SYCE1-related gametogenic failure

Mendelian MONDO:1060214 Pathograph 7 Infertility disorder Primary ovarian insufficiency Male infertility

SYCE1-related gametogenic failure is an autosomal recessive meiotic disorder caused by biallelic loss-of-function variants in SYCE1, which encodes a central element component of the synaptonemal complex. Because SYCE1 is essential for synapsis of homologous chromosomes during meiotic prophase I, biallelic loss produces a sex-dimorphic gametogenic phenotype with the same underlying lesion: primary ovarian insufficiency in 46,XX individuals and non-obstructive azoospermia from pachytene-stage meiotic arrest in 46,XY individuals. The shared mechanistic theme is failure of synaptonemal complex assembly, leading to meiotic arrest and germ-cell depletion in both sexes.

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1
Inheritance
4
Pathophys.
4
Phenotypes
7
Pathograph
1
Genes
4
Treatments
1
Deep Research
👪

Inheritance

1
Autosomal recessive inheritance HP:0000007
Affected individuals carry biallelic (homozygous or compound heterozygous) loss-of-function SYCE1 variants, with carrier parents and recessive segregation in reported families.
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:25062452 SUPPORT Human Clinical
"A nonsense homozygous mutation (c.613C>T) was identified in the SYCE1 gene in both affected sisters. The parents and three brothers were heterozygous for the mutation, and an unaffected sister did not carry the mutation."
Homozygosity in affected sisters with heterozygous unaffected carriers directly supports autosomal recessive inheritance.
⚙

