STAG3-related gametogenic failure

Mendelian MONDO:0014321 Pathograph 9 Show in embeddings browser Primary ovarian insufficiency Female infertility Non-obstructive azoospermia Male infertility

STAG3-related gametogenic failure is a recessive meiotic disorder caused by biallelic loss-of-function variants in STAG3, the meiosis-specific stromal antigen (STAG) subunit of the cohesin ring. STAG3 is the only meiosis-specific cohesin subunit shared by all four meiosis-specific cohesin complexes, and its loss destabilizes the other meiotic cohesins, disrupting chromosome-axis formation, synaptonemal complex assembly between homologous chromosomes, and meiotic DNA repair. Germ cells consequently arrest in early meiotic prophase I and are eliminated by apoptosis, depleting the gamete pool in both sexes. The human spectrum is dyadic: biallelic STAG3 variants cause primary / premature ovarian insufficiency (premature ovarian failure 8) in 46,XX individuals and non-obstructive azoospermia from spermatogenic (meiotic) arrest in 46,XY individuals, including a single family in which a homozygous missense variant segregated with POI in a proband and NOA in her brother. The shared mechanistic theme is meiotic cohesin instability with prophase I arrest and germ-cell depletion.

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1
Inheritance
4
Pathophys.
4
Phenotypes
9
Pathograph
1
Genes
2
Medical Actions
👪

Inheritance

1
Autosomal recessive inheritance HP:0000007
Reported families carry biallelic (homozygous or compound-heterozygous) loss-of-function STAG3 variants segregating with disease in a recessive pattern, in both the female POI and male NOA presentations.
Autosomal recessive inheritance
Show evidence (2 references)
PMID:24597867 SUPPORT Human Clinical
"Using whole-exome sequence analysis of a large consanguineous family with inherited premature ovarian failure, we identified a homozygous 1-bp deletion inducing a frameshift mutation in STAG3 on chromosome 7."
A homozygous frameshift variant in a consanguineous family establishes autosomal-recessive transmission of STAG3-related ovarian failure.
PMID:31682730 SUPPORT Human Clinical
"Two compound-heterozygous variants in STAG3"
Compound-heterozygous STAG3 variants causing male meiotic arrest support recessive transmission in the male presentation as well.
⚙

Pathophysiology

4
Meiotic cohesin instability and synaptonemal complex disruption
STAG3 is the meiosis-specific stromal-antigen subunit of the cohesin ring and is the only meiosis-specific cohesin subunit present in all four meiosis-specific cohesin complexes. Biallelic STAG3 loss destabilizes the other meiotic cohesin subunits and disrupts their localization to the chromosome axes, impairing meiotic sister-chromatid cohesion and assembly of the synaptonemal complex that synapses homologous chromosomes.
STAG3 hgnc:11356
meiotic sister chromatid cohesion GO:0051177 ↓ DECREASED synaptonemal complex assembly GO:0007130 ↓ DECREASED
Downstream
Prophase I meiotic arrest and germ cell apoptosis Failure of cohesion, axis formation, and synapsis leaves homologs unpaired and recombination unresolved, triggering prophase I arrest of the affected germ cells.
Show evidence (4 references)
PMID:24597867 SUPPORT Human Clinical
"STAG3 encodes a meiosis-specific subunit of the cohesin ring, which ensures correct sister chromatid cohesion."
This establishes STAG3 as the meiosis-specific cohesin subunit required for sister-chromatid cohesion.
PMID:31682730 SUPPORT Human Clinical
"In both women and men, STAG3 encodes for a meiosis-specific protein that is crucial for the functionality of meiotic cohesin complexes."
This confirms in humans of both sexes that STAG3 is essential for meiotic cohesin complex function.
PMID:24992337 SUPPORT Model Organism
"The instability of meiosis-specific cohesins observed in Stag3 mutants results in aberrant DNA repair processes, and disruption of synapsis between homologous chromosomes."
In Stag3-mutant mouse germ cells, cohesin instability disrupts synapsis and DNA repair, the molecular lesion underlying the human disorder.
