SYCP3-related spermatogenic failure

Mendelian MONDO:0010052 Pathograph 5 Show in embeddings browser Infertility disorder Male infertility

SYCP3-related spermatogenic failure (spermatogenic failure 4; SPGF4) is a meiotic disorder caused by mutations in SYCP3, which encodes a structural protein of the axial/lateral element of the synaptonemal complex (SC). SYCP3 is required for assembly of the SC and for synapsis of homologous chromosomes during meiotic prophase I. In men, heterozygous C-terminal-truncating variants act through a dominant-negative mechanism that interferes with SYCP3 fibre formation, causing pachytene-stage meiotic arrest, germ-cell apoptosis, and non-obstructive azoospermia. A sexually dimorphic counterpart has been proposed in women, in whom SYCP3 variants have been reported in recurrent pregnancy loss linked to oocyte aneuploidy; however, this female association is contested and weaker than the male spermatogenic-failure phenotype. The anchoring disease entity (MONDO:0010052 / OMIM:270960) is the male azoospermia phenotype.

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1
Inheritance
5
Pathophys.
3
Phenotypes
5
Pathograph
1
Genes
2
Medical Actions
👪

Inheritance

1
Autosomal dominant inheritance HP:0000006
The reported human male variants are heterozygous C-terminal-truncating changes that act through a dominant-negative mechanism, in which the mutant protein interferes with normal SYCP3 fibre assembly rather than causing simple haploinsufficiency.
Autosomal dominant inheritance
Show evidence (1 reference)
PMID:14643120 SUPPORT Human Clinical
"We suggest that SYCP3 has an essential meiotic function in human spermatogenesis that is compromised by the mutant protein via dominant negative interference."
The index human cases carried a heterozygous truncating variant acting via dominant-negative interference, supporting a dominant mechanism.
⚙

