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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:

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

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

• 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)

• 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)

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

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.

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 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

Sources (web)

• LOVD disease #07135 – POF25, OMIM:621002
• LOVD SPATA22 c.203del variant record
• Radboudumc ovarian insufficiency panel (POF25 621002; SPGF96 621001)
• PanelApp Australia – SPATA22 (POI panel)
• PanelApp Australia – SPATA22 (panel 137)
• GeneCards – SPATA22
• ZFIN – zebrafish spata22
• Xia et al. 2026, Reprod Biol Endocrinol (SPATA22 heterozygous POI)
• Frontiers in Genetics 2022 article cited in search (contents not confirmed)

Reference Validation

Checked with linkml-reference-validator 0.3.0.

All extracted references resolved successfully.

Term Validation

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

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.