+ 1 more reference
Prophase I meiotic arrest and germ cell apoptosis
Germ cells that fail to synapse and complete meiotic recombination arrest during meiotic prophase I and are eliminated by apoptosis rather than maturing into functional gametes, depleting the germ-cell pool in both sexes.
germ cell CL:0000586
apoptotic process GO:0006915 ↑ INCREASED
Downstream
Ovarian follicle depletion and primary ovarian insufficiency In 46,XX individuals, oocyte loss during meiotic progression exhausts the ovarian follicle pool and produces primary ovarian insufficiency.
Spermatogenic arrest and non-obstructive azoospermia In 46,XY individuals, the same germ-cell arrest produces spermatogenic failure with absence of mature sperm.
Show evidence (2 references)
PMID:24992337 SUPPORT Model Organism
"These defects result in early prophase I arrest and apoptosis in both male and female germ cells."
This documents prophase I arrest with germ-cell apoptosis on STAG3 loss in both sexes.
PMID:31682730 SUPPORT Human Clinical
"germ cells did not develop further than zygotene and showed drastic chromosome aberrations."
In the affected man, meiotic spreads showed germ-cell arrest at zygotene with chromosome aberrations, the human correlate of prophase I arrest.
Ovarian follicle depletion and primary ovarian insufficiency
Loss of oocytes during meiotic prophase depletes the ovarian reserve, presenting clinically as primary / premature ovarian insufficiency and primary amenorrhea in 46,XX individuals.
oocyte CL:0000023
female gamete generation GO:0007292 ↓ DECREASED
Downstream
Premature ovarian insufficiency The female branch presents clinically as primary / premature ovarian insufficiency.
Primary amenorrhea Severe ovarian failure in affected girls presents with primary amenorrhea.
Show evidence (2 references)
PMID:24597867 SUPPORT Model Organism
"Female mice devoid of Stag3 are sterile, and their fetal oocytes are arrested at early prophase I, leading to oocyte depletion at 1 week of age."
Stag3-null female mice show oocyte arrest and depletion, modeling the ovarian-reserve loss seen in patients.
PMID:28393351 SUPPORT Human Clinical
"Two homozygous germline truncation mutations in STAG3 gene had been reported to causes POI in consanguineous families."
Independent consanguineous families establish biallelic STAG3 loss as a cause of primary ovarian insufficiency.
Spermatogenic arrest and non-obstructive azoospermia
In 46,XY individuals, STAG3 loss arrests spermatocytes in meiotic prophase I, producing complete meiotic arrest and non-obstructive azoospermia.
spermatocyte CL:0000017
male gamete generation GO:0048232 ↓ DECREASED
Downstream
Non-obstructive azoospermia The male branch presents clinically as non-obstructive azoospermia.
Male infertility Complete meiotic arrest produces male infertility.
Show evidence (2 references)
PMID:31682730 SUPPORT Human Clinical
"Sequence variants affecting protein function of STAG3 cause male infertility due to meiotic arrest."
This establishes STAG3 loss as a cause of male infertility from meiotic arrest.
PMID:32634216 SUPPORT Human Clinical
"Here, we study a case of familial infertility including a proband with POI and her brother with NOA."
A single family with a proband (POI) and her brother (NOA) demonstrates the dyadic male spermatogenic-failure branch.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for STAG3-related gametogenic failure Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

4
Premature ovarian insufficiency Reproductive HP:0008209
Show evidence (1 reference)
PMID:28393351 SUPPORT Human Clinical
"Two homozygous germline truncation mutations in STAG3 gene had been reported to causes POI in consanguineous families."
Multiple independent families confirm STAG3 as a cause of primary ovarian insufficiency.
Context-specific annotations (1)
FEMALE
Reported in 46,XX individuals with biallelic STAG3 variants.
Show evidence (1 reference)
PMID:24597867 SUPPORT Human Clinical
"Using whole-exome sequence analysis of a large consanguineous family with inherited premature ovarian failure, we identified a homozygous 1-bp deletion inducing a frameshift mutation in STAG3 on chromosome 7."
The index family establishes STAG3-related premature ovarian failure.