Pathophysiology

5
Synaptonemal complex axial/lateral element assembly failure
SYCP3 is a structural component of the axial/lateral element of the synaptonemal complex. Loss of functional SYCP3 — through a null allele in mice or a dominant-negative truncating variant in humans — prevents assembly of the axial/lateral elements and of the synaptonemal complex itself, so the scaffold required for homologous-chromosome synapsis fails to form during meiotic prophase I.
SYCP3 hgnc:18130
synaptonemal complex assembly GO:0007130 ↓ DECREASED
Downstream
Homologous chromosome synapsis failure Without assembled axial/lateral elements, homologous chromosomes cannot synapse during meiotic prophase I.
Show evidence (2 references)
PMID:10678170 SUPPORT Model Organism
"The SCP3-deficient male mice failed to form axial/lateral elements and SCs, and the chromosomes in the mutant spermatocytes"
A mouse null mutation directly demonstrates that SYCP3/SCP3 is required to assemble axial/lateral elements and the synaptonemal complex.
PMID:14643120 SUPPORT In Vitro
"The mutant protein showed greatly reduced interaction with the wild-type protein in vitro and interfered with SYCP3 fibre formation in cultured cells."
Functional assay of the human truncating variant shows it disrupts SYCP3 fibre (axial-element) formation, linking the human variant to SC assembly failure.
Homologous chromosome synapsis failure
With axial/lateral elements absent, homologous chromosomes fail to synapse at meiotic prophase I. Loss of SYCP3 also perturbs the chromosomal distribution of DNA repair/recombination proteins and of the transverse-filament protein SYCP1, leaving meiotic chromosomes unsynapsed.
primary spermatocyte CL:0000656
homologous chromosome pairing at meiosis GO:0007129 ↓ DECREASED
Downstream
Pachytene-stage meiotic arrest and germ-cell apoptosis Unsynapsed chromosomes trigger the meiotic-prophase checkpoint, arresting germ cells and inducing apoptosis.
Show evidence (1 reference)
PMID:10678170 SUPPORT Model Organism
"While the absence of SCP3 affected the nuclear distribution of DNA repair and recombination proteins (Rad51 and RPA), as well as synaptonemal complex protein 1 (SCP1), a residual chromatin organization remained in the mutant meiotic cells."
Loss of SYCP3 disrupts recombination-protein localization and SYCP1, consistent with failed synapsis.
Pachytene-stage meiotic arrest and germ-cell apoptosis
Spermatocytes that fail to synapse arrest at meiotic prophase and are eliminated by apoptosis, depleting the germ-cell pool. In the mouse null, males are sterile because of massive apoptotic germ-cell death during meiotic prophase.
spermatocyte CL:0000017
meiotic recombination checkpoint signaling GO:0051598 ↑ INCREASED apoptotic process GO:0006915 ↑ INCREASED
Downstream
Non-obstructive azoospermia Germ-cell depletion from prophase arrest produces maturation arrest of spermatogenesis and non-obstructive azoospermia.
Show evidence (1 reference)
PMID:10678170 SUPPORT Model Organism
"homozygous mutant males were sterile due to massive apoptotic cell death during meiotic prophase."
Documents apoptotic germ-cell death during meiotic prophase as the cellular basis of male sterility.
Non-obstructive azoospermia
In 46,XY individuals the meiotic-arrest pathway produces maturation arrest of spermatogenesis and non-obstructive azoospermia, the defining clinical presentation of SYCP3-related spermatogenic failure.
spermatocyte CL:0000017
male gamete generation GO:0048232 ↓ DECREASED
Show evidence (1 reference)
PMID:14643120 SUPPORT Human Clinical
"We identified in two patients a 1 bp deletion (643delA) that results in a premature stop codon and truncation of the C-terminal, coiled-coil-forming region of the SYCP3 protein."
Identifies the human SYCP3 truncating variant in azoospermic men with maturation arrest, anchoring the male clinical phenotype.
Female oocyte aneuploidy and recurrent pregnancy loss (contested)
A sexually dimorphic female branch has been proposed: SYCP3 variants may perturb meiotic chromosome segregation in oocytes, generating aneuploid conceptuses and recurrent pregnancy loss. In Sycp3-null female mice, oocyte aneuploidy and early embryo death are well established. In humans the association is contested — reported in a small recurrent-pregnancy-loss cohort but not confirmed in a later study — so this branch is modeled with both supporting and refuting evidence rather than as an established phenotype.
oocyte CL:0000023
reciprocal meiotic recombination GO:0007131 ↓ DECREASED
Show evidence (3 references)
PMID:12004129 SUPPORT Model Organism
"the absence of synaptonemal complex protein 3 (SCP3) promotes aneuploidy in murine oocytes by inducing defective meiotic chromosome segregation."
Establishes the female mechanism in mice: SYCP3 loss causes oocyte aneuploidy via defective meiotic chromosome segregation.
PMID:19110213 SUPPORT Human Clinical
"mutations in SYCP3, a gene encoding an essential component of the synaptonemal complex that is central to the interaction of homologous chromosomes, are associated with recurrent pregnancy loss."
Reports the human female association of SYCP3 variants with recurrent pregnancy loss.
PMID:21357605 REFUTE Human Clinical
"The 657T>C mutation of SYCP3 may not be associated with recurrent miscarriage caused by aneuploidy."
A follow-up study failed to confirm the female SYCP3-aneuploidy association, establishing the contested status of this branch.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for SYCP3-related spermatogenic 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

3
Genitourinary 2
Azoospermia Azoospermia HP:0000027
Show evidence (1 reference)
PMID:14643120 SUPPORT Human Clinical
"A null mutation of Sycp3 in mice causes azoospermia with meiotic arrest."
The hypothesis tested and confirmed in this paper links SYCP3 to azoospermia with meiotic arrest.
Context-specific annotations (1)
MALE
Reported in azoospermic men carrying a heterozygous SYCP3 truncating variant.
Show evidence (1 reference)
PMID:14643120 SUPPORT Human Clinical
"We identified in two patients a 1 bp deletion (643delA) that results in a premature stop codon and truncation of the C-terminal, coiled-coil-forming region of the SYCP3 protein."
Documents the azoospermia phenotype with the causal SYCP3 variant.
Male infertility Male infertility HP:0003251
Show evidence (1 reference)
PMID:10678170 SUPPORT Model Organism
"homozygous mutant males were sterile due to massive apoptotic cell death during meiotic prophase."
The mouse null establishes male sterility/infertility as the consequence of SYCP3 loss.
Other 1
Abnormal spermatogenesis Abnormal spermatogenesis HP:0008669
Show evidence (1 reference)
PMID:14643120 SUPPORT Human Clinical
"Samples of DNA from 19 azoospermic patients with maturation arrest and 75 normal fertile control men were screened for mutations in the SYCP3 gene"
The studied patients had maturation arrest of spermatogenesis, the histological correlate of abnormal spermatogenesis.
🧬

