SYCP2-related spermatogenic failure

👪

Inheritance

2

Autosomal dominant HP:0000006

Heterozygous loss-of-function SYCP2 alleles have been reported in men with cryptozoospermia, azoospermia and oligoasthenozoospermia across several independent studies, and a formal ClinGen-framework reassessment concluded that the accumulated genetic and experimental evidence supports an autosomal dominant pattern.

Autosomal dominant inheritance

Show evidence (1 reference)

PMID:39202451 SUPPORT Human Clinical

"These cases, combined with the previously reported cases, provide strong genetic evidence supporting an autosomal dominant inheritance pattern."

A ClinGen-framework reassessment concluding that the aggregate genetic evidence supports autosomal dominant inheritance.

Autosomal recessive HP:0000007

A homozygous SYCP2 loss-of-function variant was identified in a man with non-obstructive azoospermia and inherited from heterozygous parents who reproduced naturally. The authors argue from that pedigree that the gene-disease relationship is recessive rather than dominant. This block and the autosomal dominant block above are both curated deliberately; see the entry notes and the open discussion.

Autosomal recessive inheritance

Show evidence (1 reference)

PMID:37337432 SUPPORT Human Clinical

"Thus, this study revealed that SYCP2 associated with NOA segregates in an autosomal recessive inheritance pattern, rather than an autosomal dominant pattern."

States the recessive conclusion drawn from a pedigree in which the heterozygous parents reproduced naturally.

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Discussions and Knowledge Gaps

1

Is SYCP2-related spermatogenic failure autosomal dominant, autosomal recessive, or both — and if heterozygous loss of function is pathogenic, why were the heterozygous parents in the reported recessive pedigree fertile?

KNOWLEDGE GAP gap_sycp2_mode_of_inheritance_contested

Attached to

pathophysiology#SYCP2 Loss-of-Function Variants disease#SYCP2-related spermatogenic failure

This is a live disagreement in the primary literature, not a gap in reporting. PMID:31866047 and PMID:39202451 identify heterozygous frameshift alleles in infertile men and, under the ClinGen framework, conclude that the aggregate evidence supports autosomal dominant inheritance strongly enough to put SYCP2 on diagnostic panels. PMID:37337432 reports a homozygous frameshift transmitted by heterozygous parents who conceived naturally, and concludes recessive inheritance "rather than an autosomal dominant pattern". Both cannot be unqualifiedly true of the same allele class. Reduced penetrance of heterozygous alleles would reconcile them, but no penetrance estimate exists, and the distinction determines recurrence-risk counseling and whether a heterozygous finding in an infertile man is reportable as causal.

Proposed experiments

Semen phenotyping of obligate heterozygous carriers

exp_sycp2_heterozygote_fertility_cohort

Systematically obtain semen analyses from the fertile heterozygous parents and other obligate carriers in reported SYCP2 pedigrees, to establish whether they are genuinely normozoospermic or subclinically affected.

Decision criterion

Normal semen parameters in a series of obligate heterozygotes would argue that heterozygous loss of function is insufficient and support the recessive model. Subclinical oligozoospermia would support a dominant model with variable expressivity and reframe the disagreement as one about threshold, not mechanism.

Population burden of SYCP2 loss-of-function alleles

exp_sycp2_burden_gnomad_penetrance

Estimate the frequency of heterozygous SYCP2 loss-of-function alleles in large population reference cohorts not ascertained for infertility, and compare against the frequency in azoospermic and oligozoospermic case series.

Decision criterion

A carrier frequency far exceeding the prevalence of SYCP2-attributable infertility would establish incomplete penetrance quantitatively and set an upper bound on the dominant model's contribution.

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Pathophysiology

5

SYCP2 Loss-of-Function Variants

Frameshift variants in SYCP2 truncate the protein and remove functional axial-element activity. These have been reported in the heterozygous state in men with cryptozoospermia, azoospermia and oligoasthenozoospermia, and in the homozygous state in a man with non-obstructive azoospermia.

SYCP2 hgnc:11490

Downstream

Synaptonemal Complex Axial Element Assembly Failure Loss of the axial-element protein prevents assembly of the axial/lateral elements of the synaptonemal complex.

Show evidence (2 references)

PMID:31866047 SUPPORT Human Clinical

"Exome sequencing of infertile males revealed three heterozygous SYCP2 frameshift variants in additional subjects with cryptozoospermia and azoospermia."

Reports the heterozygous frameshift alleles in independently ascertained infertile men.

PMID:39202451 SUPPORT Human Clinical

"Whole exome sequencing (WES) and subsequent Sanger sequencing revealed novel heterozygous loss-of-function (LOF) variants in SYCP2"

Independent replication of heterozygous loss-of-function alleles in three further unrelated patients.

SYCP2 Overexpression from Enhancer Adoption

A de novo balanced translocation, t(20;22)(q13.3;q11.2), drives exclusive overexpression of SYCP2 from the derivative chromosome 20 allele, attributed to adoption of an enhancer brought into range by the rearrangement. This is the mechanistic opposite of the frameshift alleles and reaches the same downstream node, consistent with the synaptonemal complex being sensitive to the stoichiometry of its structural components rather than simply to the presence of SYCP2.

SYCP2 hgnc:11490

Downstream

Synaptonemal Complex Axial Element Assembly Failure Modelling the same dysregulation in budding yeast disrupted the structural integrity of the synaptonemal complex, supporting overexpression as a route to the same lesion.

Show evidence (1 reference)

PMID:31866047 SUPPORT Human Clinical

"We identified exclusive overexpression of SYCP2 from the der(20) allele that is hypothesized to result from enhancer adoption."

Documents the overexpression and the proposed enhancer-adoption mechanism in the index subject.

Synaptonemal Complex Axial Element Assembly Failure

SYCP2 heterodimerizes with SYCP3 through a conserved coiled-coil domain and is the primary determinant of the axial/lateral elements: in a mouse mutant lacking that domain, mutant SYCP2 still localizes to axial chromosomal cores but SYCP3 does not, showing that SYCP2 is required to incorporate SYCP3 into the complex. Loss of the axial element removes the scaffold on which synapsis depends.

primary spermatocyte CL:0000656

synaptonemal complex assembly GO:0007130 ↓ DECREASED

Animal models

Sycp2 allele lacking the SYCP3-binding coiled-coil domain, homozygous Mouse Mouse recapitulates Reproduces the failure of axial/lateral element formation that defines this node, and additionally establishes the SYCP2-before-SYCP3 dependency.

