 1,000
Reported as approximately 0.1% of men for congenital absence of the vas deferens overall (bilateral and unilateral together), normalised here to 100 per 100,000. The source states this is probably an underestimate, since unilateral disease in fertile men is generally never diagnosed - so the figure is a floor, and it covers a broader concept than this entry's scope.
Show evidence (1 reference)
PMID:32025909 SUPPORT Human Clinical
"The prevalence of CAVDs in men is reported to be approximately 0.1%. However, this figure is probably underestimated, because unilateral forms of CAVD in asymptomatic fertile men are not usually diagnosed."
PARTIAL because the quoted figure is for congenital absence of the vas deferens overall rather than for the bilateral form this entry covers, and the source itself flags it as an underestimate.
⚖️

Clinical Burden

Moderate
The burden is confined to fertility - there is no organ damage, no shortened life, and no progression after the duct is lost. Against that, it is usually the reason a couple presents, and it is treatable: 39 of 46 men in a consecutive series had their own children through retrieval and ICSI. Rated MODERATE rather than LOW because the diagnosis also identifies a CFTR carrier couple, and the child at risk has cystic fibrosis - a far more serious disease than the father's.
Show evidence (2 references)
PMID:35119551 SUPPORT Human Clinical
"After proper counseling, all patients can undergo sperm retrieval from their epididymis or testis, and most of them can have their own children through ICSI."
The outcome statement behind this rating.
PMID:29216686 SUPPORT Human Clinical
"genetic counseling should be offered to couples undergoing ART to discuss the probability of having offspring that carry CFTR gene mutations"
The transmission risk that keeps this above a LOW rating.
🔀

Differential Diagnoses

1

Conditions with similar clinical presentations that must be differentiated from Congenital Bilateral Absence of Vas Deferens:

Congenital unilateral absence of the vas deferens Not Yet Curated MONDO:0800311
Overlapping Features A different clinical entity, not a milder form. Fertility is often preserved because one duct remains patent, it is frequently an incidental finding, and its genetic architecture differs - CFTR mutations account for a smaller share and 60-70% of cases have no genetic diagnosis at all, against 10-20% for the bilateral form. Explicitly out of scope for this entry.
Show evidence (1 reference)
PMID:32025909 SUPPORT Human Clinical
"despite this recent finding, 10-20% of CBAVDs and 60-70% of CUAVDs remain without a genetic diagnosis"
The differing genetic yield that supports treating unilateral disease as a separate entity.
🐁

Animal Models

4
Slc9a3 knockout mouse (obstructive azoospermia via CFTR loss)
Constitutive Slc9a3 knockout mice develop obstructive azoospermia from progressively worsening luminal secretions and calcification in the efferent ductules, epididymis, and vas deferens, driven by a dramatic loss of CFTR protein in those same tissues. The knockout was generated to study SLC9A3 as a CFTR interactor and genetic modifier rather than to model CBAVD directly, but the phenotype converges on this entry's endpoint through a third gene.
Species
Mouse
Genotype
Slc9a3 -/-
Publication
PMID:28384194
Pathograph links
Progressive Involution of Mesonephric Duct Derivatives recapitulates fidelity: moderate Loss of Slc9a3 destabilizes CFTR protein in the epididymis and vas deferens, producing the same progressive luminal obstruction and duct compromise seen with direct CFTR or ADGRG2 loss - support for this entry's claim that ductal fluid handling, not any one gene product, is the shared dependency of the mesonephric duct derivatives.
Limitations: The mechanism is indirect: SLC9A3 loss acts by reducing CFTR protein abundance rather than through a CFTR-independent route, and the mouse phenotype requires a homozygous null genotype whereas the human genetic evidence for SLC9A3 is a heterozygous single-copy deletion with no ClinGen assertion.
Readouts
CFTR protein expression in epididymis and vas deferens
Direction: DECREASED
Interpretation: Confirms the mechanistic link from SLC9A3 loss to reduced CFTR specifically in the tissues this disease affects.
Show evidence (1 reference)
PMID:28384194 SUPPORT Model Organism
"CFTR expression was dramatically decreased in the epididymis and vas deferens of Slc9a3 knockout mice"
The direct measurement of CFTR loss underlying this readout.
Luminal secretion accumulation and calcification in the excurrent ducts
Direction: INCREASED
Interpretation: Reproduces the structural endpoint of progressive duct obstruction that this node describes, albeit reached through a third gene rather than CFTR or ADGRG2 directly.
Show evidence (1 reference)
PMID:28384194 SUPPORT Model Organism
"Slc9a3-/- mice developed obstructive azoospermia because of abnormal abundant secretions and calcification in the lumen of the reproductive tract"
The histological/gross finding behind this readout.
Show evidence (1 reference)
PMID:28384194 SUPPORT Model Organism
"The Slc9a3-deficient mice with impaired male excurrent ducts in this study provide proof for our clinical findings that some Taiwanese of CBAVD carry SLC9A3 deletion but without major CFTR mutations."
The authors' own statement connecting the mouse phenotype back to the human CBAVD patients carrying SLC9A3 deletions, which is why this model is informative for this disease.
Adgrg2 (He6/Gpr64) knockout mouse (efferent duct fluid dysregulation)
The original functional evidence for this receptor in male fertility, predating the human ADGRG2-CBAVD discovery (PMID:27476656) by twelve years. Hemizygous knockout males develop age-dependent infertility from dysregulated fluid reabsorption in the efferent ductules, causing dilation and spermatozoal obstruction there and a backup of fluid into the testis - the same tissue-restricted, duct-fluid-handling mechanism this entry attributes to human ADGRG2 loss.
Species
Mouse
Genotype
He6 (Adgrg2/Gpr64) hemizygous null (7TM-domain deletion)
Publication
PMID:15367682
Pathograph links
Progressive Involution of Mesonephric Duct Derivatives partially recapitulates fidelity: moderate An isolated fluid-reabsorption defect in the efferent ductules causing duct dilation, spermatozoal obstruction, and testicular fluid backup - the same class of duct-fluid-handling failure this entry attributes to human ADGRG2 loss, from the mouse ortholog of the same receptor. Partial rather than full recapitulation: the lesion sits in a different duct segment and the duct is not lost.
Limitations: This is a constitutive knockout of the murine ortholog (then named He6/Gpr64), not a model of any specific human truncating ADGRG2 allele, and the reported pathology centers on efferent-ductule dilation and testicular fluid backup rather than the progressive vas deferens/epididymis involution described in human CBAVD.
Readouts
Efferent ductule dilation and luminal obstruction by spermatozoa
Direction: INCREASED
Interpretation: Structural correlate of the fluid-reabsorption defect, and the proximate cause of the infertility in this model.
Show evidence (1 reference)
PMID:15367682 SUPPORT Model Organism
"the ductules were found to be greatly dilated in knockout mice, and the lumen of the ductules was frequently obstructed by a large accumulation of spermatazoa"
The histological finding behind this readout. Quoted verbatim including the source's typo "spermatazoa" for "spermatozoa".
Testicular fluid accumulation and rete testis expansion
Direction: INCREASED
Interpretation: Back-pressure consequence of the efferent-duct obstruction, mirroring the entry's own account of obstruction upstream of the testis.
Show evidence (1 reference)
PMID:15367682 SUPPORT Model Organism
"leading to a backup of fluid accumulation in the testis and a subsequent stasis of spermatozoa within the efferent ducts"
The abstract's statement of the downstream testicular consequence.
Show evidence (1 reference)
PMID:15367682 SUPPORT Model Organism
"Mutant mice reveal a dysregulation of fluid reabsorbtion within the efferent ductules, leading to a backup of fluid accumulation in the testis and a subsequent stasis of spermatozoa within the efferent ducts."
The abstract's summary of the fluid-handling defect, which is why this model is informative for the duct-fluid-handling node. Quoted verbatim including the source's spelling "reabsorbtion".
CFTR-knockout rat (bilateral vasal absence and epididymal hypoplasia)
Across the animal models compared in this review, the CFTR-knockout rat is the one that comes closest to the human male reproductive phenotype, showing bilateral absence of the vas deferens together with epididymal hypoplasia. It is the model of the gene that explains the large majority of human CBAVD, and so is the reference point against which the modifier-gene models above should be read.
Species
Rat
Genotype
Cftr -/-
Publication
PMID:42380629
Pathograph links
Progressive Involution of Mesonephric Duct Derivatives recapitulates fidelity: high Loss of Cftr in the rat reproduces the defining endpoint of this node - bilateral loss of the vas deferens with an underdeveloped epididymis - in the gene that accounts for most human cases.
Limitations: The rat shows more pronounced hypospermatogenesis than men with CBAVD do, so the model overstates the testicular component of a condition that is otherwise obstructive with preserved spermatogenesis. The cited source is a comparative review rather than the primary description of the model.
Readouts
Bilateral vas deferens absence
Direction: ABOLISHED
Interpretation: The structural endpoint this node describes, observed in the knockout rat.
Show evidence (1 reference)
PMID:42380629 SUPPORT Model Organism
"showing bilateral absence of the vas deferens and epididymal hypoplasia"
The reported structural finding behind this readout.
Spermatogenic output
Direction: DECREASED
Interpretation: A divergence rather than a confirmation - the rat loses spermatogenesis to a degree human CBAVD does not, which is why this model's fidelity is qualified in the link's limitations.
Show evidence (1 reference)
PMID:42380629 SUPPORT Model Organism
"although they exhibit more pronounced hypospermatogenesis than observed in men"
The reported testicular divergence behind this readout.
Sourced from a 2026 comparative review of CF animal models rather than from the primary description of the rat itself; the review is the document that adjudicates between species, which is the claim being made here.
Show evidence (1 reference)
PMID:42380629 SUPPORT Model Organism
"CF transmembrane conductance regulator (CFTR)-knockout rats more closely reproduce the human phenotype, showing bilateral absence of the vas deferens and epididymal hypoplasia"
The review's cross-species comparison identifying this model as the closest available match to the human phenotype, which is why it is informative for this entry.
CFTR knock-in and partial-knockout mouse (fertile, no vasal phenotype)
A negative result worth recording: mouse models carrying a knock-in allele or a partial Cftr knockout generally stay fertile and do not develop the vasal phenotype, and only complete knockouts show vas deferens atresia, and then only with age. This is the species-and-allele limit on using the mouse for CBAVD, and the reason the rat above is the better reference model.
Species
Mouse
Genotype
Cftr knock-in or partial knockout (hypomorphic residual function)
Publication
PMID:42380629
Pathograph links
Progressive Involution of Mesonephric Duct Derivatives fails to recapitulate fidelity: low Residual-function Cftr alleles in the mouse leave fertility intact, so these models do not reproduce the progressive duct involution this node describes.
Limitations: The failure is specific to knock-in and partial-knockout alleles: complete Cftr-null mice do develop vas deferens atresia, but late, with aging, rather than as the prenatal-onset involution seen in humans. The cited source is a comparative review rather than the primary description of any one model, and it does not name the individual alleles behind the generalization.
Readouts
Male fertility in knock-in and partial-knockout mice
Direction: UNCHANGED
Interpretation: Preserved fertility is the observable negative: the duct is patent enough to carry spermatozoa, so the endpoint this node describes has not occurred.
Show evidence (1 reference)
PMID:42380629 SUPPORT Model Organism
"knock-in or partial knockout models usually remain fertile"
The reported fertility outcome behind this readout.
Show evidence (1 reference)
PMID:42380629 REFUTE Model Organism
"knock-in or partial knockout models usually remain fertile"
Directly contradicts the claim that these mouse models reproduce the human duct loss, which is what grades this link as a failure to recapitulate.
Show evidence (1 reference)
PMID:42380629 SUPPORT Model Organism
"Mouse models display heterogeneous phenotype: knock-in or partial knockout models usually remain fertile, whereas complete knockouts may develop vas deferens atresia with aging"
The review's summary of the mouse phenotype, establishing that residual-function alleles do not reproduce the human duct loss.
{ }

Source YAML

click to show 
name: Congenital Bilateral Absence of Vas Deferens
creation_date: '2026-08-28T23:10:00Z'
category: Mendelian
description: 'Congenital bilateral absence of the vas deferens is obstructive azoospermia with intact spermatogenesis.
  The testis works; the conduit is missing. That separation is what makes the condition treatable - sperm can
  be recovered surgically from the epididymis or testis and used for ICSI - and it is also what makes it mechanistically
  interesting, because whatever destroys the vas deferens leaves the seminiferous epithelium alone.

  Most cases are a CFTR-related disorder. The genotypes involved are not the genotypes of cystic fibrosis:
  they retain enough residual CFTR function to spare lung and pancreas while still failing in the mesonephric
  duct derivatives, which appear to be the tissue with the least tolerance for reduced anion and fluid secretion.
  The commonest configuration is one severe and one mild allele in compound heterozygosity. A smaller group
  - about 2% of cases - is X-linked, caused by loss-of-function variants in ADGRG2, an adhesion GPCR specific
  to the epididymis and efferent ducts, and those men have no CFTR abnormality at all.