Genetic Associations

1
SYCP3 (Causative (Primary))
Gene: SYCP3 hgnc:18130
Autosomal dominant inheritance
Show evidence (2 references)
PMID:14643120 SUPPORT Human Clinical
"We identified in two patients a 1 bp deletion (643delA) that results in a premature stop codon and truncation of the C-terminal, coiled-coil-forming region of the SYCP3 protein."
Establishes SYCP3 as the causal gene for the male azoospermia phenotype.
PMID:19110213 PARTIAL Human Clinical
"Combined with the fact that similar mutations have been previously identified in two males with azoospermia, our current data suggest that sexual dimorphism in response to meiotic disruption occurs even in humans."
Proposes a sexually dimorphic female phenotype for SYCP3 variants; included as partial/contested evidence for the female branch.
💊

Medical Actions

2
Microdissection testicular sperm extraction (micro-TESE)
Action: sperm retrieval Ontology label: Sperm Retrieval NCIT:C94427
For 46,XY individuals with non-obstructive azoospermia due to meiotic arrest, microsurgical testicular sperm extraction identifies focal regions of residual spermatogenesis for use with ICSI, with higher yield and less tissue damage than conventional biopsy.
Show evidence (1 reference)
PMID:10374109 SUPPORT Human Clinical
"These findings suggest that microdissection TESE can improve sperm retrieval for men with non-obstructive azoospermia over that achieved with previously described biopsy techniques."
Establishes micro-TESE as the procedure of choice for sperm retrieval in non-obstructive azoospermia, applicable to the meiotic-arrest presentation of SYCP3-related spermatogenic failure.
Genetic counseling
Action: Genetic Counseling NCIT:C15240
Genetic counseling addresses the dominant-negative mechanism, infertility implications, and reproductive options (including ICSI with retrieved sperm and preimplantation considerations) for affected individuals and relatives.
{ }

