SPATA22-related gametogenic failure

Mendelian MONDO:0975843 Pathograph 15 Show in embeddings browser Primary ovarian insufficiency Male infertility Infertility disorder

SPATA22-related gametogenic failure is an autosomal recessive meiotic recombination disorder caused by biallelic loss-of-function variants in SPATA22. SPATA22 is a germ-cell-specific protein that forms an obligate heterodimer with MEIOB; the complex binds single-stranded DNA and associates with RPA at resected meiotic double-strand breaks. Without it, germ cells start meiotic recombination but cannot complete double-strand break repair or homolog synapsis, arrest in early meiotic prophase I and are lost. The same lesion presents as premature ovarian insufficiency in 46,XX individuals and as non-obstructive azoospermia with zygotene-like spermatogenic arrest in 46,XY individuals; the founding consanguineous family had affected members of both sexes.

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Inheritance

1
Autosomal recessive inheritance HP:0000007
Affected individuals carry homozygous or compound-heterozygous SPATA22 loss-of-function variants; two of the three reported families are consanguineous.
Autosomal recessive inheritance
Show evidence (3 references)
PMID:35285020 SUPPORT Human clinical
"We performed whole-exome sequencing (WES) in members of a consanguineous family with two POI and two NOA patients to screen for potential pathogenic variants for familial POI and NOA. And a homozygous variant in SPATA22 (c.400C>T:p.R134X) was identified."
A homozygous SPATA22 nonsense variant in a consanguineous family with affected women and men supports recessive inheritance.
PMID:35285020 SUPPORT Human clinical
"One additional compound heterozygous variant in SPATA22 (c.900+1G>A and c.31C>T:p.R11X) was found in one patient with sporadic POI and validated by minigene assay."
A second, compound-heterozygous genotype in an unrelated patient is consistent with biallelic (recessive) disease.
PMID:34392356 SUPPORT Human clinical
"A homozygous SPATA22 frameshift mutation (c.203del) was identified in a patient with non-obstructive azoospermia (NOA) from a consanguineous Pakistani family"
An independent homozygous SPATA22 loss-of-function allele in a second consanguineous family supports recessive inheritance.
◆

Subtypes

2
POF25 (premature ovarian failure 25, female presentation) MONDO:0975843
SPATA22 hgnc:30705 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in SPATA22 (hgnc:30705). hgnc:30705 is a gene from the HUGO Gene Nomenclature Committee.
The female presentation of biallelic SPATA22 loss: premature ovarian insufficiency, reported in two women of the founding consanguineous family and in one unrelated woman with sporadic POI.
Show evidence (1 reference)
PMID:35285020 SUPPORT Human clinical
"Thus, this is the first report identifying SPATA22 as the causative gene for human POI."
Establishes the SPATA22 gene-disease assertion for the female presentation this subtype row carries.
SPGF96 (spermatogenic failure 96, male presentation) MONDO:0975842
SPATA22 hgnc:30705 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in SPATA22 (hgnc:30705). hgnc:30705 is a gene from the HUGO Gene Nomenclature Committee.
The male presentation of biallelic SPATA22 loss: non-obstructive azoospermia with spermatogenesis arrested at a zygotene-like stage of meiotic prophase I, reported in the founding family and in a consanguineous Pakistani family.
Show evidence (2 references)
PMID:35285020 SUPPORT Human clinical
"Histological analysis and spermatocyte spreading assay demonstrated that the spermatogenesis was arrested at a zygotene-like stage in the proband with NOA."
Documents the male presentation, non-obstructive azoospermia from meiotic arrest, in the founding family.
PMID:34392356 SUPPORT Human clinical
"A homozygous SPATA22 frameshift mutation (c.203del) was identified in a patient with non-obstructive azoospermia (NOA) from a consanguineous Pakistani family"
An independent family with the male presentation.
⚙

Pathophysiology

5
Loss of MEIOB-SPATA22 single-stranded DNA binding
SPATA22 and MEIOB form an obligate meiosis-specific heterodimer that resembles RPA, binds single-stranded DNA and associates with RPA-coated single-stranded DNA at resected meiotic double-strand breaks. Purified human SPATA22 binds single-stranded DNA on its own, and the heterodimer binds it more strongly than either protein alone. The two proteins stabilize each other: Spata22-null meiocytes fail to localize MEIOB and make less of it, and the patient frameshift c.203del abolishes the SPATA22-MEIOB interaction. Biallelic SPATA22 loss therefore removes the complex from recombination intermediates.
SPATA22 hgnc:30705 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves SPATA22 (hgnc:30705). hgnc:30705 is a gene from the HUGO Gene Nomenclature Committee. MEIOB hgnc:28569 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves MEIOB (hgnc:28569). hgnc:28569 is a gene from the HUGO Gene Nomenclature Committee.
single-stranded DNA binding GO:0003697 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased single-stranded DNA binding (GO:0003697). GO:0003697 is a molecular function from the Gene Ontology.
Downstream
Failed meiotic recombination and homolog synapsis Without the MEIOB-SPATA22 complex on single-stranded DNA, meiotic double-strand breaks are formed but not repaired and homologs do not synapse.
Show evidence (6 references)
PMID:33812231 SUPPORT In vitro / ex vivo
"Here, we show that like MEIOB, SPATA22 resembles RPA subunits and binds ssDNA."
Direct biochemical evidence that SPATA22 itself has single-stranded DNA binding activity, the molecular function lost on biallelic loss.
PMID:40296718 SUPPORT In vitro / ex vivo
"The results show that hMEIOB has low ssDNA-binding affinity and stability alone, but hSPATA22 binds to ssDNA faster and more stably and promotes ssDNA condensation. Strong binding affinity and stability to ssDNA are present when the hMEIOB-hSPATA22 heterodimer is formed."
Confirms single-stranded DNA binding by the human SPATA22 protein and by the MEIOB-SPATA22 heterodimer.
PMID:28453612 SUPPORT In vitro / ex vivo
"We find that MEIOB and SPATA22 form an obligate complex and contain defined interaction domains."
Places SPATA22 in an obligate complex with MEIOB, so SPATA22 loss removes the complex.
+ 3 more references
Failed meiotic recombination and homolog synapsis
SPATA22-deficient germ cells initiate programmed meiotic double-strand breaks but cannot complete their repair. RPA foci form normally while RAD51 foci are not maintained, consistent with a defect in the presynaptic step, and homologous chromosomes fail to synapse.
germ cell CL:0000586 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves germ cell (CL:0000586). CL:0000586 is a cell type from the Cell Ontology.
reciprocal meiotic recombination GO:0007131 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased reciprocal meiotic recombination (GO:0007131). GO:0007131 is a biological process from the Gene Ontology. homologous chromosome pairing at meiosis GO:0007129 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased homologous chromosome pairing at meiosis (GO:0007129). GO:0007129 is a biological process from the Gene Ontology.
Downstream
Early meiotic prophase I arrest and germ cell loss
Show evidence (3 references)
PMID:22011390 SUPPORT Model organism
"The Spata22 gene is essential for one or more key events of early meiotic prophase, as homologous chromosomes of mutant germ cells do not achieve normal synapsis or repair meiotic DNA double-strand breaks."
In repro42 (Spata22 nonsense) mice, germ cells fail both synapsis and meiotic double-strand break repair.
PMID:28297563 SUPPORT Model organism
"Cytological examination confirms that germ cells do not progress beyond zygonema and meiotic arrest is linked to impairment of both synapsis and DNA repair."
An independent null Spata22 allele reproduces the synapsis and DNA repair defect.
PMID:25142975 SUPPORT Model organism
"These results suggest that both formation and maintenance of Rpa foci are independent of Spata22, and the maintenance, but not the formation, of Rad51 foci requires Spata22."
In Spata22-deficient rats, the recombination defect lies downstream of RPA loading, at maintenance of RAD51 on resected DNA.
Early meiotic prophase I arrest and germ cell loss
Germ cells of both sexes stall at a zygotene-like stage of meiotic prophase I and are subsequently lost. The arrest point is earlier than the pachytene stage named in the module node it conforms to; the shared claim is meiotic arrest followed by germ-cell elimination.
germ cell CL:0000586 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves germ cell (CL:0000586). CL:0000586 is a cell type from the Cell Ontology.
meiotic cell cycle GO:0051321 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased meiotic cell cycle (GO:0051321). GO:0051321 is a biological process from the Gene Ontology. apoptotic process GO:0006915 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased apoptotic process (GO:0006915). GO:0006915 is a biological process from the Gene Ontology.
Downstream
Ovarian germ cell depletion
Spermatogenic arrest
Show evidence (3 references)
PMID:32388826 SUPPORT Model organism
"shani mutant mice phenocopy Spata22-null and Meiob-null mice: mutant cells appear to form DSBs and initiate meiotic recombination, but are unable to complete DSB repair, leading to meiotic prophase arrest, apoptosis and sterility."
A third Spata22 mouse allele shows that unrepaired breaks lead to prophase arrest and apoptotic elimination of germ cells.
PMID:22011390 SUPPORT Model organism
"Gametogenesis is profoundly affected by the mutation, and germ cells in repro42 mutant mice do not progress beyond early meiotic prophase, with subsequent germ cell loss in both males and females."
Spata22 mutant germ cells of both sexes arrest in early prophase I and are lost.
PMID:35285020 SUPPORT Human clinical
"Histological analysis and spermatocyte spreading assay demonstrated that the spermatogenesis was arrested at a zygotene-like stage in the proband with NOA."
The same zygotene-like arrest is seen in testis tissue from a man with homozygous SPATA22 loss.
Ovarian germ cell depletion
In 46,XX individuals, oocyte loss during meiotic prophase depletes the ovarian reserve and presents as premature ovarian insufficiency.
oocyte CL:0000023 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves oocyte (CL:0000023). CL:0000023 is a cell type from the Cell Ontology.
female gamete generation GO:0007292 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased female gamete generation (GO:0007292). GO:0007292 is a biological process from the Gene Ontology.
Downstream
Premature ovarian insufficiency
Irregular menstruation
Oligomenorrhea
Secondary amenorrhea
Elevated follicle-stimulating hormone
Decreased anti-Mullerian hormone
Infertility
Show evidence (1 reference)
PMID:22011390 SUPPORT Model organism
"The N-ethyl-N-nitrosourea-induced repro42 mutation, identified by a forward genetics strategy, causes both male and female infertility, with no other apparent phenotypes."
Female Spata22 mutant mice are infertile, the model counterpart of the human ovarian phenotype.
Spermatogenic arrest
In 46,XY individuals, spermatocytes arrest at a zygotene-like stage, no post-meiotic cells are produced and the ejaculate contains no sperm.
spermatocyte CL:0000017 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves spermatocyte (CL:0000017). CL:0000017 is a cell type from the Cell Ontology.
male gamete generation GO:0048232 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased male gamete generation (GO:0048232). GO:0048232 is a biological process from the Gene Ontology.
Downstream
Non-obstructive azoospermia
Spermatogenesis maturation arrest
Infertility
Show evidence (1 reference)
PMID:35285020 SUPPORT Human clinical
"Histological analysis and spermatocyte spreading assay demonstrated that the spermatogenesis was arrested at a zygotene-like stage in the proband with NOA."
Spermatogenic arrest documented in testis tissue from an affected man.
⬡