Downstream

Homologous Chromosome Synapsis Failure and Meiotic Arrest Without assembled axial/lateral elements, homologous chromosomes cannot synapse, and affected spermatocytes arrest in meiotic prophase.

Show evidence (2 references)

PMID:16717126 SUPPORT Model Organism

"the mutant SYCP2 protein localizes to axial chromosomal cores in both spermatocytes and fetal oocytes, but SYCP3 does not, demonstrating that SYCP2 is a primary determinant of AEs/LEs and, thus, is required for the incorporation of SYCP3 into SCs"

Establishes the hierarchy within the axial element: SYCP2 is upstream of SYCP3 incorporation, which is why its loss is not equivalent to SYCP3 loss.

PMID:16717126 SUPPORT In Vitro

"An evolutionarily conserved coiled coil domain in SYCP2 is required for binding to SYCP3."

Identifies the domain mediating the SYCP2-SYCP3 interaction. The quote is trimmed to the domain-mapping result so that this IN_VITRO item does not carry the "both in vitro and in vivo" clause belonging to the companion in vivo finding.

Homologous Chromosome Synapsis Failure and Meiotic Arrest

Homologous chromosomes fail to synapse and spermatocytes arrest in meiotic prophase I. In the one human testicular study cited here, histology, immunofluorescence and meiotic chromosome spreads placed the arrest at the zygotene stage. In the mouse, arrest is accompanied by spermatocyte apoptosis.

spermatocyte CL:0000017

homologous chromosome pairing at meiosis GO:0007129 ↓ DECREASED apoptotic process GO:0006915 ↑ INCREASED

Downstream

Spermatogenic Failure Elimination of arrested spermatocytes depletes the post-meiotic germ-cell pool, producing reduced or absent sperm output.

Show evidence (2 references)

PMID:37337432 SUPPORT Human Clinical

"HE, IF, and meiotic chromosomal spread analyses demonstrated that spermatogenesis was arrested at the zygotene stage in the proband with NOA."

The only human histological localization of the arrest cited here, and the reason this entry does not claim a pachytene-stage arrest.

PMID:39202451 SUPPORT Model Organism

"mice lacking the coiled-coil domain of Sycp2 exhibit impaired homologous chromosome synapsis, leading to spermatocyte apoptosis and male-specific infertility"

Supports the apoptotic elimination of arrested spermatocytes, evidenced in mouse rather than in human tissue.

Spermatogenic Failure

The clinical endpoint is male infertility across a severity spectrum: oligoasthenozoospermia, cryptozoospermia, and non-obstructive azoospermia with meiotic maturation arrest on testicular histology. The phenotype is male-limited in the human reports; the mouse counterpart is sexually dimorphic, with sterile males and subfertile females.

male gamete generation GO:0048232 ↓ DECREASED

Animal models

Sycp2 allele lacking the SYCP3-binding coiled-coil domain, homozygous Mouse Mouse partially recapitulates Male mice are sterile from a meiotic block, matching the severe end of the human phenotype.

Show evidence (1 reference)

PMID:31866047 SUPPORT Human Clinical

"provides evidence of SYCP2-mediated male infertility in humans"

The paper's own summary of what it establishes about the human phenotype.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

5

Genitourinary 2

Male Infertility HP:0003251

Show evidence (1 reference)

PMID:31866047 SUPPORT Human Clinical

"provides evidence of SYCP2-mediated male infertility in humans"

Establishes male infertility as the human phenotype of this gene.

Azoospermia HP:0000027

Show evidence (1 reference)

PMID:37337432 SUPPORT Human Clinical

"Herein, we showed a homozygous loss-of-function variant in SYCP2 (c.2689_2690insT) in an NOA-affected patient."

Documents non-obstructive azoospermia in a SYCP2 patient.

Other 3

Oligozoospermia HP:0000798

Show evidence (1 reference)

PMID:31866047 SUPPORT Human Clinical

"One such subject, DGAP230, has severe oligozoospermia and 46,XY,t(20;22)(q13.3;q11.2)."

Documents severe oligozoospermia in the index subject.

Reduced Sperm Motility HP:0012207

Show evidence (1 reference)

PMID:39202451 SUPPORT Human Clinical

"This study investigates the genetic cause of infertility for three unrelated Chinese patients with oligoasthenozoospermia."

Documents the asthenozoospermic component of the phenotype in three unrelated patients.

Abnormal Spermatogenesis HP:0008669

Show evidence (1 reference)

PMID:37337432 SUPPORT Human Clinical

"HE, IF, and meiotic chromosomal spread analyses demonstrated that spermatogenesis was arrested at the zygotene stage in the proband with NOA."

Documents arrested spermatogenesis on testicular histology.

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Genetic Associations

1

SYCP2 (Heterozygous or homozygous loss-of-function variants, and translocation-mediated overexpression)

Gene: SYCP2 hgnc:11490 relationship_type: CAUSATIVE

Show evidence (2 references)

PMID:39202451 SUPPORT Human Clinical

"Collectively, this updated assessment of the genetic and experimental evidence upgrades the gene-disease association strength of SYCP2 and autosomal dominant male infertility from on the border of limited and moderate to strong."

Records the ClinGen-framework validity classification and the upgrade, which is the best available summary statement of how strong this gene-disease relationship is.

PMID:31866047 SUPPORT Human Clinical

"this investigation illustrates the power of precision cytogenetics for annotation of the infertile genome, suggests that these mechanisms should be considered as an alternative etiology to that of segregation of unbalanced gametes in infertile men harboring a BCA"

Establishes the translocation-mediated dysregulation route and distinguishes it from the unbalanced-gamete explanation usually invoked for a balanced chromosomal aberration.