  The most useful distinction in this entry is not between those two genes but between two developmental timings.
  CAVD associated with a solitary kidney carries CFTR mutations at conspicuously low rates, and the coincidence
  of absent duct and absent kidney points to a failure of mesonephric duct organogenesis - an early, structural
  event. CFTR- and ADGRG2-related disease looks different: the duct forms and then involutes, progressively,
  later in fetal life and possibly beyond birth. This entry covers the second. The renal-anomaly group is a
  developmental field defect that happens to share a clinical endpoint.'
disease_term:
  preferred_term: congenital bilateral absence of vas deferens
  term:
    id: MONDO:0018801
    label: congenital bilateral absence of vas deferens
synonyms:
- CBAVD
- congenital bilateral aplasia of vas deferens
- congenital bilateral agenesis of vas deferens
- CFTR-related CBAVD
parents:
- Male Infertility
has_subtypes:
- name: CFTR-related
  display_name: CFTR-related CBAVD
  description: The large majority. Patients carry CFTR variants - usually one severe and one mild allele in
    compound heterozygosity - whose combined residual function is above the threshold for pulmonary and pancreatic
    disease but below what the mesonephric duct derivatives require. Reported CFTR-positive rates vary with
    ascertainment and testing depth, and are consistently lower in men who also have a solitary kidney.
  evidence:
  - reference: PMID:33000223
    reference_title: 'Mutations of the cystic fibrosis transmembrane conductance regulator gene in males with
      congenital bilateral absence of the vas deferens: Reproductive implications and genetic counseling (Review).'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 60-70% of patients with CBAVD carry pathogenic CFTR mutations (Online Mendelian Inheritance in
      Man no. 602421), usually one severe and one mild, in compound heterozygosity
    explanation: Gives both the frequency and the characteristic compound-heterozygous allele configuration
      that defines this subtype.
  subtype_term:
    preferred_term: congenital bilateral aplasia of vas deferens from CFTR mutation
    term:
      id: MONDO:0010178
      label: congenital bilateral aplasia of vas deferens from CFTR mutation
  genes:
  - preferred_term: CFTR
    term:
      id: hgnc:1884
      label: CFTR
- name: ADGRG2-related
  display_name: X-linked ADGRG2-related CBAVD
  description: About 2% of cases. Hemizygous truncating variants in ADGRG2, which encodes an adhesion G protein-coupled
    receptor expressed specifically in the epididymis and efferent ducts. These men are CFTR-negative, and
    because the inheritance is X-linked the recurrence risk and the counselling are entirely different from
    the CFTR case - which is the practical reason the subtype matters.
  evidence:
  - reference: PMID:27476656
    reference_title: Truncating Mutations in the Adhesion G Protein-Coupled Receptor G2 Gene ADGRG2 Cause an
      X-Linked Congenital Bilateral Absence of Vas Deferens.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We identified three protein-truncating hemizygous mutations, c.1545dupT (p.Glu516Ter), c.2845delT
      (p.Cys949AlafsTer81), and c.2002_2006delinsAGA (p.Leu668ArgfsTer21), in ADGRG2, encoding the epididymal-
      and efferent-ducts-specific adhesion G protein-coupled receptor G2, in four subjects, including two related
      individuals with X-linked transmission of their infertility.
    explanation: The discovery report establishing ADGRG2 as an X-linked cause and naming the tissue specificity
      of the receptor.
  subtype_term:
    preferred_term: vas deferens, congenital bilateral aplasia of, X-linked
    term:
      id: MONDO:0010511
      label: vas deferens, congenital bilateral aplasia of, X-linked
  genes:
  - preferred_term: ADGRG2
    term:
      id: hgnc:4516
      label: ADGRG2
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: For the CFTR-related form. Two CFTR alleles are required, typically one severe and one mild
    in compound heterozygosity - the mild allele is what keeps the phenotype confined to the genital tract.
  evidence:
  - reference: PMID:33000223
    reference_title: 'Mutations of the cystic fibrosis transmembrane conductance regulator gene in males with
      congenital bilateral absence of the vas deferens: Reproductive implications and genetic counseling (Review).'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: usually one severe and one mild, in compound heterozygosity
    explanation: The allele configuration underlying the recessive mode in this disease.
- name: X-linked recessive
  inheritance_term:
    preferred_term: X-linked recessive inheritance
    term:
      id: HP:0001419
      label: X-linked recessive inheritance
  description: For the ADGRG2-related form. Hemizygous loss-of-function variants transmitted through carrier
    females, established from families with X-linked transmission of infertility.
  evidence:
  - reference: PMID:32025909
    reference_title: Genetics of the congenital absence of the vas deferens.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Approximately 2% of the cases of CAVD are hemizygous for a loss-of-function mutation in the ADGRG2
      gene that may cause a familial form of X-linked infertility.
    explanation: Establishes both the X-linked mode and the share of cases it accounts for.
pathophysiology:
- name: Residual-Function CFTR Genotype
  genes:
  - preferred_term: CFTR
    term:
      id: hgnc:1884
      label: CFTR
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  description: 'A CFTR genotype that reduces chloride and bicarbonate conductance without abolishing it. This
    is the defining feature of the disease and the reason it is not cystic fibrosis: the same gene, a different
    point on the residual- function axis. The threshold that matters is tissue-specific, and the mesonephric
    duct derivatives sit at the sensitive end of it - so a genotype that leaves lung and pancreas essentially
    normal still fails here.'
  genetic_context:
    gene:
      preferred_term: CFTR
      term:
        id: hgnc:1884
        label: CFTR
    functional_impact_category: PARTIAL_LOSS_OF_FUNCTION
  molecular_functions:
  - preferred_term: chloride channel activity
    modifier: DECREASED
    term:
      id: GO:0005254
      label: chloride channel activity
  biological_processes:
  - preferred_term: chloride transmembrane transport
    modifier: DECREASED
    term:
      id: GO:1902476
      label: chloride transmembrane transport
  cell_types:
  - preferred_term: genital tract epithelial cell
    term:
      id: CL:0000066
      label: epithelial cell
  downstream:
  - target: Impaired Luminal Fluid and Anion Secretion
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:33000223
    reference_title: 'Mutations of the cystic fibrosis transmembrane conductance regulator gene in males with
      congenital bilateral absence of the vas deferens: Reproductive implications and genetic counseling (Review).'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Mutations in the CFTR gene impair the normal function of chloride channels and prevent them from
      regulating the flow of chloride ions and water across the cell membrane
    explanation: The molecular consequence of the CFTR genotype at this node.
  - reference: PMID:33000223
    reference_title: 'Mutations of the cystic fibrosis transmembrane conductance regulator gene in males with
      congenital bilateral absence of the vas deferens: Reproductive implications and genetic counseling (Review).'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: a normal amount of functional CFTR protein may be required to ensure the normal development of
      the vas deferens
    explanation: States the dose-sensitivity of the vas deferens that this node describes as a tissue-specific
      threshold.
- name: Impaired Luminal Fluid and Anion Secretion
  biological_scale: CELLULAR
  mechanism_confidence: ESTABLISHED
  description: CFTR in the apical membrane of genital tract epithelium drives anion and therefore water movement
    into the lumen. With reduced conductance the luminal secretion becomes scanty and viscous. Fluid secretion
    is required for normal mesonephric duct development, so this is the step at which an ion-transport defect
    becomes a developmental one.
  biological_processes:
  - preferred_term: chloride transmembrane transport
    modifier: DECREASED
    term:
      id: GO:1902476
      label: chloride transmembrane transport
  cell_types:
  - preferred_term: epididymal epithelial cell
    term:
      id: CL:0000068
      label: duct epithelial cell
  locations:
  - preferred_term: mesonephric duct
    term:
      id: UBERON:0003074
      label: mesonephric duct
  notes: >-
    Checked CL for a term anatomically scoped to the mesonephric/Wolffian duct epithelium (mesonephric duct,
    efferent duct, and epididymal duct epithelial cells) - none exists. CL has organ-specific duct epithelial
    cells for kidney collecting duct, prostatic duct, and lactiferous duct, but nothing for the male excurrent
    ducts, so the generic "duct epithelial cell" (CL:0000068) is bound rather than reaching for a wrong-organ
    match. That is the most specific accurate term available: the mesonephric duct epithelium is a duct
    epithelium, so this is not a case where a broader binding is safer.
  downstream:
  - target: Progressive Involution of Mesonephric Duct Derivatives
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:33000223
    reference_title: 'Mutations of the cystic fibrosis transmembrane conductance regulator gene in males with
      congenital bilateral absence of the vas deferens: Reproductive implications and genetic counseling (Review).'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: It has also been demonstrated that fluid secretion is necessary for the normal development of
      the mesonephric duct
    explanation: The link from secretion to duct development that this node turns on.
  - reference: PMID:33000223
    reference_title: 'Mutations of the cystic fibrosis transmembrane conductance regulator gene in males with
      congenital bilateral absence of the vas deferens: Reproductive implications and genetic counseling (Review).'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: resulting in the production of highly viscous mucus by epithelial cells of the male genital tract
    explanation: Describes the luminal consequence of the secretory defect.
- name: Loss of ADGRG2 Signalling in Efferent Ducts
  genes:
  - preferred_term: ADGRG2
    term:
      id: hgnc:4516
      label: ADGRG2
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  description: The alternative entry point. ADGRG2 is an adhesion GPCR expressed specifically in the epididymis
    and efferent ducts, where it is required for fluid reabsorption. Hemizygous truncating variants abolish
    it. That a receptor governing duct fluid handling and a channel governing duct fluid secretion both produce
    the same anatomical endpoint is the strongest argument that luminal fluid balance, rather than any one
    gene product, is what the mesonephric duct derivatives depend on.
  genetic_context:
    gene:
      preferred_term: ADGRG2
      term:
        id: hgnc:4516
        label: ADGRG2
    functional_impact_category: LOSS_OF_FUNCTION
  locations:
  - preferred_term: epididymis
    term:
      id: UBERON:0001301
      label: epididymis
  downstream:
  - target: Progressive Involution of Mesonephric Duct Derivatives
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:27476656
    reference_title: Truncating Mutations in the Adhesion G Protein-Coupled Receptor G2 Gene ADGRG2 Cause an
      X-Linked Congenital Bilateral Absence of Vas Deferens.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: ADGRG2, encoding the epididymal- and efferent-ducts-specific adhesion G protein-coupled receptor
      G2
    explanation: Establishes the tissue-restricted expression that makes loss of this receptor produce an isolated
      genital phenotype.
  - reference: PMID:27476656
    reference_title: Truncating Mutations in the Adhesion G Protein-Coupled Receptor G2 Gene ADGRG2 Cause an
      X-Linked Congenital Bilateral Absence of Vas Deferens.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Previous studies have demonstrated that Adgrg2-knockout male mice develop obstructive infertility.
    explanation: The model-organism support for ADGRG2 causing obstructive infertility, cited as prior work
      in the human discovery report.
- name: Progressive Involution of Mesonephric Duct Derivatives
  biological_scale: TISSUE
  mechanism_confidence: PROVISIONAL
  description: 'The duct is formed and then lost. Fetal studies report the vas deferens obstructed and degenerating
    by mucus at 12-18 weeks, with the process worsening as gestation continues - so this is involution of a
    structure that developed, not failure to develop one. The timing is the load-bearing point of this entry:
    it distinguishes CFTR- and ADGRG2-related disease from the CAVD that accompanies renal agenesis, where
    the duct appears never to have formed properly at all.'
  biological_processes:
  - preferred_term: chloride transmembrane transport
    modifier: DECREASED
    term:
      id: GO:1902476
      label: chloride transmembrane transport
  locations:
  - preferred_term: vas deferens
    term:
      id: UBERON:0001000
      label: vas deferens
  - preferred_term: epididymis
    term:
      id: UBERON:0001301
      label: epididymis
  - preferred_term: seminal vesicle
    term:
      id: UBERON:0000998
      label: seminal vesicle
  downstream:
  - target: Obstructive Azoospermia with Preserved Spermatogenesis
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:32025909
    reference_title: Genetics of the congenital absence of the vas deferens.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: unlike CAVDs related to CFTR or ADGRG2 mutations, which might be the result of progressive degeneration
      that begins later in fetal life and probably continues after birth
    explanation: States the progressive-involution model and explicitly contrasts it with the early-organogenesis
      group, which is the distinction this node records.
  - reference: PMID:33000223
    reference_title: 'Mutations of the cystic fibrosis transmembrane conductance regulator gene in males with
      congenital bilateral absence of the vas deferens: Reproductive implications and genetic counseling (Review).'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In 12-18 week-old abortive fetuses with CFTR gene mutations, the vas deferens is obstructed and
      denatured by mucus, and the vas deferens may be further aggravated in embryonic development
    explanation: The fetal observation that dates the involution and shows it worsening across gestation.
- name: Obstructive Azoospermia with Preserved Spermatogenesis
  biological_scale: ORGANISM
  mechanism_confidence: ESTABLISHED
  description: The clinical endpoint. Spermatozoa are produced normally in the testis but have no route out,
    so the ejaculate is azoospermic, low in volume, acidic and depleted of the seminal vesicle contribution
    - fructose in particular. Testis size and FSH are normal or near-normal, which is what separates this biochemically
    from non-obstructive azoospermia and is why surgical retrieval works.
  locations:
  - preferred_term: vas deferens
    term:
      id: UBERON:0001000
      label: vas deferens
  evidence:
  - reference: PMID:29216686
    reference_title: 'Congenital bilateral absence of the vas deferens as an atypical form of cystic fibrosis:
      reproductive implications and genetic counseling.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Diagnosis of CBAVD is generally based on these criteria: presence of normal to slightly small
      sized testicles, non-palpable vas deferens, normal plasma levels of FSH (Follicle-Stimulating Hormone),
      and reduced ejaculate volume'
    explanation: The clinical picture of preserved testicular function with an absent conduit.
  - reference: PMID:33000223
    reference_title: 'Mutations of the cystic fibrosis transmembrane conductance regulator gene in males with
      congenital bilateral absence of the vas deferens: Reproductive implications and genetic counseling (Review).'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The hallmarks of CBAVD include azoospermia, reduced semen volume (<1 ml), pH value (≤7.0) and
      seminal fructose, as well as decreased production of spermatozoa in the testicles.
    explanation: The semen findings recorded at this node.
  - reference: PMID:20301428
    reference_title: Cystic Fibrosis.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: male infertility due to hypoplasia or aplasia of the vas deferens
    explanation: The GeneReviews statement of the mechanism, listed among the morbidities of CFTR dysfunction.
phenotypes:
- category: Reproductive
  name: Obstructive Azoospermia
  frequency: VERY_FREQUENT
  description: Absence of spermatozoa in the ejaculate despite ongoing spermatogenesis. This is the presenting
    finding in nearly all cases, since the condition is otherwise asymptomatic.
  phenotype_term:
    preferred_term: Azoospermia
    term:
      id: HP:0000027
      label: Azoospermia
  evidence:
  - reference: PMID:33000223
    reference_title: 'Mutations of the cystic fibrosis transmembrane conductance regulator gene in males with
      congenital bilateral absence of the vas deferens: Reproductive implications and genetic counseling (Review).'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The hallmarks of CBAVD include azoospermia, reduced semen volume (<1 ml), pH value (≤7.0) and
      seminal fructose
    explanation: Names azoospermia first among the hallmark findings.
- category: Reproductive
  name: Absent Vas Deferens
  frequency: VERY_FREQUENT
  description: Bilaterally non-palpable vasa deferentia on examination - the anatomical finding that names
    the condition and that a careful scrotal examination detects without imaging.
  phenotype_term:
    preferred_term: Absent vas deferens
    term:
      id: HP:0012873
      label: Absent vas deferens
  evidence:
  - reference: PMID:29216686
    reference_title: 'Congenital bilateral absence of the vas deferens as an atypical form of cystic fibrosis:
      reproductive implications and genetic counseling.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Diagnosis of CBAVD is generally based on these criteria: presence of normal to slightly small
      sized testicles, non-palpable vas deferens, normal plasma levels of FSH (Follicle-Stimulating Hormone),
      and reduced ejaculate volume'
    explanation: Places bilaterally non-palpable vasa deferentia among the diagnostic criteria, alongside the
      preserved testicular size and normal FSH that mark the obstruction as the lesion.
- category: Reproductive
  name: Male Infertility
  frequency: VERY_FREQUENT
  description: Primary infertility, and usually the reason for presentation. CBAVD accounts for a small but
    consistent share of male infertility and a substantially larger share of obstructive azoospermia specifically.
  phenotype_term:
    preferred_term: Male infertility
    term:
      id: HP:0003251
      label: Male infertility
  evidence:
  - reference: PMID:33000223
    reference_title: 'Mutations of the cystic fibrosis transmembrane conductance regulator gene in males with
      congenital bilateral absence of the vas deferens: Reproductive implications and genetic counseling (Review).'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Congenital bilateral absence of the vas deferens (CBAVD) accounts for 2-6% of male infertility
      cases and up to 25% of cases of obstructive azoospermia
    explanation: Quantifies the contribution to male infertility and to obstructive azoospermia.
- category: Reproductive
  name: Seminal Vesicle Abnormality
  frequency: FREQUENT
  description: Atrophy, hypoplasia or absence of the seminal vesicles. This is why the ejaculate is low in
    volume and fructose-poor as well as azoospermic - the seminal vesicles supply most of the volume. An MRI
    series found only 2 of 51 men with congenital absence of the vas deferens had a normal seminal vesicle.
  phenotype_term:
    preferred_term: Abnormal seminal vesicle morphology
    term:
      id: HP:6000190
      label: Abnormal seminal vesicle morphology
  evidence:
  - reference: PMID:33000223
    reference_title: 'Mutations of the cystic fibrosis transmembrane conductance regulator gene in males with
      congenital bilateral absence of the vas deferens: Reproductive implications and genetic counseling (Review).'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: atrophy or absence of seminal vesicle and cauda epididymis
    explanation: Documents seminal vesicle involvement alongside the epididymis.
  - reference: PMID:41255074
    reference_title: 'Evaluation of the congenital absence of the vas deferens with magnetic resonance imaging:
      preliminary findings.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Only 2 out of 51 patients (3.9%) had a standard SV.
    explanation: Quantifies how nearly universal seminal vesicle abnormality is on MRI in this population.
- category: Reproductive
  name: Epididymal Abnormality
  frequency: FREQUENT
  description: Atrophy or absence of the cauda epididymis. Modelled separately from the seminal vesicle because
    the two are different organs with different HPO terms, and because the epididymis is where sperm are recovered
    surgically - its state bears directly on whether retrieval succeeds.
  phenotype_term:
    preferred_term: Abnormal epididymis morphology
    term:
      id: HP:0009714
      label: Abnormal epididymis morphology
  evidence:
  - reference: PMID:33000223
    reference_title: 'Mutations of the cystic fibrosis transmembrane conductance regulator gene in males with
      congenital bilateral absence of the vas deferens: Reproductive implications and genetic counseling (Review).'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: atrophy or absence of seminal vesicle and cauda epididymis
    explanation: Documents cauda epididymis involvement.
biochemical:
- name: Seminal Fructose
  presence: Decreased
  frequency: FREQUENT
  biomarker_term:
    preferred_term: fructose
    term:
      id: CHEBI:28757
      label: fructose
  context: >-
    Fructose is contributed to the ejaculate almost entirely by the seminal vesicles, so an undetectable
    or low level is the biochemical correlate of the seminal-vesicle atrophy this entry already models,
    alongside the low volume and acidic pH that come from the same missing contribution.
  readouts:
  - target: Seminal Vesicle Abnormality
    relationship: READOUT_OF
    direction: THRESHOLD_DEPENDENT
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Undetectable or low seminal fructose is the semen-analysis correlate of seminal vesicle
      involvement, used alongside low volume and acidic pH to build the CBAVD semen picture.
    evidence:
    - reference: PMID:29216686
      reference_title: 'Congenital bilateral absence of the vas deferens as an atypical form of cystic
        fibrosis: reproductive implications and genetic counseling.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "azoospermic, acidic pH, undetectable or low fructose concentrations (normal: >25 μM)"
      explanation: Names low/undetectable seminal fructose as one of the semen-analysis hallmarks, alongside
        the normal reference threshold.
  evidence:
  - reference: PMID:29216686
    reference_title: 'Congenital bilateral absence of the vas deferens as an atypical form of cystic fibrosis:
      reproductive implications and genetic counseling.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "azoospermic, acidic pH, undetectable or low fructose concentrations (normal: >25 μM)"
    explanation: Establishes the biochemical finding and its normal reference threshold in this population.
genetic:
- name: CFTR
  gene_term:
    preferred_term: CFTR
    term:
      id: hgnc:1884
      label: CFTR
  relationship_type: CAUSATIVE
  notes: 'The dominant cause, and the allele class that defines it is the intronic poly-T tract. The 5T variant
    - written IVS8-5T in the older numbering and IVS9-5T in the newer - reduces exon-skipping fidelity and
    so lowers the amount of full-length CFTR transcript without abolishing it. That is the unnamed "mild allele"
    in the compound-heterozygous configuration this entry describes, and in a Chinese CBAVD series it was the
    only recurrent variant: no other CFTR hotspot appeared, and no ADGRG2 variants were found at all.