Pathograph

Use Group by to collapse related nodes into one box. Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for SPATA22-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

9
Endocrine 2
Elevated follicle-stimulating hormone Elevated circulating follicle stimulating hormone level HP:0008232 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Elevated follicle-stimulating hormone, annotated with Elevated circulating follicle stimulating hormone level (HP:0008232). HP:0008232 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42098781 SUPPORT Human clinical
"Hormonal profiling revealed markedly elevated basal FSH levels (> 40 IU/L) and significantly diminished AMH levels (< 1.1 ng/ml) in all affected individuals."
Markedly elevated basal FSH was found in every affected woman.
Context-specific annotations (1)
FEMALE
Decreased anti-Mullerian hormone Decreased circulating antimullerian hormone circulation HP:0031103 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased anti-Mullerian hormone, annotated with Decreased circulating antimullerian hormone circulation (HP:0031103). HP:0031103 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42098781 SUPPORT Human clinical
"Hormonal profiling revealed markedly elevated basal FSH levels (> 40 IU/L) and significantly diminished AMH levels (< 1.1 ng/ml) in all affected individuals."
Diminished AMH was found in every affected woman.
Context-specific annotations (1)
FEMALE
Genitourinary 7
Premature ovarian insufficiency HP:0008209 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Premature ovarian insufficiency (HP:0008209). HP:0008209 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:35285020 SUPPORT Human clinical
"We performed whole-exome sequencing (WES) in members of a consanguineous family with two POI and two NOA patients to screen for potential pathogenic variants for familial POI and NOA."
Two women in the founding SPATA22 family had premature ovarian insufficiency.
PMID:35285020 SUPPORT Human clinical
"One additional compound heterozygous variant in SPATA22 (c.900+1G>A and c.31C>T:p.R11X) was found in one patient with sporadic POI and validated by minigene assay."
A further, unrelated woman with compound-heterozygous SPATA22 variants had premature ovarian insufficiency.
PMID:42098781 SUPPORT Human clinical
"Through genetic screening, we identified an independent POI pedigree with four affected infertile female members (III-1, III-2, III-3, and III-4)."
Four women carrying the c.31C>T and c.900+1G>A SPATA22 variants had premature ovarian insufficiency.
Context-specific annotations (1)
FEMALE
Non-obstructive azoospermia HP:0011961 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Non-obstructive azoospermia (HP:0011961). HP:0011961 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:35285020 SUPPORT Human clinical
"We performed whole-exome sequencing (WES) in members of a consanguineous family with two POI and two NOA patients to screen for potential pathogenic variants for familial POI and NOA."
Two men in the founding SPATA22 family had non-obstructive azoospermia.
PMID:34392356 SUPPORT Human clinical
"A homozygous SPATA22 frameshift mutation (c.203del) was identified in a patient with non-obstructive azoospermia (NOA) from a consanguineous Pakistani family"
An independent homozygous SPATA22 patient with non-obstructive azoospermia.
Context-specific annotations (1)
MALE
Spermatogenesis maturation arrest HP:0031038 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Spermatogenesis maturation arrest (HP:0031038). HP:0031038 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35285020 SUPPORT Human clinical
"Histological analysis and spermatocyte spreading assay demonstrated that the spermatogenesis was arrested at a zygotene-like stage in the proband with NOA."
Direct histological and cytological documentation of meiotic maturation arrest.
Context-specific annotations (1)
MALE
Irregular menstruation HP:0000858 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Irregular menstruation (HP:0000858). HP:0000858 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42098781 SUPPORT Human clinical
"All affected individuals presented with the core clinical manifestations of POI, including irregular menstrual cycles, oligomenorrhea, and secondary amenorrhea."
Irregular menstrual cycles were reported in every affected woman.
Context-specific annotations (1)
FEMALE
Oligomenorrhea HP:0000876 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Oligomenorrhea (HP:0000876). HP:0000876 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42098781 SUPPORT Human clinical
"All affected individuals presented with the core clinical manifestations of POI, including irregular menstrual cycles, oligomenorrhea, and secondary amenorrhea."
Oligomenorrhea is named among the core manifestations in the affected women.
Context-specific annotations (1)
FEMALE
Secondary amenorrhea HP:0000869 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Secondary amenorrhea (HP:0000869). HP:0000869 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42098781 SUPPORT Human clinical
"All affected individuals presented with the core clinical manifestations of POI, including irregular menstrual cycles, oligomenorrhea, and secondary amenorrhea."
Secondary amenorrhea is named among the core manifestations in the affected women.
Context-specific annotations (1)
FEMALE
Infertility HP:0000789 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Infertility (HP:0000789). HP:0000789 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:42098781 SUPPORT Human clinical
"in a POI family without known causes, where four affected individuals presented with infertility."
All four affected women in this pedigree were infertile.
PMID:34392356 SUPPORT Human clinical
"Two consanguineous Pakistani families with four patients (three men and one woman) suffering from primary infertility were recruited."
The SPATA22 homozygous man was one of the patients recruited for primary infertility; the other family in this study carries a MEIOB variant.
🧬

Genetic Associations

1
SPATA22 (Causative (Primary))
Gene: SPATA22 hgnc:30705 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is SPATA22 (hgnc:30705). hgnc:30705 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (2 references)
PMID:35285020 SUPPORT Human clinical
"Thus, this is the first report identifying SPATA22 as the causative gene for human POI."
Establishes SPATA22 as the causal gene for the ovarian presentation.
PMID:34392356 SUPPORT Human clinical
"Thus, our study suggests that SPATA22 and MEIOB may both be causative genes for human infertility."
An independent family supports SPATA22 as a cause of male infertility; the authors state the conclusion cautiously.
🔬

Biochemical Markers

2
Serum follicle-stimulating hormone (INCREASED)
Show evidence (1 reference)
PMID:42098781 SUPPORT Human clinical
"Hormonal profiling revealed markedly elevated basal FSH levels (> 40 IU/L) and significantly diminished AMH levels (< 1.1 ng/ml) in all affected individuals."
Reports elevated basal FSH in every affected woman.
Serum anti-Mullerian hormone (DECREASED)
Show evidence (1 reference)
PMID:42098781 SUPPORT Human clinical
"Hormonal profiling revealed markedly elevated basal FSH levels (> 40 IU/L) and significantly diminished AMH levels (< 1.1 ng/ml) in all affected individuals."
Reports diminished AMH in every affected woman.
{ }