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Medical Actions

2

Microdissection Testicular Sperm Extraction with ICSI

Action: sperm retrieval Ontology label: Sperm Retrieval NCIT:C94427

The primary management pathway for non-obstructive azoospermia due to meiotic arrest. Microsurgical testicular sperm extraction searches the testis for focal regions of residual spermatogenesis, with higher yield and less tissue removal than conventional biopsy; retrieved sperm are used for intracytoplasmic sperm injection. It is squarely in scope here because residual sperm production is documented in this disorder: reported patients span oligoasthenozoospermia and cryptozoospermia as well as complete azoospermia.

Mechanism Target:

BYPASSES Spermatogenic Failure — Retrieval plus ICSI circumvents the failure of sperm output rather than correcting the meiotic defect that causes it. Any sperm recovered still derive from spermatocytes that completed meiosis.

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, the presentation at the severe end of this disorder's spectrum.

Genetic Counseling

Action: Genetic Counseling NCIT:C15240

Counseling is complicated by the unresolved mode of inheritance: recurrence risk differs substantially depending on whether heterozygous loss-of-function is sufficient. The reported recessive pedigree, in which heterozygous carrier parents reproduced naturally, is directly relevant to what a carrier is told.

Show evidence (1 reference)

PMID:37337432 SUPPORT Human Clinical

"And this variant was inherited from heterozygous parental carriers by natural reproduction."

The observation that bears directly on recurrence-risk counseling for heterozygous carriers.

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Diagnosis

2

Exome Sequencing with Male Infertility Gene Panel

Whole exome sequencing with Sanger confirmation identifies the causal SYCP2 variants. The ClinGen-framework upgrade to "strong" clinical validity is what qualifies SYCP2 for inclusion on diagnostic male infertility gene panels and for prioritization in exome and genome analyses, so the classification has a direct diagnostic consequence.

Genetic Testing NCIT:C15709

Show evidence (1 reference)

PMID:39202451 SUPPORT Human Clinical

"The reclassification improves SYCP2 variant interpretation and qualifies it for the inclusion on diagnostic male infertility gene panels and prioritization in whole exome or genome studies for related phenotypes."

States the diagnostic consequence of the validity reclassification.

Cytogenetic Analysis for Balanced Chromosomal Rearrangement

In an infertile man carrying a balanced chromosomal aberration, the default explanation is production of unbalanced gametes. The SYCP2 index case shows that a balanced rearrangement can instead act by dysregulating a fertility gene at a breakpoint, which changes what a cytogenetic finding means and argues for looking at genes near the breakpoints.

Genetic Testing NCIT:C15709

Show evidence (1 reference)

PMID:31866047 SUPPORT Human Clinical

"While BCAs may reduce fertility by production of unbalanced gametes, a chromosomal rearrangement may also disrupt or dysregulate genes important in fertility."

States the alternative interpretation of a balanced rearrangement in an infertile man.

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Animal Models

1

Sycp2 allele lacking the SYCP3-binding coiled-coil domain, homozygous Mouse

A targeted mouse allele deleting the evolutionarily conserved coiled-coil domain through which SYCP2 binds SYCP3. It is the source of the mechanistic hierarchy this entry curates: mutant SYCP2 still reaches axial chromosomal cores while SYCP3 does not, showing SYCP2 is the primary determinant of the axial element rather than an equal partner of SYCP3.

Species

Mouse

Genotype

Sycp2 allele lacking the SYCP3-binding coiled-coil domain, homozygous

Genes

SYCP2 hgnc:11490

Publication

PMID:16717126

Pathograph links

Synaptonemal Complex Axial Element Assembly Failure recapitulates fidelity: high Reproduces the failure of axial/lateral element formation that defines this node, and additionally establishes the SYCP2-before-SYCP3 dependency.

Limitations: The engineered allele is a domain deletion, whereas the reported human alleles are frameshift truncations or, in one case, translocation-driven overexpression; the model therefore does not test whether human alleles act by the same route, and cannot model the overexpression trigger at all.

Readouts

Axial/lateral element formation in spermatocytes

Direction: ABOLISHED

Interpretation: Absence of axial/lateral elements and of chromosomal synapsis in mutant spermatocytes.

Show evidence (1 reference)

PMID:16717126 SUPPORT Model Organism

"Sycp2 mutant spermatocytes exhibit failure in the formation of AEs and chromosomal synapsis."

The histological measurement behind this readout.

Show evidence (1 reference)

PMID:16717126 SUPPORT Model Organism

"the mutant SYCP2 protein localizes to axial chromosomal cores in both spermatocytes and fetal oocytes, but SYCP3 does not, demonstrating that SYCP2 is a primary determinant of AEs/LEs and, thus, is required for the incorporation of SYCP3 into SCs"

Supports treating this model as informative for the axial-element node, and supplies the dependency ordering.

Spermatogenic Failure partially recapitulates fidelity: moderate Male mice are sterile from a meiotic block, matching the severe end of the human phenotype.

Limitations: The phenotype is sexually dimorphic in the mouse, with subfertile females, whereas the human disorder as reported is male-limited and no female phenotype has been described. The mouse is also all-or-nothing, so it does not model the oligoasthenozoospermic and cryptozoospermic presentations that make up much of the human spectrum.

Show evidence (1 reference)

PMID:16717126 SUPPORT Model Organism

"males are sterile because of a block in meiosis, whereas females are subfertile with sharply reduced litter size"

PARTIAL because the same sentence that establishes the male phenotype also records a female phenotype the human disorder has not been shown to have.

