👪

Inheritance

1

Autosomal recessive inheritance HP:0000007

Affected women are homozygous for HSF2BP missense variants; in the founding consanguineous family both parents and the fertile siblings are heterozygous carriers.

Autosomal recessive inheritance

Show evidence (2 references)

PMID:32845237 SUPPORT Human clinical

"All affected family members are homozygous for the variant, and the healthy relatives are heterozygous carriers."

Recessive segregation of HSF2BP p.Ser167Leu in the founding family.

PMID:35174157 SUPPORT Human clinical

"only two homozygous missense variations (following recessive inheritance pattern) were found, c.382T > C (p.C128R) and c.557T > C (p.L186P)"

Two further homozygous patients in a sporadic POI cohort, consistent with recessive inheritance.

⚙

Pathophysiology

4

HSF2BP Partial Loss of Function

The disease alleles reduce HSF2BP function without abolishing it. p.Ser167Leu lowers the protein level of HSF2BP and of its stabilizing partner BRME1, and p.Cys128Arg and p.Leu186Pro reduce its nuclear localization. HSF2BP binds a conserved region of BRCA2 between the BRC repeats and the DNA-binding domain, and the HSF2BP-BRME1 complex brings BRCA2 to meiotic double-strand breaks.

HSF2BP hgnc:5226

Genetic context variant_origin: GERMLINE functional_impact_category: PARTIAL_LOSS_OF_FUNCTION

BRCA2 binding GO:0005515 ↓ DECREASED

Animal models

Hsf2bp S167L knock-in mouse Mouse recapitulates Carries the patient allele, which lowers HSF2BP and BRME1 protein.

Downstream

Impaired Recombinase Loading and Crossover Formation in Oocytes

Show evidence (4 references)

PMID:32845237 SUPPORT Model organism

"The S167L human recessive POI variant behave as a hypomorphic allele in mice, which results in a reduction of the protein expression/stability of itself and of its partner BRME1 in vivo and in transfected cells."

The founding allele reduces HSF2BP and BRME1 protein in mouse meiocytes and transfected cells.

PMID:35174157 SUPPORT In vitro / ex vivo

"Functional studies revealed the variations adversely affected the DNA repair capacity of HSF2BP due to disturbed nuclear localization"

The two sporadic-case alleles impair HSF2BP in cultured cells.

PMID:31242413 SUPPORT In vitro / ex vivo

"The BRCA2-HSF2BP interaction is highly evolutionarily conserved and maps to armadillo repeats in HSF2BP and a 68-amino acid region between the BRC repeats and the DNA binding domain of human BRCA2 (Gly2270-Thr2337) encoded by exons 12 and 13."

Defines the BRCA2 interaction that the HSF2BP complex provides.

+ 1 more reference

Impaired Recombinase Loading and Crossover Formation in Oocytes

Without enough HSF2BP-BRME1, BRCA2 does not efficiently load RAD51 and DMC1 onto resected meiotic double-strand breaks. In knockout oocytes break formation and resection look normal (RPA2 foci), recombinase foci fall by about half, homolog synapsis is delayed, and fewer crossovers form. The defect is milder in oocytes than in spermatocytes, and Hsf2bp-null females remain fertile.

oocyte CL:0000023

DNA recombinase assembly GO:0000730 ↓ DECREASED double-strand break repair via homologous recombination GO:0000724 ↓ DECREASED reciprocal meiotic recombination GO:0007131 ↓ DECREASED

Animal models

Hsf2bp knockout mouse Mouse recapitulates Knockout oocytes form breaks normally but load fewer recombinase foci.

Hsf2bp S167L knock-in mouse Mouse recapitulates Knock-in oocytes have fewer RAD51/DMC1 foci and fewer crossovers.

Downstream

Oocyte Elimination in Meiotic Prophase

Show evidence (2 references)

PMID:30760716 SUPPORT Model organism

"However, there were significant reductions in the numbers of DMC1 and RAD51 foci in Meilb2−⁄− oocytes compared to WT oocytes"

Hsf2bp (Meilb2) knockout oocytes load fewer recombinase foci in zygotene, while break formation and resection (RPA2 foci) are normal.

PMID:32845237 SUPPORT Model organism

"In agreement with the lower presence of recombinases, the number of COs (measured as interstitial CDK2 foci) was also reduced in Hsf2bpS167L/S167L oocytes, and a stronger reduction was observed in Hsf2bp-/- oocytes"

Crossovers are reduced in oocytes carrying the human allele, and more so in null oocytes.

Oocyte Elimination in Meiotic Prophase

Oocytes that fail to repair meiotic breaks are eliminated before primordial follicles form, so fewer oocytes enter the follicle reserve.

oocyte CL:0000023

Downstream

Ovarian Follicle Depletion

Show evidence (1 reference)

PMID:30760716 SUPPORT INDIRECT Model organism

"Meilb2 KO female mice also show similar phenotypes but milder than males, and they have a massive reduction in the number of oocytes and suffer from subfertility."

Oocyte numbers fall sharply in knockout females. The quote reports the loss; the mechanism of elimination is inferred from the checkpoint node in the module.

Ovarian Follicle Depletion

Loss of oocytes leaves a small follicle reserve that is used up early. Affected women have a spontaneous menarche and some years of irregular cycles before ovarian function stops. The two sporadic patients had atrophic ovaries with no visible follicles; in the founding family, one twin's ovaries were normal on ultrasound.

oocyte CL:0000023

female gamete generation GO:0007292 ↓ DECREASED

Animal models

Hsf2bp knockout mouse Mouse partially recapitulates Knockout females have fewer follicles of every stage and smaller litters, but remain fertile.

Hsf2bp S167L knock-in mouse Mouse fails to recapitulate Follicle numbers are normal at 13 months; female fertility is only mildly reduced.

Downstream

Premature ovarian insufficiency

Secondary amenorrhea

Oligomenorrhea

Female infertility

Elevated circulating follicle stimulating hormone level Loss of follicles removes ovarian negative feedback on the pituitary.

Elevated circulating luteinizing hormone level Loss of follicles removes ovarian negative feedback on the pituitary.

Decreased serum estradiol Without growing follicles the ovary makes little estradiol.

Show evidence (2 references)

PMID:35174157 SUPPORT Human clinical

"Ultrasound examination showed the two patients had atrophic ovaries without follicles"

Both sporadic patients have ovaries with no follicles on ultrasound.

PMID:32845237 SUPPORT Model organism

"in contrast with the drastic reduction of the follicle pool in Hsf2bp-/- ovaries"

Null mice lose most of the follicle pool.

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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.