Source YAML

click to show 
name: SPATA22-related gametogenic failure
creation_date: "2026-10-15T12:00:00Z"
category: Mendelian
description: >-
  SPATA22-related gametogenic failure is an autosomal recessive meiotic
  recombination disorder caused by biallelic loss-of-function variants in
  SPATA22. SPATA22 is a germ-cell-specific protein that forms an obligate
  heterodimer with MEIOB; the complex binds single-stranded DNA and associates
  with RPA at resected meiotic double-strand breaks. Without it, germ cells start
  meiotic recombination but cannot complete double-strand break repair or
  homolog synapsis, arrest in early meiotic prophase I and are lost. The same
  lesion presents as premature ovarian insufficiency in 46,XX individuals and as
  non-obstructive azoospermia with zygotene-like spermatogenic arrest in 46,XY
  individuals; the founding consanguineous family had affected members of both
  sexes.
disease_term:
  preferred_term: SPATA22-related gametogenic failure
  term:
    id: MONDO:0975843
    label: premature ovarian failure 25
parents:
- Primary ovarian insufficiency
- Male infertility
- Infertility disorder
synonyms:
- premature ovarian failure 25
- POF25
- spermatogenic failure 96
- SPGF96
- SPATA22 deficiency
notes: >-
  MONDO has no gene-level SPATA22 grouping class. It splits the presentations
  into MONDO:0975843 (premature ovarian failure 25; OMIM:621002) and
  MONDO:0975842 (spermatogenic failure 96; OMIM:621001), both naming SPATA22 as
  the causal gene. This entry follows the HFM1-, STAG3- and SYCE1-related
  gametogenic failure entries: one mechanism-first entry anchored on the ovarian
  term, with both MONDO classes carried as subtype rows, because the lesion, the
  MEIOB-SPATA22 recombination node and the meiotic arrest are shared and only
  the gamete lineage differs. A 2026 report (PMID:42098781) titles its POI
  pedigree "heterozygous", but the two variants it names, c.31C>T (p.Arg11Ter)
  and c.900+1G>A, are the same pair PMID:35285020 reported as compound
  heterozygous in a sporadic POI patient. The 2026 paper does not report their
  phase or per-individual segregation, so its human data are compatible with
  biallelic, recessive disease. Its claim that one variant suffices rests on a
  Spata22+/- mouse model, in which the authors also propose a non-meiotic
  granulosa-cell mechanism. That mechanism is not modelled here: the
  meiotic-arrest mechanism is the one supported by the biallelic human families
  and by the null mouse and rat models. The pedigree's clinical findings (four
  affected women with menstrual disturbance, raised FSH and low AMH) are
  recorded as POF25 phenotypes. No GeneReviews chapter covers SPATA22.
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Affected individuals carry homozygous or compound-heterozygous SPATA22
    loss-of-function variants; two of the three reported families are
    consanguineous.
  evidence:
  - reference: PMID:35285020
    reference_title: "Bi-allelic SPATA22 variants cause premature ovarian insufficiency and nonobstructive azoospermia due to meiotic arrest."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We performed whole-exome sequencing (WES) in members of a consanguineous
      family with two POI and two NOA patients to screen for potential
      pathogenic variants for familial POI and NOA. And a homozygous variant in
      SPATA22 (c.400C>T:p.R134X) was identified.
    explanation: >-
      A homozygous SPATA22 nonsense variant in a consanguineous family with
      affected women and men supports recessive inheritance.
  - reference: PMID:35285020
    reference_title: "Bi-allelic SPATA22 variants cause premature ovarian insufficiency and nonobstructive azoospermia due to meiotic arrest."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      One additional compound heterozygous variant in SPATA22 (c.900+1G>A and
      c.31C>T:p.R11X) was found in one patient with sporadic POI and validated
      by minigene assay.
    explanation: >-
      A second, compound-heterozygous genotype in an unrelated patient is
      consistent with biallelic (recessive) disease.
  - reference: PMID:34392356
    reference_title: "Whole-exome sequencing of consanguineous families with infertile men and women identifies homologous mutations in SPATA22 and MEIOB."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A homozygous SPATA22 frameshift mutation (c.203del) was identified in a
      patient with non-obstructive azoospermia (NOA) from a consanguineous
      Pakistani family
    explanation: >-
      An independent homozygous SPATA22 loss-of-function allele in a second
      consanguineous family supports recessive inheritance.
has_subtypes:
- name: POF25
  display_name: POF25 (premature ovarian failure 25, female presentation)
  subtype_term:
    preferred_term: premature ovarian failure 25
    term:
      id: MONDO:0975843
      label: premature ovarian failure 25
  description: >-
    The female presentation of biallelic SPATA22 loss: premature ovarian
    insufficiency, reported in two women of the founding consanguineous family
    and in one unrelated woman with sporadic POI.
  genes:
  - preferred_term: SPATA22
    term:
      id: hgnc:30705
      label: SPATA22
  evidence:
  - reference: PMID:35285020
    reference_title: "Bi-allelic SPATA22 variants cause premature ovarian insufficiency and nonobstructive azoospermia due to meiotic arrest."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Thus, this is the first report identifying SPATA22 as the causative gene
      for human POI.
    explanation: >-
      Establishes the SPATA22 gene-disease assertion for the female
      presentation this subtype row carries.
- name: SPGF96
  display_name: SPGF96 (spermatogenic failure 96, male presentation)
  subtype_term:
    preferred_term: spermatogenic failure 96
    term:
      id: MONDO:0975842
      label: spermatogenic failure 96
  description: >-
    The male presentation of biallelic SPATA22 loss: non-obstructive
    azoospermia with spermatogenesis arrested at a zygotene-like stage of
    meiotic prophase I, reported in the founding family and in a
    consanguineous Pakistani family.
  genes:
  - preferred_term: SPATA22
    term:
      id: hgnc:30705
      label: SPATA22
  evidence:
  - reference: PMID:35285020
    reference_title: "Bi-allelic SPATA22 variants cause premature ovarian insufficiency and nonobstructive azoospermia due to meiotic arrest."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Histological analysis and spermatocyte spreading assay demonstrated that
      the spermatogenesis was arrested at a zygotene-like stage in the proband
      with NOA.
    explanation: >-
      Documents the male presentation, non-obstructive azoospermia from
      meiotic arrest, in the founding family.
  - reference: PMID:34392356
    reference_title: "Whole-exome sequencing of consanguineous families with infertile men and women identifies homologous mutations in SPATA22 and MEIOB."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A homozygous SPATA22 frameshift mutation (c.203del) was identified in a
      patient with non-obstructive azoospermia (NOA) from a consanguineous
      Pakistani family
    explanation: >-
      An independent family with the male presentation.
pathophysiology:
- name: Loss of MEIOB-SPATA22 single-stranded DNA binding
  conforms_to: "meiotic_prophase_failure#Homologous Recombination Repair of Meiotic DNA Breaks"
  biological_scale: MOLECULAR
  description: >-
    SPATA22 and MEIOB form an obligate meiosis-specific heterodimer that
    resembles RPA, binds single-stranded DNA and associates with RPA-coated
    single-stranded DNA at resected meiotic double-strand breaks. Purified human
    SPATA22 binds single-stranded DNA on its own, and the heterodimer binds it
    more strongly than either protein alone. The two proteins stabilize each
    other: Spata22-null meiocytes fail to localize MEIOB and make less of it,
    and the patient frameshift c.203del abolishes the SPATA22-MEIOB interaction.
    Biallelic SPATA22 loss therefore removes the complex from recombination
    intermediates.
  genes:
  - preferred_term: SPATA22
    term:
      id: hgnc:30705
      label: SPATA22
  - preferred_term: MEIOB
    term:
      id: hgnc:28569
      label: MEIOB
  molecular_functions:
  - preferred_term: single-stranded DNA binding
    term:
      id: GO:0003697
      label: single-stranded DNA binding
    modifier: DECREASED
  evidence:
  - reference: PMID:33812231
    reference_title: "The meiosis-specific MEIOB-SPATA22 complex cooperates with RPA to form a compacted mixed MEIOB/SPATA22/RPA/ssDNA complex."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Here, we show that like MEIOB, SPATA22 resembles RPA subunits and binds
      ssDNA.
    explanation: >-
      Direct biochemical evidence that SPATA22 itself has single-stranded DNA
      binding activity, the molecular function lost on biallelic loss.
  - reference: PMID:40296718
    reference_title: "New feature of hMEIOB and hSPATA22 binding to ssDNA from a single-molecule perspective."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The results show that hMEIOB has low ssDNA-binding affinity and stability
      alone, but hSPATA22 binds to ssDNA faster and more stably and promotes
      ssDNA condensation. Strong binding affinity and stability to ssDNA are
      present when the hMEIOB-hSPATA22 heterodimer is formed.
    explanation: >-
      Confirms single-stranded DNA binding by the human SPATA22 protein and by
      the MEIOB-SPATA22 heterodimer.
  - reference: PMID:28453612
    reference_title: "Meiosis-specific proteins MEIOB and SPATA22 cooperatively associate with the single-stranded DNA-binding replication protein A complex and DNA double-strand breaks."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We find that MEIOB and SPATA22 form an obligate complex and contain
      defined interaction domains.
    explanation: >-
      Places SPATA22 in an obligate complex with MEIOB, so SPATA22 loss removes
      the complex.
  - reference: PMID:28453612
    reference_title: "Meiosis-specific proteins MEIOB and SPATA22 cooperatively associate with the single-stranded DNA-binding replication protein A complex and DNA double-strand breaks."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Furthermore, MEIOB and SPATA22 are recruited to induced DNA double-strand
      breaks (DSBs) together but not alone.
    explanation: >-
      The complex is recruited to double-strand breaks only as a pair, which is
      why loss of SPATA22 removes MEIOB function at breaks as well.
  - reference: PMID:28297563
    reference_title: "Spermatogenesis associated 22 is required for DNA repair and synapsis of homologous chromosomes in mouse germ cells."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Analysis of Spata22Gt/Gt meiocytes confirms that SPATA22 is required for
      localization of MEIOB but not RPA (two proteins known to interact with
      SPATA22), and immunoblotting corroborates that production of MEIOB is
      indeed decreased in the absence of SPATA22.
    explanation: >-
      In null mouse meiocytes, SPATA22 loss also depletes and mislocalizes its
      partner MEIOB.
  - reference: PMID:34392356
    reference_title: "Whole-exome sequencing of consanguineous families with infertile men and women identifies homologous mutations in SPATA22 and MEIOB."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The SPATA22 mutation destroyed the interaction with MEIOB.
    explanation: >-
      The patient frameshift allele was tested in cultured cells and abolished
      binding to MEIOB, linking the human variant to loss of the complex.
  downstream:
  - target: Failed meiotic recombination and homolog synapsis
    causal_link_type: DIRECT
    description: >-
      Without the MEIOB-SPATA22 complex on single-stranded DNA, meiotic
      double-strand breaks are formed but not repaired and homologs do not
      synapse.
    evidence:
    - reference: PMID:34392356
      reference_title: "Whole-exome sequencing of consanguineous families with infertile men and women identifies homologous mutations in SPATA22 and MEIOB."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: BACKGROUND
      snippet: >-
        Meiob and Spata22 knockout mice have the same phenotypes: mutant
        spermatocytes can initiate meiotic recombination but are unable to
        complete DSB repair, leading to crossover formation failure, meiotic
        prophase arrest, and sterility.
      explanation: >-
        Background statement of the mouse knockout phenotype: loss of either
        partner leaves meiotic double-strand breaks unrepaired.