{ }

Source YAML

click to show

name: SYCP2-related spermatogenic failure
creation_date: "2026-08-24T22:05:00Z"
category: Mendelian
description: >-
  SYCP2-related spermatogenic failure (spermatogenic failure 1, SPGF1) is a
  meiotic cause of human male infertility arising from loss or dysregulation of
  SYCP2, which encodes an integral protein of the axial/lateral element of the
  synaptonemal complex. SYCP2 is the primary determinant of the axial element and
  is required to incorporate SYCP3 into the complex, so its disruption prevents
  assembly of the scaffold that homologous chromosomes need in order to synapse
  during meiotic prophase I. Affected men present across a spectrum from
  oligoasthenozoospermia and cryptozoospermia to non-obstructive azoospermia with
  meiotic arrest. Two distinct routes to the same lesion are documented:
  heterozygous frameshift (loss-of-function) alleles, and overexpression of the
  gene driven by a balanced chromosomal translocation through enhancer adoption
  — so both too little and too much SYCP2 disrupt the complex. The mode of
  inheritance is not settled, and this entry curates the disagreement rather than
  choosing a side.
disease_term:
  preferred_term: spermatogenic failure 1
  term:
    id: MONDO:0009776
    label: spermatogenic failure 1
parents:
- Infertility disorder
- Male infertility
- spermatogenic failure
synonyms:
- spermatogenic failure 1
- SPGF1
- SYCP2-related male infertility
inheritance:
- name: Autosomal dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    Heterozygous loss-of-function SYCP2 alleles have been reported in men with
    cryptozoospermia, azoospermia and oligoasthenozoospermia across several
    independent studies, and a formal ClinGen-framework reassessment concluded
    that the accumulated genetic and experimental evidence supports an autosomal
    dominant pattern.
  evidence:
  - reference: PMID:39202451
    reference_title: "Novel Loss-of-Function SYCP2 Variants in Infertile Males Upgrade the Gene-Disease Clinical Validity Classification for SYCP2 and Male Infertility to Strong."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These cases, combined with the previously reported cases, provide strong
      genetic evidence supporting an autosomal dominant inheritance pattern.
    explanation: >-
      A ClinGen-framework reassessment concluding that the aggregate genetic
      evidence supports autosomal dominant inheritance.
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    A homozygous SYCP2 loss-of-function variant was identified in a man with
    non-obstructive azoospermia and inherited from heterozygous parents who
    reproduced naturally. The authors argue from that pedigree that the
    gene-disease relationship is recessive rather than dominant. This block and
    the autosomal dominant block above are both curated deliberately; see the
    entry notes and the open discussion.
  evidence:
  - reference: PMID:37337432
    reference_title: "A homozygous frameshift variant in SYCP2 caused meiotic arrest and non-obstructive azoospermia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Thus, this study revealed that SYCP2 associated with NOA segregates in an
      autosomal recessive inheritance pattern, rather than an autosomal dominant
      pattern.
    explanation: >-
      States the recessive conclusion drawn from a pedigree in which the
      heterozygous parents reproduced naturally.
notes: >-
  **The mode of inheritance is genuinely contested and both readings are
  curated.** PMID:31866047 and PMID:39202451 report heterozygous frameshift
  alleles in infertile men and conclude autosomal dominant; PMID:37337432
  reports a homozygous frameshift inherited from fertile heterozygous parents
  and concludes autosomal recessive, explicitly "rather than an autosomal
  dominant pattern". Two `inheritance` blocks are therefore present, each
  carrying its own evidence, and the conflict is recorded as an open
  discussion. Collapsing this to one block would have required deciding a
  question the field has not decided, and the fertile heterozygous parents in
  the recessive pedigree are a real observation that a dominant model has to
  account for.

  **Two mechanistically opposite lesions converge on the same node.** Most
  reported alleles are loss-of-function frameshifts, but the index subject of
  PMID:31866047 has a balanced translocation causing *overexpression* of SYCP2
  from the derivative allele through enhancer adoption. The pathograph models
  these as two triggers feeding one synaptonemal-complex node rather than as one
  "SYCP2 dysfunction" trigger, because dosage in either direction disrupting a
  stoichiometric structural complex is the actual claim, and flattening it would
  lose the overexpression route entirely.

  **Conformance stops short of the pachytene node on purpose.** The module's
  arrest node is named for pachytene, and the mouse literature supports arrest
  with spermatocyte apoptosis. But the one human histological study cited here
  (PMID:37337432) found spermatogenesis arrested at the **zygotene** stage.
  Declaring conformance to a pachytene-specific node on the strength of a
  zygotene observation would assert a stage this disorder's human evidence does
  not support, so this entry conforms at `#Synaptonemal Complex Assembly` and
  `#Spermatogenic Arrest and Non-Obstructive Azoospermia` only.

  **Evidence-strength note.** The strongest statement available about this
  gene-disease pair is a classification, not a finding: PMID:39202451 upgrades
  SYCP2-autosomal-dominant-male-infertility from "on the border of limited and
  moderate" to **strong** under the ClinGen Gene-Disease Validity SOP. The
  dismech `EvidenceItem` model has no slot for that classification, so it is
  recorded here in prose and in the `genetic` entry's `features`. See
  monarch-initiative/dismech#9421.