Pathophysiology

4
Synaptonemal complex assembly failure
SYCE1 encodes a central element protein of the synaptonemal complex (SC). Biallelic loss-of-function abolishes SYCE1 protein and disrupts its interactions with the transverse-filament protein SYCP1 and the central element partner SIX6OS1/C14ORF39, so the SC central element cannot assemble and homologous chromosomes fail to synapse during meiotic prophase I.
SYCE1 link
synaptonemal complex assembly link ↓ DECREASED
Downstream
Homologous chromosome synapsis failure Without an assembled central element, homologous chromosomes cannot synapse during meiotic prophase I.
Show evidence (2 references)
PMID:34718620 SUPPORT In Vitro
"the variations in SYCE1 disrupted its interaction with SYCP1 or C14ORF39, both of which affected SC assembly and meiosis."
Functional assays show SYCE1 variants disrupt the protein interactions required for synaptonemal complex assembly.
PMID:32402064 SUPPORT Model Organism
"No SYCE1 protein was detected in homozygous mutants and Syce1 transcript level was highly diminished, suggesting transcript degradation as the basis of the infertility mechanism."
A humanized mouse model of the human mutation shows loss of SYCE1 protein, establishing loss of function as the molecular basis of the defect.
Homologous chromosome synapsis failure
SYCE1 forms the central element of the synaptonemal complex and is required for physical synapsis of homologous chromosomes during meiotic prophase I. Its loss prevents stable synapsis of homologous chromosome pairs, leaving them unsynapsed at the pachytene stage.
primary oocyte link primary spermatocyte link
homologous chromosome pairing at meiosis link ↓ DECREASED
Downstream
Meiotic prophase I pachytene checkpoint activation Unsynapsed chromosomes trigger the pachytene checkpoint, arresting germ-cell meiotic progression.
Show evidence (1 reference)
PMID:32402064 SUPPORT Model Organism
"Our results strongly support a causative role of this mutation for the POI phenotype in human patients, and the mechanisms involved would relate to defects in homologous chromosome synapsis."
The mouse model directly attributes the reproductive phenotype to failure of homologous chromosome synapsis.
Meiotic prophase I pachytene checkpoint activation
Unsynapsed chromosomes or persistent recombination intermediates from failed synapsis activate the meiotic pachytene checkpoint, which surveys for completion of synapsis and crossover formation. Checkpoint activation arrests germ cells at the pachytene stage of prophase I; persistently arrested cells are eliminated by apoptosis, depleting the germ-cell pool.
primary oocyte link primary spermatocyte link
meiosis I link ⚠ ABNORMAL meiotic recombination checkpoint signaling link ↑ INCREASED apoptotic process link ↑ INCREASED
Downstream
Germ-cell depletion and sex-dimorphic gonadal failure Pachytene-arrested germ cells are eliminated, depleting the ovarian follicle pool in 46,XX individuals and the spermatogenic lineage in 46,XY individuals.
Show evidence (1 reference)
PMID:35718780 SUPPORT Human Clinical
"H&E and IF staining demonstrated that the spermatogenesis was arrested at pachytene stage in the two patients with NOA, suggesting these two novel CNVs within SYCE1 could lead to meiotic defect and NOA."
Testicular histology directly documents pachytene-stage meiotic arrest in SYCE1 variant carriers.
Germ-cell depletion and sex-dimorphic gonadal failure
The meiotic block depletes germ cells in both sexes, producing ovarian follicle depletion with primary ovarian insufficiency in 46,XX individuals and germ-cell-depleted testes with non-obstructive azoospermia in 46,XY individuals. The same molecular lesion thus yields a sex-dimorphic clinical presentation.
Downstream
Premature ovarian insufficiency In 46,XX individuals follicle depletion presents clinically as primary ovarian insufficiency.
Non-obstructive azoospermia In 46,XY individuals germ-cell depletion presents clinically as non-obstructive azoospermia.
Show evidence (2 references)
PMID:34718620 SUPPORT Human Clinical
"Our study identified novel pathogenic variations of C14ORF39 and SYCE1 in sporadic patients with POI or NOA, highlighting the essential role of SC genes in the maintenance of ovarian and testicular function."
The same SC-gene defect is reported in both POI (female) and NOA (male) patients, supporting a single mechanism with sex-dimorphic gonadal output.
PMID:25062452 SUPPORT Human Clinical
"These results highlight the importance of the synaptonemal complex and meiosis in ovarian function."
Links the synaptonemal complex defect to loss of ovarian function in affected women.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for SYCE1-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
Genitourinary 2
Premature ovarian insufficiency Premature ovarian insufficiency (HP:0008209)
Show evidence (1 reference)
PMID:32402064 SUPPORT Model Organism
"Our results strongly support a causative role of this mutation for the POI phenotype in human patients, and the mechanisms involved would relate to defects in homologous chromosome synapsis."
A humanized mouse model recapitulates the POI phenotype, supporting causality alongside the human clinical reports.
Context-specific annotations (1)
FEMALE
Reported in 46,XX individuals with biallelic SYCE1 variants.
Show evidence (1 reference)
PMID:25062452 SUPPORT Human Clinical
"Two daughters of consanguineous parents (first cousins) from a 13-member family were diagnosed with POI."
Directly documents primary ovarian insufficiency as the female presentation of biallelic SYCE1 deficiency.
Primary amenorrhea Primary amenorrhea (HP:0000786)
Context-specific annotations (1)
FEMALE
Reported in the index family (two sisters with primary amenorrhea).
Show evidence (1 reference)
PMID:32402064 SUPPORT Model Organism
"a familial mutation reported in two sisters with primary amenorrhea"
The first reported human SYCE1 mutation (c.721C>T) presented as primary amenorrhea in two affected sisters, making this a canonical pre-pubertal clinical presentation in 46,XX individuals.
Other 2
Non-obstructive azoospermia Non-obstructive azoospermia (HP:0011961)
Context-specific annotations (1)
MALE
Reported in 46,XY individuals with biallelic/recessive SYCE1 variants.
Show evidence (1 reference)
PMID:35718780 SUPPORT Human Clinical
"We identified that two novel CNVs within SYCE1 are associated with meiotic arrest and male infertility."
Directly documents non-obstructive azoospermia/male infertility from SYCE1 variants.
Spermatogenic arrest Abnormal spermatogenesis (HP:0008669)
Context-specific annotations (1)
MALE
Local HPO does not expose a specific pachytene-arrest term, so this entry is anchored to the closest available abnormal-spermatogenesis ancestor while keeping the histopathologic preferred term explicit.
Show evidence (1 reference)
PMID:35718780 SUPPORT Human Clinical
"H&E and IF staining demonstrated that the spermatogenesis was arrested at pachytene stage in the two patients with NOA, suggesting these two novel CNVs within SYCE1 could lead to meiotic defect and NOA."
Histology demonstrates pachytene-stage spermatogenic arrest in affected men.
🧬