Primary amenorrhea Reproductive HP:0000786
Show evidence (1 reference)
PMID:28393351 SUPPORT Human Clinical
"2 affected sisters manifested with primary amenorrhea and partial development of secondary sexual characters"
Two affected sisters with biallelic STAG3 variants manifested with primary amenorrhea.
Context-specific annotations (1)
FEMALE
Show evidence (1 reference)
PMID:28393351 SUPPORT Human Clinical
"2 affected sisters manifested with primary amenorrhea and partial development of secondary sexual characters"
Two affected sisters with biallelic STAG3 variants presented with primary amenorrhea.
Non-obstructive azoospermia Reproductive HP:0000027
Show evidence (1 reference)
PMID:31682730 SUPPORT Human Clinical
"Our results indicate that STAG3 variants that negatively affect its protein function are a rare cause of NOA (<1% of cases)."
The male STAG3 report identifies STAG3 variants as a cause of non-obstructive azoospermia.
Context-specific annotations (1)
MALE
Reported in 46,XY individuals with biallelic STAG3 variants.
Show evidence (1 reference)
PMID:31682730 SUPPORT Human Clinical
"have been found to cause male infertility due to complete bilateral meiotic arrest in an otherwise healthy human male."
A man with compound-heterozygous STAG3 variants had complete meiotic arrest causing non-obstructive azoospermia.
Male infertility Reproductive HP:0003251
Show evidence (1 reference)
PMID:31682730 SUPPORT Human Clinical
"Sequence variants affecting protein function of STAG3 cause male infertility due to meiotic arrest."
STAG3 variants affecting protein function are explicitly reported to cause male infertility due to meiotic arrest.
Context-specific annotations (1)
MALE
Show evidence (1 reference)
PMID:31682730 SUPPORT Human Clinical
"Sequence variants affecting protein function of STAG3 cause male infertility due to meiotic arrest."
STAG3 loss of function is a cause of male infertility.
🧬

Genetic Associations

1
STAG3 (Causative (Primary))
Autosomal recessive inheritance
Show evidence (2 references)
PMID:24597867 SUPPORT Human Clinical
"STAG3 encodes a meiosis-specific subunit of the cohesin ring, which ensures correct sister chromatid cohesion."
This establishes STAG3 as the causal gene and links it to meiotic cohesin function.
PMID:32634216 SUPPORT Human Clinical
"We report the first pathogenic homozygous missense variant in STAG3 and the first STAG3 variant associated with both male and female infertility."
A homozygous missense variant segregating with both POI and NOA confirms STAG3 as the causal gene across the dyadic spectrum.
💊

Medical Actions

2
Hormone replacement therapy
Action: hormone replacement therapy Ontology label: Pharmacotherapy NCIT:C15986
Agent: estradiol CHEBI:23965
Estrogen-based hormone replacement is used in the female ovarian-failure presentation to treat hypoestrogenism, induce and maintain secondary sexual characteristics, and reduce long-term comorbidity.
Genetic counseling
Action: Genetic Counseling NCIT:C15240
Genetic counseling informs at-risk family members about recessive transmission and reproductive options. Identifying biallelic STAG3 variants in men with non-obstructive azoospermia is clinically important because germ-cell meiotic arrest predicts poor testicular sperm extraction outcomes.
Show evidence (1 reference)
PMID:31682730 SUPPORT Human Clinical
"Especially before testicular sperm extraction (TESE) for ICSI, STAG3 variants should be ruled out to prevent unnecessary interventions with frustrating outcomes for both patients and clinicians."
Identifying STAG3 variants guides counseling and avoids futile sperm retrieval in affected men.
{ }

Source YAML

click to show 
name: STAG3-related gametogenic failure
creation_date: "2026-06-07T00:00:00Z"
category: Mendelian
description: >-
  STAG3-related gametogenic failure is a recessive meiotic disorder caused by
  biallelic loss-of-function variants in STAG3, the meiosis-specific stromal
  antigen (STAG) subunit of the cohesin ring. STAG3 is the only meiosis-specific
  cohesin subunit shared by all four meiosis-specific cohesin complexes, and its
  loss destabilizes the other meiotic cohesins, disrupting chromosome-axis
  formation, synaptonemal complex assembly between homologous chromosomes, and
  meiotic DNA repair. Germ cells consequently arrest in early meiotic prophase I
  and are eliminated by apoptosis, depleting the gamete pool in both sexes. The
  human spectrum is dyadic: biallelic STAG3 variants cause primary / premature
  ovarian insufficiency (premature ovarian failure 8) in 46,XX individuals and
  non-obstructive azoospermia from spermatogenic (meiotic) arrest in 46,XY
  individuals, including a single family in which a homozygous missense variant
  segregated with POI in a proband and NOA in her brother. The shared
  mechanistic theme is meiotic cohesin instability with prophase I arrest and
  germ-cell depletion.