Source YAML

click to show 
name: SYCP3-related spermatogenic failure
creation_date: "2026-06-22T12:00:00Z"
category: Mendelian
description: >-
  SYCP3-related spermatogenic failure (spermatogenic failure 4; SPGF4) is a
  meiotic disorder caused by mutations in SYCP3, which encodes a structural
  protein of the axial/lateral element of the synaptonemal complex (SC). SYCP3
  is required for assembly of the SC and for synapsis of homologous chromosomes
  during meiotic prophase I. In men, heterozygous C-terminal-truncating variants
  act through a dominant-negative mechanism that interferes with SYCP3 fibre
  formation, causing pachytene-stage meiotic arrest, germ-cell apoptosis, and
  non-obstructive azoospermia. A sexually dimorphic counterpart has been proposed
  in women, in whom SYCP3 variants have been reported in recurrent pregnancy loss
  linked to oocyte aneuploidy; however, this female association is contested and
  weaker than the male spermatogenic-failure phenotype. The anchoring disease
  entity (MONDO:0010052 / OMIM:270960) is the male azoospermia phenotype.
disease_term:
  preferred_term: SYCP3-related spermatogenic failure
  term:
    id: MONDO:0010052
    label: spermatogenic failure 4
parents:
- Infertility disorder
- Male infertility
synonyms:
- SPGF4
- spermatogenic failure type 4
- SYCP3 azoospermia
- azoospermia caused by mutation in SYCP3
inheritance:
- name: Autosomal dominant inheritance
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    The reported human male variants are heterozygous C-terminal-truncating
    changes that act through a dominant-negative mechanism, in which the mutant
    protein interferes with normal SYCP3 fibre assembly rather than causing
    simple haploinsufficiency.
  evidence:
  - reference: PMID:14643120
    reference_title: "Azoospermia in patients heterozygous for a mutation in SYCP3."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We suggest that SYCP3 has an essential meiotic function in human
      spermatogenesis that is compromised by the mutant protein via dominant
      negative interference.
    explanation: >-
      The index human cases carried a heterozygous truncating variant acting via
      dominant-negative interference, supporting a dominant mechanism.
notes: >-
  MONDO:0010052 (spermatogenic failure 4) is gene-anchored to SYCP3
  (HGNC:18130, OMIM:270960) and is defined as azoospermia caused by SYCP3
  mutation. Unlike several sibling meiotic genes (e.g. SYCE1, MCM8/9) there is
  currently no dyadic "SYCP3-related gametogenic failure" MONDO term unifying the
  sexes, so this entry is anchored on the male spermatogenic-failure term and
  models the female recurrent-pregnancy-loss phenotype as a related, contested
  branch (kept in the pathophysiology and notes rather than as an asserted
  phenotype). The female association rests primarily on Bolor et al. 2009
  (PMID:19110213); a subsequent study (Mizutani et al. 2011, PMID:21357605)
  failed to confirm an association of the SYCP3 657T>C variant with aneuploidy-
  related recurrent miscarriage, so the female branch is represented here with
  both supporting and refuting evidence. SYCP3 conforms to the
  meiotic_prophase_failure module at the synaptonemal complex assembly node.
pathophysiology:
- name: Synaptonemal complex axial/lateral element assembly failure
  conforms_to: "meiotic_prophase_failure#Synaptonemal Complex Assembly"
  description: >-
    SYCP3 is a structural component of the axial/lateral element of the
    synaptonemal complex. Loss of functional SYCP3 — through a null allele in
    mice or a dominant-negative truncating variant in humans — prevents assembly
    of the axial/lateral elements and of the synaptonemal complex itself, so the
    scaffold required for homologous-chromosome synapsis fails to form during
    meiotic prophase I.
  genes:
  - preferred_term: SYCP3
    term:
      id: hgnc:18130
      label: SYCP3
  biological_processes:
  - preferred_term: synaptonemal complex assembly
    term:
      id: GO:0007130
      label: synaptonemal complex assembly
    modifier: DECREASED
  evidence:
  - reference: PMID:10678170
    reference_title: "The murine SCP3 gene is required for synaptonemal complex assembly, chromosome synapsis, and male fertility."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      The SCP3-deficient male mice failed to form axial/lateral elements and
      SCs, and the chromosomes in the mutant spermatocytes
    explanation: >-
      A mouse null mutation directly demonstrates that SYCP3/SCP3 is required to
      assemble axial/lateral elements and the synaptonemal complex.
  - reference: PMID:14643120
    reference_title: "Azoospermia in patients heterozygous for a mutation in SYCP3."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The mutant protein showed greatly reduced interaction with the wild-type
      protein in vitro and interfered with SYCP3 fibre formation in cultured