- name: Failed meiotic recombination and homolog synapsis
  conforms_to: "meiotic_prophase_failure#Homologous Recombination Repair of Meiotic DNA Breaks"
  biological_scale: CELLULAR
  description: >-
    SPATA22-deficient germ cells initiate programmed meiotic double-strand
    breaks but cannot complete their repair. RPA foci form normally while RAD51
    foci are not maintained, consistent with a defect in the presynaptic step,
    and homologous chromosomes fail to synapse.
  cell_types:
  - preferred_term: germ cell
    term:
      id: CL:0000586
      label: germ cell
  biological_processes:
  - preferred_term: reciprocal meiotic recombination
    term:
      id: GO:0007131
      label: reciprocal meiotic recombination
    modifier: DECREASED
  - preferred_term: homologous chromosome pairing at meiosis
    term:
      id: GO:0007129
      label: homologous chromosome pairing at meiosis
    modifier: DECREASED
  evidence:
  - reference: PMID:22011390
    reference_title: "Spata22, a novel vertebrate-specific gene, is required for meiotic progress in mouse germ cells."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      The Spata22 gene is essential for one or more key events of early meiotic
      prophase, as homologous chromosomes of mutant germ cells do not achieve
      normal synapsis or repair meiotic DNA double-strand breaks.
    explanation: >-
      In repro42 (Spata22 nonsense) mice, germ cells fail both synapsis and
      meiotic double-strand break repair.
  - reference: PMID:28297563
    reference_title: "Spermatogenesis associated 22 is required for DNA repair and synapsis of homologous chromosomes in mouse germ cells."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Cytological examination confirms that germ cells do not progress beyond
      zygonema and meiotic arrest is linked to impairment of both synapsis and
      DNA repair.
    explanation: >-
      An independent null Spata22 allele reproduces the synapsis and DNA repair
      defect.
  - reference: PMID:25142975
    reference_title: "Genetic evidence suggests that Spata22 is required for the maintenance of Rad51 foci in mammalian meiosis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      These results suggest that both formation and maintenance of Rpa foci are
      independent of Spata22, and the maintenance, but not the formation, of
      Rad51 foci requires Spata22.
    explanation: >-
      In Spata22-deficient rats, the recombination defect lies downstream of RPA
      loading, at maintenance of RAD51 on resected DNA.
  downstream:
  - target: Early meiotic prophase I arrest and germ cell loss
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:28297563
      reference_title: "Spermatogenesis associated 22 is required for DNA repair and synapsis of homologous chromosomes in mouse germ cells."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Cytological examination confirms that germ cells do not progress beyond
        zygonema and meiotic arrest is linked to impairment of both synapsis and
        DNA repair.
      explanation: >-
        The authors attribute the zygotene arrest to the synapsis and DNA repair
        failure.
- name: Early meiotic prophase I arrest and germ cell loss
  conforms_to: "meiotic_prophase_failure#Pachytene Checkpoint Arrest and Germ Cell Apoptosis"
  biological_scale: CELLULAR
  description: >-
    Germ cells of both sexes stall at a zygotene-like stage of meiotic prophase
    I and are subsequently lost. The arrest point is earlier than the pachytene
    stage named in the module node it conforms to; the shared claim is meiotic
    arrest followed by germ-cell elimination.
  cell_types:
  - preferred_term: germ cell
    term:
      id: CL:0000586
      label: germ cell
  biological_processes:
  - preferred_term: meiotic cell cycle
    term:
      id: GO:0051321
      label: meiotic cell cycle
    modifier: DECREASED
  - preferred_term: apoptotic process
    term:
      id: GO:0006915
      label: apoptotic process
    modifier: INCREASED
  evidence:
  - reference: PMID:32388826
    reference_title: "shani mutation in mouse affects splicing of Spata22 and leads to impaired meiotic recombination."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      shani mutant mice phenocopy Spata22-null and Meiob-null mice: mutant cells
      appear to form DSBs and initiate meiotic recombination, but are unable to
      complete DSB repair, leading to meiotic prophase arrest, apoptosis and
      sterility.
    explanation: >-
      A third Spata22 mouse allele shows that unrepaired breaks lead to
      prophase arrest and apoptotic elimination of germ cells.
  - reference: PMID:22011390
    reference_title: "Spata22, a novel vertebrate-specific gene, is required for meiotic progress in mouse germ cells."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Gametogenesis is profoundly affected by the mutation, and germ cells in
      repro42 mutant mice do not progress beyond early meiotic prophase, with
      subsequent germ cell loss in both males and females.
    explanation: >-
      Spata22 mutant germ cells of both sexes arrest in early prophase I and
      are lost.
  - reference: PMID:35285020
    reference_title: "Bi-allelic SPATA22 variants cause premature ovarian insufficiency and nonobstructive azoospermia due to meiotic arrest."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Histological analysis and spermatocyte spreading assay demonstrated that
      the spermatogenesis was arrested at a zygotene-like stage in the proband
      with NOA.
    explanation: >-
      The same zygotene-like arrest is seen in testis tissue from a man with
      homozygous SPATA22 loss.
  downstream:
  - target: Ovarian germ cell depletion
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:22011390
      reference_title: "Spata22, a novel vertebrate-specific gene, is required for meiotic progress in mouse germ cells."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Gametogenesis is profoundly affected by the mutation, and germ cells in
        repro42 mutant mice do not progress beyond early meiotic prophase, with
        subsequent germ cell loss in both males and females.
      explanation: >-
        Meiotic arrest is followed by germ-cell loss in females.
  - target: Spermatogenic arrest
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:22011390
      reference_title: "Spata22, a novel vertebrate-specific gene, is required for meiotic progress in mouse germ cells."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Gametogenesis is profoundly affected by the mutation, and germ cells in
        repro42 mutant mice do not progress beyond early meiotic prophase, with
        subsequent germ cell loss in both males and females.
      explanation: >-
        Meiotic arrest is followed by germ-cell loss in males, the cellular basis
        of spermatogenic arrest.
- name: Ovarian germ cell depletion
  conforms_to: "meiotic_prophase_failure#Ovarian Follicle Depletion and Primary Ovarian Insufficiency"
  biological_scale: TISSUE
  description: >-
    In 46,XX individuals, oocyte loss during meiotic prophase depletes the
    ovarian reserve and presents as premature ovarian insufficiency.
  cell_types:
  - preferred_term: oocyte
    term:
      id: CL:0000023
      label: oocyte
  biological_processes:
  - preferred_term: female gamete generation
    term:
      id: GO:0007292
      label: female gamete generation
    modifier: DECREASED
  evidence:
  - reference: PMID:22011390
    reference_title: "Spata22, a novel vertebrate-specific gene, is required for meiotic progress in mouse germ cells."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      The N-ethyl-N-nitrosourea-induced repro42 mutation, identified by a
      forward genetics strategy, causes both male and female infertility, with
      no other apparent phenotypes.
    explanation: >-
      Female Spata22 mutant mice are infertile, the model counterpart of the
      human ovarian phenotype.
  downstream:
  - target: Premature ovarian insufficiency
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:22011390
      reference_title: "Spata22, a novel vertebrate-specific gene, is required for meiotic progress in mouse germ cells."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        The N-ethyl-N-nitrosourea-induced repro42 mutation, identified by a
        forward genetics strategy, causes both male and female infertility, with
        no other apparent phenotypes.
      explanation: >-
        In Spata22 mutant mice, oocyte loss produces female infertility; the
        human counterpart of this ovarian failure is premature ovarian
        insufficiency, so the step is inferred across species.
  - target: Irregular menstruation
    causal_link_type: DIRECT
  - target: Oligomenorrhea
    causal_link_type: DIRECT
  - target: Secondary amenorrhea
    causal_link_type: DIRECT
  - target: Elevated follicle-stimulating hormone
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - loss of ovarian negative feedback on pituitary gonadotropin secretion
  - target: Decreased anti-Mullerian hormone
    causal_link_type: DIRECT
  - target: Infertility
    causal_link_type: DIRECT
- name: Spermatogenic arrest
  conforms_to: "meiotic_prophase_failure#Spermatogenic Arrest and Non-Obstructive Azoospermia"
  biological_scale: TISSUE
  description: >-
    In 46,XY individuals, spermatocytes arrest at a zygotene-like stage, no
    post-meiotic cells are produced and the ejaculate contains no sperm.
  cell_types:
  - preferred_term: spermatocyte
    term:
      id: CL:0000017
      label: spermatocyte
  biological_processes:
  - preferred_term: male gamete generation
    term:
      id: GO:0048232
      label: male gamete generation
    modifier: DECREASED
  evidence:
  - reference: PMID:35285020
    reference_title: "Bi-allelic SPATA22 variants cause premature ovarian insufficiency and nonobstructive azoospermia due to meiotic arrest."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Histological analysis and spermatocyte spreading assay demonstrated that
      the spermatogenesis was arrested at a zygotene-like stage in the proband
      with NOA.
    explanation: >-
      Spermatogenic arrest documented in testis tissue from an affected man.
  downstream:
  - target: Non-obstructive azoospermia
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:35285020
      reference_title: "Bi-allelic SPATA22 variants cause premature ovarian insufficiency and nonobstructive azoospermia due to meiotic arrest."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Histological analysis and spermatocyte spreading assay demonstrated that
        the spermatogenesis was arrested at a zygotene-like stage in the proband
        with NOA.
      explanation: >-
        In the affected man, zygotene-like spermatogenic arrest underlies his
        non-obstructive azoospermia.
  - target: Spermatogenesis maturation arrest
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:35285020
      reference_title: "Bi-allelic SPATA22 variants cause premature ovarian insufficiency and nonobstructive azoospermia due to meiotic arrest."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Histological analysis and spermatocyte spreading assay demonstrated that
        the spermatogenesis was arrested at a zygotene-like stage in the proband
        with NOA.
      explanation: >-
        Testis histology and spermatocyte spreads show the arrest directly as
        maturation arrest.
  - target: Infertility
    causal_link_type: DIRECT
phenotypes:
- name: Premature ovarian insufficiency
  category: Reproductive
  description: >-
    Women with biallelic SPATA22 variants present with premature ovarian
    insufficiency, both in the founding consanguineous family and as a sporadic
    case.
  subtype: POF25
  phenotype_term:
    preferred_term: Premature ovarian insufficiency
    term:
      id: HP:0008209
      label: Premature ovarian insufficiency
  phenotype_contexts:
  - sex: FEMALE
  evidence:
  - reference: PMID:35285020
    reference_title: "Bi-allelic SPATA22 variants cause premature ovarian insufficiency and nonobstructive azoospermia due to meiotic arrest."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We performed whole-exome sequencing (WES) in members of a consanguineous
      family with two POI and two NOA patients to screen for potential
      pathogenic variants for familial POI and NOA.
    explanation: >-
      Two women in the founding SPATA22 family had premature ovarian
      insufficiency.
  - reference: PMID:35285020