disease_term:
  preferred_term: STAG3-related gametogenic failure
  term:
    id: MONDO:0014321
    label: premature ovarian failure 8
parents:
- Primary ovarian insufficiency
- Female infertility
- Non-obstructive azoospermia
- Male infertility
synonyms:
- STAG3 deficiency
- premature ovarian failure 8
- POF8
- STAG3-related primary ovarian insufficiency
- STAG3-related non-obstructive azoospermia
notes: >-
  The exact human disease anchor available in MONDO is MONDO:0014321 (premature
  ovarian failure 8; OMIM:615723), which captures the 46,XX primary/premature
  ovarian insufficiency presentation that was the first STAG3 phenotype reported.
  The broader preferred term "STAG3-related gametogenic failure" reflects the
  conserved meiotic-cohesin mechanism and the now-documented bisexual human
  spectrum: in addition to female POI, biallelic STAG3 variants cause
  non-obstructive azoospermia from meiotic arrest in 46,XY individuals
  (van der Bijl 2019, PMID:31682730), and a single family carried a homozygous
  STAG3 missense variant segregating with POI in a proband and NOA in her brother
  (Jaillard 2020, PMID:32634216). No dyadic "STAG3-related gametogenic failure"
  grouper has yet been minted in MONDO; this entry is anchored on the female POF8
  leaf following the precedent set by HROB-related gametogenic failure. This entry
  conforms to the meiotic_prophase_failure module, placing STAG3 (the
  meiosis-specific STAG cohesin subunit) alongside the other meiotic cohesin and
  recombination factors in that series.
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Reported families carry biallelic (homozygous or compound-heterozygous)
    loss-of-function STAG3 variants segregating with disease in a recessive
    pattern, in both the female POI and male NOA presentations.
  evidence:
  - reference: PMID:24597867
    reference_title: "Mutant cohesin in premature ovarian failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Using whole-exome sequence analysis of a large consanguineous family with
      inherited premature ovarian failure, we identified a homozygous 1-bp
      deletion inducing a frameshift mutation in STAG3 on chromosome 7.
    explanation: >-
      A homozygous frameshift variant in a consanguineous family establishes
      autosomal-recessive transmission of STAG3-related ovarian failure.
  - reference: PMID:31682730
    reference_title: "Mutations in the stromal antigen 3 (STAG3) gene cause male infertility due to meiotic arrest."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Two compound-heterozygous variants in STAG3
    explanation: >-
      Compound-heterozygous STAG3 variants causing male meiotic arrest support
      recessive transmission in the male presentation as well.
pathophysiology:
- name: Meiotic cohesin instability and synaptonemal complex disruption
  conforms_to: "meiotic_prophase_failure#Synaptonemal Complex Assembly"
  description: >-
    STAG3 is the meiosis-specific stromal-antigen subunit of the cohesin ring and
    is the only meiosis-specific cohesin subunit present in all four
    meiosis-specific cohesin complexes. Biallelic STAG3 loss destabilizes the
    other meiotic cohesin subunits and disrupts their localization to the
    chromosome axes, impairing meiotic sister-chromatid cohesion and assembly of
    the synaptonemal complex that synapses homologous chromosomes.
  genes:
  - preferred_term: STAG3
    term:
      id: hgnc:11356
      label: STAG3
  biological_processes:
  - preferred_term: meiotic sister chromatid cohesion
    term:
      id: GO:0051177
      label: meiotic sister chromatid cohesion
    modifier: DECREASED
  - preferred_term: synaptonemal complex assembly
    term:
      id: GO:0007130
      label: synaptonemal complex assembly
    modifier: DECREASED
  evidence:
  - reference: PMID:24597867
    reference_title: "Mutant cohesin in premature ovarian failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      STAG3 encodes a meiosis-specific subunit of the cohesin ring, which ensures
      correct sister chromatid cohesion.
    explanation: >-
      This establishes STAG3 as the meiosis-specific cohesin subunit required for
      sister-chromatid cohesion.