Genetic Associations

1
SYCE1 (Causative (Primary))
Autosomal recessive inheritance
Show evidence (2 references)
PMID:25062452 SUPPORT Human Clinical
"We describe for the first time a homozygous mutation in SYCE1 in humans."
Establishes SYCE1 as the causal gene in human gametogenic failure.
PMID:35718780 SUPPORT Human Clinical
"We identified that two novel CNVs within SYCE1 are associated with meiotic arrest and male infertility."
Extends the causal role of SYCE1 variants to the male non-obstructive azoospermia branch.
💊

Treatments

4
Hormone replacement therapy
Action: hormone replacement therapy Ontology label: Pharmacotherapy NCIT:C15986
Agent: estradiol ↗
Estrogen-based hormone replacement is used in the ovarian-failure branch to treat hypoestrogenism, support pubertal development, and reduce long-term bone and cardiovascular risk.
Show evidence (1 reference)
PMID:25062452 PARTIAL Human Clinical
"Two daughters of consanguineous parents (first cousins) from a 13-member family were diagnosed with POI."
Anchors the ovarian-insufficiency branch for which hormone replacement is standard management.
Genetic counseling
Action: genetic counseling MAXO:0000079
Genetic counseling is appropriate because the condition is recessive and causes infertility, with implications for at-risk relatives and reproductive planning.
Show evidence (1 reference)
PMID:34718620 SUPPORT Human Clinical
"Our study identified novel pathogenic variations of C14ORF39 and SYCE1 in sporadic patients with POI or NOA, highlighting the essential role of SC genes in the maintenance of ovarian and testicular function."
Identification of causal recessive variants underpins genetic counseling and molecular diagnosis for affected families.
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 (micro-TESE) is the primary fertility intervention. By directly examining individual seminiferous tubules under optical magnification, micro-TESE identifies focal regions of residual spermatogenesis with higher yield and less tissue damage than conventional biopsy approaches, enabling ICSI in a subset of affected men.
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 SYCE1-related gametogenic failure.
Fertility preservation and oocyte cryopreservation
Action: fertility preservation Ontology label: Fertility Preservation NCIT:C71326
For 46,XX individuals who receive a molecular diagnosis before complete ovarian failure, oocyte or embryo cryopreservation can preserve fertility potential. Early diagnosis is critical, as the window for successful ovarian stimulation narrows with progression of follicle depletion. Ovarian tissue cryopreservation may be an option for pre-pubertal patients or those with severely diminished ovarian reserve.
Show evidence (1 reference)
PMID:33495935 SUPPORT Human Clinical
"Fertility preservation techniques represent a crucial opportunity for patients with genetic risk of POI."
Supports early fertility preservation counseling and oocyte cryopreservation as the indicated approach for women with genetic risk of POI, including meiotic-defect syndromes such as SYCE1-related gametogenic failure.
{ }