    p.Arg117His is the other allele worth naming, and it carries a counselling problem rather than a mechanistic
    one. It is usually in cis with the benign T7 tract, its overall phenotype is mild, and sweat chloride does
    not track severity - so a man ascertained through CBAVD cannot be reassured or alarmed on the basis of
    a sweat test. What matters is his partner''s genotype: in the French series five couples at risk of a child
    with cystic fibrosis were identified this way.


    Practically, this allele spectrum is why panel testing under-serves this disease. Standard panels are built
    around cystic-fibrosis-causing variants, and the alleles that cause isolated CBAVD are disproportionately
    the mild, intronic and rearrangement ones those panels do not carry.'
  evidence:
  - reference: PMID:29216686
    reference_title: 'Congenital bilateral absence of the vas deferens as an atypical form of cystic fibrosis:
      reproductive implications and genetic counseling.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Some mutations in the gene encoding cystic fibrosis transmembrane conductance regulator (CFTR)
      can lead to CBAVD as a monosymptomatic form of CF.
    explanation: States the relationship between the CBAVD genotype and cystic fibrosis.
  - reference: PMID:35119551
    reference_title: Genetic analysis and intracytoplasmic sperm injection outcomes of Chinese patients with
      congenital bilateral absence of vas deferens.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: There are no obvious hotspot CFTR mutations in Chinese CBAVD patients besides the IVS9-5 T allele.
    explanation: Establishes the 5T tract as the one recurrent allele in that population, and the absence of
      other hotspots.
  - reference: PMID:35119551
    reference_title: Genetic analysis and intracytoplasmic sperm injection outcomes of Chinese patients with
      congenital bilateral absence of vas deferens.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In total, 35 of 46 (76.09%) patients carried at least one variation in CFTR, but no copy number
      variants or ADGRG2 variations were found.
    explanation: The CFTR-positive rate and the absence of ADGRG2 variants in this cohort.
  - reference: PMID:23378603
    reference_title: CFTR p.Arg117His associated with CBAVD and other CFTR-related disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 97% of the patients had the intronic T7 normal variant in cis with p.Arg117His.
    explanation: The cis configuration that makes p.Arg117His mild in most carriers.
  - reference: PMID:23378603
    reference_title: CFTR p.Arg117His associated with CBAVD and other CFTR-related disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: No correlation was observed between sweat chloride concentrations and disease severity.
    explanation: Supports the statement that sweat chloride cannot be used to grade risk in these men.
  - reference: PMID:23378603
    reference_title: CFTR p.Arg117His associated with CBAVD and other CFTR-related disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Five couples at risk of CF offspring were identified and four benefited from prenatal or preimplantation
      genetic diagnoses (PND or PGD).
    explanation: Quantifies the counselling yield that follows from identifying the man's genotype.
- name: ADGRG2
  gene_term:
    preferred_term: ADGRG2
    term:
      id: hgnc:4516
      label: ADGRG2
  relationship_type: CAUSATIVE
  notes: 'X-linked, about 2% of cases, and confined to CFTR-negative men. Worth testing for precisely because
    the inheritance differs: an ADGRG2 diagnosis changes the counselling from partner CFTR screening to X-linked
    recurrence in the extended family. Penetrance is not complete. A nonsense variant, p.Ser303*, was found
    in an X-linked azoospermia pedigree and also in a male relative with normal reproductive capability, and
    genital phenotypes among carriers ranged from normal to dilated vas deferens, spermatic veins and epididymis.
    So an ADGRG2 diagnosis predicts recurrence risk in the family without predicting the phenotype of any given
    carrier.'
  evidence:
  - reference: PMID:32025909
    reference_title: Genetics of the congenital absence of the vas deferens.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Approximately 2% of the cases of CAVD are hemizygous for a loss-of-function mutation in the ADGRG2
      gene
    explanation: The share of cases attributable to ADGRG2.
  - reference: PMID:37273165
    reference_title: A novel ADGRG2 truncating variant associated with X-linked obstructive azoospermia in
      a large Chinese pedigree.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: This mutation was also unexpectedly found in a male member with normal reproductive capability.
    explanation: The incomplete-penetrance observation that qualifies ADGRG2 counselling.
- name: SLC9A3
  gene_term:
    preferred_term: SLC9A3
    term:
      id: hgnc:11073
      label: SLC9A3
  relationship_type: SUSCEPTIBILITY
  notes: 'A sodium/proton exchanger. Single-copy SLC9A3 deletions are found in Taiwanese CBAVD patients who
    carry no major CFTR mutation, and the knockout mouse gives a mechanism: losing Slc9a3 dramatically reduces
    CFTR protein in the epididymis and vas deferens and produces obstructive azoospermia.


    Recorded as SUSCEPTIBILITY rather than CAUSATIVE, and the distinction matters. The human evidence is a
    heterozygous single-copy deletion in a small number of men, with no ClinGen assertion; the causal demonstration
    is in a homozygous-null mouse. That is variants conferring susceptibility in combination with other factors,
    not variants sufficient in a mendelian sense - which is what CAUSATIVE asserts in this schema.


