Meiotic Prophase I Failure (Gametogenic Failure / Infertility)

name: Meiotic Gametogenic Failure Disorders
display_name: Meiotic Prophase I Failure (Gametogenic Failure / Infertility)
creation_date: "2026-06-13T00:00:00Z"
description: >-
  A group of reproductive disorders caused by defects in the
  machinery of meiotic prophase I — homolog pairing, synaptonemal complex
  assembly, and homologous recombination repair of programmed meiotic
  double-strand breaks. Failure to complete prophase I triggers the pachytene
  checkpoint, eliminating germ cells by apoptosis. The shared outcome is
  bilateral gametogenic failure, manifesting as primary ovarian insufficiency in
  46,XX individuals and non-obstructive azoospermia in 46,XY individuals; some
  genes additionally confer a somatic DNA-repair phenotype with cancer
  predisposition. Inheritance is autosomal recessive for most members but is not
  a criterion for membership: TEX11 is X-linked and hemizygous in affected men,
  and its phenotype is male-restricted with no ovarian or somatic counterpart.
grouping_basis:
- SHARED_MECHANISM
- SHARED_PATHWAY
grouping_rationale: >-
  Grouped on a shared meiotic mechanism: each member conforms to the
  meiotic_prophase_failure module (defective prophase I pairing/recombination ->
  pachytene checkpoint arrest -> germ cell apoptosis -> gametogenic failure).
  Members are kept as separate Disease entries because they disrupt different
  steps — synaptonemal complex assembly (SYCE1), sister-chromatid cohesion
  (STAG3), and recombination/replication-associated repair (MCM9, HROB) — and
  differ in whether a somatic cancer-predisposition phenotype accompanies the
  infertility. The criteria are NECESSARY_AND_SUFFICIENT: meiotic prophase-I
  failure both characterizes every member and flags further meiosis-gene
  infertility disorders as candidate members.
membership_criteria:
- description: >-
    A disorder is a meiotic gametogenic failure disorder if and only if it
    conforms to the meiotic prophase-failure module (a prophase I
    pairing/recombination defect causing checkpoint-mediated germ cell loss).
  criteria_semantics: NECESSARY_AND_SUFFICIENT
  logic:
    criterion_predicate: CONFORMS_TO_MODULE
    module: meiotic_prophase_failure#Pachytene Checkpoint Arrest and Germ Cell Apoptosis
    description: >-
      Conforms to the pachytene-checkpoint arrest / germ cell apoptosis node of
      the meiotic module.
members:
- member: SYCE1-related gametogenic failure
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      SYCE1 is a central-element component of the synaptonemal complex; its loss
      prevents homolog synapsis, causing primary ovarian insufficiency and
      azoospermia without a somatic phenotype.
    gene:
      preferred_term: SYCE1
      term:
        id: hgnc:28852
        label: SYCE1
- member: STAG3-related gametogenic failure
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      STAG3 is a meiosis-specific cohesin subunit required for sister-chromatid
      cohesion and axis formation; loss causes early prophase arrest with
      premature ovarian insufficiency.
    gene:
      preferred_term: STAG3
      term:
        id: hgnc:11356
        label: STAG3
- member: MCM9-related gametogenic failure
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      MCM9 functions in homologous recombination and mismatch-repair-associated
      processes; loss causes gametogenic failure together with a genomic-instability
      cancer-predisposition phenotype (the module's somatic branch).
    gene:
      preferred_term: MCM9
      term:
        id: hgnc:21484
        label: MCM9
- member: TEX11-related spermatogenic failure
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      TEX11 is the mammalian Zip4 orthologue and a subunit of the ZZS complex
      with SHOC1 and SPO16, which couples synaptonemal complex assembly to class
      I crossover formation. Its loss produces asynapsis together with a
      genome-wide reduction in crossovers, rather than either defect alone, and
      TEX11 binds SYCP2 in the synaptonemal complex lateral element, which is the
      proposed physical link between the two processes. Distinguished from every
      other member on two axes rather than one: it is the group's only X-linked
      member, hemizygous in affected men, and its phenotype is male-restricted,
      so it has no ovarian arm and no somatic DNA-repair or cancer phenotype.
    gene:
      preferred_term: TEX11
      term:
        id: hgnc:11733
        label: TEX11
- member: HROB-related gametogenic failure
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      HROB recruits the MCM8-MCM9 helicase to sites of recombinational repair;
      its loss phenocopies MCM9 deficiency with meiotic recombination failure and
      gametogenic failure.
    gene:
      preferred_term: HROB
      term:
        id: hgnc:28460
        label: HROB
notes: >-
  The differentiating axis is the prophase-I step affected (synapsis vs cohesion
  vs recombination/repair) and whether a somatic DNA-repair/cancer-predisposition
  phenotype accompanies the reproductive failure (MCM9/HROB vs SYCE1/STAG3).
  MONDO mapping: deliberately omitted. MONDO splits the reproductive readouts
  into separate sex-specific classes (spermatogenic failure MONDO:0004983;
  ovarian dysgenesis / premature ovarian insufficiency series) with no combined
  "meiotic prophase-I failure" parent spanning both sexes. This grouping is
  defined by the shared meiotic mechanism that underlies both, so no single
  MONDO class corresponds.