  - reference: PMID:31682730
    reference_title: "Mutations in the stromal antigen 3 (STAG3) gene cause male infertility due to meiotic arrest."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In both women and men, STAG3 encodes for a meiosis-specific protein that is
      crucial for the functionality of meiotic cohesin complexes.
    explanation: >-
      This confirms in humans of both sexes that STAG3 is essential for meiotic
      cohesin complex function.
  - reference: PMID:24992337
    reference_title: "Meiosis-specific cohesin component, Stag3 is essential for maintaining centromere chromatid cohesion, and required for DNA repair and synapsis between homologous chromosomes."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      The instability of meiosis-specific cohesins observed in Stag3 mutants
      results in aberrant DNA repair processes, and disruption of synapsis
      between homologous chromosomes.
    explanation: >-
      In Stag3-mutant mouse germ cells, cohesin instability disrupts synapsis and
      DNA repair, the molecular lesion underlying the human disorder.
  - reference: PMID:24992337
    reference_title: "Meiosis-specific cohesin component, Stag3 is essential for maintaining centromere chromatid cohesion, and required for DNA repair and synapsis between homologous chromosomes."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      STAG3 is the only meiosis-specific subunit that is represented within all
      four meiosis-specific cohesin complexes.
    explanation: >-
      STAG3's presence in all meiosis-specific cohesin complexes explains why its
      loss destabilizes the entire meiotic cohesin apparatus.
  downstream:
  - target: Prophase I meiotic arrest and germ cell apoptosis
    description: >-
      Failure of cohesion, axis formation, and synapsis leaves homologs unpaired
      and recombination unresolved, triggering prophase I arrest of the affected
      germ cells.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - failed homologous chromosome synapsis
    - defective meiotic recombination and DNA repair
    evidence:
    - reference: PMID:24992337
      reference_title: "Meiosis-specific cohesin component, Stag3 is essential for maintaining centromere chromatid cohesion, and required for DNA repair and synapsis between homologous chromosomes."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        These defects result in early prophase I arrest and apoptosis in both
        male and female germ cells.
      explanation: >-
        The synapsis/cohesion defects lead directly to early prophase I arrest in
        Stag3-mutant germ cells.
- name: Prophase I meiotic arrest and germ cell apoptosis
  conforms_to: "meiotic_prophase_failure#Pachytene Checkpoint Arrest and Germ Cell Apoptosis"
  description: >-
    Germ cells that fail to synapse and complete meiotic recombination arrest
    during meiotic prophase I and are eliminated by apoptosis rather than
    maturing into functional gametes, depleting the germ-cell pool in both sexes.
  cell_types:
  - preferred_term: germ cell
    term:
      id: CL:0000586
      label: germ cell
  biological_processes:
  - preferred_term: apoptotic process
    term:
      id: GO:0006915
      label: apoptotic process
    modifier: INCREASED
  evidence:
  - reference: PMID:24992337
    reference_title: "Meiosis-specific cohesin component, Stag3 is essential for maintaining centromere chromatid cohesion, and required for DNA repair and synapsis between homologous chromosomes."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      These defects result in early prophase I arrest and apoptosis in both male
      and female germ cells.
    explanation: >-
      This documents prophase I arrest with germ-cell apoptosis on STAG3 loss in
      both sexes.