Source YAML

click to show 
name: SYCE1-related gametogenic failure
creation_date: "2026-05-28T08:05:49Z"
category: Mendelian
description: >-
  SYCE1-related gametogenic failure is an autosomal recessive meiotic disorder
  caused by biallelic loss-of-function variants in SYCE1, which encodes a central
  element component of the synaptonemal complex. Because SYCE1 is essential for
  synapsis of homologous chromosomes during meiotic prophase I, biallelic loss
  produces a sex-dimorphic gametogenic phenotype with the same underlying lesion:
  primary ovarian insufficiency in 46,XX individuals and non-obstructive
  azoospermia from pachytene-stage meiotic arrest in 46,XY individuals. The
  shared mechanistic theme is failure of synaptonemal complex assembly, leading
  to meiotic arrest and germ-cell depletion in both sexes.
disease_term:
  preferred_term: SYCE1-related gametogenic failure
  term:
    id: MONDO:1060214
    label: SYCE1-related gametogenic failure
parents:
- Infertility disorder
- Primary ovarian insufficiency
- Male infertility
synonyms:
- SYCE1 deficiency
- SYCE1-associated gametogenic failure
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Affected individuals carry biallelic (homozygous or compound heterozygous)
    loss-of-function SYCE1 variants, with carrier parents and recessive
    segregation in reported families.
  evidence:
  - reference: PMID:25062452
    reference_title: "Exome sequencing reveals SYCE1 mutation associated with autosomal recessive primary ovarian insufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A nonsense homozygous mutation (c.613C>T) was identified in the SYCE1 gene
      in both affected sisters. The parents and three brothers were heterozygous
      for the mutation, and an unaffected sister did not carry the mutation.
    explanation: >-
      Homozygosity in affected sisters with heterozygous unaffected carriers
      directly supports autosomal recessive inheritance.
notes: >-
  MONDO:1060214 (SYCE1-related gametogenic failure) is a dyadic gene-axis disease
  entity minted by the ClinGen DSD/Sex-Development GCEP (affiliation 40073). This
  dismech entry is the mechanism-first complement, unifying the 46,XX POI and
  46,XY non-obstructive azoospermia presentations under the single synaptonemal
  complex assembly defect. The same SYCE1 mutation (c.613C>T, reannotated
  c.721C>T) was the first synaptonemal-complex central-element variant reported
  in humans.
pathophysiology:
- name: Synaptonemal complex assembly failure
  conforms_to: "meiotic_prophase_failure#Synaptonemal Complex Assembly"
  description: >-
    SYCE1 encodes a central element protein of the synaptonemal complex (SC).
    Biallelic loss-of-function abolishes SYCE1 protein and disrupts its
    interactions with the transverse-filament protein SYCP1 and the central
    element partner SIX6OS1/C14ORF39, so the SC central element cannot assemble
    and homologous chromosomes fail to synapse during meiotic prophase I.
  genes:
  - preferred_term: SYCE1
    term:
      id: hgnc:28852
      label: SYCE1
  biological_processes:
  - preferred_term: synaptonemal complex assembly
    term:
      id: GO:0007130
      label: synaptonemal complex assembly
    modifier: DECREASED
  evidence:
  - reference: PMID:34718620
    reference_title: "Variations of C14ORF39 and SYCE1 Identified in Idiopathic Premature Ovarian Insufficiency and Nonobstructive Azoospermia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      the variations in SYCE1 disrupted its interaction with SYCP1 or C14ORF39,
      both of which affected SC assembly and meiosis.
    explanation: >-
      Functional assays show SYCE1 variants disrupt the protein interactions
      required for synaptonemal complex assembly.
  - reference: PMID:32402064
    reference_title: "Familial primary ovarian insufficiency associated with an SYCE1 point mutation: defective meiosis elucidated in humanized mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      No SYCE1 protein was detected in homozygous mutants and Syce1 transcript
      level was highly diminished, suggesting transcript degradation as the basis
      of the infertility mechanism.
    explanation: >-
      A humanized mouse model of the human mutation shows loss of SYCE1 protein,
      establishing loss of function as the molecular basis of the defect.
  downstream:
  - target: Homologous chromosome synapsis failure
    description: >-
      Without an assembled central element, homologous chromosomes cannot
      synapse during meiotic prophase I.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:32402064
      reference_title: "Familial primary ovarian insufficiency associated with an SYCE1 point mutation: defective meiosis elucidated in humanized mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Our results strongly support a causative role of this mutation for the
        POI phenotype in human patients, and the mechanisms involved would relate
        to defects in homologous chromosome synapsis.
      explanation: >-
        The mouse model ties the SYCE1 defect mechanistically to failure of
        homologous chromosome synapsis.
- name: Homologous chromosome synapsis failure
  description: >-
    SYCE1 forms the central element of the synaptonemal complex and is required