    What the mouse does establish, and what makes SLC9A3 worth carrying at all, is that it acts by destabilising
    CFTR. So it is evidence for the entry''s central claim that the shared dependency is on ductal fluid handling
    rather than on any one gene product - reached through a modifier of CFTR abundance rather than through
    a third independent route.'
  evidence:
  - reference: PMID:28384194
    reference_title: Loss of SLC9A3 decreases CFTR protein and causes obstructed azoospermia in mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: we found that CFTR expression was dramatically decreased in the epididymis and vas deferens of
      Slc9a3 knockout mice
    explanation: The mechanistic link from SLC9A3 loss to reduced CFTR in exactly the tissues this disease
      affects.
  - reference: PMID:28384194
    reference_title: Loss of SLC9A3 decreases CFTR protein and causes obstructed azoospermia in mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Slc9a3-/- mice developed obstructive azoospermia because of abnormal abundant secretions and calcification
      in the lumen of the reproductive tract
    explanation: The phenotype, which is this disease's endpoint reached through a third gene.
  - reference: PMID:28384194
    reference_title: Loss of SLC9A3 decreases CFTR protein and causes obstructed azoospermia in mice.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Some patients have a single copy deletion of the solute carrier family 9 isoform 3 (SLC9A3) gene.
    explanation: The human genetic observation that motivated the mouse work.
  - reference: PMID:32025909
    reference_title: Genetics of the congenital absence of the vas deferens.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: How the dysfunction of CFTR, ADGRG2, or other genes such as SLC29A3 leads to this involution is
      the subject of various pathophysiological hypotheses
    explanation: Retained because it places SLC9A3 alongside the two main genes in the review literature. Note
      the source prints SLC29A3, which the CAVD literature treats as a typographical error for SLC9A3.
prevalence:
- population: Men, worldwide
  measure_type: POINT_PREVALENCE
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 100.0
  notes: Reported as approximately 0.1% of men for congenital absence of the vas deferens overall (bilateral
    and unilateral together), normalised here to 100 per 100,000. The source states this is probably an underestimate,
    since unilateral disease in fertile men is generally never diagnosed - so the figure is a floor, and it
    covers a broader concept than this entry's scope.
  evidence:
  - reference: PMID:32025909
    reference_title: Genetics of the congenital absence of the vas deferens.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The prevalence of CAVDs in men is reported to be approximately 0.1%. However, this figure is probably
      underestimated, because unilateral forms of CAVD in asymptomatic fertile men are not usually diagnosed.
    explanation: PARTIAL because the quoted figure is for congenital absence of the vas deferens overall rather
      than for the bilateral form this entry covers, and the source itself flags it as an underestimate.
diagnosis:
- name: Clinical and Semen Assessment
  description: Bilaterally non-palpable vasa on scrotal examination, with a semen profile of azoospermia, low
    volume, acidic pH and low fructose, against normal FSH and normal or near-normal testicular size. That
    combination separates obstructive from non-obstructive azoospermia before any genetic test is sent.
  diagnosis_term:
    preferred_term: physical examination
    term:
      id: NCIT:C20989
      label: Physical Examination
  evidence:
  - reference: PMID:29216686
    reference_title: 'Congenital bilateral absence of the vas deferens as an atypical form of cystic fibrosis:
      reproductive implications and genetic counseling.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Diagnosis of CBAVD is generally based on these criteria: presence of normal to slightly small
      sized testicles, non-palpable vas deferens, normal plasma levels of FSH (Follicle-Stimulating Hormone),
      and reduced ejaculate volume'
    explanation: The diagnostic criteria this entry describes.
- name: CFTR and ADGRG2 Testing with Renal Ultrasound
  description: 'CFTR testing is indicated in essentially every case, both to establish the diagnosis and because
    the result determines whether the partner needs carrier screening. ADGRG2 is the next test in CFTR-negative
    men. Renal ultrasound belongs in the same workup for a different reason: a solitary kidney marks the developmental-field
    group, in which CFTR mutations are conspicuously uncommon and a negative CFTR result is therefore expected
    rather than surprising.'
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:32025909
    reference_title: Genetics of the congenital absence of the vas deferens.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The majority of subjects with CAVD carry at least one cystic fibrosis-causing mutation that warrants
      CFTR testing and in case of a positive result, genetic counseling prior to conception.
    explanation: Establishes CFTR testing and the counselling that follows a positive result.
  - reference: PMID:32025909
    reference_title: Genetics of the congenital absence of the vas deferens.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: An important proportion of these unexplained CAVDs coexist with a solitary kidney suggesting an
      early organogenesis disorder (Wolffian duct)
    explanation: The reason renal imaging belongs in the workup - it identifies a group with a different developmental
      mechanism and a different expected genetic yield.
- name: Scrotal Ultrasound and Pelvic MRI
  description: Imaging confirms the absent vasa and characterises the seminal vesicles, which are abnormal
    in nearly every patient. MRI adds the intra-abdominal segment, which scrotal ultrasound cannot reach -
    and a dilated intra-abdominal vas deferens, seen in bilateral but not unilateral disease, is a positive
    imaging argument for acquired involution rather than primary agenesis. That makes imaging evidence for
    this entry's central mechanism and not only a diagnostic step.
  diagnosis_term:
    preferred_term: magnetic resonance imaging procedure
    term:
      id: NCIT:C16809
      label: Magnetic Resonance Imaging
  evidence:
  - reference: PMID:41255074
    reference_title: 'Evaluation of the congenital absence of the vas deferens with magnetic resonance imaging:
      preliminary findings.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The intra-abdominal part of the VD dilatation is a new finding in CAVD and was not found in patients
      with CUAVD.
    explanation: The imaging finding specific to bilateral disease.
  - reference: PMID:41255074
    reference_title: 'Evaluation of the congenital absence of the vas deferens with magnetic resonance imaging:
      preliminary findings.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Preliminary findings in this study are consistent with the theory of acquired vasal agenesis in
      CBAVD.
    explanation: An independent line of support for the progressive-involution model this entry is built on.
treatments:
- name: Surgical Sperm Retrieval with ICSI
  therapeutic_modality: SURGERY
  description: 'The definitive management, and it works because the lesion is obstructive. Sperm are recovered
    from the epididymis or testis and used for intracytoplasmic sperm injection. Outcomes in isolated CBAVD
    are notably better than in men with full cystic fibrosis: in a two-centre comparison the CF group had lower
    retrieved sperm concentration and motile count, needed rescue testicular extraction far more often, and
    had roughly half the fertilisation rate. That gradient is evidence that CFTR affects sperm function itself
    and not only the conduit - which qualifies the tidy "obstruction only" account this entry otherwise gives.'
  treatment_term:
    preferred_term: sperm retrieval
    term:
      id: NCIT:C94427
      label: Sperm Retrieval
  target_mechanisms:
  - target: Obstructive Azoospermia with Preserved Spermatogenesis
    treatment_effect: MODULATES
    description: Bypasses the missing conduit rather than restoring it. No postnatal treatment reaches the
      duct involution - but see the prenatal CFTR modulator entry, which reports the one setting in which something
      appears to.
  evidence:
  - reference: PMID:32930103
    reference_title: Sperm retrieval and intracytoplasmic sperm injection outcomes in men with cystic fibrosis
      disease versus congenital bilateral absence of the vas deferens.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The CF group also demonstrated a significantly higher rate of rescue testicular sperm extraction
      (70.0% vs 27.6%, P < 0.03) and lower fertilization rate with ICSI (32.5% vs 68.9%, P < 0.01).
    explanation: The comparative outcome data distinguishing isolated CBAVD from full cystic fibrosis.
  - reference: PMID:32930103
    reference_title: Sperm retrieval and intracytoplasmic sperm injection outcomes in men with cystic fibrosis
      disease versus congenital bilateral absence of the vas deferens.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: those with CF demonstrated lower sperm quality, greater difficulty with sperm retrieval, and worse
      ICSI outcomes compared with CBAVD-only patients
    explanation: The study's conclusion, which supports treating retrieval success in isolated CBAVD as the
      favourable case.
- name: Partner CFTR Screening and Genetic Counselling
  therapeutic_modality: OTHER
  description: Not optional. Because the man carries at least one cystic fibrosis-causing allele, a carrier
    partner puts the couple at risk of a child with classic cystic fibrosis - a far more serious disease than
    the father's. Partner screening and, where indicated, preimplantation genetic testing are what convert
    a treatable infertility into a safe one.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:29216686
    reference_title: 'Congenital bilateral absence of the vas deferens as an atypical form of cystic fibrosis:
      reproductive implications and genetic counseling.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: genetic counseling should be offered to couples undergoing ART to discuss the probability of having
      offspring that carry CFTR gene mutations
    explanation: The counselling recommendation this entry records.
  - reference: PMID:33000223
    reference_title: 'Mutations of the cystic fibrosis transmembrane conductance regulator gene in males with
      congenital bilateral absence of the vas deferens: Reproductive implications and genetic counseling (Review).'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: With the use of pre-implantation genetic diagnosis, testicular or epididymal sperm aspiration,
      intracytoplasmic sperm injection and in vitro fertilization, patients affected by CBAVD are able to have
      children who do not carry CFTR gene mutations, thereby preventing disease.
    explanation: Establishes preimplantation genetic testing as the route to avoiding transmission.
  - reference: PMID:20301428
    reference_title: Cystic Fibrosis.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Once the CFTR pathogenic variants have been identified in an affected family member, targeted
      heterozygote testing for at-risk relatives and prenatal/preimplantation genetic testing for CF are possible.
    explanation: The GeneReviews genetic-counselling position, which is the baseline this entry's counselling
      treatment follows.
- name: Intracytoplasmic Sperm Injection
  therapeutic_modality: OTHER
  description: 'Fertilisation of the partner''s oocytes with the retrieved spermatozoa. Recorded separately
    from retrieval because the two steps have different determinants: retrieval success depends on residual
    CFTR activity, while cumulative ICSI success in the same Lille cohort did not differ between cystic fibrosis
    and CFTR-related disorder groups. Once usable sperm are in hand, the CFTR genotype stops mattering as much.'
  treatment_term:
    preferred_term: intracytoplasmic sperm injection
    term:
      id: NCIT:C185482
      label: Intracytoplasmic Sperm Injection
  target_mechanisms:
  - target: Obstructive Azoospermia with Preserved Spermatogenesis
    treatment_effect: MODULATES
    description: Achieves fertilisation without the conduit.
  evidence:
  - reference: PMID:40850271
    reference_title: 'Cystic fibrosis: influence of CFTR variants on epididymal sperm recovery and ICSI results.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Cumulative success rates of ICSI did not differ significantly across groups.
    explanation: The result that separates ICSI outcome from retrieval outcome in this population.
  - reference: PMID:35119551
    reference_title: Genetic analysis and intracytoplasmic sperm injection outcomes of Chinese patients with
      congenital bilateral absence of vas deferens.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Spermatozoa were successfully retrachieved in 46 patients, and 39 of the patients had their own
      offspring through ICSI.
    explanation: The paternity rate achieved through retrieval plus ICSI in a consecutive CBAVD series. Quoted
      verbatim including the source's typo 'retrachieved' for 'retrieved'.
- name: Prenatal CFTR Modulator Therapy
  therapeutic_modality: SMALL_MOLECULE
  description: 'The one intervention that appears to reach the mechanism rather than bypass it, and it is a
    single case. A male fetus with cystic fibrosis whose heterozygous carrier mother began elexacaftor/tezacaftor/ivacaftor
    at 27+4 weeks had bilateral vasa deferentia demonstrable on ultrasound at 8 weeks of age - a structure
    absent in nearly all males with cystic fibrosis at birth.


    The timing is what makes it mechanistically informative rather than merely encouraging. Men already born
    and taking modulators show no improvement in infertility. A structure that can be preserved at 27 weeks
    and not recovered afterwards is a structure that is being lost during gestation, which is independent evidence
    for the progressive-involution model this entry is built on and against fixed early agenesis.