    reference_title: "Bi-allelic SPATA22 variants cause premature ovarian insufficiency and nonobstructive azoospermia due to meiotic arrest."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      One additional compound heterozygous variant in SPATA22 (c.900+1G>A and
      c.31C>T:p.R11X) was found in one patient with sporadic POI and validated
      by minigene assay.
    explanation: >-
      A further, unrelated woman with compound-heterozygous SPATA22 variants
      had premature ovarian insufficiency.
  - reference: PMID:42098781
    reference_title: "SPATA22 heterozygous variants drive premature ovarian insufficiency: mechanism of granulosa cells dysfunction and therapeutic potential of N-acetylcysteine (NAC) treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Through genetic screening, we identified an independent POI pedigree with
      four affected infertile female members (III-1, III-2, III-3, and III-4).
    explanation: >-
      Four women carrying the c.31C>T and c.900+1G>A SPATA22 variants had
      premature ovarian insufficiency.
- name: Non-obstructive azoospermia
  category: Reproductive
  description: >-
    Men with biallelic SPATA22 variants have non-obstructive azoospermia and
    primary infertility.
  subtype: SPGF96
  phenotype_term:
    preferred_term: Non-obstructive azoospermia
    term:
      id: HP:0011961
      label: Non-obstructive azoospermia
  phenotype_contexts:
  - sex: MALE
  evidence:
  - reference: PMID:35285020
    reference_title: "Bi-allelic SPATA22 variants cause premature ovarian insufficiency and nonobstructive azoospermia due to meiotic arrest."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We performed whole-exome sequencing (WES) in members of a consanguineous
      family with two POI and two NOA patients to screen for potential
      pathogenic variants for familial POI and NOA.
    explanation: >-
      Two men in the founding SPATA22 family had non-obstructive azoospermia.
  - reference: PMID:34392356
    reference_title: "Whole-exome sequencing of consanguineous families with infertile men and women identifies homologous mutations in SPATA22 and MEIOB."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A homozygous SPATA22 frameshift mutation (c.203del) was identified in a
      patient with non-obstructive azoospermia (NOA) from a consanguineous
      Pakistani family
    explanation: >-
      An independent homozygous SPATA22 patient with non-obstructive
      azoospermia.
- name: Spermatogenesis maturation arrest
  category: Reproductive
  description: >-
    Testicular histology and spermatocyte spreads show arrest of
    spermatogenesis at a zygotene-like stage of meiotic prophase I.
  subtype: SPGF96
  phenotype_term:
    preferred_term: Spermatogenesis maturation arrest
    term:
      id: HP:0031038
      label: Spermatogenesis maturation arrest
  phenotype_contexts:
  - sex: MALE
  evidence:
  - reference: PMID:35285020
    reference_title: "Bi-allelic SPATA22 variants cause premature ovarian insufficiency and nonobstructive azoospermia due to meiotic arrest."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Histological analysis and spermatocyte spreading assay demonstrated that
      the spermatogenesis was arrested at a zygotene-like stage in the proband
      with NOA.
    explanation: >-
      Direct histological and cytological documentation of meiotic maturation
      arrest.
- name: Irregular menstruation
  category: Reproductive
  description: >-
    All four affected women in the PMID:42098781 pedigree had irregular menstrual cycles.
  subtype: POF25
  phenotype_term:
    preferred_term: Irregular menstruation
    term:
      id: HP:0000858
      label: Irregular menstruation
  phenotype_contexts:
  - sex: FEMALE
  evidence:
  - reference: PMID:42098781
    reference_title: "SPATA22 heterozygous variants drive premature ovarian insufficiency: mechanism of granulosa cells dysfunction and therapeutic potential of N-acetylcysteine (NAC) treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All affected individuals presented with the core clinical manifestations
      of POI, including irregular menstrual cycles, oligomenorrhea, and
      secondary amenorrhea.
    explanation: >-
      Irregular menstrual cycles were reported in every affected woman.
- name: Oligomenorrhea
  category: Reproductive
  description: >-
    Infrequent menses were part of the presentation of the affected women.
  subtype: POF25
  phenotype_term:
    preferred_term: Oligomenorrhea
    term:
      id: HP:0000876
      label: Oligomenorrhea
  phenotype_contexts:
  - sex: FEMALE
  evidence:
  - reference: PMID:42098781
    reference_title: "SPATA22 heterozygous variants drive premature ovarian insufficiency: mechanism of granulosa cells dysfunction and therapeutic potential of N-acetylcysteine (NAC) treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All affected individuals presented with the core clinical manifestations
      of POI, including irregular menstrual cycles, oligomenorrhea, and
      secondary amenorrhea.
    explanation: >-
      Oligomenorrhea is named among the core manifestations in the affected women.
- name: Secondary amenorrhea
  category: Reproductive
  description: >-
    Menses stopped after having started, consistent with ovarian failure after puberty.
  subtype: POF25
  phenotype_term:
    preferred_term: Secondary amenorrhea
    term:
      id: HP:0000869
      label: Secondary amenorrhea
  phenotype_contexts:
  - sex: FEMALE
  evidence:
  - reference: PMID:42098781
    reference_title: "SPATA22 heterozygous variants drive premature ovarian insufficiency: mechanism of granulosa cells dysfunction and therapeutic potential of N-acetylcysteine (NAC) treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All affected individuals presented with the core clinical manifestations
      of POI, including irregular menstrual cycles, oligomenorrhea, and
      secondary amenorrhea.
    explanation: >-
      Secondary amenorrhea is named among the core manifestations in the affected women.
- name: Elevated follicle-stimulating hormone
  category: Endocrine
  description: >-
    Basal FSH was above 40 IU/L in all affected women, reflecting loss of ovarian feedback.
  subtype: POF25
  phenotype_term:
    preferred_term: Elevated follicle-stimulating hormone
    term:
      id: HP:0008232
      label: Elevated circulating follicle stimulating hormone level
  phenotype_contexts:
  - sex: FEMALE
  evidence:
  - reference: PMID:42098781
    reference_title: "SPATA22 heterozygous variants drive premature ovarian insufficiency: mechanism of granulosa cells dysfunction and therapeutic potential of N-acetylcysteine (NAC) treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hormonal profiling revealed markedly elevated basal FSH levels (> 40 IU/L)
      and significantly diminished AMH levels (< 1.1 ng/ml) in all affected
      individuals.
    explanation: >-
      Markedly elevated basal FSH was found in every affected woman.
- name: Decreased anti-Mullerian hormone
  category: Endocrine
  description: >-
    AMH was below 1.1 ng/ml in all affected women, reflecting a depleted follicle pool.
  subtype: POF25
  phenotype_term:
    preferred_term: Decreased anti-Mullerian hormone
    term:
      id: HP:0031103
      label: Decreased circulating antimullerian hormone circulation
  phenotype_contexts:
  - sex: FEMALE
  evidence:
  - reference: PMID:42098781
    reference_title: "SPATA22 heterozygous variants drive premature ovarian insufficiency: mechanism of granulosa cells dysfunction and therapeutic potential of N-acetylcysteine (NAC) treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hormonal profiling revealed markedly elevated basal FSH levels (> 40 IU/L)
      and significantly diminished AMH levels (< 1.1 ng/ml) in all affected
      individuals.
    explanation: >-
      Diminished AMH was found in every affected woman.
- name: Infertility
  category: Reproductive
  description: >-
    Affected women and men are infertile: women from premature ovarian
    insufficiency and men from non-obstructive azoospermia.
  phenotype_term:
    preferred_term: Infertility
    term:
      id: HP:0000789
      label: Infertility
  evidence:
  - reference: PMID:42098781
    reference_title: "SPATA22 heterozygous variants drive premature ovarian insufficiency: mechanism of granulosa cells dysfunction and therapeutic potential of N-acetylcysteine (NAC) treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      in a POI family without known causes, where four affected individuals
      presented with infertility.
    explanation: >-
      All four affected women in this pedigree were infertile.
  - reference: PMID:34392356
    reference_title: "Whole-exome sequencing of consanguineous families with infertile men and women identifies homologous mutations in SPATA22 and MEIOB."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Two consanguineous Pakistani families with four patients (three men and
      one woman) suffering from primary infertility were recruited.
    explanation: >-
      The SPATA22 homozygous man was one of the patients recruited for primary
      infertility; the other family in this study carries a MEIOB variant.
biochemical:
- name: Serum follicle-stimulating hormone
  presence: INCREASED
  subtype: POF25
  biomarker_term:
    preferred_term: Elevated circulating follicle stimulating hormone level
    term:
      id: HP:0008232
      label: Elevated circulating follicle stimulating hormone level
  notes: Basal FSH above 40 IU/L in all four affected women of the PMID:42098781 pedigree.
  evidence:
  - reference: PMID:42098781
    reference_title: "SPATA22 heterozygous variants drive premature ovarian insufficiency: mechanism of granulosa cells dysfunction and therapeutic potential of N-acetylcysteine (NAC) treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hormonal profiling revealed markedly elevated basal FSH levels (> 40 IU/L)
      and significantly diminished AMH levels (< 1.1 ng/ml) in all affected
      individuals.
    explanation: >-
      Reports elevated basal FSH in every affected woman.
- name: Serum anti-Mullerian hormone
  presence: DECREASED
  subtype: POF25
  biomarker_term:
    preferred_term: Decreased circulating antimullerian hormone circulation
    term:
      id: HP:0031103
      label: Decreased circulating antimullerian hormone circulation
  notes: AMH below 1.1 ng/ml in all four affected women of the PMID:42098781 pedigree.
  evidence:
  - reference: PMID:42098781
    reference_title: "SPATA22 heterozygous variants drive premature ovarian insufficiency: mechanism of granulosa cells dysfunction and therapeutic potential of N-acetylcysteine (NAC) treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hormonal profiling revealed markedly elevated basal FSH levels (> 40 IU/L)
      and significantly diminished AMH levels (< 1.1 ng/ml) in all affected
      individuals.
    explanation: >-
      Reports diminished AMH in every affected woman.
genetic:
- name: SPATA22
  gene_term:
    preferred_term: SPATA22
    term:
      id: hgnc:30705
      label: SPATA22
  association: Causative (Primary)
  relationship_type: CAUSATIVE
  evidence:
  - reference: PMID:35285020
    reference_title: "Bi-allelic SPATA22 variants cause premature ovarian insufficiency and nonobstructive azoospermia due to meiotic arrest."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Thus, this is the first report identifying SPATA22 as the causative gene
      for human POI.
    explanation: >-
      Establishes SPATA22 as the causal gene for the ovarian presentation.
  - reference: PMID:34392356
    reference_title: "Whole-exome sequencing of consanguineous families with infertile men and women identifies homologous mutations in SPATA22 and MEIOB."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Thus, our study suggests that SPATA22 and MEIOB may both be causative
      genes for human infertility.
    explanation: >-
      An independent family supports SPATA22 as a cause of male infertility;
      the authors state the conclusion cautiously.
  notes: >-
    SPATA22 encodes a germ-cell-specific partner of MEIOB. Three biallelic
    families or probands are published with phase-consistent genotypes
    (PMID:35285020: one consanguineous homozygous family and one sporadic
    compound heterozygote; PMID:34392356: one consanguineous homozygous
    family). A fourth pedigree (PMID:42098781) carries the same two variants as
    the PMID:35285020 compound heterozygote with phase not reported, so it is
    probably a further biallelic family. No ClinGen
    gene-disease validity classification was found for this pair, so
    gene_disease_validity is left absent.
📚