  Research input: `research/Spermatogenic_Failure_1-deep-research-perplexity.md`,
  which cleared the NEC preflight against MONDO:0009776 (PASS; SYCP2 mentioned
  235 times, next-nearest gene SYCP3 at 23). It returned no PMIDs in its body,
  so all references here were located independently in PubMed and fetched with
  `just fetch-reference`.
pathophysiology:
- name: SYCP2 Loss-of-Function Variants
  biological_scale: MOLECULAR
  description: >-
    Frameshift variants in SYCP2 truncate the protein and remove functional
    axial-element activity. These have been reported in the heterozygous state in
    men with cryptozoospermia, azoospermia and oligoasthenozoospermia, and in the
    homozygous state in a man with non-obstructive azoospermia.
  genes:
  - preferred_term: SYCP2
    term:
      id: hgnc:11490
      label: SYCP2
  evidence:
  - reference: PMID:31866047
    reference_title: "SYCP2 Translocation-Mediated Dysregulation and Frameshift Variants Cause Human Male Infertility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Exome sequencing of infertile males revealed three heterozygous SYCP2
      frameshift variants in additional subjects with cryptozoospermia and
      azoospermia.
    explanation: >-
      Reports the heterozygous frameshift alleles in independently ascertained
      infertile men.
  - reference: PMID:39202451
    reference_title: "Novel Loss-of-Function SYCP2 Variants in Infertile Males Upgrade the Gene-Disease Clinical Validity Classification for SYCP2 and Male Infertility to Strong."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Whole exome sequencing (WES) and subsequent Sanger sequencing revealed novel
      heterozygous loss-of-function (LOF) variants in SYCP2
    explanation: >-
      Independent replication of heterozygous loss-of-function alleles in three
      further unrelated patients.
  downstream:
  - target: Synaptonemal Complex Axial Element Assembly Failure
    description: >-
      Loss of the axial-element protein prevents assembly of the axial/lateral
      elements of the synaptonemal complex.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:16717126
      reference_title: "Mouse SYCP2 is required for synaptonemal complex assembly and chromosomal synapsis during male meiosis."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Sycp2 mutant spermatocytes exhibit failure in the formation of AEs and
        chromosomal synapsis.
      explanation: >-
        Direct demonstration in a mouse mutant that loss of SYCP2 function causes
        axial-element formation failure.
- name: SYCP2 Overexpression from Enhancer Adoption
  biological_scale: MOLECULAR
  description: >-
    A de novo balanced translocation, t(20;22)(q13.3;q11.2), drives exclusive
    overexpression of SYCP2 from the derivative chromosome 20 allele, attributed
    to adoption of an enhancer brought into range by the rearrangement. This is
    the mechanistic opposite of the frameshift alleles and reaches the same
    downstream node, consistent with the synaptonemal complex being sensitive to
    the stoichiometry of its structural components rather than simply to the
    presence of SYCP2.
  genes:
  - preferred_term: SYCP2
    term:
      id: hgnc:11490
      label: SYCP2
  evidence:
  - reference: PMID:31866047
    reference_title: "SYCP2 Translocation-Mediated Dysregulation and Frameshift Variants Cause Human Male Infertility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified exclusive overexpression of SYCP2 from the der(20) allele that
      is hypothesized to result from enhancer adoption.
    explanation: >-
      Documents the overexpression and the proposed enhancer-adoption mechanism in
      the index subject.
  downstream:
  - target: Synaptonemal Complex Axial Element Assembly Failure
    description: >-
      Modelling the same dysregulation in budding yeast disrupted the structural
      integrity of the synaptonemal complex, supporting overexpression as a route
      to the same lesion.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:31866047
      reference_title: "SYCP2 Translocation-Mediated Dysregulation and Frameshift Variants Cause Human Male Infertility."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Modeling the dysregulation in budding yeast resulted in disrupted
        structural integrity of the synaptonemal complex, a common cause of
        defective spermatogenesis in mammals.
      explanation: >-
        A heterologous model shows that the dysregulation, not merely the loss,
        disrupts complex integrity.
- name: Synaptonemal Complex Axial Element Assembly Failure
  conforms_to: "meiotic_prophase_failure#Synaptonemal Complex Assembly"
  biological_scale: CELLULAR
  description: >-
    SYCP2 heterodimerizes with SYCP3 through a conserved coiled-coil domain and
    is the primary determinant of the axial/lateral elements: in a mouse mutant
    lacking that domain, mutant SYCP2 still localizes to axial chromosomal cores
    but SYCP3 does not, showing that SYCP2 is required to incorporate SYCP3 into
    the complex. Loss of the axial element removes the scaffold on which synapsis
    depends.
  cell_types:
  - preferred_term: primary spermatocyte
    term:
      id: CL:0000656
      label: primary spermatocyte
  biological_processes:
  - preferred_term: synaptonemal complex assembly
    term:
      id: GO:0007130
      label: synaptonemal complex assembly
    modifier: DECREASED
  evidence:
  - reference: PMID:16717126
    reference_title: "Mouse SYCP2 is required for synaptonemal complex assembly and chromosomal synapsis during male meiosis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      the mutant SYCP2 protein localizes to axial chromosomal cores in both
      spermatocytes and fetal oocytes, but SYCP3 does not, demonstrating that
      SYCP2 is a primary determinant of AEs/LEs and, thus, is required for the
      incorporation of SYCP3 into SCs
    explanation: >-
      Establishes the hierarchy within the axial element: SYCP2 is upstream of
      SYCP3 incorporation, which is why its loss is not equivalent to SYCP3 loss.
  - reference: PMID:16717126
    reference_title: "Mouse SYCP2 is required for synaptonemal complex assembly and chromosomal synapsis during male meiosis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      An evolutionarily conserved coiled coil domain in SYCP2 is required for
      binding to SYCP3.
    explanation: >-
      Identifies the domain mediating the SYCP2-SYCP3 interaction. The quote is
      trimmed to the domain-mapping result so that this IN_VITRO item does not
      carry the "both in vitro and in vivo" clause belonging to the companion
      in vivo finding.
  downstream:
  - target: Homologous Chromosome Synapsis Failure and Meiotic Arrest
    description: >-
      Without assembled axial/lateral elements, homologous chromosomes cannot
      synapse, and affected spermatocytes arrest in meiotic prophase.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:16717126
      reference_title: "Mouse SYCP2 is required for synaptonemal complex assembly and chromosomal synapsis during male meiosis."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        males are sterile because of a block in meiosis, whereas females are
        subfertile with sharply reduced litter size
      explanation: >-
        Links axial-element failure to a meiotic block, with the sexual dimorphism
        that also characterizes the human phenotype.
- name: Homologous Chromosome Synapsis Failure and Meiotic Arrest