    n=1, uncontrolled, and the ethical position for a heterozygous fetus - who would not develop the disease
    - is unresolved. Recorded because of what it establishes about the mechanism, not as a management recommendation.'
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_mechanisms:
  - target: Progressive Involution of Mesonephric Duct Derivatives
    treatment_effect: INHIBITS
    description: Restores CFTR function during the window in which the duct is still present, apparently arresting
      the involution.
  evidence:
  - reference: PMID:41654435
    reference_title: Prenatal initiation of elexacaftor/tezacaftor/ivacaftor via carrier mother prevents congenital
      bilateral absence of vas deferens in a male infant with cystic fibrosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Remarkably, ultrasound at 8 weeks demonstrated bilateral vas deferens, a structure typically absent
      in nearly all male patients with CF at birth.
    explanation: The observation itself, and the reason it is remarkable.
  - reference: PMID:41654435
    reference_title: Prenatal initiation of elexacaftor/tezacaftor/ivacaftor via carrier mother prevents congenital
      bilateral absence of vas deferens in a male infant with cystic fibrosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: These findings suggest that prenatal CFTR modulation - even when initiated late in gestation -
      may alter the trajectory of CF-related organ manifestations, including male reproductive development.
    explanation: The authors' own hedged interpretation, which this entry does not strengthen.
  - reference: PMID:39288989
    reference_title: 'Use of CFTR modulators in pregnancy: new information for neonatal, paediatrics and midwifery
      teams.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: At present male patients taking CFTR modulators have not shown improvement in infertility.
    explanation: 'The postnatal complement: modulators given after birth do not restore fertility, which is
      what makes the prenatal timing the load-bearing variable.'
animal_models:
- name: Slc9a3 knockout mouse (obstructive azoospermia via CFTR loss)
  species: Mouse
  genotype: Slc9a3 -/-
  publication: PMID:28384194
  description: >-
    Constitutive Slc9a3 knockout mice develop obstructive azoospermia from progressively worsening
    luminal secretions and calcification in the efferent ductules, epididymis, and vas deferens, driven
    by a dramatic loss of CFTR protein in those same tissues. The knockout was generated to study SLC9A3
    as a CFTR interactor and genetic modifier rather than to model CBAVD directly, but the phenotype
    converges on this entry's endpoint through a third gene.
  evidence:
  - reference: PMID:28384194
    reference_title: Loss of SLC9A3 decreases CFTR protein and causes obstructed azoospermia in mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: The Slc9a3-deficient mice with impaired male excurrent ducts in this study provide proof for
      our clinical findings that some Taiwanese of CBAVD carry SLC9A3 deletion but without major CFTR mutations.
    explanation: The authors' own statement connecting the mouse phenotype back to the human CBAVD patients
      carrying SLC9A3 deletions, which is why this model is informative for this disease.
  modeled_mechanisms:
  - target: Progressive Involution of Mesonephric Duct Derivatives
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Loss of Slc9a3 destabilizes CFTR protein in the epididymis and vas deferens, producing the same
      progressive luminal obstruction and duct compromise seen with direct CFTR or ADGRG2 loss - support
      for this entry's claim that ductal fluid handling, not any one gene product, is the shared dependency
      of the mesonephric duct derivatives.
    limitations: >-
      The mechanism is indirect: SLC9A3 loss acts by reducing CFTR protein abundance rather than through
      a CFTR-independent route, and the mouse phenotype requires a homozygous null genotype whereas the
      human genetic evidence for SLC9A3 is a heterozygous single-copy deletion with no ClinGen assertion.
    readouts:
    - name: CFTR protein expression in epididymis and vas deferens
      target: Progressive Involution of Mesonephric Duct Derivatives
      direction: DECREASED
      interpretation: >-
        Confirms the mechanistic link from SLC9A3 loss to reduced CFTR specifically in the tissues this
        disease affects.
      evidence:
      - reference: PMID:28384194
        reference_title: Loss of SLC9A3 decreases CFTR protein and causes obstructed azoospermia in mice.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: CFTR expression was dramatically decreased in the epididymis and vas deferens of Slc9a3
          knockout mice
        explanation: The direct measurement of CFTR loss underlying this readout.
    - name: Luminal secretion accumulation and calcification in the excurrent ducts
      target: Progressive Involution of Mesonephric Duct Derivatives
      direction: INCREASED
      interpretation: >-
        Reproduces the structural endpoint of progressive duct obstruction that this node describes,
        albeit reached through a third gene rather than CFTR or ADGRG2 directly.
      evidence:
      - reference: PMID:28384194
        reference_title: Loss of SLC9A3 decreases CFTR protein and causes obstructed azoospermia in mice.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: Slc9a3-/- mice developed obstructive azoospermia because of abnormal abundant secretions
          and calcification in the lumen of the reproductive tract
        explanation: The histological/gross finding behind this readout.
- name: Adgrg2 (He6/Gpr64) knockout mouse (efferent duct fluid dysregulation)
  species: Mouse
  genotype: He6 (Adgrg2/Gpr64) hemizygous null (7TM-domain deletion)
  publication: PMID:15367682
  description: >-
    The original functional evidence for this receptor in male fertility, predating the human ADGRG2-CBAVD
    discovery (PMID:27476656) by twelve years. Hemizygous knockout males develop age-dependent infertility
    from dysregulated fluid reabsorption in the efferent ductules, causing dilation and spermatozoal
    obstruction there and a backup of fluid into the testis - the same tissue-restricted, duct-fluid-handling
    mechanism this entry attributes to human ADGRG2 loss.
  evidence:
  - reference: PMID:15367682
    reference_title: Targeted deletion of the epididymal receptor HE6 results in fluid dysregulation and male
      infertility.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Mutant mice reveal a dysregulation of fluid reabsorbtion within the efferent ductules, leading
      to a backup of fluid accumulation in the testis and a subsequent stasis of spermatozoa within the
      efferent ducts.
    explanation: The abstract's summary of the fluid-handling defect, which is why this model is informative
      for the duct-fluid-handling node. Quoted verbatim including the source's spelling "reabsorbtion".
  modeled_mechanisms:
  - target: Progressive Involution of Mesonephric Duct Derivatives
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >-
      An isolated fluid-reabsorption defect in the efferent ductules causing duct dilation, spermatozoal
      obstruction, and testicular fluid backup - the same class of duct-fluid-handling failure this entry
      attributes to human ADGRG2 loss, from the mouse ortholog of the same receptor. Partial rather than
      full recapitulation: the lesion sits in a different duct segment and the duct is not lost.
    limitations: >-
      This is a constitutive knockout of the murine ortholog (then named He6/Gpr64), not a model of any
      specific human truncating ADGRG2 allele, and the reported pathology centers on efferent-ductule
      dilation and testicular fluid backup rather than the progressive vas deferens/epididymis involution
      described in human CBAVD.
    readouts:
    - name: Efferent ductule dilation and luminal obstruction by spermatozoa
      target: Progressive Involution of Mesonephric Duct Derivatives
      direction: INCREASED
      interpretation: >-
        Structural correlate of the fluid-reabsorption defect, and the proximate cause of the infertility
        in this model.
      evidence:
      - reference: PMID:15367682
        reference_title: Targeted deletion of the epididymal receptor HE6 results in fluid dysregulation and
          male infertility.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: the ductules were found to be greatly dilated in knockout mice, and the lumen of the ductules
          was frequently obstructed by a large accumulation of spermatazoa
        explanation: The histological finding behind this readout. Quoted verbatim including the source's
          typo "spermatazoa" for "spermatozoa".
    - name: Testicular fluid accumulation and rete testis expansion
      target: Progressive Involution of Mesonephric Duct Derivatives
      direction: INCREASED
      interpretation: >-
        Back-pressure consequence of the efferent-duct obstruction, mirroring the entry's own account of
        obstruction upstream of the testis.
      evidence:
      - reference: PMID:15367682
        reference_title: Targeted deletion of the epididymal receptor HE6 results in fluid dysregulation and
          male infertility.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: leading to a backup of fluid accumulation in the testis and a subsequent stasis of spermatozoa
          within the efferent ducts
        explanation: The abstract's statement of the downstream testicular consequence.
- name: CFTR-knockout rat (bilateral vasal absence and epididymal hypoplasia)
  species: Rat
  genotype: Cftr -/-
  publication: PMID:42380629
  description: >-
    Across the animal models compared in this review, the CFTR-knockout rat is the one that comes closest
    to the human male reproductive phenotype, showing bilateral absence of the vas deferens together with
    epididymal hypoplasia. It is the model of the gene that explains the large majority of human CBAVD,
    and so is the reference point against which the modifier-gene models above should be read.
  notes: >-
    Sourced from a 2026 comparative review of CF animal models rather than from the primary description of
    the rat itself; the review is the document that adjudicates between species, which is the claim being
    made here.
  evidence:
  - reference: PMID:42380629
    reference_title: 'Male reproductive phenotype in cystic fibrosis: comparison of existing animal models.'
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: CF transmembrane conductance regulator (CFTR)-knockout rats more closely reproduce the human
      phenotype, showing bilateral absence of the vas deferens and epididymal hypoplasia
    explanation: The review's cross-species comparison identifying this model as the closest available match
      to the human phenotype, which is why it is informative for this entry.
  modeled_mechanisms:
  - target: Progressive Involution of Mesonephric Duct Derivatives
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >-
      Loss of Cftr in the rat reproduces the defining endpoint of this node - bilateral loss of the vas
      deferens with an underdeveloped epididymis - in the gene that accounts for most human cases.
    limitations: >-
      The rat shows more pronounced hypospermatogenesis than men with CBAVD do, so the model overstates the
      testicular component of a condition that is otherwise obstructive with preserved spermatogenesis. The
      cited source is a comparative review rather than the primary description of the model.
    readouts:
    - name: Bilateral vas deferens absence
      target: Progressive Involution of Mesonephric Duct Derivatives
      direction: ABOLISHED
      interpretation: >-
        The structural endpoint this node describes, observed in the knockout rat.
      evidence:
      - reference: PMID:42380629
        reference_title: 'Male reproductive phenotype in cystic fibrosis: comparison of existing animal models.'
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: showing bilateral absence of the vas deferens and epididymal hypoplasia
        explanation: The reported structural finding behind this readout.
    - name: Spermatogenic output
      target: Progressive Involution of Mesonephric Duct Derivatives
      direction: DECREASED
      interpretation: >-
        A divergence rather than a confirmation - the rat loses spermatogenesis to a degree human CBAVD does
        not, which is why this model's fidelity is qualified in the link's limitations.
      evidence:
      - reference: PMID:42380629
        reference_title: 'Male reproductive phenotype in cystic fibrosis: comparison of existing animal models.'
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: although they exhibit more pronounced hypospermatogenesis than observed in men
        explanation: The reported testicular divergence behind this readout.
- name: CFTR knock-in and partial-knockout mouse (fertile, no vasal phenotype)
  species: Mouse
  genotype: Cftr knock-in or partial knockout (hypomorphic residual function)
  publication: PMID:42380629
  description: >-
    A negative result worth recording: mouse models carrying a knock-in allele or a partial Cftr knockout
    generally stay fertile and do not develop the vasal phenotype, and only complete knockouts show vas
    deferens atresia, and then only with age. This is the species-and-allele limit on using the mouse for
    CBAVD, and the reason the rat above is the better reference model.
  evidence:
  - reference: PMID:42380629
    reference_title: 'Male reproductive phenotype in cystic fibrosis: comparison of existing animal models.'
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: 'Mouse models display heterogeneous phenotype: knock-in or partial knockout models usually remain
      fertile, whereas complete knockouts may develop vas deferens atresia with aging'
    explanation: The review's summary of the mouse phenotype, establishing that residual-function alleles do
      not reproduce the human duct loss.
  modeled_mechanisms:
  - target: Progressive Involution of Mesonephric Duct Derivatives
    relationship: FAILS_TO_RECAPITULATE
    fidelity: LOW
    description: >-
      Residual-function Cftr alleles in the mouse leave fertility intact, so these models do not reproduce
      the progressive duct involution this node describes.
    limitations: >-
      The failure is specific to knock-in and partial-knockout alleles: complete Cftr-null mice do develop
      vas deferens atresia, but late, with aging, rather than as the prenatal-onset involution seen in
      humans. The cited source is a comparative review rather than the primary description of any one model,
      and it does not name the individual alleles behind the generalization.
    evidence:
    - reference: PMID:42380629
      reference_title: 'Male reproductive phenotype in cystic fibrosis: comparison of existing animal models.'
      supports: REFUTE
      evidence_source: MODEL_ORGANISM
      snippet: knock-in or partial knockout models usually remain fertile
      explanation: Directly contradicts the claim that these mouse models reproduce the human duct loss,
        which is what grades this link as a failure to recapitulate.
    readouts:
    - name: Male fertility in knock-in and partial-knockout mice
      target: Progressive Involution of Mesonephric Duct Derivatives
      direction: UNCHANGED
      interpretation: >-
        Preserved fertility is the observable negative: the duct is patent enough to carry spermatozoa, so
        the endpoint this node describes has not occurred.
      evidence:
      - reference: PMID:42380629
        reference_title: 'Male reproductive phenotype in cystic fibrosis: comparison of existing animal models.'
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: knock-in or partial knockout models usually remain fertile
        explanation: The reported fertility outcome behind this readout.
differential_diagnoses:
- name: Congenital unilateral absence of the vas deferens
  description: A different clinical entity, not a milder form. Fertility is often preserved because one duct
    remains patent, it is frequently an incidental finding, and its genetic architecture differs - CFTR mutations
    account for a smaller share and 60-70% of cases have no genetic diagnosis at all, against 10-20% for the
    bilateral form. Explicitly out of scope for this entry.
  evidence:
  - reference: PMID:32025909
    reference_title: Genetics of the congenital absence of the vas deferens.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: despite this recent finding, 10-20% of CBAVDs and 60-70% of CUAVDs remain without a genetic diagnosis
    explanation: The differing genetic yield that supports treating unilateral disease as a separate entity.
  disease_term:
    preferred_term: vas deferens, congenital unilateral aplasia of
    term:
      id: MONDO:0800311
      label: vas deferens, congenital unilateral aplasia of
discussions:
- discussion_id: cbavd_two_developmental_timings
  kind: KNOWLEDGE_GAP
  attaches_to:
  - pathophysiology#Progressive Involution of Mesonephric Duct Derivatives
  - differential_diagnoses#Congenital unilateral absence of the vas deferens
  prompt: Is CAVD with a solitary kidney the same disease as CFTR-related CAVD, or a developmental field defect
    that shares an endpoint?
  rationale: 'Two lines of evidence say these are different processes. CAVD occurring with renal agenesis has
    a conspicuously low CFTR mutation rate - low enough that the reviewed literature describes CFTR mutations
    as absent in that group - and the co-occurrence of an absent duct with an absent kidney points at the mesonephric
    duct itself, from which both derive. Against that, CFTR- and ADGRG2-related disease shows a duct that formed
    and then degenerated, with fetal specimens at 12-18 weeks showing obstruction and denaturation by mucus
    that worsens as gestation proceeds.

    If that reading is right, then "CBAVD" as currently used names two mechanistically distinct conditions
    - an early organogenesis failure and a late progressive involution - that a clinician cannot separate without
    a renal ultrasound. It would explain the otherwise puzzling 10-20% of bilateral cases with no genetic diagnosis
    despite deep CFTR testing, and it would mean those men are not simply awaiting a better CFTR panel.

    What is missing is direct evidence. No study has compared duct histology across the two groups at matched
    gestational ages, and the renal-anomaly group has not been systematically exome-sequenced for developmental
    regulators of the mesonephric duct. Until it is, the distinction rests on an inference from mutation yield
    and a co-occurring anomaly.'
  proposed_experiments:
  - experiment_id: cbavd_renal_anomaly_group_exome
    name: Exome sequencing of CAVD stratified by renal ultrasound
    description: Sequence CFTR-negative CAVD cohorts stratified by the presence or absence of a solitary kidney,
      testing whether the renal-anomaly group is enriched for variants in mesonephric duct developmental regulators
      rather than in ion transport genes.
    would_support:
    - pathophysiology#Progressive Involution of Mesonephric Duct Derivatives
    supporting_outcome:
    - The renal-anomaly group is enriched for developmental regulators and depleted of ion-transport variants,
      establishing two distinct genetic architectures behind one clinical endpoint.
    refuting_outcome:
    - Both groups converge on ion-transport and duct-maintenance genes, meaning the renal anomaly reflects
      severity along one mechanism rather than a separate one.
references:
- reference: PMID:32025909
  title: Genetics of the congenital absence of the vas deferens.
- reference: PMID:27476656
  title: Truncating Mutations in the Adhesion G Protein-Coupled Receptor G2 Gene ADGRG2 Cause an X-Linked Congenital
    Bilateral Absence of Vas Deferens.
- reference: PMID:29216686
  title: 'Congenital bilateral absence of the vas deferens as an atypical form of cystic fibrosis: reproductive
    implications and genetic counseling.'
- reference: PMID:33000223
  title: 'Mutations of the cystic fibrosis transmembrane conductance regulator gene in males with congenital
    bilateral absence of the vas deferens: Reproductive implications and genetic counseling (Review).'
- reference: PMID:32930103
  title: Sperm retrieval and intracytoplasmic sperm injection outcomes in men with cystic fibrosis disease
    versus congenital bilateral absence of the vas deferens.
- reference: PMID:20301428
  title: Cystic Fibrosis.
  tags:
  - GeneReviews
- reference: PMID:23378603
  title: CFTR p.Arg117His associated with CBAVD and other CFTR-related disorders.
- reference: PMID:28384194
  title: Loss of SLC9A3 decreases CFTR protein and causes obstructed azoospermia in mice.
- reference: PMID:35119551
  title: Genetic analysis and intracytoplasmic sperm injection outcomes of Chinese patients with congenital
    bilateral absence of vas deferens.
- reference: PMID:37273165
  title: A novel ADGRG2 truncating variant associated with X-linked obstructive azoospermia in a large Chinese
    pedigree.
- reference: PMID:39288989
  title: 'Use of CFTR modulators in pregnancy: new information for neonatal, paediatrics and midwifery teams.'
- reference: PMID:40850271
  title: 'Cystic fibrosis: influence of CFTR variants on epididymal sperm recovery and ICSI results.'
- reference: PMID:41255074
  title: 'Evaluation of the congenital absence of the vas deferens with magnetic resonance imaging: preliminary
    findings.'
- reference: PMID:41654435
  title: Prenatal initiation of elexacaftor/tezacaftor/ivacaftor via carrier mother prevents congenital bilateral
    absence of vas deferens in a male infant with cystic fibrosis.
notes: 'Scope. This entry covers isolated congenital bilateral absence of the vas deferens - the CFTR-related
  and ADGRG2-related forms in which the genital tract is the only affected system. It is deliberately distinct
  from kb/disorders/Cystic_Fibrosis.yaml, which models Vas Deferens Agenesis as one phenotype node of multisystem
  CF. The content that has no home in the CF entry is what justifies a separate one: the residual-function
  CFTR genotype threshold, the X-linked ADGRG2 route which involves CFTR not at all, and the distinction from
  the renal-anomaly developmental group.

  Of MONDO:0018801''s three descendants, the two bilateral forms (MONDO:0010178 CFTR-related, MONDO:0010511
  X-linked) are modelled here as has_subtypes because they converge on one pathograph. Congenital unilateral
  aplasia (MONDO:0800311) is recorded as a differential diagnosis rather than a subtype - fertility is often
  preserved and the genetic architecture differs.

  Deep research. Curated with a single OpenScientist deep-research report (research/Congenital_Bilateral_Absence_of_Vas_Deferens-deep-research-openscientist.md).
  Its reference validation reported 25/25 citations verified. Its term validation reported needs_review with
  five mislabelled terms, including MONDO:0009299 offered under the bare label "MONDO" when the ontology calls
  it "46 XX gonadal dysgenesis". No CURIE in this entry was taken from the report; every binding here was resolved
  independently against the term caches and OLS.