  - reference: PMID:31682730
    reference_title: "Mutations in the stromal antigen 3 (STAG3) gene cause male infertility due to meiotic arrest."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      germ cells did not develop further than zygotene and showed drastic
      chromosome aberrations.
    explanation: >-
      In the affected man, meiotic spreads showed germ-cell arrest at zygotene
      with chromosome aberrations, the human correlate of prophase I arrest.
  downstream:
  - target: Ovarian follicle depletion and primary ovarian insufficiency
    description: >-
      In 46,XX individuals, oocyte loss during meiotic progression exhausts the
      ovarian follicle pool and produces primary ovarian insufficiency.
    causal_link_type: DIRECT
  - target: Spermatogenic arrest and non-obstructive azoospermia
    description: >-
      In 46,XY individuals, the same germ-cell arrest produces spermatogenic
      failure with absence of mature sperm.
    causal_link_type: DIRECT
- name: Ovarian follicle depletion and primary ovarian insufficiency
  conforms_to: "meiotic_prophase_failure#Ovarian Follicle Depletion and Primary Ovarian Insufficiency"
  description: >-
    Loss of oocytes during meiotic prophase depletes the ovarian reserve,
    presenting clinically as primary / premature ovarian insufficiency and
    primary amenorrhea in 46,XX individuals.
  cell_types:
  - preferred_term: oocyte
    term:
      id: CL:0000023
      label: oocyte
  biological_processes:
  - preferred_term: female gamete generation
    term:
      id: GO:0007292
      label: female gamete generation
    modifier: DECREASED
  evidence:
  - reference: PMID:24597867
    reference_title: "Mutant cohesin in premature ovarian failure."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Female mice devoid of Stag3 are sterile, and their fetal oocytes are
      arrested at early prophase I, leading to oocyte depletion at 1 week of age.
    explanation: >-
      Stag3-null female mice show oocyte arrest and depletion, modeling the
      ovarian-reserve loss seen in patients.
  - reference: PMID:28393351
    reference_title: "Whole-exome sequencing identifies a homozygous donor splice-site mutation in STAG3 that causes primary ovarian insufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Two homozygous germline truncation mutations in STAG3 gene had been
      reported to causes POI in consanguineous families.
    explanation: >-
      Independent consanguineous families establish biallelic STAG3 loss as a
      cause of primary ovarian insufficiency.
  downstream:
  - target: Premature ovarian insufficiency
    description: >-
      The female branch presents clinically as primary / premature ovarian
      insufficiency.
    causal_link_type: DIRECT
  - target: Primary amenorrhea
    description: >-
      Severe ovarian failure in affected girls presents with primary amenorrhea.
    causal_link_type: DIRECT
- name: Spermatogenic arrest and non-obstructive azoospermia
  conforms_to: "meiotic_prophase_failure#Spermatogenic Arrest and Non-Obstructive Azoospermia"
  description: >-
    In 46,XY individuals, STAG3 loss arrests spermatocytes in meiotic prophase I,
    producing complete meiotic arrest and non-obstructive azoospermia.
  cell_types:
  - preferred_term: spermatocyte
    term:
      id: CL:0000017
      label: spermatocyte
  biological_processes:
  - preferred_term: male gamete generation
    term:
      id: GO:0048232
      label: male gamete generation
    modifier: DECREASED
  evidence:
  - reference: PMID:31682730
    reference_title: "Mutations in the stromal antigen 3 (STAG3) gene cause male infertility due to meiotic arrest."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Sequence variants affecting protein function of STAG3 cause male
      infertility due to meiotic arrest.
    explanation: >-
      This establishes STAG3 loss as a cause of male infertility from meiotic
      arrest.
  - reference: PMID:32634216
    reference_title: "STAG3 homozygous missense variant causes primary ovarian insufficiency and male non-obstructive azoospermia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we study a case of familial infertility including a proband with POI
      and her brother with NOA.
    explanation: >-
      A single family with a proband (POI) and her brother (NOA) demonstrates the
      dyadic male spermatogenic-failure branch.
  downstream:
  - target: Non-obstructive azoospermia
    description: >-
      The male branch presents clinically as non-obstructive azoospermia.
    causal_link_type: DIRECT
  - target: Male infertility
    description: >-
      Complete meiotic arrest produces male infertility.
    causal_link_type: DIRECT
phenotypes:
- name: Premature ovarian insufficiency
  category: Reproductive
  description: >-
    Affected 46,XX individuals present with primary / premature ovarian
    insufficiency.