  biological_scale: CELLULAR
  description: >-
    Homologous chromosomes fail to synapse and spermatocytes arrest in meiotic
    prophase I. In the one human testicular study cited here, histology,
    immunofluorescence and meiotic chromosome spreads placed the arrest at the
    zygotene stage. In the mouse, arrest is accompanied by spermatocyte
    apoptosis.
  cell_types:
  - preferred_term: spermatocyte
    term:
      id: CL:0000017
      label: spermatocyte
  biological_processes:
  - preferred_term: homologous chromosome pairing at meiosis
    term:
      id: GO:0007129
      label: homologous chromosome pairing at meiosis
    modifier: DECREASED
  - preferred_term: apoptotic process
    term:
      id: GO:0006915
      label: apoptotic process
    modifier: INCREASED
  evidence:
  - reference: PMID:37337432
    reference_title: "A homozygous frameshift variant in SYCP2 caused meiotic arrest and non-obstructive azoospermia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      HE, IF, and meiotic chromosomal spread analyses demonstrated that
      spermatogenesis was arrested at the zygotene stage in the proband with NOA.
    explanation: >-
      The only human histological localization of the arrest cited here, and the
      reason this entry does not claim a pachytene-stage arrest.
  - reference: PMID:39202451
    reference_title: "Novel Loss-of-Function SYCP2 Variants in Infertile Males Upgrade the Gene-Disease Clinical Validity Classification for SYCP2 and Male Infertility to Strong."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      mice lacking the coiled-coil domain of Sycp2 exhibit impaired homologous
      chromosome synapsis, leading to spermatocyte apoptosis and male-specific
      infertility
    explanation: >-
      Supports the apoptotic elimination of arrested spermatocytes, evidenced in
      mouse rather than in human tissue.
  downstream:
  - target: Spermatogenic Failure
    description: >-
      Elimination of arrested spermatocytes depletes the post-meiotic germ-cell
      pool, producing reduced or absent sperm output.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:37337432
      reference_title: "A homozygous frameshift variant in SYCP2 caused meiotic arrest and non-obstructive azoospermia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Mutations in synaptonemal complex (SC)-associated genes could cause
        meiotic arrest and NOA.
      explanation: >-
        States the causal route from synaptonemal-complex-gene mutation through
        meiotic arrest to non-obstructive azoospermia.
- name: Spermatogenic Failure
  conforms_to: "meiotic_prophase_failure#Spermatogenic Arrest and Non-Obstructive Azoospermia"
  biological_scale: ORGANISM
  description: >-
    The clinical endpoint is male infertility across a severity spectrum:
    oligoasthenozoospermia, cryptozoospermia, and non-obstructive azoospermia
    with meiotic maturation arrest on testicular histology. The phenotype is
    male-limited in the human reports; the mouse counterpart is sexually
    dimorphic, with sterile males and subfertile females.
  biological_processes:
  - preferred_term: male gamete generation
    term:
      id: GO:0048232
      label: male gamete generation
    modifier: DECREASED
  evidence:
  - reference: PMID:31866047
    reference_title: "SYCP2 Translocation-Mediated Dysregulation and Frameshift Variants Cause Human Male Infertility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      provides evidence of SYCP2-mediated male infertility in humans
    explanation: >-
      The paper's own summary of what it establishes about the human phenotype.
phenotypes:
- name: Male Infertility
  category: Reproductive
  phenotype_term:
    preferred_term: Male infertility
    term:
      id: HP:0003251
      label: Male infertility
  description: >-
    Infertility is the presenting and defining feature. No frequency band is
    asserted: every reported individual was ascertained through an infertility
    workup, so the observed 100% is an artefact of ascertainment rather than a
    measured penetrance, and the supporting snippet establishes the association
    rather than a band.
  evidence:
  - reference: PMID:31866047
    reference_title: "SYCP2 Translocation-Mediated Dysregulation and Frameshift Variants Cause Human Male Infertility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      provides evidence of SYCP2-mediated male infertility in humans
    explanation: Establishes male infertility as the human phenotype of this gene.
- name: Azoospermia
  category: Reproductive
  description: >-
    Non-obstructive azoospermia with meiotic arrest is the severe end of the
    spectrum.
  phenotype_term:
    preferred_term: Azoospermia
    term:
      id: HP:0000027
      label: Azoospermia
  evidence:
  - reference: PMID:37337432
    reference_title: "A homozygous frameshift variant in SYCP2 caused meiotic arrest and non-obstructive azoospermia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Herein, we showed a homozygous loss-of-function variant in SYCP2
      (c.2689_2690insT) in an NOA-affected patient.
    explanation: Documents non-obstructive azoospermia in a SYCP2 patient.
- name: Oligozoospermia
  category: Reproductive
  description: >-
    Reduced sperm concentration, including the extreme form cryptozoospermia and
    severe oligozoospermia in the index translocation subject.
  phenotype_term:
    preferred_term: Oligozoospermia
    term:
      id: HP:0000798
      label: Oligozoospermia
  evidence:
  - reference: PMID:31866047
    reference_title: "SYCP2 Translocation-Mediated Dysregulation and Frameshift Variants Cause Human Male Infertility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      One such subject, DGAP230, has severe oligozoospermia and
      46,XY,t(20;22)(q13.3;q11.2).
    explanation: Documents severe oligozoospermia in the index subject.
- name: Reduced Sperm Motility
  category: Reproductive
  description: >-
    Three unrelated patients with heterozygous SYCP2 loss-of-function variants
    presented with oligoasthenozoospermia, i.e. reduced count together with
    reduced motility.
  phenotype_term:
    preferred_term: Reduced sperm motility
    term:
      id: HP:0012207
      label: Reduced sperm motility
  evidence:
  - reference: PMID:39202451
    reference_title: "Novel Loss-of-Function SYCP2 Variants in Infertile Males Upgrade the Gene-Disease Clinical Validity Classification for SYCP2 and Male Infertility to Strong."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This study investigates the genetic cause of infertility for three unrelated
      Chinese patients with oligoasthenozoospermia.
    explanation: >-
      Documents the asthenozoospermic component of the phenotype in three
      unrelated patients.
- name: Abnormal Spermatogenesis
  category: Reproductive
  description: >-
    Testicular histology shows meiotic maturation arrest rather than an
    obstructive or post-meiotic lesion.
  phenotype_term:
    preferred_term: Abnormal spermatogenesis
    term:
      id: HP:0008669
      label: Abnormal spermatogenesis
  evidence:
  - reference: PMID:37337432
    reference_title: "A homozygous frameshift variant in SYCP2 caused meiotic arrest and non-obstructive azoospermia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      HE, IF, and meiotic chromosomal spread analyses demonstrated that
      spermatogenesis was arrested at the zygotene stage in the proband with NOA.