    for physical synapsis of homologous chromosomes during meiotic prophase I.
    Its loss prevents stable synapsis of homologous chromosome pairs, leaving
    them unsynapsed at the pachytene stage.
  cell_types:
  - preferred_term: primary oocyte
    term:
      id: CL:0000654
      label: primary oocyte
  - 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:32402064
    reference_title: "Familial primary ovarian insufficiency associated with an SYCE1 point mutation: defective meiosis elucidated in humanized mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Our results strongly support a causative role of this mutation for the
      POI phenotype in human patients, and the mechanisms involved would relate
      to defects in homologous chromosome synapsis.
    explanation: >-
      The mouse model directly attributes the reproductive phenotype to
      failure of homologous chromosome synapsis.
  downstream:
  - target: Meiotic prophase I pachytene checkpoint activation
    description: >-
      Unsynapsed chromosomes trigger the pachytene checkpoint, arresting
      germ-cell meiotic progression.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:35718780
      reference_title: "Novel copy number variations within SYCE1 caused meiotic arrest and non-obstructive azoospermia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        H&E and IF staining demonstrated that the spermatogenesis was arrested at
        pachytene stage in the two patients with NOA, suggesting these two novel
        CNVs within SYCE1 could lead to meiotic defect and NOA.
      explanation: >-
        Pachytene-stage arrest on histology documents that synapsis failure
        leads to checkpoint-mediated meiotic block.
- name: Meiotic prophase I pachytene checkpoint activation
  conforms_to: "meiotic_prophase_failure#Pachytene Checkpoint Arrest and Germ Cell Apoptosis"
  description: >-
    Unsynapsed chromosomes or persistent recombination intermediates from failed
    synapsis activate the meiotic pachytene checkpoint, which surveys for
    completion of synapsis and crossover formation. Checkpoint activation arrests
    germ cells at the pachytene stage of prophase I; persistently arrested cells
    are eliminated by apoptosis, depleting the germ-cell pool.
  cell_types:
  - preferred_term: primary oocyte
    term:
      id: CL:0000654
      label: primary oocyte
  - preferred_term: primary spermatocyte
    term:
      id: CL:0000656
      label: primary spermatocyte
  biological_processes:
  - preferred_term: meiosis I
    term:
      id: GO:0007127
      label: meiosis I
    modifier: ABNORMAL
  - 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:35718780
    reference_title: "Novel copy number variations within SYCE1 caused meiotic arrest and non-obstructive azoospermia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      H&E and IF staining demonstrated that the spermatogenesis was arrested at
      pachytene stage in the two patients with NOA, suggesting these two novel
      CNVs within SYCE1 could lead to meiotic defect and NOA.
    explanation: >-
      Testicular histology directly documents pachytene-stage meiotic arrest
      in SYCE1 variant carriers.
  downstream:
  - target: Germ-cell depletion and sex-dimorphic gonadal failure
    description: >-
      Pachytene-arrested germ cells are eliminated, depleting the ovarian
      follicle pool in 46,XX individuals and the spermatogenic lineage in 46,XY
      individuals.
    causal_link_type: DIRECT
- name: Germ-cell depletion and sex-dimorphic gonadal failure
  description: >-
    The meiotic block depletes germ cells in both sexes, producing ovarian
    follicle depletion with primary ovarian insufficiency in 46,XX individuals
    and germ-cell-depleted testes with non-obstructive azoospermia in 46,XY
    individuals. The same molecular lesion thus yields a sex-dimorphic clinical
    presentation.
  evidence:
  - reference: PMID:34718620
    reference_title: "Variations of C14ORF39 and SYCE1 Identified in Idiopathic Premature Ovarian Insufficiency and Nonobstructive Azoospermia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our study identified novel pathogenic variations of C14ORF39 and SYCE1 in
      sporadic patients with POI or NOA, highlighting the essential role of SC
      genes in the maintenance of ovarian and testicular function.
    explanation: >-
      The same SC-gene defect is reported in both POI (female) and NOA (male)
      patients, supporting a single mechanism with sex-dimorphic gonadal output.
  - reference: PMID:25062452
    reference_title: "Exome sequencing reveals SYCE1 mutation associated with autosomal recessive primary ovarian insufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These results highlight the importance of the synaptonemal complex and
      meiosis in ovarian function.
    explanation: >-
      Links the synaptonemal complex defect to loss of ovarian function in
      affected women.
  downstream:
  - target: Premature ovarian insufficiency
    description: >-
      In 46,XX individuals follicle depletion presents clinically as primary
      ovarian insufficiency.
    causal_link_type: DIRECT
  - target: Non-obstructive azoospermia
    description: >-
      In 46,XY individuals germ-cell depletion presents clinically as
      non-obstructive azoospermia.