  phenotype_term:
    preferred_term: Premature ovarian insufficiency
    term:
      id: HP:0008209
      label: Premature ovarian insufficiency
  phenotype_contexts:
  - sex: FEMALE
    notes: Reported in 46,XX individuals with biallelic STAG3 variants.
    evidence:
    - reference: PMID:24597867
      reference_title: "Mutant cohesin in premature ovarian failure."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Using whole-exome sequence analysis of a large consanguineous family with
        inherited premature ovarian failure, we identified a homozygous 1-bp
        deletion inducing a frameshift mutation in STAG3 on chromosome 7.
      explanation: >-
        The index family establishes STAG3-related premature ovarian failure.
  evidence:
  - reference: PMID:28393351
    reference_title: "Whole-exome sequencing identifies a homozygous donor splice-site mutation in STAG3 that causes primary ovarian insufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Two homozygous germline truncation mutations in STAG3 gene had been
      reported to causes POI in consanguineous families.
    explanation: >-
      Multiple independent families confirm STAG3 as a cause of primary ovarian
      insufficiency.
- name: Primary amenorrhea
  category: Reproductive
  description: >-
    Affected girls present with primary amenorrhea and incomplete development of
    secondary sexual characteristics.
  phenotype_term:
    preferred_term: Primary amenorrhea
    term:
      id: HP:0000786
      label: Primary amenorrhea
  phenotype_contexts:
  - sex: FEMALE
    evidence:
    - reference: PMID:28393351
      reference_title: "Whole-exome sequencing identifies a homozygous donor splice-site mutation in STAG3 that causes primary ovarian insufficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        2 affected sisters manifested with primary amenorrhea and partial
        development of secondary sexual characters
      explanation: >-
        Two affected sisters with biallelic STAG3 variants presented with primary
        amenorrhea.
  evidence:
  - reference: PMID:28393351
    reference_title: "Whole-exome sequencing identifies a homozygous donor splice-site mutation in STAG3 that causes primary ovarian insufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      2 affected sisters manifested with primary amenorrhea and partial
      development of secondary sexual characters
    explanation: >-
      Two affected sisters with biallelic STAG3 variants manifested with primary
      amenorrhea.
- name: Non-obstructive azoospermia
  category: Reproductive
  description: >-
    Affected 46,XY individuals present with non-obstructive azoospermia due to
    complete meiotic arrest of spermatogenesis.
  phenotype_term:
    preferred_term: Azoospermia
    term:
      id: HP:0000027
      label: Azoospermia
  phenotype_contexts:
  - sex: MALE
    notes: Reported in 46,XY individuals with biallelic STAG3 variants.
    evidence:
    - reference: PMID:31682730
      reference_title: "Mutations in the stromal antigen 3 (STAG3) gene cause male infertility due to meiotic arrest."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        have been found to cause male infertility due to complete bilateral
        meiotic arrest in an otherwise healthy human male.
      explanation: >-
        A man with compound-heterozygous STAG3 variants had complete meiotic
        arrest causing non-obstructive azoospermia.
  evidence:
  - reference: PMID:31682730
    reference_title: "Mutations in the stromal antigen 3 (STAG3) gene cause male infertility due to meiotic arrest."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our results indicate that STAG3 variants that negatively affect its protein function are a rare cause of NOA (<1% of cases)."
    explanation: >-
      The male STAG3 report identifies STAG3 variants as a cause of
      non-obstructive azoospermia.
- name: Male infertility
  category: Reproductive
  description: >-
    Biallelic STAG3 variants cause male infertility from spermatogenic
    (meiotic) arrest.
  phenotype_term:
    preferred_term: Male infertility
    term:
      id: HP:0003251
      label: Male infertility
  phenotype_contexts:
  - sex: MALE
    evidence:
    - reference: PMID:31682730
      reference_title: "Mutations in the stromal antigen 3 (STAG3) gene cause male infertility due to meiotic arrest."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Sequence variants affecting protein function of STAG3 cause male
        infertility due to meiotic arrest.
      explanation: >-
        STAG3 loss of function is a cause of male infertility.
  evidence:
  - reference: PMID:31682730
    reference_title: "Mutations in the stromal antigen 3 (STAG3) gene cause male infertility due to meiotic arrest."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sequence variants affecting protein function of STAG3 cause male infertility due to meiotic arrest."
