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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Conditions with similar clinical presentations that must be differentiated from Congenital Bilateral Absence of Vas Deferens:
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
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:0000066
label: epithelial cell
locations:
- preferred_term: mesonephric duct
term:
id: UBERON:0003074
label: mesonephric duct
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
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.
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.'
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.
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.
CBAVD is overwhelmingly a genetic disorder, principally a genital manifestation of CFTR dysfunction.
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.
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.
Isolated CBAVD is typically caused by a trans-heterozygous combination of one severe CF-causing allele plus one mild/variable allele:
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).
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].
The only "environmental" (i.e., non-germline) modifier with proven effect is pharmacologic — prenatal CFTR modulator exposure (protective; Section 6).
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.
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.
| 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 |
CBAVD has no medical cure for the anatomic defect; management is fertility-focused plus genetic counseling.
Gene therapy, cell therapy, RNA therapeutics, immunotherapy, and chemotherapy have no established role in CBAVD.
| 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.
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).
| 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).
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.
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.
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 |
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 dysgenesisHP:0000798 (1 mention) - the report calls it "Abnormality of the vas deferens"; HP calls it OligozoospermiaHP:0012869 (1 mention) - the report calls it "Decreased ejaculate volume"; HP calls it Acephalic spermatozoaHP:0011878 (1 mention) - the report calls it "Abnormality of the seminal vesicle"; HP calls it Abnormal platelet membrane protein expressionHP:0000029 (1 mention) - the report calls it "Abnormality of the epididymis"; HP calls it Testicular atrophyThe 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 spermatogenesisUBERON:0000079 (1 mention) - the report calls it "Body system: male reproductive/genital system"; UBERON calls it male reproductive system**The report gives these identifiers more than one name of its own:
GO:0016324 - called "apical plasma membrane", "Subcellular:** apical plasma membrane"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.