    causal_link_type: DIRECT
phenotypes:
- name: Premature ovarian insufficiency
  category: Reproductive
  description: >-
    Reported 46,XX individuals present with primary ovarian insufficiency,
    ranging from absent pubertal maturation to early ovarian failure.
  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 SYCE1 variants.
    evidence:
    - reference: PMID:25062452
      reference_title: "Exome sequencing reveals SYCE1 mutation associated with autosomal recessive primary ovarian insufficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Two daughters of consanguineous parents (first cousins) from a 13-member
        family were diagnosed with POI.
      explanation: >-
        Directly documents primary ovarian insufficiency as the female
        presentation of biallelic SYCE1 deficiency.
  evidence:
  - reference: PMID:32402064
    reference_title: "Familial primary ovarian insufficiency associated with an SYCE1 point mutation: defective meiosis elucidated in humanized mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Our results strongly support a causative role of this mutation for the POI
      phenotype in human patients, and the mechanisms involved would relate to
      defects in homologous chromosome synapsis.
    explanation: >-
      A humanized mouse model recapitulates the POI phenotype, supporting
      causality alongside the human clinical reports.
- name: Primary amenorrhea
  category: Reproductive
  description: >-
    46,XX individuals presenting before puberty may show absent pubertal
    maturation with primary amenorrhea due to early ovarian failure from
    germ-cell depletion. This was the presenting complaint in the index
    family carrying the first reported human SYCE1 mutation.
  phenotype_term:
    preferred_term: Primary amenorrhea
    term:
      id: HP:0000786
      label: Primary amenorrhea
  phenotype_contexts:
  - sex: FEMALE
    notes: Reported in the index family (two sisters with primary amenorrhea).
    evidence:
    - reference: PMID:32402064
      reference_title: "Familial primary ovarian insufficiency associated with an SYCE1 point mutation: defective meiosis elucidated in humanized mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "a familial mutation reported in two sisters with primary amenorrhea"
      explanation: >-
        The first reported human SYCE1 mutation (c.721C>T) presented as primary
        amenorrhea in two affected sisters, making this a canonical pre-pubertal
        clinical presentation in 46,XX individuals.
- name: Non-obstructive azoospermia
  category: Reproductive
  description: >-
    In 46,XY individuals SYCE1 deficiency causes non-obstructive azoospermia due
    to pachytene-stage meiotic arrest of spermatogenesis.
  phenotype_term:
    preferred_term: Non-obstructive azoospermia
    term:
      id: HP:0011961
      label: Non-obstructive azoospermia
  phenotype_contexts:
  - sex: MALE
    notes: Reported in 46,XY individuals with biallelic/recessive SYCE1 variants.
    evidence:
    - reference: PMID:35718780
      reference_title: "Novel copy number variations within SYCE1 caused meiotic arrest and non-obstructive azoospermia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We identified that two novel CNVs within SYCE1 are associated with
        meiotic arrest and male infertility.
      explanation: >-
        Directly documents non-obstructive azoospermia/male infertility from
        SYCE1 variants.
- name: Spermatogenic arrest
  category: Reproductive
  description: >-
    Testicular histopathology shows arrest of spermatogenesis at the pachytene
    stage of meiosis, the male correlate of the shared meiotic block.
  phenotype_term:
    preferred_term: Pachytene-stage spermatogenic arrest
    term:
      id: HP:0008669
      label: Abnormal spermatogenesis
  phenotype_contexts:
  - sex: MALE
    notes: >-
      Local HPO does not expose a specific pachytene-arrest term, so this entry
      is anchored to the closest available abnormal-spermatogenesis ancestor
      while keeping the histopathologic preferred term explicit.
    evidence:
    - reference: PMID:35718780
      reference_title: "Novel copy number variations within SYCE1 caused meiotic arrest and non-obstructive azoospermia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        H&E and IF staining demonstrated that the spermatogenesis was arrested at
        pachytene stage in the two patients with NOA, suggesting these two novel
        CNVs within SYCE1 could lead to meiotic defect and NOA.
      explanation: >-
        Histology demonstrates pachytene-stage spermatogenic arrest in affected
        men.
genetic:
- name: SYCE1
  association: Causative (Primary)
  gene_term:
    preferred_term: SYCE1
    term:
      id: hgnc:28852
      label: SYCE1
  inheritance:
  - name: Autosomal recessive inheritance
    evidence:
    - reference: PMID:25062452
      reference_title: "Exome sequencing reveals SYCE1 mutation associated with autosomal recessive primary ovarian insufficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        A nonsense homozygous mutation (c.613C>T) was identified in the SYCE1
        gene in both affected sisters. The parents and three brothers were
        heterozygous for the mutation, and an unaffected sister did not carry the
        mutation.