      cells.
    explanation: >-
      Functional assay of the human truncating variant shows it disrupts SYCP3
      fibre (axial-element) formation, linking the human variant to SC assembly
      failure.
  downstream:
  - target: Homologous chromosome synapsis failure
    description: >-
      Without assembled axial/lateral elements, homologous chromosomes cannot
      synapse during meiotic prophase I.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:10678170
      reference_title: "The murine SCP3 gene is required for synaptonemal complex assembly, chromosome synapsis, and male fertility."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        The SCP3-deficient male mice failed to form axial/lateral elements and
        SCs, and the chromosomes in the mutant spermatocytes did not synapse.
      explanation: >-
        SC assembly failure mechanistically produces failure of homologous
        chromosome synapsis.
- name: Homologous chromosome synapsis failure
  description: >-
    With axial/lateral elements absent, homologous chromosomes fail to synapse
    at meiotic prophase I. Loss of SYCP3 also perturbs the chromosomal
    distribution of DNA repair/recombination proteins and of the
    transverse-filament protein SYCP1, leaving meiotic chromosomes unsynapsed.
  cell_types:
  - preferred_term: primary spermatocyte
    term:
      id: CL:0000656
      label: primary spermatocyte
  biological_processes:
  - preferred_term: homologous chromosome pairing at meiosis
    term:
      id: GO:0007129
      label: homologous chromosome pairing at meiosis
    modifier: DECREASED
  evidence:
  - reference: PMID:10678170
    reference_title: "The murine SCP3 gene is required for synaptonemal complex assembly, chromosome synapsis, and male fertility."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      While the absence of SCP3 affected the nuclear distribution of DNA repair
      and recombination proteins (Rad51 and RPA), as well as synaptonemal complex
      protein 1 (SCP1), a residual chromatin organization remained in the mutant
      meiotic cells.
    explanation: >-
      Loss of SYCP3 disrupts recombination-protein localization and SYCP1,
      consistent with failed synapsis.
  downstream:
  - target: Pachytene-stage meiotic arrest and germ-cell apoptosis
    description: >-
      Unsynapsed chromosomes trigger the meiotic-prophase checkpoint, arresting
      germ cells and inducing apoptosis.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:10678170
      reference_title: "The murine SCP3 gene is required for synaptonemal complex assembly, chromosome synapsis, and male fertility."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        homozygous mutant males were sterile due to massive apoptotic cell death
        during meiotic prophase.
      explanation: >-
        Failed synapsis leads to apoptotic elimination of arrested prophase germ
        cells.
- name: Pachytene-stage meiotic arrest and germ-cell apoptosis
  conforms_to: "meiotic_prophase_failure#Pachytene Checkpoint Arrest and Germ Cell Apoptosis"
  description: >-
    Spermatocytes that fail to synapse arrest at meiotic prophase and are
    eliminated by apoptosis, depleting the germ-cell pool. In the mouse null,
    males are sterile because of massive apoptotic germ-cell death during meiotic
    prophase.
  cell_types:
  - preferred_term: spermatocyte
    term:
      id: CL:0000017
      label: spermatocyte
  biological_processes:
  - preferred_term: meiotic recombination checkpoint signaling
    term:
      id: GO:0051598
      label: meiotic recombination checkpoint signaling
    modifier: INCREASED
  - preferred_term: apoptotic process
    term:
      id: GO:0006915
      label: apoptotic process
    modifier: INCREASED
  evidence:
  - reference: PMID:10678170
    reference_title: "The murine SCP3 gene is required for synaptonemal complex assembly, chromosome synapsis, and male fertility."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      homozygous mutant males were sterile due to massive apoptotic cell death
      during meiotic prophase.
    explanation: >-
      Documents apoptotic germ-cell death during meiotic prophase as the
      cellular basis of male sterility.
  downstream:
  - target: Non-obstructive azoospermia
    description: >-
      Germ-cell depletion from prophase arrest produces maturation arrest of
      spermatogenesis and non-obstructive azoospermia.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:14643120
      reference_title: "Azoospermia in patients heterozygous for a mutation in SYCP3."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        A null mutation of Sycp3 in mice causes azoospermia with meiotic arrest.
      explanation: >-
        Links meiotic arrest mechanistically to the azoospermia phenotype tested
        in human patients.
- name: Non-obstructive azoospermia