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Phenotypes

7

Endocrine 3

Elevated circulating follicle stimulating hormone level HP:0008232

Show evidence (3 references)

PMID:35174157 SUPPORT Human clinical

"| POI-1 | Homozygous | c.382T>C | p.C128R | LP | 11 | 24 | 79.09 |"

Patient POI-1 had serum FSH of 79.09 IU/L; the cohort's diagnostic threshold was FSH above 25 IU/L. POI-2 had 71.37 IU/L.

PMID:35174157 SUPPORT Human clinical

"at least twice serum FSH >25 IU/L at an internal of 4–6 weeks"

The FSH criterion every patient in the cohort met, including both HSF2BP homozygotes.

PMID:35174157 SUPPORT Human clinical

"| POI-2 | Homozygous | c.557T>C | p.L186P | LP | 16 | 16 | 71.37 |"

Patient POI-2 had serum FSH of 71.37 IU/L.

Elevated circulating luteinizing hormone level HP:0011969

Show evidence (1 reference)

PMID:35174157 SUPPORT Human clinical

"| POI-1 | Homozygous | c.382T>C | p.C128R | LP | 11 | 24 | 79.09 | 21.63 |"

Table 1 row for POI-1; LH 21.63 IU/L. POI-2 had LH 38.61 IU/L. The paper gives no LH reference range; both values are above the usual follicular-phase range.

Decreased serum estradiol HP:0008214

Show evidence (1 reference)

PMID:35174157 SUPPORT Human clinical

"| POI-2 | Homozygous | c.557T>C | p.L186P | LP | 16 | 16 | 71.37 | 38.61 | <5.0 |"

Table 1 row for POI-2; estradiol below 5.0 pg/mL. POI-1 had 5.0 pg/mL.

Genitourinary 4

Premature ovarian insufficiency HP:0008209

Onset: YOUNG ADULT

Show evidence (2 references)

PMID:32845237 SUPPORT Human clinical

"Of the five daughters, three are affected with POI and presented with early secondary amenorrhea."

POI in the three homozygous sisters of the founding family.

PMID:35174157 SUPPORT Human clinical

"two novel pathogenic homozygous variations of HSF2BP were identified in two patients with sporadic POI"

POI in two unrelated homozygous patients.

Secondary amenorrhea HP:0000869

Show evidence (2 references)

PMID:32845237 SUPPORT Human clinical

"They had menarche at normal age (at 13–14) but with irregular menses that stopped around 25."

Normal menarche followed by loss of menses in the founding family.

PMID:35174157 SUPPORT Human clinical

"Patient POI-1, who carried HSF2BP p.C128R, experienced menarche at 11 years old, underwent irregular menstrual cycle (2–12 months per menstrual cycle) since 13 years old, and suffered amenorrhea at 24 years of age."

Secondary amenorrhea at 24 in a sporadic patient.

Oligomenorrhea HP:0000876

Show evidence (2 references)

PMID:32845237 SUPPORT Human clinical

"III-1 became amenorrheic at age 24 and III-2 at age 25, both after irregular menstruations since menarche."

Irregular menses preceded amenorrhea in both twins.

PMID:35174157 SUPPORT Human clinical

"Patient POI-2, who carried HSF2BP p.L186P, experienced menarche at 16 years old, followed by an irregular menstrual cycle that ceased at the age of 18."

Irregular cycles after menarche in the second sporadic patient.

Female infertility HP:0008222

Show evidence (1 reference)

PMID:32845237 SUPPORT Human clinical

"Only one of the patients affected by POI could have a child with the help of a fertility treatment"

Two of the three affected sisters had no children; the third conceived only with treatment.

🧬

Genetic Associations

1

HSF2BP (Causal)

Gene: HSF2BP hgnc:5226 relationship_type: CAUSATIVE

Show evidence (2 references)

PMID:32845237 SUPPORT Human clinical

"Using whole-exome sequencing in a family with three cases of POI, we identified the candidate missense variant S167L in HSF2BP, an essential meiotic gene."

First report linking HSF2BP to POI.

PMID:35174157 SUPPORT Human clinical

"In this study, through the largest in-house WES database of 1,030 patients with sporadic POI, we identified two novel homozygous variations in HSF2BP (c.382T>C, p.C128R; c.557T>C, p.L186P)."

Independent patients with different homozygous HSF2BP alleles.

Variants (3)

p.Ser167Leu

c.500C>T (rs200655253), homozygous in three sisters of Israeli Arab origin born to first-cousin parents. Very rare in gnomAD and never seen homozygous in public databases. A knock-in mouse shows it is a hypomorphic allele that lowers HSF2BP and BRME1 protein levels.

Show evidence (1 reference)

PMID:32845237 SUPPORT Model organism

"Functional analysis of the HSF2BP-S167L variant in mouse showed that it behaves as a hypomorphic allele compared to a new loss-of-function (knock-out) mouse model."

The human allele, knocked into the mouse, partially reduces HSF2BP function.

p.Cys128Arg

c.382T>C, homozygous in a sporadic Chinese patient (POI-1) with amenorrhea at 24. The source is internally inconsistent on ACMG class: its text calls both of its variants VUS, while its Table 1 lists them as likely pathogenic. The mutant protein is less nuclear in transfected cells.

Show evidence (1 reference)

PMID:35174157 SUPPORT In vitro / ex vivo

"An in vitro functional study revealed that both variations impaired the nuclear location of HSF2BP and affected its DNA repair capacity."

Functional assay of p.Cys128Arg and p.Leu186Pro in cultured cells.

p.Leu186Pro

c.557T>C, homozygous in a second sporadic Chinese patient (POI-2) whose irregular menses stopped in her late teens (at 18 in the text, 16 in Table 1). ACMG class is given as VUS in the text and likely pathogenic in Table 1. The mutant protein is less nuclear in transfected cells.

Show evidence (1 reference)

PMID:35174157 SUPPORT In vitro / ex vivo

"However, the signals of two mutant proteins (C128R and L186P) localizing in the nucleus were significantly lower than those of the wild-type protein"

Reduced nuclear localization of the mutant protein in HeLa and KGN cells.

💊

Medical Actions

1

Hormone replacement therapy

Action: Hormone Replacement Therapy NCIT:C15599

Agent: estradiol CHEBI:23965 progesterone CHEBI:17026

Platform: Small molecule

There is no HSF2BP-directed therapy. As for other causes of POI, estrogen with progestogen replaces ovarian hormones to limit the bone, cardiovascular and other consequences of early estrogen loss; it does not restore fertility, for which donor oocytes are the usual option. The progestogen is bound as progesterone because the ChEBI progestogen class is a role term that the agent slot does not admit; other progestogens are equally used.

Target Phenotypes: Premature ovarian insufficiency HP:0008209

Show evidence (1 reference)

PMID:39652037 SUPPORT REVIEW SYNTHESIS Other

"Although hormone therapy (HT) can mitigate some of these effects"

The 2024 ESHRE POI guideline; applies to POI of any cause, not tested specifically in HSF2BP-related disease.

🔬

Diagnosis

1

Exome sequencing

All reported cases were found by exome sequencing of POI patients. There is no biochemical test specific to the cause.

whole exome sequencing NCIT:C101295

Show evidence (1 reference)

PMID:32845237 SUPPORT Human clinical

"Using whole-exome sequencing in a family with three cases of POI, we identified the candidate missense variant S167L in HSF2BP"

The founding family was solved by exome sequencing.

🐁

Animal Models

2

Hsf2bp knockout mouse

Independent Hsf2bp (Meilb2) knockout lines are male-sterile with spermatocyte arrest; females are subfertile with fewer RAD51/DMC1 foci in oocytes and a large loss of follicles.

Species

Mouse

Genotype

Hsf2bp-/-

Publication

PMID:30760716

Pathograph links

Impaired Recombinase Loading and Crossover Formation in Oocytes recapitulates fidelity: high Knockout oocytes form breaks normally but load fewer recombinase foci.

Show evidence (1 reference)

PMID:30760716 SUPPORT Model organism

"we concluded that MEILB2 is also required for recombinase recruitment in female meiosis"

Recombinase recruitment defect in knockout oocytes.

Ovarian Follicle Depletion partially recapitulates fidelity: moderate Knockout females have fewer follicles of every stage and smaller litters, but remain fertile.

Limitations: The null mouse keeps enough follicles to breed, whereas homozygous women with partial loss-of-function alleles lose ovarian function in early adulthood. The knockout is also a complete loss of function, which no patient carries.

Divergences from the human mechanism

species mismatch qualifying

Mouse oocytes tolerate the recombinase-loading defect better than human oocytes, so a null mouse ovary is less affected than the ovary of a woman with a hypomorphic allele.

Show evidence (1 reference)

PMID:30760716 SUPPORT Model organism

"Meilb2−⁄− females exhibited reduced follicle formation and a subfertile phenotype"

Reduced follicles and subfertility, short of ovarian failure.

Hsf2bp S167L knock-in mouse

Mice homozygous for the human founding allele have fewer RAD51/DMC1 foci and crossovers in oocytes and a significant reduction in litters, but a normal follicle count.

Species

Mouse

Genotype

Hsf2bp S167L/S167L

Publication

PMID:32845237

Pathograph links

HSF2BP Partial Loss of Function recapitulates fidelity: high Carries the patient allele, which lowers HSF2BP and BRME1 protein.

Show evidence (1 reference)

PMID:32845237 SUPPORT Model organism

"Functional analysis of the HSF2BP-S167L variant in mouse showed that it behaves as a hypomorphic allele"

The human allele is hypomorphic in mouse.

Impaired Recombinase Loading and Crossover Formation in Oocytes recapitulates fidelity: high Knock-in oocytes have fewer RAD51/DMC1 foci and fewer crossovers.

Show evidence (1 reference)

PMID:32845237 SUPPORT Model organism

"the number of COs (measured as interstitial CDK2 foci) was also reduced in Hsf2bpS167L/S167L oocytes"

Crossover reduction in oocytes carrying the patient allele.

Ovarian Follicle Depletion fails to recapitulate fidelity: low Follicle numbers are normal at 13 months; female fertility is only mildly reduced.

Limitations: The mouse does not develop ovarian insufficiency with the allele that causes it in women, which the authors attribute to lower sensitivity of mice to hypomorphic alleles and to more error-prone human female meiosis.

Divergences from the human mechanism

species mismatch invalidating

The S167L knock-in shows the recombination defect but not the follicle depletion, so it cannot model the ovarian outcome of the human disease.

Show evidence (2 references)

PMID:32845237 SUPPORT Model organism

"Histological analysis of Hsf2bpS167L/S167L ovaries revealed no apparent differences in the number of follicles in comparison to wild-type (WT) animals"

No follicle loss in knock-in females.

+ 1 more reference

{ }

Source YAML

click to show

name: Premature Ovarian Failure 19
creation_date: "2026-10-20T23:40:00Z"
category: Mendelian
synonyms:
- POF19
- HSF2BP-related primary ovarian insufficiency
- HSF2BP-related premature ovarian insufficiency
description: >-
  Premature ovarian failure 19 (POF19) is an autosomal recessive form of
  primary ovarian insufficiency caused by biallelic variants in HSF2BP (heat
  shock transcription factor 2 binding protein, also called MEILB2). HSF2BP is
  a germline protein that binds BRCA2 and, with its partner BRME1, is needed to
  load the recombinases RAD51 and DMC1 onto programmed DNA double-strand breaks
  in meiotic prophase I. Three homozygous missense alleles have been reported:
  p.Ser167Leu in a consanguineous family with three affected sisters, and
  p.Cys128Arg and p.Leu186Pro in two unrelated women from a cohort of 1,030
  sporadic POI cases. Affected women have a spontaneous menarche, irregular
  menses, and loss of menses between their late teens and mid-twenties, with
  high FSH and LH; the two sporadic patients had atrophic ovaries without
  follicles on ultrasound. In mice, loss of Hsf2bp reduces
  recombinase loading and crossovers in oocytes and depletes the follicle pool;
  the p.Ser167Leu allele behaves as a hypomorph. No affected men have been
  reported, although Hsf2bp loss blocks spermatogenesis in mice.
disease_term:
  preferred_term: premature ovarian failure 19
  term:
    id: MONDO:0030985
    label: premature ovarian failure 19
parents:
- Primary Ovarian Insufficiency
- Meiotic Disorder
notes: >-
  Scope: this entry covers the 46,XX ovarian phenotype of biallelic HSF2BP
  variants, matching MONDO:0030985. Human evidence comes from three families
  (PMID:32845237, PMID:35174157). No man homozygous for a disease-causing
  HSF2BP allele has been studied; the founding family had no homozygous male,
  and the Felipe-Medina paper cites an Icelandic report of two healthy
  siblings homozygous for HSF2BP p.Gly224Ter who had no children, which is
  not enough to add a male phenotype here. One affected sister in the founding
  family had short stature, cubitus valgus and short fourth and fifth
  metacarpals, which her sisters did not share; it is not recorded as a
  disease feature. No GeneReviews chapter and no POF19-specific prevalence
  figure were found.
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Affected women are homozygous for HSF2BP missense variants; in the founding
    consanguineous family both parents and the fertile siblings are
    heterozygous carriers.
  evidence:
  - reference: PMID:32845237
    reference_title: "A missense in HSF2BP causing primary ovarian insufficiency affects meiotic recombination by its novel interactor C19ORF57/BRME1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All affected family members are homozygous for the variant, and the
      healthy relatives are heterozygous carriers.
    explanation: >-
      Recessive segregation of HSF2BP p.Ser167Leu in the founding family.
  - reference: PMID:35174157
    reference_title: "Pathogenic Variations of Homologous Recombination Gene HSF2BP Identified in Sporadic Patients With Premature Ovarian Insufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      only two homozygous missense variations (following recessive inheritance
      pattern) were found, c.382T > C (p.C128R) and c.557T > C (p.L186P)
    explanation: >-
      Two further homozygous patients in a sporadic POI cohort, consistent
      with recessive inheritance.
genetic:
- name: HSF2BP
  gene_term:
    preferred_term: HSF2BP
    term:
      id: hgnc:5226
      label: HSF2BP
  association: Causal
  relationship_type: CAUSATIVE
  notes: >-
    Three homozygous missense variants are reported (NM_007031.2):
    c.500C>T p.Ser167Leu, c.382T>C p.Cys128Arg and c.557T>C p.Leu186Pro. Six
    other HSF2BP variants found in the same sporadic cohort were not
    biallelic and were not reported as causal.
  evidence:
  - reference: PMID:32845237
    reference_title: "A missense in HSF2BP causing primary ovarian insufficiency affects meiotic recombination by its novel interactor C19ORF57/BRME1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Using whole-exome sequencing in a family with three cases of POI, we
      identified the candidate missense variant S167L in HSF2BP, an essential
      meiotic gene.
    explanation: >-
      First report linking HSF2BP to POI.
  - reference: PMID:35174157
    reference_title: "Pathogenic Variations of Homologous Recombination Gene HSF2BP Identified in Sporadic Patients With Premature Ovarian Insufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In this study, through the largest in-house WES database of 1,030
      patients with sporadic POI, we identified two novel homozygous
      variations in HSF2BP (c.382T>C, p.C128R; c.557T>C, p.L186P).
    explanation: >-
      Independent patients with different homozygous HSF2BP alleles.
  variants:
  - name: p.Ser167Leu
    description: >-
      c.500C>T (rs200655253), homozygous in three sisters of Israeli Arab
      origin born to first-cousin parents. Very rare in gnomAD and never seen
      homozygous in public databases. A knock-in mouse shows it is a
      hypomorphic allele that lowers HSF2BP and BRME1 protein levels.
    evidence:
    - reference: PMID:32845237
      reference_title: "A missense in HSF2BP causing primary ovarian insufficiency affects meiotic recombination by its novel interactor C19ORF57/BRME1."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Functional analysis of the HSF2BP-S167L variant in mouse showed that
        it behaves as a hypomorphic allele compared to a new loss-of-function
        (knock-out) mouse model.
      explanation: >-
        The human allele, knocked into the mouse, partially reduces HSF2BP
        function.
  - name: p.Cys128Arg
    description: >-
      c.382T>C, homozygous in a sporadic Chinese patient (POI-1) with
      amenorrhea at 24. The source is internally inconsistent on ACMG class:
      its text calls both of its variants VUS, while its Table 1 lists them as
      likely pathogenic. The mutant protein is less nuclear in transfected
      cells.
    evidence:
    - reference: PMID:35174157
      reference_title: "Pathogenic Variations of Homologous Recombination Gene HSF2BP Identified in Sporadic Patients With Premature Ovarian Insufficiency."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        An in vitro functional study revealed that both variations impaired
        the nuclear location of HSF2BP and affected its DNA repair capacity.
      explanation: >-
        Functional assay of p.Cys128Arg and p.Leu186Pro in cultured cells.
  - name: p.Leu186Pro
    description: >-
      c.557T>C, homozygous in a second sporadic Chinese patient (POI-2) whose
      irregular menses stopped in her late teens (at 18 in the text, 16 in
      Table 1). ACMG class is given as VUS in the text and likely pathogenic
      in Table 1. The mutant protein is less nuclear in transfected cells.
    evidence:
    - reference: PMID:35174157
      reference_title: "Pathogenic Variations of Homologous Recombination Gene HSF2BP Identified in Sporadic Patients With Premature Ovarian Insufficiency."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        However, the signals of two mutant proteins (C128R and L186P)
        localizing in the nucleus were significantly lower than those of the
        wild-type protein
      explanation: >-
        Reduced nuclear localization of the mutant protein in HeLa and KGN
        cells.
pathophysiology:
- name: HSF2BP Partial Loss of Function
  description: >-
    The disease alleles reduce HSF2BP function without abolishing it.
    p.Ser167Leu lowers the protein level of HSF2BP and of its stabilizing
    partner BRME1, and p.Cys128Arg and p.Leu186Pro reduce its nuclear localization.
    HSF2BP binds a conserved region of BRCA2 between the BRC repeats and the
    DNA-binding domain, and the HSF2BP-BRME1 complex brings BRCA2 to meiotic
    double-strand breaks.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: HSF2BP
    term:
      id: hgnc:5226
      label: HSF2BP
  molecular_functions:
  - preferred_term: BRCA2 binding
    term:
      id: GO:0005515
      label: protein binding
    modifier: DECREASED
  genetic_context:
    variant_origin: GERMLINE
    functional_impact_category: PARTIAL_LOSS_OF_FUNCTION
  notes: >-
    Protein binding is the only molecular function GO annotates HSF2BP with
    (IPI, including PMID:31242413); GO has no BRCA2-binding term, so the
    partner is named in preferred_term. The modifier reflects less HSF2BP
    protein available to bind, not a measured loss of binding affinity.
  evidence:
  - reference: PMID:32845237
    reference_title: "A missense in HSF2BP causing primary ovarian insufficiency affects meiotic recombination by its novel interactor C19ORF57/BRME1."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      The S167L human recessive POI variant behave as a hypomorphic allele in
      mice, which results in a reduction of the protein expression/stability
      of itself and of its partner BRME1 in vivo and in transfected cells.
    explanation: >-
      The founding allele reduces HSF2BP and BRME1 protein in mouse meiocytes
      and transfected cells.
  - reference: PMID:35174157
    reference_title: "Pathogenic Variations of Homologous Recombination Gene HSF2BP Identified in Sporadic Patients With Premature Ovarian Insufficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Functional studies revealed the variations adversely affected the DNA
      repair capacity of HSF2BP due to disturbed nuclear localization
    explanation: >-
      The two sporadic-case alleles impair HSF2BP in cultured cells.
  - reference: PMID:31242413
    reference_title: "HSF2BP Interacts with a Conserved Domain of BRCA2 and Is Required for Mouse Spermatogenesis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The BRCA2-HSF2BP interaction is highly evolutionarily conserved and maps
      to armadillo repeats in HSF2BP and a 68-amino acid region between the
      BRC repeats and the DNA binding domain of human BRCA2 (Gly2270-Thr2337)
      encoded by exons 12 and 13.
    explanation: >-
      Defines the BRCA2 interaction that the HSF2BP complex provides.
  - reference: PMID:30760716
    reference_title: "A meiosis-specific BRCA2 binding protein recruits recombinases to DNA double-strand breaks to ensure homologous recombination."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We conclude that localization of BRCA2 to meiotic DSBs is mediated by
      MEILB2, which is an integral mechanism to repair abundant meiotic DSBs.
    explanation: >-
      Normal function: HSF2BP brings BRCA2 to meiotic breaks (shown mainly
      in spermatocytes).
  downstream:
  - target: Impaired Recombinase Loading and Crossover Formation in Oocytes
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:32845237
      reference_title: "A missense in HSF2BP causing primary ovarian insufficiency affects meiotic recombination by its novel interactor C19ORF57/BRME1."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Meiocytes bearing the HSF2BP-S167L variant showed a strongly decreased
        staining of both HSF2BP and BRME1 at the recombination nodules and a
        reduced number of the foci formed by the recombinases RAD51/DMC1, thus
        leading to a lower frequency of crossovers.
      explanation: >-
        In knock-in mice, the human allele lowers HSF2BP-BRME1 at
        recombination sites, and with it recombinase foci and crossovers.
- name: Impaired Recombinase Loading and Crossover Formation in Oocytes
  conforms_to: "meiotic_prophase_failure#Homologous Recombination Repair of Meiotic DNA Breaks"
  description: >-
    Without enough HSF2BP-BRME1, BRCA2 does not efficiently load RAD51 and
    DMC1 onto resected meiotic double-strand breaks. In knockout oocytes break formation and resection
    look normal (RPA2 foci), recombinase foci fall by about half, homolog
    synapsis is delayed, and fewer crossovers form. The defect is milder in
    oocytes than in spermatocytes, and Hsf2bp-null females remain fertile.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: oocyte
    term:
      id: CL:0000023
      label: oocyte
  biological_processes:
  - preferred_term: DNA recombinase assembly
    term:
      id: GO:0000730
      label: DNA recombinase assembly
    modifier: DECREASED
  - preferred_term: double-strand break repair via homologous recombination
    term:
      id: GO:0000724
      label: double-strand break repair via homologous recombination
    modifier: DECREASED
  - preferred_term: reciprocal meiotic recombination
    term:
      id: GO:0007131
      label: reciprocal meiotic recombination
    modifier: DECREASED
  evidence:
  - reference: PMID:30760716
    reference_title: "A meiosis-specific BRCA2 binding protein recruits recombinases to DNA double-strand breaks to ensure homologous recombination."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      However, there were significant reductions in the numbers of DMC1 and
      RAD51 foci in Meilb2−⁄− oocytes compared to WT oocytes
    explanation: >-
      Hsf2bp (Meilb2) knockout oocytes load fewer recombinase foci in
      zygotene, while break formation and resection (RPA2 foci) are normal.
  - reference: PMID:32845237
    reference_title: "A missense in HSF2BP causing primary ovarian insufficiency affects meiotic recombination by its novel interactor C19ORF57/BRME1."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      In agreement with the lower presence of recombinases, the number of COs
      (measured as interstitial CDK2 foci) was also reduced in
      Hsf2bpS167L/S167L oocytes, and a stronger reduction was observed in
      Hsf2bp-/- oocytes
    explanation: >-
      Crossovers are reduced in oocytes carrying the human allele, and more
      so in null oocytes.
  downstream:
  - target: Oocyte Elimination in Meiotic Prophase
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:30760716
      reference_title: "A meiosis-specific BRCA2 binding protein recruits recombinases to DNA double-strand breaks to ensure homologous recombination."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        suggesting that a large portion of oocytes were eliminated during
        early development prior to the formation of primordial follicles
      explanation: >-
        The authors attribute the follicle deficit in knockout ovaries to
        loss of oocytes with prophase I defects.
- name: Oocyte Elimination in Meiotic Prophase
  conforms_to: "meiotic_prophase_failure#Pachytene Checkpoint Arrest and Germ Cell Apoptosis"
  description: >-
    Oocytes that fail to repair meiotic breaks are eliminated before
    primordial follicles form, so fewer oocytes enter the follicle reserve.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: oocyte
    term:
      id: CL:0000023
      label: oocyte
  notes: >-
    No apoptosis assay has been reported in Hsf2bp-mutant oocytes; the node
    records oocyte loss, and no apoptosis term is bound for that reason.
  evidence:
  - reference: PMID:30760716
    reference_title: "A meiosis-specific BRCA2 binding protein recruits recombinases to DNA double-strand breaks to ensure homologous recombination."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Meilb2 KO female mice also show similar phenotypes but milder than
      males, and they have a massive reduction in the number of oocytes and
      suffer from subfertility.
    explanation: >-
      Oocyte numbers fall sharply in knockout females. The quote reports the
      loss; the mechanism of elimination is inferred from the checkpoint
      node in the module.
  downstream:
  - target: Ovarian Follicle Depletion
    causal_link_type: DIRECT
- name: Ovarian Follicle Depletion
  conforms_to: "meiotic_prophase_failure#Ovarian Follicle Depletion and Primary Ovarian Insufficiency"
  description: >-
    Loss of oocytes leaves a small follicle reserve that is used up early.
    Affected women have a spontaneous menarche and some years of irregular
    cycles before ovarian function stops. The two sporadic patients had
    atrophic ovaries with no visible follicles; in the founding family, one
    twin's ovaries were normal on ultrasound.
  biological_scale: TISSUE
  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:35174157
    reference_title: "Pathogenic Variations of Homologous Recombination Gene HSF2BP Identified in Sporadic Patients With Premature Ovarian Insufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Ultrasound examination showed the two patients had atrophic ovaries
      without follicles
    explanation: >-
      Both sporadic patients have ovaries with no follicles on ultrasound.
  - reference: PMID:32845237
    reference_title: "A missense in HSF2BP causing primary ovarian insufficiency affects meiotic recombination by its novel interactor C19ORF57/BRME1."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      in contrast with the drastic reduction of the follicle pool in
      Hsf2bp-/- ovaries
    explanation: >-
      Null mice lose most of the follicle pool.
  downstream:
  - target: Premature ovarian insufficiency
    causal_link_type: DIRECT
  - target: Secondary amenorrhea
    causal_link_type: DIRECT
  - target: Oligomenorrhea
    causal_link_type: DIRECT
  - target: Female infertility
    causal_link_type: DIRECT
  - target: Elevated circulating follicle stimulating hormone level
    causal_link_type: DIRECT
    description: >-
      Loss of follicles removes ovarian negative feedback on the pituitary.
  - target: Elevated circulating luteinizing hormone level
    causal_link_type: DIRECT
    description: >-
      Loss of follicles removes ovarian negative feedback on the pituitary.
  - target: Decreased serum estradiol
    causal_link_type: DIRECT
    description: >-
      Without growing follicles the ovary makes little estradiol.
phenotypes:
- name: Premature ovarian insufficiency
  category: Reproductive
  description: >-
    Cessation of ovarian function before age 40 in all reported homozygous
    women, after a spontaneous menarche.
  phenotype_term:
    preferred_term: Premature ovarian insufficiency
    term:
      id: HP:0008209
      label: Premature ovarian insufficiency
    onset:
      onset_category: YOUNG_ADULT
      notes: >-
        Menses stopped around age 25 in the founding family (amenorrhea at 24
        and 25 in the twins) and at 24 in patient POI-1; patient POI-2 stopped
        menstruating at 18 according to the text of PMID:35174157, or 16
        according to its Table 1.
  evidence:
  - reference: PMID:32845237
    reference_title: "A missense in HSF2BP causing primary ovarian insufficiency affects meiotic recombination by its novel interactor C19ORF57/BRME1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Of the five daughters, three are affected with POI and presented with
      early secondary amenorrhea.
    explanation: >-
      POI in the three homozygous sisters of the founding family.
  - reference: PMID:35174157
    reference_title: "Pathogenic Variations of Homologous Recombination Gene HSF2BP Identified in Sporadic Patients With Premature Ovarian Insufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      two novel pathogenic homozygous variations of HSF2BP were identified in
      two patients with sporadic POI
    explanation: >-
      POI in two unrelated homozygous patients.
- name: Secondary amenorrhea
  category: Reproductive
  description: >-
    Menses begin at a normal age and then stop.
  phenotype_term:
    preferred_term: Secondary amenorrhea
    term:
      id: HP:0000869
      label: Secondary amenorrhea
  evidence:
  - reference: PMID:32845237
    reference_title: "A missense in HSF2BP causing primary ovarian insufficiency affects meiotic recombination by its novel interactor C19ORF57/BRME1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      They had menarche at normal age (at 13–14) but with irregular menses
      that stopped around 25.
    explanation: >-
      Normal menarche followed by loss of menses in the founding family.
  - reference: PMID:35174157
    reference_title: "Pathogenic Variations of Homologous Recombination Gene HSF2BP Identified in Sporadic Patients With Premature Ovarian Insufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patient POI-1, who carried HSF2BP p.C128R, experienced menarche at 11
      years old, underwent irregular menstrual cycle (2–12 months per
      menstrual cycle) since 13 years old, and suffered amenorrhea at 24 years
      of age.
    explanation: >-
      Secondary amenorrhea at 24 in a sporadic patient.
- name: Oligomenorrhea
  category: Reproductive
  description: >-
    Irregular, infrequent menses from soon after menarche until menses stop.
  phenotype_term:
    preferred_term: Oligomenorrhea
    term:
      id: HP:0000876
      label: Oligomenorrhea
  evidence:
  - reference: PMID:32845237
    reference_title: "A missense in HSF2BP causing primary ovarian insufficiency affects meiotic recombination by its novel interactor C19ORF57/BRME1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      III-1 became amenorrheic at age 24 and III-2 at age 25, both after
      irregular menstruations since menarche.
    explanation: >-
      Irregular menses preceded amenorrhea in both twins.
  - reference: PMID:35174157
    reference_title: "Pathogenic Variations of Homologous Recombination Gene HSF2BP Identified in Sporadic Patients With Premature Ovarian Insufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patient POI-2, who carried HSF2BP p.L186P, experienced menarche at 16
      years old, followed by an irregular menstrual cycle that ceased at the
      age of 18.
    explanation: >-
      Irregular cycles after menarche in the second sporadic patient.
- name: Elevated circulating follicle stimulating hormone level
  category: Endocrine
  description: >-
    FSH in the postmenopausal range, the laboratory finding that defines POI.
  phenotype_term:
    preferred_term: Elevated circulating follicle stimulating hormone level
    term:
      id: HP:0008232
      label: Elevated circulating follicle stimulating hormone level
  evidence:
  - reference: PMID:35174157
    reference_title: "Pathogenic Variations of Homologous Recombination Gene HSF2BP Identified in Sporadic Patients With Premature Ovarian Insufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      | POI-1 | Homozygous | c.382T>C | p.C128R | LP | 11 | 24 | 79.09 |
    explanation: >-
      Patient POI-1 had serum FSH of 79.09 IU/L; the cohort's diagnostic
      threshold was FSH above 25 IU/L. POI-2 had 71.37 IU/L.
  - reference: PMID:35174157
    reference_title: "Pathogenic Variations of Homologous Recombination Gene HSF2BP Identified in Sporadic Patients With Premature Ovarian Insufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      at least twice serum FSH >25 IU/L at an internal of 4–6 weeks
    explanation: >-
      The FSH criterion every patient in the cohort met, including both
      HSF2BP homozygotes.
  - reference: PMID:35174157
    reference_title: "Pathogenic Variations of Homologous Recombination Gene HSF2BP Identified in Sporadic Patients With Premature Ovarian Insufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      | POI-2 | Homozygous | c.557T>C | p.L186P | LP | 16 | 16 | 71.37 |
    explanation: >-
      Patient POI-2 had serum FSH of 71.37 IU/L.
- name: Elevated circulating luteinizing hormone level
  category: Endocrine
  description: >-
    Raised LH accompanies the raised FSH of ovarian failure.
  phenotype_term:
    preferred_term: Elevated circulating luteinizing hormone level
    term:
      id: HP:0011969
      label: Elevated circulating luteinizing hormone level
  evidence:
  - reference: PMID:35174157
    reference_title: "Pathogenic Variations of Homologous Recombination Gene HSF2BP Identified in Sporadic Patients With Premature Ovarian Insufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      | POI-1 | Homozygous | c.382T>C | p.C128R | LP | 11 | 24 | 79.09 | 21.63 |
    explanation: >-
      Table 1 row for POI-1; LH 21.63 IU/L. POI-2 had LH 38.61 IU/L. The
      paper gives no LH reference range; both values are above the usual
      follicular-phase range.
- name: Decreased serum estradiol
  category: Endocrine
  description: >-
    Estradiol at or below the assay floor of 5 pg/mL in both sporadic
    patients.
  phenotype_term:
    preferred_term: Decreased serum estradiol
    term:
      id: HP:0008214
      label: Decreased serum estradiol
  evidence:
  - reference: PMID:35174157
    reference_title: "Pathogenic Variations of Homologous Recombination Gene HSF2BP Identified in Sporadic Patients With Premature Ovarian Insufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      | POI-2 | Homozygous | c.557T>C | p.L186P | LP | 16 | 16 | 71.37 | 38.61 | <5.0 |
    explanation: >-
      Table 1 row for POI-2; estradiol below 5.0 pg/mL. POI-1 had 5.0 pg/mL.
- name: Female infertility
  category: Reproductive
  description: >-
    Infertility; one of the three sisters in the founding family had one child
    after fertility treatment, consistent with a hypomorphic allele.
  phenotype_term:
    preferred_term: Female infertility
    term:
      id: HP:0008222
      label: Female infertility
  evidence:
  - reference: PMID:32845237
    reference_title: "A missense in HSF2BP causing primary ovarian insufficiency affects meiotic recombination by its novel interactor C19ORF57/BRME1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Only one of the patients affected by POI could have a child with the
      help of a fertility treatment
    explanation: >-
      Two of the three affected sisters had no children; the third conceived
      only with treatment.
diagnosis:
- name: Exome sequencing
  diagnosis_term:
    preferred_term: whole exome sequencing
    term:
      id: NCIT:C101295
      label: Whole Exome Sequencing
  description: >-
    All reported cases were found by exome sequencing of POI patients. There is
    no biochemical test specific to the cause.
  evidence:
  - reference: PMID:32845237
    reference_title: "A missense in HSF2BP causing primary ovarian insufficiency affects meiotic recombination by its novel interactor C19ORF57/BRME1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Using whole-exome sequencing in a family with three cases of POI, we
      identified the candidate missense variant S167L in HSF2BP
    explanation: >-
      The founding family was solved by exome sequencing.
treatments:
- name: Hormone replacement therapy
  description: >-
    There is no HSF2BP-directed therapy. As for other causes of POI, estrogen
    with progestogen replaces ovarian hormones to limit the bone,
    cardiovascular and other consequences of early estrogen loss; it does not
    restore fertility, for which donor oocytes are the usual option. The
    progestogen is bound as progesterone because the ChEBI progestogen class
    is a role term that the agent slot does not admit; other progestogens are
    equally used.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Hormone Replacement Therapy
    term:
      id: NCIT:C15599
      label: Hormone Replacement Therapy
    therapeutic_agent:
    - preferred_term: estradiol
      term:
        id: CHEBI:23965
        label: estradiol
    - preferred_term: progesterone
      term:
        id: CHEBI:17026
        label: progesterone
  target_phenotypes:
  - preferred_term: Premature ovarian insufficiency
    term:
      id: HP:0008209
      label: Premature ovarian insufficiency
  evidence:
  - reference: PMID:39652037
    reference_title: "Evidence-based guideline: Premature Ovarian Insufficiency."
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: OTHER
    snippet: >-
      Although hormone therapy (HT) can mitigate some of these effects
    explanation: >-
      The 2024 ESHRE POI guideline; applies to POI of any cause, not tested
      specifically in HSF2BP-related disease.
animal_models:
- name: Hsf2bp knockout mouse
  species: Mouse
  genotype: Hsf2bp-/-
  publication: PMID:30760716
  description: >-
    Independent Hsf2bp (Meilb2) knockout lines are male-sterile with
    spermatocyte arrest; females are subfertile with fewer RAD51/DMC1 foci in
    oocytes and a large loss of follicles.
  modeled_mechanisms:
  - target: Impaired Recombinase Loading and Crossover Formation in Oocytes
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >-
      Knockout oocytes form breaks normally but load fewer recombinase foci.
    evidence:
    - reference: PMID:30760716
      reference_title: "A meiosis-specific BRCA2 binding protein recruits recombinases to DNA double-strand breaks to ensure homologous recombination."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        we concluded that MEILB2 is also required for recombinase recruitment
        in female meiosis
      explanation: >-
        Recombinase recruitment defect in knockout oocytes.
  - target: Ovarian Follicle Depletion
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >-
      Knockout females have fewer follicles of every stage and smaller
      litters, but remain fertile.
    limitations: >-
      The null mouse keeps enough follicles to breed, whereas homozygous women
      with partial loss-of-function alleles lose ovarian function in early
      adulthood. The knockout is also a complete loss of function, which no
      patient carries.
    divergences:
    - divergence_type: SPECIES_MISMATCH
      materiality: QUALIFYING
      description: >-
        Mouse oocytes tolerate the recombinase-loading defect better than
        human oocytes, so a null mouse ovary is less affected than the ovary
        of a woman with a hypomorphic allele.
    evidence:
    - reference: PMID:30760716
      reference_title: "A meiosis-specific BRCA2 binding protein recruits recombinases to DNA double-strand breaks to ensure homologous recombination."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Meilb2−⁄− females exhibited reduced follicle formation and a subfertile
        phenotype
      explanation: >-
        Reduced follicles and subfertility, short of ovarian failure.
- name: Hsf2bp S167L knock-in mouse
  species: Mouse
  genotype: Hsf2bp S167L/S167L
  publication: PMID:32845237
  description: >-
    Mice homozygous for the human founding allele have fewer RAD51/DMC1 foci
    and crossovers in oocytes and a significant reduction in litters, but a
    normal follicle count.
  modeled_mechanisms:
  - target: HSF2BP Partial Loss of Function
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >-
      Carries the patient allele, which lowers HSF2BP and BRME1 protein.
    evidence:
    - reference: PMID:32845237
      reference_title: "A missense in HSF2BP causing primary ovarian insufficiency affects meiotic recombination by its novel interactor C19ORF57/BRME1."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Functional analysis of the HSF2BP-S167L variant in mouse showed that
        it behaves as a hypomorphic allele
      explanation: >-
        The human allele is hypomorphic in mouse.
  - target: Impaired Recombinase Loading and Crossover Formation in Oocytes
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >-
      Knock-in oocytes have fewer RAD51/DMC1 foci and fewer crossovers.
    evidence:
    - reference: PMID:32845237
      reference_title: "A missense in HSF2BP causing primary ovarian insufficiency affects meiotic recombination by its novel interactor C19ORF57/BRME1."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        the number of COs (measured as interstitial CDK2 foci) was also
        reduced in Hsf2bpS167L/S167L oocytes
      explanation: >-
        Crossover reduction in oocytes carrying the patient allele.
  - target: Ovarian Follicle Depletion
    relationship: FAILS_TO_RECAPITULATE
    fidelity: LOW
    description: >-
      Follicle numbers are normal at 13 months; female fertility is only
      mildly reduced.
    limitations: >-
      The mouse does not develop ovarian insufficiency with the allele that
      causes it in women, which the authors attribute to lower sensitivity of
      mice to hypomorphic alleles and to more error-prone human female meiosis.
    divergences:
    - divergence_type: SPECIES_MISMATCH
      materiality: INVALIDATING
      description: >-
        The S167L knock-in shows the recombination defect but not the
        follicle depletion, so it cannot model the ovarian outcome of the
        human disease.
    evidence:
    - reference: PMID:32845237
      reference_title: "A missense in HSF2BP causing primary ovarian insufficiency affects meiotic recombination by its novel interactor C19ORF57/BRME1."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Histological analysis of Hsf2bpS167L/S167L ovaries revealed no apparent
        differences in the number of follicles in comparison to wild-type (WT)
        animals
      explanation: >-
        No follicle loss in knock-in females.
    - reference: PMID:32845237
      reference_title: "A missense in HSF2BP causing primary ovarian insufficiency affects meiotic recombination by its novel interactor C19ORF57/BRME1."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        the sub-fertility observed in HSF2BP-S167L females appears to be
        milder in comparison to the phenotype of the human patients
      explanation: >-
        The authors state the mouse phenotype is milder than the human one.