      explanation: >-
        Supports recessive transmission at the gene level.
  evidence:
  - reference: PMID:25062452
    reference_title: "Exome sequencing reveals SYCE1 mutation associated with autosomal recessive primary ovarian insufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We describe for the first time a homozygous mutation in SYCE1 in humans.
    explanation: >-
      Establishes SYCE1 as the causal gene in human gametogenic failure.
  - reference: PMID:35718780
    reference_title: "Novel copy number variations within SYCE1 caused meiotic arrest and non-obstructive azoospermia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified that two novel CNVs within SYCE1 are associated with meiotic
      arrest and male infertility.
    explanation: >-
      Extends the causal role of SYCE1 variants to the male non-obstructive
      azoospermia branch.
  notes: >-
    SYCE1 encodes synaptonemal complex central element protein 1, a component of
    the SC central element essential for synapsis of homologous chromosomes
    during meiotic prophase I.
treatments:
- name: Hormone replacement therapy
  description: >-
    Estrogen-based hormone replacement is used in the ovarian-failure branch to
    treat hypoestrogenism, support pubertal development, and reduce long-term
    bone and cardiovascular risk.
  treatment_term:
    preferred_term: hormone replacement therapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: estradiol
      term:
        id: CHEBI:23965
        label: estradiol
  evidence:
  - reference: PMID:25062452
    reference_title: "Exome sequencing reveals SYCE1 mutation associated with autosomal recessive primary ovarian insufficiency."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Two daughters of consanguineous parents (first cousins) from a 13-member
      family were diagnosed with POI.
    explanation: >-
      Anchors the ovarian-insufficiency branch for which hormone replacement is
      standard management.
- name: Genetic counseling
  description: >-
    Genetic counseling is appropriate because the condition is recessive and
    causes infertility, with implications for at-risk relatives and reproductive
    planning.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: MAXO:0000079
      label: genetic counseling
  evidence:
  - reference: PMID:34718620
    reference_title: "Variations of C14ORF39 and SYCE1 Identified in Idiopathic Premature Ovarian Insufficiency and Nonobstructive Azoospermia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our study identified novel pathogenic variations of C14ORF39 and SYCE1 in
      sporadic patients with POI or NOA, highlighting the essential role of SC
      genes in the maintenance of ovarian and testicular function.
    explanation: >-
      Identification of causal recessive variants underpins genetic counseling
      and molecular diagnosis for affected families.
- name: Microdissection testicular sperm extraction (micro-TESE)
  description: >-
    For 46,XY individuals with non-obstructive azoospermia due to meiotic arrest,
    microsurgical testicular sperm extraction (micro-TESE) is the primary fertility
    intervention. By directly examining individual seminiferous tubules under
    optical magnification, micro-TESE identifies focal regions of residual
    spermatogenesis with higher yield and less tissue damage than conventional
    biopsy approaches, enabling ICSI in a subset of affected men.
  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 SYCE1-related gametogenic failure.
- name: Fertility preservation and oocyte cryopreservation
  description: >-
    For 46,XX individuals who receive a molecular diagnosis before complete
    ovarian failure, oocyte or embryo cryopreservation can preserve fertility
    potential. Early diagnosis is critical, as the window for successful
    ovarian stimulation narrows with progression of follicle depletion.
    Ovarian tissue cryopreservation may be an option for pre-pubertal patients
    or those with severely diminished ovarian reserve.
  treatment_term:
    preferred_term: fertility preservation
    term:
      id: NCIT:C71326
      label: Fertility Preservation
  evidence:
  - reference: PMID:33495935
    reference_title: "Fertility preservation for genetic diseases leading to premature ovarian insufficiency (POI)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Fertility preservation techniques represent a crucial opportunity for
      patients with genetic risk of POI.
    explanation: >-
      Supports early fertility preservation counseling and oocyte cryopreservation
      as the indicated approach for women with genetic risk of POI, including
      meiotic-defect syndromes such as SYCE1-related gametogenic failure.
diagnosis:
- name: Targeted molecular testing
  description: >-
    Exome or panel-based sequencing confirms the diagnosis by identifying
    biallelic pathogenic SYCE1 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:35718780
    reference_title: "Novel copy number variations within SYCE1 caused meiotic arrest and non-obstructive azoospermia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Whole-exome sequencing (WES) was conducted in the two patients with NOA.
    explanation: >-
      Supports molecular (exome) testing as the route to a SYCE1 diagnosis.
📚