    explanation: >-
      STAG3 variants affecting protein function are explicitly reported to cause
      male infertility due to meiotic arrest.
genetic:
- name: STAG3
  association: Causative (Primary)
  inheritance:
  - name: Autosomal recessive inheritance
    evidence:
    - reference: PMID:24597867
      reference_title: "Mutant cohesin in premature ovarian failure."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        we identified a homozygous 1-bp deletion inducing a frameshift mutation
        in STAG3 on chromosome 7.
      explanation: >-
        A homozygous variant in a consanguineous family supports recessive
        transmission.
  evidence:
  - reference: PMID:24597867
    reference_title: "Mutant cohesin in premature ovarian failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      STAG3 encodes a meiosis-specific subunit of the cohesin ring, which ensures
      correct sister chromatid cohesion.
    explanation: >-
      This establishes STAG3 as the causal gene and links it to meiotic cohesin
      function.
  - reference: PMID:32634216
    reference_title: "STAG3 homozygous missense variant causes primary ovarian insufficiency and male non-obstructive azoospermia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report the first pathogenic homozygous missense variant in STAG3 and the
      first STAG3 variant associated with both male and female infertility.
    explanation: >-
      A homozygous missense variant segregating with both POI and NOA confirms
      STAG3 as the causal gene across the dyadic spectrum.
  notes: >-
    STAG3 (stromal antigen 3) encodes the meiosis-specific stromal-antigen
    subunit of the cohesin ring, the only meiosis-specific cohesin subunit shared
    by all four meiosis-specific cohesin complexes. Biallelic loss-of-function
    variants cause premature ovarian failure 8 (OMIM:615723) in females and
    non-obstructive azoospermia in males.
treatments:
- name: Hormone replacement therapy
  description: >-
    Estrogen-based hormone replacement is used in the female ovarian-failure
    presentation to treat hypoestrogenism, induce and maintain secondary sexual
    characteristics, and reduce long-term comorbidity.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: hormone replacement therapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: estradiol
      term:
        id: CHEBI:23965
        label: estradiol
  notes: >-
    Hormone replacement addresses the consequences of ovarian failure but does
    not restore fertility; affected individuals are infertile from germ-cell
    depletion.
- name: Genetic counseling
  description: >-
    Genetic counseling informs at-risk family members about recessive
    transmission and reproductive options. Identifying biallelic STAG3 variants
    in men with non-obstructive azoospermia is clinically important because
    germ-cell meiotic arrest predicts poor testicular sperm extraction outcomes.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:31682730
    reference_title: "Mutations in the stromal antigen 3 (STAG3) gene cause male infertility due to meiotic arrest."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Especially before testicular sperm extraction (TESE) for ICSI, STAG3
      variants should be ruled out to prevent unnecessary interventions with
      frustrating outcomes for both patients and clinicians.
    explanation: >-
      Identifying STAG3 variants guides counseling and avoids futile sperm
      retrieval in affected men.
diagnosis:
- name: Targeted molecular testing
  description: >-
    Exome or panel-based sequencing confirms the diagnosis by identifying
    biallelic pathogenic STAG3 variants in individuals with primary ovarian
    insufficiency or non-obstructive azoospermia.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: MAXO:0000127
      label: genetic testing
  evidence:
  - reference: PMID:28393351
    reference_title: "Whole-exome sequencing identifies a homozygous donor splice-site mutation in STAG3 that causes primary ovarian insufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Whole-exome and Sanger sequencing identified a homozygous donor splice-site
      mutation (NM_012447.2: c.1573+5G>A) in the STAG3 gene.
    explanation: >-
      Whole-exome plus Sanger sequencing is the diagnostic approach that
      identifies biallelic STAG3 variants.
  - reference: PMID:32634216
    reference_title: "STAG3 homozygous missense variant causes primary ovarian insufficiency and male non-obstructive azoospermia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We performed whole-exome sequencing (WES) and identified a homozygous STAG3
      missense variant that segregated with infertility.
    explanation: >-
      Whole-exome sequencing identified the segregating STAG3 variant in the
      dyadic family.