References & Deep Research

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (1)

Create: SPATA22-related gametogenic failure (POF25 / SPGF96) · 2026-10-15T15:43:13Z · View source

New mechanism-first entry for biallelic SPATA22 disease, anchored on MONDO:0975843 (premature ovarian failure 25) with MONDO:0975843 and MONDO:0975842 (spermatogenic failure 96) carried as POF25 and SPGF96 subtype rows, following the HFM1-, STAG3- and SYCE1-related gametogenic failure entries. Deep research: research/SPATA22-related_gametogenic_failure-deep-research-claude_code.md (claude_code provider; 14/14 references resolved, 0 unresolved CURIEs; its one flagged item, PMID:34392356 attributed via LOVD, was fetched and read directly). just preflight-dr could not be run because no local MONDO build is present. The pathograph runs SPATA22 loss of single-stranded DNA binding (GO:0003697, sourced from PMID:33812231 and PMID:40296718, both reporting SPATA22 itself binds ssDNA; QuickGO carries only protein binding for SPATA22) to failed meiotic recombination and synapsis, early prophase I arrest with germ-cell loss, and sex-specific ovarian depletion and spermatogenic arrest, conforming to the meiotic_prophase_failure module. A 2026 heterozygous POI report (PMID:42098781) is recorded in notes and not modelled. No treatments were added because no SPATA22-specific management source was found. Validated with validate, validate-terms, count-verified-snippets (all verified), check-causal-targets, check-entity-refs, check-duplicate-keys and the gene-activity-grounding ratchet against origin/main.

Claude Code ▸
SPATA22-related gametogenic failure (MONDO:0975843): research report
claude-haiku-5-5, claude-opus-5-5 9 citations 2026-10-15T15:37:37.914238

I'm searching the web for more human SPATA22 case reports, because the PubMed tool wasn't permitted.

SPATA22-related gametogenic failure (MONDO:0975843): research report

Status: Prepared 2026-10-15 for curating kb/disorders/SPATA22-related_gametogenic_failure.yaml.

Sources: The primary literature comes from 11 cached references_cache/PMID_*.md files in this worktree. All quotes below are copied from those files. Database identifiers (OMIM, LOVD, PanelApp) come from web searches. The PubMed search tool was not permitted in this session, so the literature sweep is not exhaustive.

Ontology CURIEs: Every HPO/GO/CL/UBERON/HGNC/NCIT identifier below is a lead only. They were written from general knowledge and not looked up. Each must be checked with runoak, the term cache or just validate-terms before it is bound.

0. Curation flags (read first)

  1. The MONDO label does not match the entry's scope. The draft YAML binds MONDO:0975843 with the label "premature ovarian failure 25", which is the female phenotype only. OMIM splits the condition in two:
  2. POF25 (OMIM 621002) for the female phenotype.
  3. Spermatogenic failure 96 (SPGF96, OMIM 621001) for the male phenotype.

Both are autosomal recessive and both map to SPATA22 (OMIM gene 617673) (LOVD disease #07135; Radboudumc panel). The entry's name and description cover both sexes. Decide one of two options: - Keep MONDO:0975843 as the primary term and add the SPGF96 MONDO term (if one exists) as a has_subtypes entry or a mapping. - Treat the male form as a subtype.

Either way, do not leave a two-sex description on a female-only term without noting it.

  1. The inheritance evidence conflicts. All the biallelic evidence (human and mouse) supports autosomal recessive inheritance, with heterozygous carriers fertile (mouse repro42, rat tm). A 2026 paper (PMID:42098781) reports heterozygous SPATA22 variants in a pedigree with premature ovarian insufficiency (POI) and reduced fertility in Spata22+/− mice. Record this as a separate, lower-confidence claim (a RISK_FACTOR/susceptibility row or a KNOWLEDGE_GAP), not as proof of dominant inheritance.