  GeneReviews. PubMed surfaces no dedicated CBAVD or CFTR-Related Disorders chapter; the relevant chapter is
  Cystic Fibrosis (PMID:20301428), which covers vas deferens aplasia as a CF morbidity and carries the counselling
  and preimplantation-testing content. It is tagged and cited here. Searches run: "CFTR-Related Disorders GeneReviews",
  "CFTR-Related Disorders[Book]", "cystic fibrosis GeneReviews[TI]" and a books-database query, none of which
  returned a CBAVD-specific chapter.'
clinical_burden:
  burden_level: MODERATE
  rationale: 'The burden is confined to fertility - there is no organ damage, no shortened life, and no progression
    after the duct is lost. Against that, it is usually the reason a couple presents, and it is treatable:
    39 of 46 men in a consecutive series had their own children through retrieval and ICSI. Rated MODERATE
    rather than LOW because the diagnosis also identifies a CFTR carrier couple, and the child at risk has
    cystic fibrosis - a far more serious disease than the father''s.'
  evidence:
  - reference: PMID:35119551
    reference_title: Genetic analysis and intracytoplasmic sperm injection outcomes of Chinese patients with
      congenital bilateral absence of vas deferens.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: After proper counseling, all patients can undergo sperm retrieval from their epididymis or testis,
      and most of them can have their own children through ICSI.
    explanation: The outcome statement behind this rating.
  - reference: PMID:29216686
    reference_title: 'Congenital bilateral absence of the vas deferens as an atypical form of cystic fibrosis:
      reproductive implications and genetic counseling.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: genetic counseling should be offered to couples undergoing ART to discuss the probability of having
      offspring that carry CFTR gene mutations
    explanation: The transmission risk that keeps this above a LOW rating.
progression:
- phase: Fetal and early postnatal
  notes: 'The window in which the disease happens. The duct forms, is obstructed and degraded by mucus by 12-18
    weeks, and the process worsens as gestation proceeds and probably continues after birth. After that it
    is static: there is no adult progression, and the clinical course is a fixed obstructive azoospermia. The
    therapeutic corollary is in the prenatal CFTR modulator entry - restoration during this window preserved
    the duct in one reported case, while postnatal modulators do not restore fertility.'
  evidence:
  - reference: PMID:32025909
    reference_title: Genetics of the congenital absence of the vas deferens.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: unlike CAVDs related to CFTR or ADGRG2 mutations, which might be the result of progressive degeneration
      that begins later in fetal life and probably continues after birth
    explanation: The timing of the process, which is what makes this a progression record with a closing window
      rather than an ongoing course.
📚

References & Deep Research

References

14
PMID:32025909
Genetics of the congenital absence of the vas deferens.
No top-level findings curated for this source.
PMID:27476656
Truncating Mutations in the Adhesion G Protein-Coupled Receptor G2 Gene ADGRG2 Cause an X-Linked Congenital Bilateral Absence of Vas Deferens.
No top-level findings curated for this source.
PMID:29216686
Congenital bilateral absence of the vas deferens as an atypical form of cystic fibrosis: reproductive implications and genetic counseling.
No top-level findings curated for this source.
PMID:33000223
Mutations of the cystic fibrosis transmembrane conductance regulator gene in males with congenital bilateral absence of the vas deferens: Reproductive implications and genetic counseling (Review).
No top-level findings curated for this source.
PMID:32930103
Sperm retrieval and intracytoplasmic sperm injection outcomes in men with cystic fibrosis disease versus congenital bilateral absence of the vas deferens.
No top-level findings curated for this source.
PMID:20301428
Cystic Fibrosis.
No top-level findings curated for this source.
PMID:23378603
CFTR p.Arg117His associated with CBAVD and other CFTR-related disorders.
No top-level findings curated for this source.
PMID:28384194
Loss of SLC9A3 decreases CFTR protein and causes obstructed azoospermia in mice.
No top-level findings curated for this source.
PMID:35119551
Genetic analysis and intracytoplasmic sperm injection outcomes of Chinese patients with congenital bilateral absence of vas deferens.
No top-level findings curated for this source.
PMID:37273165
A novel ADGRG2 truncating variant associated with X-linked obstructive azoospermia in a large Chinese pedigree.
No top-level findings curated for this source.
PMID:39288989
Use of CFTR modulators in pregnancy: new information for neonatal, paediatrics and midwifery teams.
No top-level findings curated for this source.
PMID:40850271
Cystic fibrosis: influence of CFTR variants on epididymal sperm recovery and ICSI results.
No top-level findings curated for this source.
PMID:41255074
Evaluation of the congenital absence of the vas deferens with magnetic resonance imaging: preliminary findings.
No top-level findings curated for this source.
PMID:41654435
Prenatal initiation of elexacaftor/tezacaftor/ivacaftor via carrier mother prevents congenital bilateral absence of vas deferens in a male infant with cystic fibrosis.
No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (3)

Record notes

Scope. This entry covers isolated congenital bilateral absence of the vas deferens - the CFTR-related and ADGRG2-related forms in which the genital tract is the only affected system. It is deliberately distinct from kb/disorders/Cystic_Fibrosis.yaml, which models Vas Deferens Agenesis as one phenotype node of multisystem CF. The content that has no home in the CF entry is what justifies a separate one: the residual-function CFTR genotype threshold, the X-linked ADGRG2 route which involves CFTR not at all, and the distinction from the renal-anomaly developmental group. Of MONDO:0018801's three descendants, the two bilateral forms (MONDO:0010178 CFTR-related, MONDO:0010511 X-linked) are modelled here as has_subtypes because they converge on one pathograph. Congenital unilateral aplasia (MONDO:0800311) is recorded as a differential diagnosis rather than a subtype - fertility is often preserved and the genetic architecture differs. Deep research. Curated with a single OpenScientist deep-research report (research/Congenital_Bilateral_Absence_of_Vas_Deferens-deep-research-openscientist.md). Its reference validation reported 25/25 citations verified. Its term validation reported needs_review with five mislabelled terms, including MONDO:0009299 offered under the bare label "MONDO" when the ontology calls it "46 XX gonadal dysgenesis". No CURIE in this entry was taken from the report; every binding here was resolved independently against the term caches and OLS. GeneReviews. PubMed surfaces no dedicated CBAVD or CFTR-Related Disorders chapter; the relevant chapter is Cystic Fibrosis (PMID:20301428), which covers vas deferens aplasia as a CF morbidity and carries the counselling and preimplantation-testing content. It is tagged and cited here. Searches run: "CFTR-Related Disorders GeneReviews", "CFTR-Related Disorders[Book]", "cystic fibrosis GeneReviews[TI]" and a books-database query, none of which returned a CBAVD-specific chapter.

Review round: qualify Adgrg2 model, add CFTR rat/mouse models · 2026-09-15T05:21:23Z · View source

Addressed the ai4c-reviewer CHANGES_REQUESTED round on PR #10669. (1) The Adgrg2/He6 knockout mouse link was asserting RECAPITULATES against 'Progressive Involution of Mesonephric Duct Derivatives' while its own limitations text recorded that the mouse shows efferent-ductule dilation and testicular fluid backup rather than the duct involution the node describes; downgraded to PARTIALLY_RECAPITULATES and said why in the link description. (2) The animal_models section had been created with only a modifier gene (SLC9A3) and a ~2% X-linked cause (ADGRG2), omitting CFTR, which the entry itself says explains most cases; added a CFTR-knockout rat model (RECAPITULATES, fidelity HIGH, hypospermatogenesis divergence in limitations, two readouts) and a CFTR knock-in/partial-knockout mouse model (FAILS_TO_RECAPITULATE with both limitations and evidence, since residual-function alleles leave fertility intact). Both cite the already-cached comparative review PMID:42380629. (3) Took the three reviewer suggestions: rebound the epididymal epithelial cell descriptor from CL:0000066 (epithelial cell) to the more specific and still accurate CL:0000068 (duct epithelial cell), rewriting the note to keep the record of the absent male-excurrent-duct term; changed the seminal fructose readout direction from PRESENT_ABSENT to THRESHOLD_DEPENDENT to match its own quoted >25 microM cutoff; added frequency: FREQUENT from the deep-research grading. Validation: just validate (67/67 snippets verified), just validate-terms, just check-entity-refs, just check-causal-targets, just check-duplicate-keys all pass. Note quote_role is not yet in this branch's schema copy, so the review-sourced evidence items carry evidence_source: MODEL_ORGANISM without it.

Create: Congenital_Bilateral_Absence_of_Vas_Deferens · 2026-08-28T22:08:54Z · View source

De novo curation of congenital bilateral absence of the vas deferens, MONDO:0018801, claimed via issue #9941. One OpenScientist deep-research report was run: research/Congenital_Bilateral_Absence_of_Vas_Deferens-deep-research-openscientist.md. Reference validation reported 25/25 verified; term validation reported five mislabelled terms, including MONDO:0009299 offered under the bare label MONDO when the ontology calls it 46 XX gonadal dysgenesis. No CURIE from the report was bound; all bindings were resolved independently against the term caches and OLS. Scoped to isolated CBAVD with CFTR-related and ADGRG2-related has_subtypes; congenital unilateral aplasia is recorded as a differential diagnosis rather than a subtype. Validated with just validate at 53/53 snippets verified after two rounds of review, which added the poly-T tract and variant spectrum, prenatal CFTR modulator therapy, corrected anatomy on the seminal vesicle phenotype, subtype MONDO bindings, prognosis and the GeneReviews baseline. SLC9A3 is recorded as SUSCEPTIBILITY: the human evidence is a heterozygous single-copy deletion in a small series and the causal demonstration is in a homozygous-null mouse, which is short of what CAUSATIVE asserts.

OpenScientist ▸
1. Disease Information
openscientist-autonomous 25 citations 2026-08-28T22:04:47.735476

1. Disease Information

CBAVD is a congenital malformation of the male reproductive tract characterized by the bilateral absence (aplasia) or atresia of the vasa deferentia — the paired muscular ducts that transport spermatozoa from the epididymis to the ejaculatory ducts. The result is a mechanical (obstructive) block to sperm transport, giving obstructive azoospermia despite normal testicular sperm production. It is frequently accompanied by anomalies of adjacent Wolffian-duct derivatives (seminal vesicles, distal epididymis, ejaculatory ducts).

Key identifiers

Resource Identifier
OMIM 277180 (CBAVD)
Orphanet ORPHA:48
MONDO MONDO:0009299
ICD-10 Q55.4 (congenital absence/aplasia/hypoplasia of vas deferens)
ICD-11 LB77.0
MeSH Vas Deferens / abnormalities

Synonyms / alternative names: CBAVD; congenital bilateral aplasia of the vas deferens; congenital absence of the vas deferens (CAVD, when unspecified laterality); bilateral vasal agenesis; part of the "congenital absence of the vas deferens" (CAVD) family that also includes congenital unilateral absence of the vas deferens (CUAVD).

Data source type: The evidence base is derived from aggregated disease-level resources (OMIM, Orphanet, cohort studies, meta-analyses) supplemented by individual patient reports (case reports of ADGRG2 pedigrees, MRI series, prenatal ETI case). It is a well-curated Mendelian/complex reproductive disorder rather than an EHR-derived entity.

2. Etiology

Causal factors — predominantly genetic

CBAVD is overwhelmingly a genetic disorder, principally a genital manifestation of CFTR dysfunction.

  • CFTR (autosomal recessive, predominant). The majority of CBAVD men carry at least one CF-causing CFTR variant. "The majority of subjects with CAVD carry at least one cystic fibrosis-causing mutation that warrants CFTR testing" PMID: 32025909. In a large Chinese isolated-CAVD (iCAVD) cohort (n=199), "CFTR and ADGRG2 variants were identified in 74.87% of iCAVD patients, with CFTR being the predominant pathogenic gene" PMID: 42199298.
  • ADGRG2 (X-linked recessive, ~2%). "Approximately 2% of the cases of CAVD are hemizygous for a loss-of-function mutation in the ADGRG2 gene that may cause a familial form of X-linked infertility" PMID: 32025909.
  • Developmental / Wolffian-duct defect (subset with renal agenesis). CFTR-negative cases frequently coexist with a solitary kidney, indicating an early organogenesis disorder (see Section 5 and Section 6).
  • Unexplained (10–20%). A residual fraction lacks an identified molecular cause.

Risk factors

  • Genetic risk factors: biallelic CFTR variants (a severe allele such as p.Phe508del combined with a mild/variable allele — e.g., IVS8-5T poly-T with long TG tract, or p.Arg117His-T7); hemizygous truncating ADGRG2 variants; candidate developmental variants (FREM1, WNT2B, TBX6) in the renal-anomaly subtype. The IVS9-5T (poly-T 5T) allele is a major low-penetrance risk allele, especially in East Asian populations.
  • Environmental risk factors: No established toxic, occupational, infectious, or lifestyle exposure causes CBAVD. It is a developmental/genetic disorder; sex is male-only (defining), and family history of CF or CBAVD is relevant.

Protective factors

  • Genetic: By definition, the wild-type / functional CFTR and ADGRG2 alleles are "protective"; the poly-T 7T/9T tracts confer normal splicing/function versus the risk-associated 5T.
  • Environmental / therapeutic: Prenatal CFTR-modulator therapy (ETI) prevents CBAVD in genetically susceptible fetuses (Section 6, Finding F006) — an intervention that restores CFTR channel function during the fetal critical window.

Gene–environment interactions

The clearest gene–environment interaction is pharmacologic restoration of CFTR function in utero. The poly-T/TG polymorphic tract is itself a cis-genetic modifier of splicing that determines residual CFTR activity and hence penetrance of the genital phenotype (the TG12-T5 combination reduces CFTR function; PMID: 42572672). No classical toxin-by-gene interaction has been documented.

3. Phenotypes

CBAVD presents in otherwise healthy, normally virilized men, typically discovered during infertility evaluation (adult-onset presentation of a congenital anatomic defect).

Phenotype Type Onset / severity / frequency Suggested HPO
Non-palpable / absent bilateral vas deferens Physical/clinical sign Congenital; bilateral; ~100% (defining) HP:0000798 (Abnormality of the vas deferens); "Aplasia of the vas deferens"
Obstructive azoospermia Laboratory abnormality Congenital anatomic cause, detected in adulthood; severe; ~100% HP:0000027 (Azoospermia)
Low ejaculate volume Laboratory/clinical Congenital; frequent HP:0012869 (Decreased ejaculate volume)
Low semen pH (acidic) Laboratory Frequent Abnormal seminal pH
Low/absent seminal fructose Laboratory Frequent (reflects seminal-vesicle involvement) —
Seminal vesicle agenesis/hypoplasia Physical/imaging Variable — bilateral agenesis, unilateral agenesis, or present HP:0011878 (Abnormality of the seminal vesicle)
Epididymal partial absence Physical/imaging Variable; genotype-correlated HP:0000029 (Abnormality of the epididymis)
Male infertility Clinical outcome Adult; severe; ~100% HP:0003251 (Male infertility)
Unilateral renal agenesis (subset) Physical/imaging Congenital; in developmental subtype HP:0000122 (Unilateral renal agenesis)

Supporting evidence. "The incidence of congenital bilateral absence of the vas deferens (CBAVD) in infertile men is 1-2%" PMID: 35109852. Seminal-vesicle involvement is variable: among 47 CBAVD patients, "29 had bilateral agenesis of the seminal vesicles, 9 had unilateral agenesis, and 9 had bilateral presence" PMID: 40533736. Epididymal involvement tracks with CFTR genotype: "patients carrying at least one non-5 T variant were associated with an 8.17-fold increased risk of epididymal partial absence compared to those having the homozygous 5 T mutation" PMID: 39592508.