References & Deep Research

Deep Research

1
Falcon ▸
Mechanistic Hypothesis Search
Edison Scientific Literature 4 citations 2026-05-28T23:59:49.099085

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Mechanistic Hypothesis Search

You are evaluating a specific disease mechanism hypothesis for the Disorder Mechanisms Knowledge Base. Use the seed claims below, then search for supporting, qualifying, or missing evidence. Prefer primary literature where available, but clearly label review-level support.

Target Disease

  • Disease name: SYCE1-related gametogenic failure
  • Mondo: MONDO:1060214
  • Category: Mendelian

Seed Hypothesis

SYCE1-related gametogenic failure is caused by biallelic SYCE1 loss or damaging variants. SYCE1 is a synaptonemal-complex central element protein. Loss disrupts central element assembly and SYCE1 interactions with SYCP1 and C14ORF39/SIX6OS1, causing homologous chromosome synapsis failure during meiotic prophase I. Unsynapsed chromosomes lead to pachytene-stage meiotic arrest/checkpoint activation and germ-cell depletion. The same mechanism produces primary ovarian insufficiency or primary amenorrhea in 46,XX individuals and non-obstructive azoospermia or spermatogenic arrest in 46,XY individuals.

Seed Evidence From Existing Curation

  • PMID:25062452, human clinical: "A nonsense homozygous mutation (c.613C>T) was identified in the SYCE1 gene in both affected sisters. The parents and three brothers were heterozygous for the mutation, and an unaffected sister did not carry the mutation."
  • PMID:25062452, human clinical: "These results highlight the importance of the synaptonemal complex and meiosis in ovarian function."
  • PMID:32402064, model organism: "No SYCE1 protein was detected in homozygous mutants and Syce1 transcript level was highly diminished, suggesting transcript degradation as the basis of the infertility mechanism."
  • PMID:32402064, model organism: "Our results strongly support a causative role of this mutation for the POI phenotype in human patients, and the mechanisms involved would relate to defects in homologous chromosome synapsis."
  • PMID:32402064, model organism/context: "a familial mutation reported in two sisters with primary amenorrhea"
  • PMID:34718620, in vitro/functional and human cohort: "the variations in SYCE1 disrupted its interaction with SYCP1 or C14ORF39, both of which affected SC assembly and meiosis."
  • PMID:34718620, human clinical: "Our study identified novel pathogenic variations of C14ORF39 and SYCE1 in sporadic patients with POI or NOA, highlighting the essential role of SC genes in the maintenance of ovarian and testicular function."
  • PMID:35718780, human clinical: "H&E and IF staining demonstrated that the spermatogenesis was arrested at pachytene stage in the two patients with NOA, suggesting these two novel CNVs within SYCE1 could lead to meiotic defect and NOA."

Required Output

  1. Executive judgment on whether the seed mechanism is supported, partially supported, or weakly supported.
  2. Evidence matrix with citation, evidence type, claim tested, key finding, confidence, and limitations.
  3. Clinical spectrum summary: 46,XX POI/primary amenorrhea; 46,XY non-obstructive azoospermia/spermatogenic arrest; any biochemical or histologic findings such as FSH/AMH, follicle depletion, pachytene arrest.
  4. Variant and inheritance summary: variant classes, families/cohorts, biallelic inheritance, CNVs/deletions, loss of function.
  5. Mechanistic causal chain from SYCE1 variant to synaptonemal complex assembly failure, homologous chromosome synapsis failure, pachytene arrest/checkpoint activation, germ-cell apoptosis/depletion, and sex-dimorphic reproductive phenotype.
  6. Diagnostics and management implications: genetic testing, semen analysis, testicular biopsy, hormone replacement for POI, fertility preservation/oocyte cryopreservation, micro-TESE/ICSI context, genetic counseling.
  7. Ontology suggestions by label only: HPO phenotypes, GO biological processes, CL cell types, treatment/action terms.
  8. Knowledge gaps and weak claims: distinguish human direct evidence from mouse/model inference; identify claims needing full-text verification or additional cohorts.
  9. Curation leads: specific updates that might be considered for the SYCE1 entry, but label them as leads requiring curator verification.

Do not fabricate PMIDs. If a source cannot be retrieved by the tool, state that clearly and use the seed evidence cautiously.

Warning: no contexts were retrieved, so this answer is not grounded in evidence but is instead a direct response from the agent model.

This run produced no retrievable papers and no citable context IDs, so I cannot generate a tool-grounded, properly cited mechanistic hypothesis evaluation within the system’s constraints; the system rejects answers without citations.

Seed PubMed pointers for manual verification: - https://pubmed.ncbi.nlm.nih.gov/25062452/ - https://pubmed.ncbi.nlm.nih.gov/32402064/ - https://pubmed.ncbi.nlm.nih.gov/34718620/ - https://pubmed.ncbi.nlm.nih.gov/35718780/

Artifacts