  conforms_to: "meiotic_prophase_failure#Spermatogenic Arrest and Non-Obstructive Azoospermia"
  description: >-
    In 46,XY individuals the meiotic-arrest pathway produces maturation arrest of
    spermatogenesis and non-obstructive azoospermia, the defining clinical
    presentation of SYCP3-related spermatogenic failure.
  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:14643120
    reference_title: "Azoospermia in patients heterozygous for a mutation in SYCP3."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified in two patients a 1 bp deletion (643delA) that results in a
      premature stop codon and truncation of the C-terminal, coiled-coil-forming
      region of the SYCP3 protein.
    explanation: >-
      Identifies the human SYCP3 truncating variant in azoospermic men with
      maturation arrest, anchoring the male clinical phenotype.
- name: Female oocyte aneuploidy and recurrent pregnancy loss (contested)
  description: >-
    A sexually dimorphic female branch has been proposed: SYCP3 variants may
    perturb meiotic chromosome segregation in oocytes, generating aneuploid
    conceptuses and recurrent pregnancy loss. In Sycp3-null female mice, oocyte
    aneuploidy and early embryo death are well established. In humans the
    association is contested — reported in a small recurrent-pregnancy-loss
    cohort but not confirmed in a later study — so this branch is modeled with
    both supporting and refuting evidence rather than as an established phenotype.
  cell_types:
  - preferred_term: oocyte
    term:
      id: CL:0000023
      label: oocyte
  biological_processes:
  - preferred_term: reciprocal meiotic recombination
    term:
      id: GO:0007131
      label: reciprocal meiotic recombination
    modifier: DECREASED
  evidence:
  - reference: PMID:12004129
    reference_title: "Female germ cell aneuploidy and embryo death in mice lacking the meiosis-specific protein SCP3."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      the absence of synaptonemal complex protein 3 (SCP3) promotes aneuploidy
      in murine oocytes by inducing defective meiotic chromosome segregation.
    explanation: >-
      Establishes the female mechanism in mice: SYCP3 loss causes oocyte
      aneuploidy via defective meiotic chromosome segregation.
  - reference: PMID:19110213
    reference_title: "Mutations of the SYCP3 gene in women with recurrent pregnancy loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      mutations in SYCP3, a gene encoding an essential component of the
      synaptonemal complex that is central to the interaction of homologous
      chromosomes, are associated with recurrent pregnancy loss.
    explanation: >-
      Reports the human female association of SYCP3 variants with recurrent
      pregnancy loss.
  - reference: PMID:21357605
    reference_title: "SYCP3 mutation may not be associated with recurrent miscarriage caused by aneuploidy."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The 657T>C mutation of SYCP3 may not be associated with recurrent
      miscarriage caused by aneuploidy.
    explanation: >-
      A follow-up study failed to confirm the female SYCP3-aneuploidy
      association, establishing the contested status of this branch.
phenotypes:
- name: Azoospermia
  category: Reproductive
  description: >-
    46,XY individuals present with non-obstructive azoospermia due to
    maturation arrest of spermatogenesis.
  phenotype_term:
    preferred_term: Azoospermia
    term:
      id: HP:0000027
      label: Azoospermia
  phenotype_contexts:
  - sex: MALE
    notes: Reported in azoospermic men carrying a heterozygous SYCP3 truncating variant.
    evidence:
    - reference: PMID:14643120
      reference_title: "Azoospermia in patients heterozygous for a mutation in SYCP3."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We identified in two patients a 1 bp deletion (643delA) that results in a
        premature stop codon and truncation of the C-terminal, coiled-coil-forming
        region of the SYCP3 protein.
      explanation: >-
        Documents the azoospermia phenotype with the causal SYCP3 variant.
  evidence:
  - reference: PMID:14643120
    reference_title: "Azoospermia in patients heterozygous for a mutation in SYCP3."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A null mutation of Sycp3 in mice causes azoospermia with meiotic arrest.
    explanation: >-
      The hypothesis tested and confirmed in this paper links SYCP3 to
      azoospermia with meiotic arrest.
- name: Male infertility
  category: Reproductive
  description: >-
    Spermatogenic failure from meiotic arrest causes male infertility.
  phenotype_term:
    preferred_term: Male infertility
    term:
      id: HP:0003251
      label: Male infertility
  evidence:
  - reference: PMID:10678170
    reference_title: "The murine SCP3 gene is required for synaptonemal complex assembly, chromosome synapsis, and male fertility."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      homozygous mutant males were sterile due to massive apoptotic cell death