Quality-of-life impact. The dominant impact is infertility and its psychosocial burden; there is no pain, disability, or systemic morbidity in isolated CBAVD. Because sperm retrieval + ICSI achieves paternity in most couples, the long-term QoL impact is limited relative to systemic diseases. Men should also be counseled about the possibility of an underlying CFTR-related disorder (e.g., pancreatitis, sinopulmonary disease) that may manifest later.

4. Genetic / Molecular Information

Causal genes

  • CFTR (HGNC:1884; OMIM 602421; chr7q31.2) — cystic fibrosis transmembrane conductance regulator; a cAMP-activated Cl⁻/HCO₃⁻ channel. Predominant cause of CBAVD.
  • ADGRG2 (HGNC:18023; OMIM 300572; chrXp22.13) — adhesion GPCR G2 (GPR64), epididymal- and efferent-duct-specific. X-linked cause (~2%).
  • Candidate developmental genes: FREM1, WNT2B, TBX6 in CFTR-negative CBAVD with renal anomalies PMID: 40921938.

Pathogenic variants — CFTR

Isolated CBAVD is typically caused by a trans-heterozygous combination of one severe CF-causing allele plus one mild/variable allele:

  • p.Phe508del (F508del) — the classic severe deletion; predominant in Europeans.
  • Poly-T / TG tract (IVS8-5T; c.1210-34TG(n)T(m)) — the T5 allele with a long TG repeat reduces exon-9 inclusion and lowers functional CFTR. "the combination of T5 with longer TG repeats is associated with reduced CFTR function" — as in a compound heterozygote p.Phe508del + TG12T5 PMID: 42572672.
  • p.Arg117His — associated with CBAVD and other CFTR-related disorders; a French cohort (n=179) found "83 isolated CBAVD, 67 other CFTR-related phenotypes" with an overall mild phenotype PMID: 23378603.
  • IVS9-5T — the most common allele in Chinese CBAVD (~54.5%), with regional variants such as p.Gln1352His (c.4056G>C).

Variant classification follows ACMG/AMP tiers (pathogenic / likely pathogenic / VUS). Variant types include missense (p.Arg117His), in-frame deletion (p.Phe508del), splice-modulating poly-T/TG tracts, nonsense, frameshift, and deep-intronic/large rearrangements — hence the recommendation for whole-exon + flanking + rearrangement CFTR screening in CAVD PMID: 40065563. Origin is germline. Functional consequence is loss of function (reduced Cl⁻/HCO₃⁻ conductance).

Pathogenic variants — ADGRG2

Hemizygous protein-truncating variants: "c.1545dupT (p.Glu516Ter), c.2845delT (p.Cys949AlafsTer81), and c.2002_2006delinsAGA (p.Leu668ArgfsTer21)" PMID: 27476656; additional c.G118T (p.Glu40) and the nonsense c.908C>G (p.Ser303) PMID: 37273165. These are loss-of-function, X-linked, maternally inherited, and typically absent from population databases. Western blot confirms a truncated ADGRG2 protein [PMID: 37273165].

Modifier genes / epigenetics / chromosomal abnormalities

  • Modifiers: the poly-T/TG tract functions as the principal cis-modifier of CFTR splicing and penetrance. SLC9A3 interacts functionally with CFTR (Sections 6/7).
  • Epigenetics: No disease-specific DNA-methylation or histone signature has been established for CBAVD.
  • Chromosomal abnormalities: Not a primary cause. A single case report describes a 47,XYY mosaic karyotype coexisting with CBAVD PMID: 35109852; this appears coincidental rather than causal.

5. Environmental Information

  • Environmental factors / toxins / radiation / occupational exposure: None established as causal. CBAVD is a developmental-genetic disorder.
  • Lifestyle factors (smoking, diet, alcohol, exercise): No demonstrated role in causation.
  • Infectious agents: Not applicable — CBAVD is congenital and non-infectious. (Acquired vasal obstruction from infection or vasectomy is a separate differential diagnosis, not CBAVD.)

The only "environmental" (i.e., non-germline) modifier with proven effect is pharmacologic — prenatal CFTR modulator exposure (protective; Section 6).

6. Mechanism / Pathophysiology

Two etiologic subtypes (bimodal pathogenesis)

CBAVD arises through two mechanistically distinct routes, a key organizing insight of this investigation (Finding F005):

          ┌─────────────────────────────────────────────┐
          │   CBAVD  (obstructive azoospermia)           │
          └─────────────────────────────────────────────┘
                     │
┌────────────────────────────┴───────────────────────────────┐
│                                                              │
 (A) DEGENERATIVE subtype                              (B) DEVELOPMENTAL subtype
  CFTR / ADGRG2 loss-of-function                        Mesonephric (Wolffian) duct
  → abnormal luminal Cl⁻/HCO₃⁻ &                        maldevelopment (early organogenesis)
    fluid transport                                     → ureteric bud + duct derivatives
  → progressive fetal atresia/                            affected
    degeneration of vas deferens                        → vasal agenesis + UNILATERAL
    beginning later in fetal life                         RENAL AGENESIS / solitary kidney
  → kidneys SPARED                                      candidate genes: FREM1, WNT2B, TBX6

Evidence for the split: "An important proportion of these unexplained CAVDs coexist with a solitary kidney suggesting an early organogenesis disorder (Wolffian duct), unlike CAVDs related to CFTR or ADGRG2 mutations, which might be the result of progressive degeneration that begins later in fetal life" PMID: 32025909. The shared embryology of the developmental subtype: "The embryonic insult that results in unilateral renal agenesis may involve not only the ureteral bud but also other mesonephric duct derivatives, including the seminal vesicles, vas deferens, and epididymis" PMID: 16985610. MRI data support acquired/progressive vasal agenesis in the CFTR-type: "Preliminary findings in this study are consistent with the theory of acquired vasal agenesis in CBAVD" PMID: 41255074.

Molecular pathways and protein dysfunction

  • CFTR pathway (degenerative subtype). CFTR is a cAMP-activated Cl⁻ and HCO₃⁻ channel governing the luminal microenvironment of the male tract. Loss of function disturbs anion/fluid secretion and the HCO₃⁻/soluble adenylyl cyclase/cAMP/CREB and NF-κB/COX-2/PGE₂ signaling axes relevant to tract development and sperm function: "CFTR is emerging as a versatile player with roles in mediating different signaling pathways... in addition to its long-recognized role in electrolyte and fluid transport that regulates the luminal microenvironment of the male reproductive tract" PMID: 22709980. Abnormal luminal fluid handling is thought to drive the progressive atresia of the vas: "cystic fibrosis (CF) leads to infertility in over 95% of cases, due to early and progressive atresia of the vas deferens, resulting in obstructive azoospermia" PMID: 42380629.
  • ADGRG2 pathway (X-linked subtype). ADGRG2 is an adhesion GPCR expressed apically in non-ciliated efferent-duct epithelium: "ADGRG2 expression was restricted to the apical membranes of non-ciliated epithelia in human efferent ducts" PMID: 32314195. Loss of function causes obstructive infertility by disrupting efferent-duct fluid reabsorption (recapitulated in Adgrg2-knockout mice: "Adgrg2-knockout male mice develop obstructive infertility" PMID: 27476656).
  • SLC9A3 (NHE3) interaction. SLC9A3 loss reduces CFTR protein and causes obstruction: "depleted Slc9a3 in male mice causes infertility due to the abnormal dilated lumen of the rete testis and efferent ductules" PMID: 28384194 — implicating a shared ion-transport/CFTR-stability module.

Cellular processes, cell types, and compartments

  • Cell types (CL): ductal epithelial cells of the vas deferens/epididymis; non-ciliated efferent-duct epithelial cells (ADGRG2⁺); seminal-vesicle epithelium.
  • Cellular process: disrupted transepithelial anion/fluid transport → luminal microenvironment failure → epithelial/duct degeneration and atresia (degenerative subtype) or failed duct morphogenesis (developmental subtype).
  • Subcellular compartments (GO CC): apical plasma membrane (GO:0016324) — site of CFTR and ADGRG2 function; anion channel activity.
  • Suggested GO BP: GO:0006821 (chloride transport), GO:0055085 (transmembrane transport), GO:0048754 (branching morphogenesis of an epithelial tube), GO:0035239 (tube morphogenesis), GO:0007283 (spermatogenesis — preserved).

Critical window — a therapeutic mechanism

The degenerative subtype is preventable in utero. In a male CF infant (homozygous F508del) whose carrier mother began ETI at 27+4 weeks: "ultrasound at 8 weeks demonstrated bilateral vas deferens, a structure typically absent in nearly all male patients with CF at birth" and "These findings suggest that prenatal CFTR modulation - even when initiated late" can preserve the duct PMID: 41654435. Conversely, "At present male patients taking CFTR modulators have not shown improvement in infertility" PMID: 39288989 — establishing that restoration must occur before the duct is lost.

7. Anatomical Structures Affected

  • Organ level (primary): vas deferens (UBERON:0001000) — bilateral. Secondary/associated: epididymis (UBERON:0001301), seminal vesicle (UBERON:0000998), ejaculatory duct, efferent ducts (UBERON:0003074). Kidney (UBERON:0002113) in the developmental subtype (unilateral renal agenesis).
  • Body system: male reproductive/genital system (UBERON:0000079); urinary system involvement in the renal-anomaly subtype.
  • Tissue / cell level: ductal epithelium (transporting epithelium) and surrounding smooth muscle of the vas; non-ciliated efferent-duct epithelial cells (ADGRG2⁺). Testicular seminiferous tissue is preserved (spermatogenesis intact).
  • Subcellular: apical plasma membrane (GO:0016324); anion channel machinery.
  • Localization / lateralization: bilateral by definition (CBAVD); the CAVD family also includes unilateral (CUAVD) and asymmetric presentations. Seminal-vesicle and epididymal involvement is frequently asymmetric PMID: 40533736.

8. Temporal Development

  • Onset: Congenital — the anatomic defect is present at (or develops before) birth. In the degenerative CFTR subtype, atresia is "early and progressive" during fetal life [PMID: 42380629]; the developmental subtype originates at early organogenesis. Clinically, however, the disorder is usually detected in adulthood during infertility work-up (insidious, asymptomatic until then).
  • Progression: The structural defect is fixed/non-progressive after birth (the vas is already absent). There are no post-natal "stages." Disease course is stable and lifelong; the associated infertility is chronic unless overcome by ART.
  • Patterns / critical periods: The single actionable critical period is fetal — CFTR function must be preserved during gestation to prevent vasal loss (prenatal ETI, [PMID: 41654435]). No spontaneous remission occurs.

9. Inheritance and Population

Epidemiology

  • Prevalence: "The prevalence of CAVDs in men is reported to be approximately 0.1%" PMID: 32025909 (likely underestimated).
  • Frequency in male infertility: CBAVD accounts for 1–2% of infertile men PMID: 35109852.
  • Incidence: Not precisely established (congenital, detected at reproductive age).

Inheritance (genetic etiology)

Feature CFTR-related CBAVD ADGRG2-related CBAVD
Pattern Autosomal recessive (biallelic) X-linked recessive (hemizygous)
Share of cases ~70–80% ~2%
Penetrance Incomplete/variable, modulated by poly-T/TG tract High but variable
Expressivity Variable (isolated CBAVD ↔ broader CFTR-RD) Variable (one carrier had normal fertility)
Reproductive risk Offspring CF risk if partner carries severe allele X-linked transmission via carrier mothers
  • Penetrance / expressivity: Variable and incomplete for the genital phenotype; sweat chloride does not correlate with severity in p.Arg117His carriers PMID: 23378603. For ADGRG2, an obligate-carrier male with the p.Ser303 variant had normal fertility*, illustrating variable expressivity PMID: 37273165.
  • Genetic anticipation / mitochondrial inheritance: Not applicable.
  • Founder effects / geographic allele spectra: Population-specific. p.Phe508del predominates in Europeans; IVS9-5T is the most common allele in Chinese CBAVD (~54.5%) with regional p.Gln1352His. "There are no obvious hotspot CFTR mutations in Chinese CBAVD patients besides the IVS9-5 T allele" PMID: 35119551.
  • Consanguinity / carrier frequency: CFTR carrier frequency is high in populations with elevated CF prevalence (up to ~1/25 in Europeans), underpinning the reproductive-risk concern. ~10% of iCAVD couples share pathogenic CFTR variants: "10.14% of couples carried shared pathogenic or likely pathogenic CFTR variants" PMID: 42199298.

Population demographics

  • Sex: male only (defining).
  • Geographic variation of variants: European vs East Asian allele spectra differ markedly (above).
  • Age distribution: presents at reproductive age (typically 20s–40s at infertility work-up).

10. Diagnostics

Clinical tests

  • Physical exam: bilateral non-palpable vasa deferentia — the cornerstone finding.
  • Semen analysis (laboratory): azoospermia, low ejaculate volume, low (acidic) pH, low/absent fructose (reflecting seminal-vesicle contribution). Normal serum FSH/testosterone and normal testicular volume support an obstructive (not spermatogenic) cause.
  • Imaging: scrotal ultrasound (confirms absent/atretic vas, evaluates epididymis), transrectal ultrasound (seminal vesicles, ejaculatory ducts), and MRI for the intra-abdominal vas and seminal-vesicle pathology — "detailed findings are obtained by MRI even in the evaluation of the intra-abdominal part of the VD" PMID: 41255074. Renal ultrasound is mandatory to detect solitary kidney (developmental subtype).
  • Biopsy/histopathology: testicular biopsy shows preserved spermatogenesis (not routinely needed).

Genetic testing

  • Recommended approach: Comprehensive CFTR analysis first — including full exon + flanking-region sequencing, the poly-T/TG tract, and large-rearrangement detection — because standard panels miss deep-intronic and rearrangement alleles: "the urgent need for extensive CFTR screening, including sequencing of whole exons and flanking regions and detection of large rearrangements and deep intronic CF-causing variants" PMID: 40065563. If CFTR is negative and renal ultrasound is normal, test ADGRG2: "Pathogenic variants in ADGRG2 are important to look for when CFTR analysis is negative and renal ultrasonography is normal" PMID: 41886210.
  • Modalities: targeted CFTR single-gene/panel testing; WES/WGS for unexplained cases and developmental candidate genes (FREM1, WNT2B, TBX6); karyotype only if a broader syndrome is suspected.

Clinical criteria & differential diagnosis

  • Diagnosis rests on the triad of non-palpable vasa + obstructive azoospermia + low-volume acidic fructose-negative semen, confirmed by imaging and genetics.
  • Differential diagnosis: other causes of obstructive azoospermia (ejaculatory-duct obstruction, post-infectious or post-vasectomy obstruction, Young syndrome) and non-obstructive azoospermia (distinguished by normal FSH/testicular volume and preserved spermatogenesis in CBAVD).