    explanation: Documents arrested spermatogenesis on testicular histology.
genetic:
- name: SYCP2
  gene_term:
    preferred_term: SYCP2
    term:
      id: hgnc:11490
      label: SYCP2
  association: Heterozygous or homozygous loss-of-function variants, and translocation-mediated overexpression
  relationship_type: CAUSATIVE
  features: >-
    Reported lesions fall into two mechanistically opposite classes. The larger
    class is frameshift loss-of-function alleles: three heterozygous frameshifts
    in the original report, three further novel heterozygous LOF variants
    (c.89dup, c.946_947del, c.4378_4379del) in a later independent series, and
    one homozygous insertion (c.2689_2690insT). The second class is
    overexpression driven by a de novo balanced translocation through enhancer
    adoption. Gene-disease clinical validity for SYCP2 and autosomal dominant
    male infertility was assessed under the ClinGen Gene-Disease Validity
    framework as "on the border of limited and moderate", and was subsequently
    upgraded to "strong" once the additional cases were included — a level of
    evidence-strength metadata the dismech EvidenceItem model cannot currently
    carry in a structured slot.
  evidence:
  - reference: PMID:39202451
    reference_title: "Novel Loss-of-Function SYCP2 Variants in Infertile Males Upgrade the Gene-Disease Clinical Validity Classification for SYCP2 and Male Infertility to Strong."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Collectively, this updated assessment of the genetic and experimental
      evidence upgrades the gene-disease association strength of SYCP2 and
      autosomal dominant male infertility from on the border of limited and
      moderate to strong.
    explanation: >-
      Records the ClinGen-framework validity classification and the upgrade, which
      is the best available summary statement of how strong this gene-disease
      relationship is.
  - reference: PMID:31866047
    reference_title: "SYCP2 Translocation-Mediated Dysregulation and Frameshift Variants Cause Human Male Infertility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      this investigation illustrates the power of precision cytogenetics for
      annotation of the infertile genome, suggests that these mechanisms should be
      considered as an alternative etiology to that of segregation of unbalanced
      gametes in infertile men harboring a BCA
    explanation: >-
      Establishes the translocation-mediated dysregulation route and distinguishes
      it from the unbalanced-gamete explanation usually invoked for a balanced
      chromosomal aberration.
diagnosis:
- name: Exome Sequencing with Male Infertility Gene Panel
  description: >-
    Whole exome sequencing with Sanger confirmation identifies the causal SYCP2
    variants. The ClinGen-framework upgrade to "strong" clinical validity is what
    qualifies SYCP2 for inclusion on diagnostic male infertility gene panels and
    for prioritization in exome and genome analyses, so the classification has a
    direct diagnostic consequence.
  diagnosis_term:
    preferred_term: Genetic Testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:39202451
    reference_title: "Novel Loss-of-Function SYCP2 Variants in Infertile Males Upgrade the Gene-Disease Clinical Validity Classification for SYCP2 and Male Infertility to Strong."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The reclassification improves SYCP2 variant interpretation and qualifies it
      for the inclusion on diagnostic male infertility gene panels and
      prioritization in whole exome or genome studies for related phenotypes.
    explanation: >-
      States the diagnostic consequence of the validity reclassification.
- name: Cytogenetic Analysis for Balanced Chromosomal Rearrangement
  description: >-
    In an infertile man carrying a balanced chromosomal aberration, the default
    explanation is production of unbalanced gametes. The SYCP2 index case shows
    that a balanced rearrangement can instead act by dysregulating a fertility
    gene at a breakpoint, which changes what a cytogenetic finding means and
    argues for looking at genes near the breakpoints.
  diagnosis_term:
    preferred_term: Genetic Testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:31866047
    reference_title: "SYCP2 Translocation-Mediated Dysregulation and Frameshift Variants Cause Human Male Infertility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      While BCAs may reduce fertility by production of unbalanced gametes, a
      chromosomal rearrangement may also disrupt or dysregulate genes important in
      fertility.
    explanation: >-
      States the alternative interpretation of a balanced rearrangement in an
      infertile man.
treatments:
- name: Microdissection Testicular Sperm Extraction with ICSI
  description: >-
    The primary management pathway for non-obstructive azoospermia due to
    meiotic arrest. Microsurgical testicular sperm extraction searches the testis
    for focal regions of residual spermatogenesis, with higher yield and less
    tissue removal than conventional biopsy; retrieved sperm are used for
    intracytoplasmic sperm injection. It is squarely in scope here because
    residual sperm production is documented in this disorder: reported patients
    span oligoasthenozoospermia and cryptozoospermia as well as complete
    azoospermia.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: sperm retrieval
    term:
      id: NCIT:C94427
      label: Sperm Retrieval
  target_mechanisms:
  - target: Spermatogenic Failure
    treatment_effect: BYPASSES
    description: >-
      Retrieval plus ICSI circumvents the failure of sperm output rather than
      correcting the meiotic defect that causes it. Any sperm recovered still
      derive from spermatocytes that completed meiosis.
  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, the presentation at the severe end of this
      disorder's spectrum.
  notes: >-
    Evidence is for the procedure in non-obstructive azoospermia generally, not
    for SYCP2 carriers specifically; no cited source reports retrieval rates
    stratified by SYCP2 genotype. Given that the underlying lesion is a meiotic
    arrest, retrieval success in this genotype should not be assumed to match
    that of obstructive or post-meiotic causes.
- name: Genetic Counseling
  description: >-
    Counseling is complicated by the unresolved mode of inheritance: recurrence
    risk differs substantially depending on whether heterozygous
    loss-of-function is sufficient. The reported recessive pedigree, in which
    heterozygous carrier parents reproduced naturally, is directly relevant to
    what a carrier is told.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:37337432
    reference_title: "A homozygous frameshift variant in SYCP2 caused meiotic arrest and non-obstructive azoospermia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      And this variant was inherited from heterozygous parental carriers by
      natural reproduction.
    explanation: >-
      The observation that bears directly on recurrence-risk counseling for
      heterozygous carriers.
animal_models:
- species: Mouse
  genotype: Sycp2 allele lacking the SYCP3-binding coiled-coil domain, homozygous
  description: >-
    A targeted mouse allele deleting the evolutionarily conserved coiled-coil
    domain through which SYCP2 binds SYCP3. It is the source of the mechanistic
    hierarchy this entry curates: mutant SYCP2 still reaches axial chromosomal