  2. The human case count is very small. I found about three to four published families/probands:

Report Variant(s) Affected individuals
Yao 2022, PMID:35285020 Homozygous p.R134X 2 POI and 2 NOA in one consanguineous family
Yao 2022, PMID:35285020 Compound heterozygous c.900+1G>A / p.R11X 1 sporadic POI
PMID:34392356 (attributed via LOVD/PanelApp; citation not verified) Homozygous c.203del, p.Leu68TrpfsTer4 1 NOA man

The details of PMID:34392356 must be fetched and checked before it is used.

1. Disease information

Overview. This is an autosomal recessive disorder of meiotic homologous recombination. Biallelic loss-of-function variants in SPATA22 stop germ cells in early meiotic prophase I. The result is premature ovarian insufficiency in 46,XX individuals and non-obstructive azoospermia (NOA) from meiotic arrest in 46,XY individuals. No phenotype outside the gonads has been reported in humans or animal models.

  • PMID:35285020 (human, primary result): "Bi-allelic SPATA22 variants cause premature ovarian insufficiency and nonobstructive azoospermia due to meiotic arrest." (title)
  • PMID:35285020: "Thus, this is the first report identifying SPATA22 as the causative gene for human POI."

Identifiers

Resource ID
MONDO MONDO:0975843 ("premature ovarian failure 25")
OMIM (female phenotype) 621002, POF25
OMIM (male phenotype) 621001, SPGF96
OMIM (gene) 617673, SPATA22
LOVD disease #07135
Gene location 17p13.3 (LOVD lists the c.203del variant at NC_000017.10:g.3366032del)
HGNC to verify (candidate hgnc:30705; must be checked)
Orphanet, ICD-10/11, MeSH No gene-specific code. Umbrella codes: ICD-10 E28.3 (primary ovarian failure), N46.0 (azoospermia); MeSH "Primary Ovarian Insufficiency", "Azoospermia"

Synonyms: POF25; premature ovarian failure 25; spermatogenic failure 96; SPATA22-related POI/NOA; SPATA22-related meiotic arrest.

Data provenance: Individual-patient case reports from whole-exome sequencing (WES) of families, plus aggregated gene-curation resources (OMIM, LOVD, PanelApp Australia).

2. Etiology

Cause: Germline biallelic loss-of-function variants in SPATA22 (nonsense, canonical splice, frameshift).

Risk factors: - Consanguinity. The index family was consanguineous (PMID:35285020: "members of a consanguineous family with two POI and two NOA patients"), as was the c.203del proband. - Heterozygous variants (contested). Possible heterozygous susceptibility to POI (PMID:42098781: "Two heterozygous pathogenic SPATA22 variants were identified in a POI pedigree with four affected infertile individuals"). This is a single report and conflicts with recessive transmission in other families.

Environmental, protective and gene–environment factors: None known. Oxidative stress has been proposed as a downstream mediator in granulosa cells (PMID:42098781, mouse/in vitro).

3. Phenotypes

Phenotype Candidate HPO term (verify) Sex Onset Evidence
Premature ovarian insufficiency HP:0008209 Premature ovarian insufficiency F Adolescence to young adulthood PMID:35285020
Primary or secondary amenorrhea HP:0000786 / HP:0000869 F Puberty / adult Expected with POI. Individual-level detail is in the full text, not the abstract
Hypergonadotropic hypogonadism (raised FSH) HP:0000815 Both — Expected from POI/NOA biochemistry. Confirm from the full text
Non-obstructive azoospermia HP:0011961 Non-obstructive azoospermia (or HP:0000027 Azoospermia) M Adult (presents with infertility) PMID:35285020
Spermatocyte meiotic arrest (zygotene-like) on testis histology Cellular phenotype; no exact HPO term (consider HP:0012205 globozoospermia? No, wrong concept. Use a free-text cellular phenotype) M — PMID:35285020: "spermatogenesis was arrested at a zygotene-like stage in the proband with NOA"
Infertility HP:0000789 Infertility Both — PMID:35285020, PMID:42098781
  • Severity and course: Complete gametogenic failure in males. In females, POI that presumably progresses to complete ovarian failure (the mouse shows oocyte loss).
  • Frequency: No frequencies are available. With fewer than 10 patients, every listed feature is present in all reported cases of the matching sex.
  • Quality of life: No disease-specific data. The burden is infertility, plus the consequences of estrogen deficiency in women (bone, cardiovascular, menopausal symptoms).

4. Genetic and molecular information

Gene. SPATA22 (spermatogenesis associated 22) is vertebrate-specific and expressed mainly in germ cells. - PMID:22011390: "a nonsense mutation in Spata22, a hitherto uncharacterized gene conserved among bony vertebrates. Expression of both transcript and protein is restricted predominantly to germ cells of both sexes."

Reported variants (NM_001170698.2 per LOVD; check the transcript)

Variant Type Zygosity Phenotype Source
c.400C>T, p.(Arg134*) Nonsense Homozygous 2 POI and 2 NOA, consanguineous Chinese family PMID:35285020
c.900+1G>A Canonical splice donor (minigene-validated) Compound heterozygous with the variant below Sporadic POI PMID:35285020
c.31C>T, p.(Arg11*) Nonsense Compound heterozygous with the variant above Sporadic POI PMID:35285020
c.203del, p.(Leu68Trpfs*4) Frameshift Homozygous NOA (affected status of a homozygous brother unknown) LOVD (pathogenic, recessive); attributed to PMID:34392356 / "Wu 2022". Verify
Two heterozygous variants (identities in the full text) — Heterozygous POI pedigree PMID:42098781
  • Mechanism class: Loss of function. In mice, nonsense and splice alleles abolish the protein.
  • PMID:22011390: "Germ cells of repro42 mutant mice express Spata22 transcript, but not SPATA22 protein."
  • PMID:32388826: "leads to incorrect splicing of the Spata22 mRNA, ultimately resulting in no detectable SPATA22 protein."
  • Variant origin: Germline. No somatic involvement.
  • Population frequency: Not established here. Check gnomAD for loss-of-function carrier frequency.
  • ClinGen gene–disease validity: No assertion found. PanelApp Australia rates SPATA22 high-evidence (green) on its POI and spermatogenic-failure panels (PanelApp POI).
  • Modifier genes, epigenetics, chromosomal abnormalities: None reported.
  • Gene family relation: MEIOB is the obligate partner. Biallelic MEIOB variants cause the same phenotype in both sexes (PMID:31000419), which strengthens the case for pathogenicity through the shared complex.

5. Environmental information

Not applicable. There are no environmental, lifestyle or infectious causes.

6. Mechanism and pathophysiology

Ordered causal chain

  1. Biallelic SPATA22 truncating or splice variants lead to absent SPATA22 protein (nonsense-mediated decay or aberrant splicing).
  2. Shown in mice (PMID:22011390, PMID:32388826). Inferred in humans from variant class and a minigene assay (PMID:35285020).
  3. Loss of SPATA22 destabilizes its obligate partner MEIOB and abolishes the MEIOB–SPATA22 heterodimer.
  4. PMID:24240703: "chromatin localization and stability of MEIOB depends on SPATA22 and vice versa."
  5. PMID:28453612: "MEIOB and SPATA22 form an obligate complex."
  6. In human cells, SPATA22 is also needed to bring MEIOB into the nucleus (PMID:36331299: "the NLS in the OB domain of hMEIOB and interaction with hSPATA22 are required for hMEIOB nuclear localization"). This step is in vitro.
  7. Without the complex, RPA-coated single-stranded DNA (ssDNA) at meiotic double-strand break (DSB) resection intermediates is not properly bound, compacted or processed.
  8. PMID:33812231: "MEIOB and SPATA22 interact with the preformed RPA complex... and condense RPA-coated ssDNA in vitro."
  9. PMID:28453612: "MEIOB and SPATA22 are recruited to induced DNA double-strand breaks (DSBs) together but not alone."
  10. PMID:40296718 (human proteins): "hSPATA22 binds to ssDNA faster and more stably and promotes ssDNA condensation."
  11. This leads to failed DSB repair and disordered recombination. DSBs form, but DMC1 strand-exchange foci are lost early and BLM-positive foci build up abnormally.
  12. PMID:32388826: "mutant cells appear to form DSBs and initiate meiotic recombination, but are unable to complete DSB repair... shani mutants show precocious loss of DMC1 foci and improper accumulation of BLM-positive recombination foci."
  13. This in turn causes failed homologous synapsis.
  14. PMID:22011390: "homologous chromosomes of mutant germ cells do not achieve normal synapsis or repair meiotic DNA double-strand breaks."
  15. This triggers prophase I arrest (zygotene-like) and apoptotic germ cell elimination (presumed meiotic checkpoint; the checkpoint pathway was not dissected for SPATA22).
  16. PMID:32388826: "leading to meiotic prophase arrest, apoptosis and sterility."
  17. Human testis: arrest at a zygotene-like stage (PMID:35285020).
  18. The outcome then branches by sex:
  19. 7a (male): No post-meiotic spermatids, leading to non-obstructive azoospermia.
  20. 7b (female): Fetal oocytes are lost in prophase I, giving a depleted primordial follicle pool and then POI with hypergonadotropic hypogonadism.
    • Oocyte loss is shown in mice (PMID:22011390: "subsequent germ cell loss in both males and females"). The human ovarian histology is inferred.
  21. 7c (possible somatic branch; contested, mouse/in vitro): SPATA22 deficiency in granulosa cells leads to DNA damage and oxidative stress, then granulosa-cell dysfunction and ovarian insufficiency (PMID:42098781). This is proposed for heterozygotes. Model it under a separate mechanistic_hypotheses group (status EMERGING).