Screening

  • Partner CFTR carrier screening is essential before ART (couple co-carrier risk ~10%).
  • Cascade testing of family members for ADGRG2 pedigrees.

11. Outcome / Prognosis

  • Survival / mortality: Isolated CBAVD carries no excess mortality; life expectancy is normal. Prognosis for survival is excellent. (Men should nonetheless be evaluated for a broader CFTR-related disorder that could have its own morbidity.)
  • Morbidity / function: The sole functional impact is infertility; no disability or organ failure in isolated disease.
  • Fertility outcome (the key prognostic domain): Excellent with ART. Because spermatogenesis is preserved, surgical sperm retrieval + ICSI is highly successful: in a Chinese cohort, "Spermatozoa were successfully retrieved in 46 patients, and 39 of the patients had their own offspring through ICSI" (≈85% paternity) PMID: 35119551.
  • Prognostic factors:
  • Residual CFTR activity predicts retrieval success — MESA extraction failure was higher in CF than CFTR-RD: "Extraction failure rates were 18.6% for cystic fibrosis and 3.9% for CFTR-RD (P = 0.01)", and worse with no residual activity (27.9% vs 3.7% failure, P<0.001) PMID: 40850271.
  • Sperm motility predicts ICSI outcome: "the clinical pregnancy rates, embryo implantation rates, and live birth rates in the high motility group were significantly increased" PMID: 34313208.
  • Complications: principally reproductive/ART-related (e.g., risk of transmitting CF to offspring; rare ART complications such as monochorionic/conjoined twinning after embryo transfer, PMID: 42215739).

12. Treatment

CBAVD has no medical cure for the anatomic defect; management is fertility-focused plus genetic counseling.

Assisted reproduction (mainstay)

  • Surgical sperm retrieval: MESA (microsurgical epididymal sperm aspiration), PESA (percutaneous epididymal sperm aspiration), TESE (testicular sperm extraction). (NCIT: Sperm Retrieval; Testicular Sperm Extraction.)
  • ICSI (intracytoplasmic sperm injection): the definitive route to biological paternity; ~85% success in achieving offspring [PMID: 35119551]. (NCIT: Intracytoplasmic Sperm Injection.)
  • Optimization: select high-motility sperm to maximize live-birth rate [PMID: 34313208].

CFTR modulator therapy — a disease-modifying frontier

  • Prenatal ETI (elexacaftor/tezacaftor/ivacaftor) can prevent CBAVD when administered to the fetus via a carrier mother during gestation PMID: 41654435. This is investigational and raises ethical/consent questions for heterozygous fetuses PMID: 39543810.
  • Postnatal modulators do NOT reverse established CBAVD/infertility PMID: 39288989.

Pharmacogenomics / personalized medicine

  • Genotype-guided counseling: CFTR genotype informs residual function, retrieval prognosis, CFTR-RD surveillance, and modulator eligibility.
  • Couple-level genotyping guides preimplantation genetic testing (PGT) to avoid transmitting CF.

Not applicable

Gene therapy, cell therapy, RNA therapeutics, immunotherapy, and chemotherapy have no established role in CBAVD.

13. Prevention

  • Primary prevention: Prenatal CFTR-modulator therapy is the only demonstrated means of preventing the vasal defect itself (investigational) [PMID: 41654435]. Broadly, primary prevention is limited because CBAVD is congenital/genetic.
  • Secondary prevention / early detection: Genetic diagnosis at infertility work-up enables timely ART and CFTR-RD surveillance.
  • Tertiary prevention: Optimizing sperm-retrieval/ICSI protocols and PGT to prevent CF offspring.
  • Genetic screening & counseling (central): CFTR carrier screening of both partners before ART is essential; ~10% of couples are co-carriers [PMID: 42199298]. Options include preimplantation genetic diagnosis and prenatal testing. Comprehensive CFTR screening (exons + flanking + rearrangements) is recommended before ART [PMID: 40065563].
  • Immunization / public-health / environmental measures: Not applicable (non-infectious, non-environmental).

14. Other Species / Natural Disease

  • Taxonomy affected (models): Rattus norvegicus (rat, NCBI:txid10116), Mus musculus (mouse, NCBI:txid10090), plus large-animal CF models — ferret, pig, sheep, rabbit.
  • Orthologous genes: Cftr (rat/mouse), Adgrg2, Slc9a3 orthologs.
  • Natural / comparative disease: CF animal models frequently show absent vas deferens/epididymis with normal testicular histology, mirroring human CBAVD: "CFTR-knockout rats more closely reproduce the human phenotype, showing bilateral absence of the vas deferens and epididymal hypoplasia, although they exhibit more pronounced hypospermatogenesis than observed in men" PMID: 42380629. Evolutionary conservation of CFTR-dependent duct development underlies the cross-species recapitulation.
  • Transmission / zoonosis: Not applicable (genetic malformation).

15. Model Organisms

Model Genetic manipulation Phenotype recapitulation Key limitation
CFTR-knockout rat Complete Cftr KO Best model — bilateral vas absence + epididymal hypoplasia More severe hypospermatogenesis than men
Mouse — knock-in / partial KO Hypomorphic Usually remain fertile Fails to model vasal absence
Mouse — complete Cftr KO Full KO May develop vas atresia with aging Age-dependent, heterogeneous
Large animals (ferret, pig, sheep, rabbit) CF models Frequently absent vas/epididymis, normal testis Cost, husbandry
Adgrg2-knockout mouse Adgrg2 KO Obstructive infertility (efferent-duct model) Models ADGRG2 subtype only
Slc9a3-knockout mouse Slc9a3 KO Obstructive azoospermia; reduced CFTR in epididymis/vas Models NHE3/CFTR interaction

Supporting quotes. "knock-in or partial knockout models usually remain fertile, whereas complete knockouts may develop vas deferens atresia with aging" PMID: 42380629. "Adgrg2-knockout male mice develop obstructive infertility" PMID: 27476656. "depleted Slc9a3 in male mice causes infertility due to the abnormal dilated lumen of the rete testis and efferent ductules" PMID: 28384194.

Applications: these models allow study of CFTR-dependent duct morphogenesis, the fetal critical window for modulator rescue, efferent-duct fluid handling (ADGRG2/SLC9A3), and CFTR-modulator pharmacology. Databases: MGI, RGD, IMPC/KOMP, IMSR.

Mechanistic Model / Interpretation

CBAVD is best conceptualized as a convergent obstructive-azoospermia phenotype reached by two upstream routes:

UPSTREAM CAUSE                    MID-STREAM MECHANISM                    DOWNSTREAM PHENOTYPE
─────────────────────────────────────────────────────────────────────────────────────────────
CFTR biallelic LoF ──►  ↓ apical Cl⁻/HCO₃⁻ & fluid transport ──►  progressive fetal ─┐
(severe + mild allele;   (HCO₃⁻/sAC/cAMP; NF-κB/COX-2)             vasal atresia      │
 poly-T/TG modifier)                                              (kidneys spared)    │
                                                                      ├─► Bilateral
ADGRG2 hemizygous LoF ─► efferent-duct epithelial dysfunction ──► efferent/vasal ─────┤   absent vas
(X-linked, ~2%)          (adhesion GPCR, fluid reabsorption)      obstruction         │   → obstructive
                                                                      │   azoospermia
Wolffian-duct           failed duct + ureteric-bud morphogenesis ─► vasal agenesis ───┘   (SPERMATOGENESIS
maldevelopment          (FREM1/WNT2B/TBX6?)                        + UNILATERAL RENAL     PRESERVED)
(developmental subtype)                                            AGENESIS

Upstream vs downstream: the genetic lesion (CFTR/ADGRG2 LoF or a developmental-gene defect) is upstream; disrupted epithelial ion/fluid transport (or failed morphogenesis) is the mid-stream mechanism; duct atresia/agenesis and consequent obstructive azoospermia are downstream. The testis is not in the causal chain — spermatogenesis is preserved, which is precisely why sperm retrieval + ICSI works. The presence/absence of a solitary kidney is the single most useful clinical discriminator between the developmental and degenerative subtypes and should redirect genetic testing (renal-anomaly → developmental genes; normal kidneys + CFTR-negative → ADGRG2).

Evidence Base

PMID Contribution Supports finding
32025909 Genetics review — CFTR predominance, ADGRG2 ~2%, prevalence 0.1%, developmental/degenerative split F001, F005, F009
42199298 Large Chinese iCAVD cohort — 74.87% CFTR/ADGRG2; 10.14% couple co-carriers F001, F009
27476656 Original ADGRG2 truncating variants; Adgrg2-KO mouse F002, F007
32314195 ADGRG2 efferent-duct localization; novel LoF variant F002
35109852 CBAVD incidence 1–2%; 47,XYY mosaic case F003
40533736 Seminal-vesicle status distribution (47 patients) F003
39592508 Non-5T → 8.17× epididymal partial-absence risk F003
42380629 CF male reproductive phenotype; CFTR-KO rat best model F004, F007
23378603 p.Arg117His CBAVD/CFTR-RD spectrum; couples at CF risk F004
16985610 Mesonephric-duct embryology of renal + vasal agenesis F005
40921938 FREM1/WNT2B/TBX6 in CFTR-negative CBAVD with renal anomalies F005
41255074 MRI evidence for acquired/progressive vasal agenesis F005
41654435 Prenatal ETI prevents CBAVD (case) F006
39288989 Postnatal modulators do not reverse infertility F006
28384194 SLC9A3 KO → obstructive azoospermia, ↓CFTR F007
35119551 ICSI outcomes; Chinese allele spectrum (IVS9-5T) F008, F009
40850271 Residual CFTR activity predicts MESA success F008
34313208 Sperm motility predicts ICSI outcome F008
40065563 Meta-analysis; comprehensive CFTR screening needed Diagnostics
42572672 TG12T5 splicing variant in CFTR-RD Section 4
37273165 ADGRG2 p.Ser303*; carrier with normal fertility Sections 4, 9
41886210 ADGRG2 testing when CFTR-negative + normal kidneys Diagnostics
22709980 CFTR signaling pathways in male fertility Section 6
39543810 CFTR modulators & reproductive health; fetal exposure Sections 12, 13

Consistency: Findings are mutually reinforcing across independent European and East Asian cohorts, case reports, MRI series, and multiple animal models. No major contradictions were identified; the chief tension is the "progressive degeneration" vs "developmental agenesis" debate, which the two-subtype model reconciles (degenerative = CFTR/ADGRG2, kidneys spared; developmental = Wolffian-duct defect, renal agenesis).

Limitations and Knowledge Gaps

  1. Unexplained fraction (10–20%). A substantial minority of CBAVD lacks a molecular diagnosis; developmental genes (FREM1, WNT2B, TBX6) are candidates but not yet validated at scale.
  2. Single-case evidence for prenatal prevention. The ETI-prevents-CBAVD observation rests on one infant [PMID: 41654435]; timing, dosing, the true critical window, and long-term/heterozygote safety are unknown, with unresolved ethical questions.
  3. Penetrance/expressivity poorly quantified. The poly-T/TG modifier and the normal-fertility ADGRG2 carrier show incomplete penetrance that is not yet predictable at the individual level.
  4. Model limitations. No model perfectly reproduces isolated human CBAVD; rats over-express hypospermatogenesis, and most mouse models remain fertile.
  5. Epidemiology. Prevalence (~0.1%) is likely underestimated; incidence and non-European/non-East-Asian allele spectra are under-characterized.
  6. Epigenetics. No disease-specific epigenetic signature has been defined.
  7. Long-term offspring outcomes after prenatal modulator exposure are unstudied.

Proposed Follow-up Experiments / Actions

  1. Systematic renal imaging + developmental-gene panel (FREM1, WNT2B, TBX6, and broader WES/WGS) in all CFTR/ADGRG2-negative CBAVD to validate the developmental subtype and expand the gene set.
  2. Registry/prospective study of prenatal CFTR-modulator exposure with structured male genital-tract follow-up (vas patency by ultrasound, later fertility) to define the fetal critical window, efficacy, and safety.
  3. Functional dissection of the ADGRG2–CFTR–SLC9A3 module in efferent-duct organoids/animal models to map shared fluid-transport mechanisms.
  4. Genotype-stratified sperm-retrieval outcome studies to formalize residual-CFTR-activity and motility as pre-procedure prognostic tools (building on [PMID: 40850271], [PMID: 34313208]).
  5. Universal comprehensive CFTR screening protocol (exons + flanking + poly-T/TG + rearrangements + deep-intronic) with mandatory partner carrier screening and PGT counseling before ART.
  6. Population-specific allele catalogues beyond European/Chinese cohorts to improve carrier-screening panels globally.
  7. Longitudinal CFTR-RD surveillance of isolated-CBAVD men to quantify later pancreatic/sinopulmonary risk.

Report compiled from a 5-iteration autonomous investigation: 9 confirmed findings, 27 papers reviewed. Evidence types span human clinical cohorts, case reports, imaging series, in vitro studies, and model-organism data.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 25
Resolved 25
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 25
On topic 18
Off topic 0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome Count
Terms checked 23
Resolved 20
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 3
Terms whose name was checked 15
Terms named correctly 7
Terms named as a different term 5
Terms whose name is worth a second look 3

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

  • MONDO:0009299 (2 mentions) - the report calls it "MONDO"; MONDO calls it 46 XX gonadal dysgenesis
  • HP:0000798 (1 mention) - the report calls it "Abnormality of the vas deferens"; HP calls it Oligozoospermia
  • HP:0012869 (1 mention) - the report calls it "Decreased ejaculate volume"; HP calls it Acephalic spermatozoa
  • HP:0011878 (1 mention) - the report calls it "Abnormality of the seminal vesicle"; HP calls it Abnormal platelet membrane protein expression
  • HP:0000029 (1 mention) - the report calls it "Abnormality of the epididymis"; HP calls it Testicular atrophy

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

  • GO:0016324 (2 mentions) - the report calls it "apical plasma membrane", "Subcellular: apical plasma membrane"; GO calls it apical plasma membrane**
  • GO:0007283 (1 mention) - the report calls it "spermatogenesis — preserved"; GO calls it spermatogenesis
  • UBERON:0000079 (1 mention) - the report calls it "Body system: male reproductive/genital system"; UBERON calls it male reproductive system**

Terms named inconsistently

The report gives these identifiers more than one name of its own:

  • GO:0016324 - called "apical plasma membrane", "Subcellular:** apical plasma membrane"

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA.