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Premature Ovarian Failure 19 (POF19): research report

Verification status. Sources I could read were search-result summaries only. The proxy refused direct fetches of the eLife and PMC full text, and PubMed needed cookies. Anything not seen in a result is marked [unverified]. Quotes are not exact abstract text and must be re-checked with just fetch-reference before use as snippets. I give no PMID for the founding paper because none appeared in my results.

1. Disease information

POF19 is a rare autosomal recessive form of primary ovarian insufficiency (POI), meaning loss of ovarian function before age 40. Its gene is HSF2BP (21q22). Only one family is reported in the sources I saw (see section 3).

Orphanet, ICD-10/11 and MeSH identifiers were not found [unverified]. The condition is disease-level and derived from one pedigree plus mouse work, not from EHR data.

2. Etiology

• Cause: biallelic HSF2BP variants. The reported allele is the missense p.Ser167Leu (S167L), a hypomorph in mouse. The nucleotide change was not confirmed in my sources. c.500C>T is only my inference from the codon change.
• Risk and protective factors: none specific to POF19 are documented. Generic POI risks (chemotherapy, radiation, autoimmunity, FMR1 premutation) are not relevant to this entry. No gene-environment interaction data were found.

3. Phenotypes

Source: the 2020 eLife paper (article, PMC7498267). The family is consanguineous: the parents are first cousins of Moslem-Arab origin. Three of five daughters, including a monozygotic twin pair, are affected. They had irregular menses from menarche, then early secondary amenorrhea at ages 24 and 25. One summary mentions elevated gonadotropins and low estradiol [unverified: figures and the third sister's details not seen].

Age at onset is early adulthood (about 24–25 years). Quality-of-life data are not available.

4. Genetic and molecular information

• Gene: HSF2BP (heat shock transcription factor 2 binding protein). Use lowercase hgnc: in the KB, with the CURIE looked up via runoak, not typed from memory.
• Variant: S167L, homozygous in affected sisters. The gnomAD frequency is about 0.00018 and the GME frequency about 0.0005, so it is very rare.
• Functional consequence: partial loss of function. The eLife abstract summary calls it a hypomorph compared with a new knockout mouse.
• ACMG classification: not found in ClinVar or ClinGen [unverified].
• Modifiers, epigenetics, chromosomal abnormalities: none reported.

5. Environmental information

No environmental, lifestyle or infectious factors are reported.

6. Mechanism and pathophysiology

Causal chain (steps 1–3 are demonstrated in mouse and biochemically; step 4 is inferred for humans):

1. Homozygous HSF2BP S167L reduces the amount and function of HSF2BP in meiocytes.
2. HSF2BP is a BRCA2 partner and a stabilizing partner of C19ORF57/BRME1. Together they bind BRCA2, RAD51, RPA and PALB2. Reduced HSF2BP lowers HSF2BP and BRME1 signal at recombination nodules.
3. Fewer RAD51/DMC1 foci form, which impairs meiotic double-strand-break repair and lowers crossover frequency. Mutant mouse females have reduced fertility and smaller litters.

4. Oocyte and follicle loss follows, which is inferred for women. The result is early depletion of the ovarian reserve, then secondary amenorrhea and infertility.

5. Mouse knockout: three independent knockouts have nearly identical phenotypes. Published descriptions I saw cover male meiotic failure and spermatogenesis arrest. I found no female knockout detail.

6. Later work: Sci Adv 2023 describes BRME1 disassembling the BRCA2–HSF2BP ring (article). A Nat Commun 2021 paper (article) shows that deleting BRCA2's HSF2BP-binding region does not reproduce the HSF2BP-null meiotic defect.
7. Suggested terms:
8. GO: meiotic recombination (GO:0007131), double-strand break repair via homologous recombination (GO:0000724), oogenesis (GO:0048477), oocyte maturation (GO:0001556). All [unverified]; look up before binding.
9. CL: oocyte (CL:0000023), primary oocyte.
10. Omics: none available.

7. Anatomical structures affected

• Organ: ovary (UBERON:0000992), within the female reproductive/endocrine system.
• Cell and subcellular level: oocytes and ovarian follicles; the nucleus (meiotic chromosomes, recombination nodules).
• Lateralization: bilateral.

8. Temporal development

Onset is in early adulthood, after normal menarche. The course is progressive: irregular cycles, then amenorrhea. Remission and critical-period data are not available.

9. Inheritance and population

• Autosomal recessive (HP:0000007).
• Consanguinity is present in the one family.
• Penetrance and expressivity are unknown; all homozygous sisters were affected as far as I saw.
• There is no evidence of anticipation or germline mosaicism.
• A founder effect is possible in the Arab family but was not evaluated.
• Prevalence is unknown, and only a single family is reported.
• Sex ratio is not applicable beyond affected females. Whether homozygous males are infertile is not reported in the human data.

10. Diagnostics

• Labs: FSH, LH and estradiol (high gonadotropins and low estradiol are the standard POI pattern); AMH is not reported.
• Genetic testing: whole-exome sequencing found the variant. A POI gene panel including HSF2BP is reasonable. Karyotype and FMR1 testing are standard first-line exclusions for POI.
• Differential diagnosis: other recessive meiosis and DNA-repair POI genes (for example HFM1, MCM8, MCM9, STAG3), Turner syndrome, FMR1 premutation, autoimmune oophoritis and iatrogenic POI.

11. Prognosis

Ovarian function is lost permanently. Survival data are not available. Expected complications are those of estrogen deficiency (bone loss and cardiovascular risk), which I draw from general POI knowledge, not from POF19 sources.

12. Treatment

No POF19-specific therapy exists. Management is as for POI:

• Hormone replacement therapy. NCIT: Pharmacotherapy (NCIT:C15986), with estrogen/progestogen as therapeutic_agent bound to CHEBI.
• Bone and cardiovascular monitoring.
• Fertility options: oocyte donation, and early fertility counseling.
• Genetic counseling (NCIT:C15240).

No trials were identified, and I did not search ClinicalTrials.gov. Pharmacogenomics is not applicable.

13. Prevention

• Genetic counseling for relatives, with carrier testing of siblings in affected families.
• Prenatal or preimplantation testing is possible in principle once the familial variant is known.
• No primary prevention exists.

14. Other species

Orthologs are in mouse and other mammals. OMIA data were not checked. No natural disease is known.

15. Model organisms

• Mouse knockouts (three independent lines): meiotic failure, described in the sources I saw mainly in males.
• Hsf2bp S167L knock-in mouse (eLife 2020): hypomorphic. Females have reduced fertility and smaller litters. Meiocytes show reduced HSF2BP/BRME1 at recombination nodules, fewer RAD51/DMC1 foci and lower crossover frequency.
• Cell and biochemical systems: co-immunoprecipitation of the BRME1/HSF2BP complex with BRCA2, RAD51, RPA and PALB2.
• Fidelity: the S167L mouse recapitulates reduced female fertility, but the human phenotype is early ovarian failure, so fidelity is partial. A modeled_mechanisms link should note this limitation.
• Mouse-resource entries (MGI, IMPC, genOway knockout) were not verified.

Gaps to close before curating

1. Fetch the eLife paper and its PMID with just fetch-reference (DOI 10.7554/eLife.56996, PMC7498267), then copy snippets from the cached text.
2. Confirm the HGVS nucleotide change, the hormone values, the third sister's data and the female knockout phenotype.
3. Read OMIM 619245 and the ClinGen validity record directly. Check ClinVar for HSF2BP variants.
4. Search PubMed for additional HSF2BP POI families published after 2020.
5. Run just check-genereviews for a GeneReviews baseline. A POI chapter may exist, though I expect no POF19-specific one.

Sources

• NORD: Premature ovarian failure 19
• DrugMap disease DIS60A1W
• OMIM 619245 mirror
• Disease Ontology DOID:0112278
• eLife 2020;9:e56996 and PMC7498267
• bioRxiv preprint
• Nat Commun 2021, BRCA2–HSF2BP
• Sci Adv 2023, BRCA2–HSF2BP ring disassembly by BRME1
• Reprod Biol Endocrinol 2024, POI genetics review

Reference Validation

Checked with linkml-reference-validator 0.3.0.

4 of 5 references resolved; the rest could not be looked up either way.

Term Validation

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

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

• MONDO:0030985 (1 mention) - the report calls it "MONDO"; MONDO calls it premature ovarian failure 19
• DOID:0112278 (5 mentions) - the report calls it "synonyms POF19, POI19"; DOID calls it primary ovarian insufficiency 19

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:0000858 (1 mention) - the report calls it "Irregular menstruation, oligomenorrhea"; HP calls it Irregular menstruation
• HP:0000837 (1 mention) - the report calls it "Elevated FSH / hypergonadotropism"; HP calls it Increased circulating gonadotropin level, and lists "Elevated serum gonadotropins" among its other names
• GO:0007131 (1 mention) - the report calls it "GO: meiotic recombination"; GO calls it reciprocal meiotic recombination, and lists "female meiotic recombination" among its other names
• CL:0000023 (1 mention) - the report calls it "CL: oocyte"; CL calls it oocyte
• UBERON:0000992 (1 mention) - the report calls it "Organ: ovary"; UBERON calls it ovary**, and lists "animal ovary" among its other names
• HP:0000007 (1 mention) - the report calls it "Autosomal recessive"; HP calls it Autosomal recessive inheritance, and lists "Autosomal recessive" among its other names