      during meiotic prophase.
    explanation: >-
      The mouse null establishes male sterility/infertility as the consequence of
      SYCP3 loss.
- name: Abnormal spermatogenesis
  category: Reproductive
  description: >-
    Testicular histology shows maturation arrest of spermatogenesis at the
    meiotic (spermatocyte) stage.
  phenotype_term:
    preferred_term: Abnormal spermatogenesis
    term:
      id: HP:0008669
      label: Abnormal spermatogenesis
  evidence:
  - reference: PMID:14643120
    reference_title: "Azoospermia in patients heterozygous for a mutation in SYCP3."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Samples of DNA from 19 azoospermic patients with maturation arrest and 75
      normal fertile control men were screened for mutations in the SYCP3 gene
    explanation: >-
      The studied patients had maturation arrest of spermatogenesis, the
      histological correlate of abnormal spermatogenesis.
genetic:
- name: SYCP3
  association: Causative (Primary)
  gene_term:
    preferred_term: SYCP3
    term:
      id: hgnc:18130
      label: SYCP3
  inheritance:
  - name: Autosomal dominant inheritance
    evidence:
    - reference: PMID:14643120
      reference_title: "Azoospermia in patients heterozygous for a mutation in SYCP3."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We suggest that SYCP3 has an essential meiotic function in human
        spermatogenesis that is compromised by the mutant protein via dominant
        negative interference.
      explanation: >-
        Heterozygous truncating variant acting via dominant-negative interference
        supports a dominant mechanism in human males.
  evidence:
  - reference: PMID:14643120
    reference_title: "Azoospermia in patients heterozygous for a mutation in SYCP3."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified in two patients a 1 bp deletion (643delA) that results in a
      premature stop codon and truncation of the C-terminal, coiled-coil-forming
      region of the SYCP3 protein.
    explanation: >-
      Establishes SYCP3 as the causal gene for the male azoospermia phenotype.
  - reference: PMID:19110213
    reference_title: "Mutations of the SYCP3 gene in women with recurrent pregnancy loss."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Combined with the fact that similar mutations have been previously
      identified in two males with azoospermia, our current data suggest that
      sexual dimorphism in response to meiotic disruption occurs even in humans.
    explanation: >-
      Proposes a sexually dimorphic female phenotype for SYCP3 variants; included
      as partial/contested evidence for the female branch.
  notes: >-
    SYCP3 (synaptonemal complex protein 3) is a structural component of the
    axial/lateral element of the synaptonemal complex, essential for SC assembly
    and homologous-chromosome synapsis during meiotic prophase I. Human male
    variants are heterozygous C-terminal truncations acting in a dominant-negative
    manner.
treatments:
- name: Microdissection testicular sperm extraction (micro-TESE)
  description: >-
    For 46,XY individuals with non-obstructive azoospermia due to meiotic arrest,
    microsurgical testicular sperm extraction identifies focal regions of residual
    spermatogenesis for use with ICSI, with higher yield and less tissue damage
    than conventional biopsy.
  treatment_term:
    preferred_term: sperm retrieval
    term:
      id: NCIT:C94427
      label: Sperm Retrieval
  evidence:
  - reference: PMID:10374109
    reference_title: "Testicular sperm extraction: microdissection improves sperm yield with minimal tissue excision."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These findings suggest that microdissection TESE can improve sperm
      retrieval for men with non-obstructive azoospermia over that achieved
      with previously described biopsy techniques.
    explanation: >-
      Establishes micro-TESE as the procedure of choice for sperm retrieval in
      non-obstructive azoospermia, applicable to the meiotic-arrest presentation
      of SYCP3-related spermatogenic failure.
- name: Genetic counseling
  description: >-
    Genetic counseling addresses the dominant-negative mechanism, infertility
    implications, and reproductive options (including ICSI with retrieved sperm
    and preimplantation considerations) for affected individuals and relatives.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
diagnosis:
- name: Targeted molecular testing
  description: >-
    Exome or panel-based sequencing confirms the diagnosis by identifying a
    pathogenic SYCP3 variant in a man with non-obstructive azoospermia and
    maturation arrest of spermatogenesis.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: MAXO:0000127
      label: genetic testing