📚

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: Premature_Ovarian_Failure_19 · 2026-10-21T00:08:59Z · View source

New entry for HSF2BP-related premature ovarian failure 19 (MONDO:0030985; OMIM 619245), claimed in #15074, modelled on Premature_Ovarian_Failure_20 and conforming to meiotic_prophase_failure. Human evidence is the founding consanguineous family with homozygous p.Ser167Leu (PMID:32845237) and two sporadic homozygous patients, p.Cys128Arg and p.Leu186Pro, from a 1,030-patient POI cohort (PMID:35174157). Mechanism evidence is from Hsf2bp knockout and S167L knock-in mice (PMID:30760716, PMID:32845237) and the BRCA2-binding study (PMID:31242413). Most snippets were taken from cached full texts read directly. PMID:35174157 contradicts itself in two places, which the entry records rather than resolving: ACMG class (VUS in its text, LP in Table 1) and POI-2's age at amenorrhea (18 in the text, 16 in Table 1). Deep research: falcon was requested but had no usable key, so the --fallback run went to openscientist. That report failed just preflight-dr. It never names HSF2BP and is about ZSWIM7 (ovarian dysgenesis 10, already curated in 46_XX_Gonadal_Dysgenesis), so it was discarded and not committed, and the reference-cache rewrites its validation made were reverted. A claude_code report then passed preflight-dr (HSF2BP 19 mentions; BRCA2 is the binding partner, not a rival disease). It was committed, but its fetches of the primary papers were blocked, so it contributed no facts beyond the sources above. A subagent self-review found 13 issues. All were addressed except one: the downstream edges from follicle depletion to the phenotype nodes remain uncited textbook physiology. Validation: just validate, validate-terms, count-verified-snippets (38/38), check-entity-refs, check-causal-targets and the offline snippet/prose gates all pass. After PR review, the CI gene-activity-grounding gate required a molecular function on the HSF2BP node; GO:0005515 protein binding (GO's only HSF2BP molecular-function annotation) was bound, and an uncited reference cache (PMID:34794894) was dropped.

Claude Code ▸

Premature Ovarian Failure 19 (POF19): research report

claude-haiku-5-5, claude-sonnet-5-5 10 citations 2026-10-21T00:07:49.811545

I'll start by loading the search tools.

I'm gathering primary-source details on the HSF2BP paper. The direct fetches of the eLife and PMC pages were refused by the proxy, so I'm checking the proxy status and trying other routes.

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).

Item	Value	Source
OMIM	619245	DrugMap and OMIM mirror (secondary; the OMIM page itself was not read)
MONDO	MONDO:0030985	DrugMap, NORD
DOID	DOID:0112278 (synonyms POF19, POI19)	Disease Ontology
MedGen	C5543229 / 1779702 (the two IDs conflict across sources)	MedGen via search
ClinGen-style gene-disease evidence	"Limited"	DrugMap

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].

Phenotype	Suggested HPO	Frequency
Secondary amenorrhea	HP:0000869	3/3 reported
Irregular menstruation, oligomenorrhea	HP:0000858	3/3 reported
Premature ovarian failure	HP:0008209	3/3 reported
Female infertility	HP:0008222	Implied
Elevated FSH / hypergonadotropism	HP:0000837	[unverified]

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):

Homozygous HSF2BP S167L reduces the amount and function of HSF2BP in meiocytes.
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.
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.
Oocyte and follicle loss follows, which is inferred for women. The result is early depletion of the ovarian reserve, then secondary amenorrhea and infertility.
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.
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.
Suggested terms:
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.
CL: oocyte (CL:0000023), primary oocyte.
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

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

Sources

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome	Count
References checked	5
Resolved	4
Unresolved (possible confabulation)	0
Unverifiable	1
References weighed for topical relevance	4
On topic	1
Off topic	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.

Outcome	Count
Terms checked	16
Resolved	16
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	0
Terms whose name was checked	12
Terms named correctly	4
Terms named as a different term	2
Terms whose name is worth a second look	6

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

Premature Ovarian Failure 19

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Premature Ovarian Failure 19 (POF19): research report

1. Disease information

2. Etiology

3. Phenotypes

4. Genetic and molecular information

5. Environmental information

6. Mechanism and pathophysiology

7. Anatomical structures affected

8. Temporal development

9. Inheritance and population

10. Diagnostics

11. Prognosis

12. Treatment

13. Prevention

14. Other species

15. Model organisms

Gaps to close before curating

Sources

Reference Validation

Term Validation

Terms the report names something else

Terms whose name is worth a second look