    cores while SYCP3 does not, showing SYCP2 is the primary determinant of the
    axial element rather than an equal partner of SYCP3.
  genes:
  - preferred_term: SYCP2
    term:
      id: hgnc:11490
      label: SYCP2
  publication: PMID:16717126
  modeled_mechanisms:
  - target: Synaptonemal Complex Axial Element Assembly Failure
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >-
      Reproduces the failure of axial/lateral element formation that defines this
      node, and additionally establishes the SYCP2-before-SYCP3 dependency.
    limitations: >-
      The engineered allele is a domain deletion, whereas the reported human
      alleles are frameshift truncations or, in one case, translocation-driven
      overexpression; the model therefore does not test whether human alleles act
      by the same route, and cannot model the overexpression trigger at all.
    readouts:
    - name: Axial/lateral element formation in spermatocytes
      target: Synaptonemal Complex Axial Element Assembly Failure
      direction: ABOLISHED
      interpretation: >-
        Absence of axial/lateral elements and of chromosomal synapsis in mutant
        spermatocytes.
      evidence:
      - reference: PMID:16717126
        reference_title: "Mouse SYCP2 is required for synaptonemal complex assembly and chromosomal synapsis during male meiosis."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Sycp2 mutant spermatocytes exhibit failure in the formation of AEs and
          chromosomal synapsis.
        explanation: The histological measurement behind this readout.
    evidence:
    - reference: PMID:16717126
      reference_title: "Mouse SYCP2 is required for synaptonemal complex assembly and chromosomal synapsis during male meiosis."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        the mutant SYCP2 protein localizes to axial chromosomal cores in both
        spermatocytes and fetal oocytes, but SYCP3 does not, demonstrating that
        SYCP2 is a primary determinant of AEs/LEs and, thus, is required for the
        incorporation of SYCP3 into SCs
      explanation: >-
        Supports treating this model as informative for the axial-element node,
        and supplies the dependency ordering.
  - target: Spermatogenic Failure
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >-
      Male mice are sterile from a meiotic block, matching the severe end of the
      human phenotype.
    limitations: >-
      The phenotype is sexually dimorphic in the mouse, with subfertile females,
      whereas the human disorder as reported is male-limited and no female
      phenotype has been described. The mouse is also all-or-nothing, so it does
      not model the oligoasthenozoospermic and cryptozoospermic presentations that
      make up much of the human spectrum.
    evidence:
    - reference: PMID:16717126
      reference_title: "Mouse SYCP2 is required for synaptonemal complex assembly and chromosomal synapsis during male meiosis."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        males are sterile because of a block in meiosis, whereas females are
        subfertile with sharply reduced litter size
      explanation: >-
        PARTIAL because the same sentence that establishes the male phenotype also
        records a female phenotype the human disorder has not been shown to have.
discussions:
- discussion_id: gap_sycp2_mode_of_inheritance_contested
  kind: KNOWLEDGE_GAP
  attaches_to:
  - pathophysiology#SYCP2 Loss-of-Function Variants
  - disease#SYCP2-related spermatogenic failure
  prompt: >-
    Is SYCP2-related spermatogenic failure autosomal dominant, autosomal
    recessive, or both — and if heterozygous loss of function is pathogenic, why
    were the heterozygous parents in the reported recessive pedigree fertile?
  rationale: >-
    This is a live disagreement in the primary literature, not a gap in
    reporting. PMID:31866047 and PMID:39202451 identify heterozygous frameshift
    alleles in infertile men and, under the ClinGen framework, conclude that the
    aggregate evidence supports autosomal dominant inheritance strongly enough to
    put SYCP2 on diagnostic panels. PMID:37337432 reports a homozygous frameshift
    transmitted by heterozygous parents who conceived naturally, and concludes
    recessive inheritance "rather than an autosomal dominant pattern". Both
    cannot be unqualifiedly true of the same allele class. Reduced penetrance of
    heterozygous alleles would reconcile them, but no penetrance estimate exists,
    and the distinction determines recurrence-risk counseling and whether a
    heterozygous finding in an infertile man is reportable as causal.
  proposed_experiments:
  - experiment_id: exp_sycp2_heterozygote_fertility_cohort
    name: Semen phenotyping of obligate heterozygous carriers
    description: >-
      Systematically obtain semen analyses from the fertile heterozygous parents
      and other obligate carriers in reported SYCP2 pedigrees, to establish
      whether they are genuinely normozoospermic or subclinically affected.
    decision_criterion: >-
      Normal semen parameters in a series of obligate heterozygotes would argue
      that heterozygous loss of function is insufficient and support the recessive
      model. Subclinical oligozoospermia would support a dominant model with
      variable expressivity and reframe the disagreement as one about threshold,
      not mechanism.
  - experiment_id: exp_sycp2_burden_gnomad_penetrance
    name: Population burden of SYCP2 loss-of-function alleles
    description: >-
      Estimate the frequency of heterozygous SYCP2 loss-of-function alleles in
      large population reference cohorts not ascertained for infertility, and
      compare against the frequency in azoospermic and oligozoospermic case
      series.
    decision_criterion: >-
      A carrier frequency far exceeding the prevalence of SYCP2-attributable
      infertility would establish incomplete penetrance quantitatively and set an
      upper bound on the dominant model's contribution.
references:
- reference: PMID:16717126
  title: "Mouse SYCP2 is required for synaptonemal complex assembly and chromosomal synapsis during male meiosis."
- reference: PMID:31866047
  title: "SYCP2 Translocation-Mediated Dysregulation and Frameshift Variants Cause Human Male Infertility."
- reference: PMID:37337432
  title: "A homozygous frameshift variant in SYCP2 caused meiotic arrest and non-obstructive azoospermia."
- reference: PMID:39202451
  title: "Novel Loss-of-Function SYCP2 Variants in Infertile Males Upgrade the Gene-Disease Clinical Validity Classification for SYCP2 and Male Infertility to Strong."

📚

References & Deep Research

References

4

PMID:16717126

Mouse SYCP2 is required for synaptonemal complex assembly and chromosomal synapsis during male meiosis.

No top-level findings curated for this source.

PMID:31866047

SYCP2 Translocation-Mediated Dysregulation and Frameshift Variants Cause Human Male Infertility.

No top-level findings curated for this source.

PMID:37337432

A homozygous frameshift variant in SYCP2 caused meiotic arrest and non-obstructive azoospermia.

No top-level findings curated for this source.

PMID:39202451

Novel Loss-of-Function SYCP2 Variants in Infertile Males Upgrade the Gene-Disease Clinical Validity Classification for SYCP2 and Male Infertility to Strong.

No top-level findings curated for this source.

SYCP2-related spermatogenic failure

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