Candidate GO terms (verify)

Term Use
GO:0007131 reciprocal meiotic recombination —
GO:0000724 double-strand break repair via homologous recombination —
GO:0007130 synaptonemal complex assembly —
GO:0007129 homologous chromosome pairing at meiosis —
GO:0003697 single-stranded DNA binding Molecular function
GO:0051321 meiotic cell cycle —
GO:0007283 spermatogenesis —
GO:0048477 oogenesis —
GO:0006915 apoptotic process Downstream germ cell loss

Candidate CL terms (verify): - CL:0000017 spermatocyte (primary spermatocyte CL:0000656) - CL:0000023 oocyte (primary oocyte CL:0000654) - CL:0000501 granulosa cell (branch 7c)

Pathways and other layers: - Pathways: Reactome "Meiotic recombination" (R-HSA-912446). - Metabolic and immune: None. - Omics: No disease-specific transcriptomic, proteomic or single-cell data found.

7. Anatomical structures

  • Organs (verify UBERON IDs): Testis (UBERON:0000473), seminiferous tubule (UBERON:0001343), ovary (UBERON:0000992). Both sides are affected. No other organs are involved.
  • Subcellular compartments:
  • Nucleus and meiotic chromosomes/chromatin: recombination foci associated with chromosome axes (PMID:24240703: "co-localize in foci that are associated with meiotic chromosomes").
  • Candidate GO cellular-component terms: GO:0005634 nucleus; GO:0000794 condensed nuclear chromosome.

8. Temporal development

  • Onset: Congenital/developmental. Meiotic failure happens in the fetus (oocytes) or at puberty (spermatocytes). It shows clinically at puberty or adulthood as amenorrhea/POI or infertility.
  • Course: Lifelong, not reversible. Natural history data are lacking.
  • Critical window: Female fertility preservation (oocyte or ovarian-tissue cryopreservation) is possible only while follicles remain. It is not clear whether any follicles survive in null females (null mice lose oocytes early).

9. Inheritance and population

Item Finding
Inheritance Autosomal recessive (HP:0000007; verify). OMIM, LOVD and all families with biallelic variants agree. A single report suggests heterozygous susceptibility (see flag 2)
Penetrance Complete for gonadal failure in reported biallelic cases. The affected status of one homozygous brother of the c.203del proband is unknown
Consanguinity Prominent
Founder effects None known
Populations Chinese (PMID:35285020, PMID:42098781) and one other consanguineous family (population not confirmed)
Prevalence Unknown, ultra-rare. Fewer than 10 published patients
Prevalence class CASES_IN_LITERATURE / ULTRA_RARE
Background POI affects about 1–3% of women under 40 (quoted in PMID:31000419). SPATA22 explains only a tiny fraction: Yao et al. screened an in-house idiopathic POI WES database and found one further case. Xia et al. screened 608 POI patients and found one pedigree
Sex ratio Both sexes affected equally

10. Diagnostics

  • Laboratory:
  • FSH/LH (raised), estradiol (low) and AMH (low or undetectable) in women.
  • Semen analysis (azoospermia, normal volume), raised FSH and normal karyotype in men.
  • Histology: Testicular biopsy shows meiotic arrest at the spermatocyte (zygotene-like) stage. Spermatocyte spreads with SYCP3/γH2AX immunostaining show asynapsis (PMID:35285020).
  • Genetic testing:
  • Rule out first: karyotype (Turner syndrome, 47,XXY), Y-chromosome AZF microdeletions, and FMR1 premutation in women.
  • Then: WES or a POI/NOA gene panel. SPATA22 is on PanelApp Australia and Radboudumc panels.
  • Splice variants need RNA studies or a minigene assay (as for c.900+1G>A).
  • Differential diagnosis: Other meiotic-recombination POI/NOA genes, including MEIOB (phenocopy, PMID:31000419), STAG3, SYCE1, MSH4, MSH5, HFM1, ZSWIM7, SPIDR, DMC1, MCM8/9, TEX11 (X-linked), MEI1 and REC114. Also non-genetic POI (autoimmune, iatrogenic).
  • Screening: Cascade carrier testing and testing of siblings in consanguineous families. No newborn screening.

11. Outcome and prognosis

  • Survival: Normal life expectancy is expected; no mortality is attributable to the disease.
  • Morbidity, males: Permanent sterility. Microdissection TESE is expected to fail with complete meiotic arrest, but no SPATA22-specific sperm-retrieval data were found.
  • Morbidity, females: Infertility, plus long-term consequences of estrogen deficiency (osteoporosis, cardiovascular risk, menopausal symptoms) without hormone replacement therapy (HRT).

12. Treatment

There is no disease-modifying therapy.

Treatment Candidate NCIT term (verify) Notes
Hormone replacement therapy (estrogen/progestin) for POI NCIT:C15986 Pharmacotherapy (+ therapeutic_agent estradiol, from CHEBI) Standard POI care for bone and cardiovascular protection
Oocyte donation / IVF Assisted reproductive procedure term (look up) Only route to pregnancy for affected women
Donor sperm / adoption — Males
Genetic counseling NCIT:C15240 Genetic Counseling —
N-acetylcysteine Experimental only Partially rescued Spata22+/− mouse fertility and granulosa-cell defects (PMID:42098781: "The antioxidant NAC effectively rescued GCs defects, and partially restored Spata22+/- mice fertility"). No human data. Record as preclinical evidence (MODEL_ORGANISM/IN_VITRO)

No clinical trials were found.

13. Prevention

  • Primary prevention is not applicable.
  • Options are genetic counseling, carrier testing of relatives, and preimplantation or prenatal testing for at-risk couples (25% recurrence for carrier × carrier).
  • Consider fertility preservation counseling for asymptomatic homozygous sisters identified early, though its effectiveness is unproven.

14. Other species and natural disease

  • Conservation: The gene is conserved across bony vertebrates (PMID:22011390). A zebrafish ortholog is annotated in ZFIN (ZFIN).
  • Rodents: The tremor rat (tm/tm) is a spontaneous rat mutant with sterility from a deletion that includes Spata22.
  • PMID:23903057: "Spata22 was identified as the gene responsible for the failure of gametogenesis to progress beyond meiosis I in tm homozygous rats by a transgenic rescue experiment."
  • Its tremor/epilepsy phenotype comes from other deleted genes.
  • Veterinary: No naturally occurring disease known in companion animals or livestock (OMIA not checked).

15. Model organisms

Model Allele Phenotype Fidelity / limitations PMID
Mouse repro42 (ENU) Nonsense; no protein Infertility in both sexes, no other phenotype; prophase I arrest, asynapsis, unrepaired DSBs, germ cell loss High for the gonadal phenotype 22011390
Mouse shani (ENU) Exonic splicing-enhancer point mutation, mis-splicing, no protein Phenocopies null: DSBs form but are not repaired, early DMC1 loss, BLM foci, apoptosis, sterility High; a model for splice-class human variants 32388826
Mouse Meiob−/− Partner knockout Same sterility in both sexes; MEIOB/SPATA22 mutually dependent Pathway phenocopy 24240703
Rat tm/tm ~240 kb deletion including Spata22 + ≥12 genes Gonadal hypoplasia, meiosis I arrest; rescued by Spata22 transgene Contiguous-gene confound (tremor) 23903057
Mouse Spata22+/− Heterozygous Reported reduced ovarian function and fertility, granulosa-cell DNA damage/oxidative stress, partial NAC rescue Single report; conflicts with fertile heterozygotes in earlier models 42098781
Cell-free / HEK293 systems Human and mouse proteins ssDNA binding, RPA interaction, nuclear import IN_VITRO; no meiotic context 28453612, 33812231, 36331299, 40296718

Model limitations. - The human and rodent proteins differ in sequence. PMID:40296718: "the amino acid sequences of the two proteins are inconsistent in humans and rodents, which leads to functional differences in meiosis." - Mouse oocyte loss is a reasonable stand-in for human POI, but human ovarian histology is not available. This is a candidate HUMAN_MODEL_MISMATCH discussion.

Evidence summary by source type

Source type PMIDs
Human clinical 35285020 (primary), 42098781 (heterozygous; contested), 34392356 (needs verifying), 31000419 (MEIOB phenocopy, supporting)
Model organism 22011390, 32388826, 23903057, 24240703, 42098781 (mouse arm)
In vitro 28453612, 33812231, 36331299, 40296718

Sources (web)

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome Count
References checked 14
Resolved 14
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 14
On topic 9
Off topic 0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome Count
Terms checked 32
Resolved 31
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 1
Terms whose name was checked 2
Terms named correctly 1
Terms named as a different term 0
Terms whose name is worth a second look 1

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

  • HP:0000815 (1 mention) - the report calls it "Hypergonadotropic hypogonadism (raised FSH)"; HP calls it Hypergonadotropic hypogonadism

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: OMIM.

31 of 32 terms resolved to a current term; the rest could not be looked up either way.