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 autosomal recessive 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.
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: 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.