HROB-related gametogenic failure

Mendelian MONDO:0971176 Pathograph 13 Show in embeddings browser Primary ovarian insufficiency Ovarian dysgenesis Female infertility

HROB-related gametogenic failure is a recessive meiotic DNA-repair disorder caused by biallelic loss-of-function variants in HROB (also known as C17orf53 or MCM8IP). HROB encodes the OB-fold factor that recruits and activates the MCM8-MCM9 helicase during homologous-recombination repair of DNA breaks, including the programmed double-strand breaks of meiotic prophase I. The human spectrum reported to date is female: primary ovarian insufficiency, ovarian dysgenesis with hypergonadotropic hypogonadism, and delayed puberty (ovarian dysgenesis 11, OMIM:620897). Hrob-mutant mice are infertile in both sexes from germ-cell depletion with prophase I meiotic arrest, so an analogous male spermatogenic-failure branch is predicted but has not yet been reported in humans. The shared mechanistic theme is failed homologous recombination during meiosis with germ-cell loss.

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1
Inheritance
4
Pathophys.
8
Phenotypes
13
Pathograph
1
Genes
1
Medical Actions
👪

Inheritance

1
Autosomal recessive inheritance HP:0000007
Reported families carry biallelic (homozygous or compound-heterozygous) loss-of-function HROB variants segregating with disease in a recessive pattern.
Autosomal recessive inheritance
Show evidence (2 references)
PMID:34707299 SUPPORT Human Clinical
"two genes, REC8 and HROB, not previously associated with autosomal recessive POI."
This supports autosomal-recessive transmission of HROB-related primary ovarian insufficiency.
PMID:38105698 SUPPORT Human Clinical
"carried heterozygous variants of HROB gene c.718C>T (p.Arg240*) and c.1351C>T (p.Arg451*), which were inherited from their parents respectively and consistent with autosomal recessive inheritance."
This family shows compound-heterozygous HROB nonsense variants segregating as autosomal recessive disease.
⚙

Pathophysiology

4
Impaired homologous recombination
HROB is the OB-fold factor that recruits and activates the MCM8-MCM9 helicase at sites of DNA damage to drive recombination-associated DNA synthesis. Biallelic HROB loss therefore disables MCM8-MCM9-dependent homologous recombination, leaving meiotic and repair-associated DNA breaks unresolved.
HROB hgnc:28460
double-strand break repair via homologous recombination GO:0000724 ↓ DECREASED
Downstream
Prophase I meiotic arrest and germ cell depletion Unresolved meiotic recombination intermediates block progression through prophase I, leading to germ-cell arrest and depletion.
Show evidence (3 references)
PMID:31467087 SUPPORT In Vitro
"C17orf53/HROB is an OB-fold-containing factor involved in HR that acts by recruiting the MCM8-MCM9 helicase to sites of DNA damage to promote DNA synthesis."
This places HROB upstream of the MCM8-MCM9 helicase in homologous recombination.
PMID:32528060 SUPPORT In Vitro
"MCM8IP directly associates with MCM8-9, a helicase complex mutated in primary ovarian insufficiency, and RPA1."
This links HROB/MCM8IP physically to the MCM8-9 helicase whose loss causes primary ovarian insufficiency.
PMID:32528060 SUPPORT In Vitro
"MCM8IP stimulates the helicase activity of MCM8-9."
This shows HROB/MCM8IP is required to activate the MCM8-9 helicase, so its loss impairs recombination-associated DNA synthesis.
Prophase I meiotic arrest and germ cell depletion
Germ cells that cannot complete homologous recombination arrest during meiotic prophase I and are eliminated rather than maturing into functional gametes, depleting the germ-cell pool.
germ cell CL:0000586
apoptotic process GO:0006915 ↑ INCREASED
Downstream
Ovarian follicle depletion and primary ovarian insufficiency In 46,XX individuals, germ-cell depletion exhausts the ovarian follicle pool and produces primary ovarian insufficiency / ovarian dysgenesis.
Spermatogenic arrest (predicted male branch) In male mice the same germ-cell depletion produces spermatogenic failure; an analogous male branch is predicted in humans but not yet reported.
Show evidence (1 reference)
PMID:31467087 SUPPORT Model Organism
"Mice with targeted mutations in Hrob are infertile due to depletion of germ cells and display phenotypes consistent with a prophase I meiotic arrest."
This documents prophase I arrest with germ-cell depletion on HROB loss.
Ovarian follicle depletion and primary ovarian insufficiency
Loss of oocytes during meiotic progression depletes the ovarian reserve, presenting clinically as primary ovarian insufficiency, ovarian dysgenesis, and hypergonadotropic hypogonadism in 46,XX individuals.
oocyte CL:0000023
female gamete generation GO:0007292 ↓ DECREASED
Downstream
Premature ovarian insufficiency The female branch presents clinically as primary / premature ovarian insufficiency.
Hypergonadotropic hypogonadism Ovarian failure produces hypergonadotropic hypogonadism with elevated gonadotropins and low anti-Mullerian hormone.
Aplasia of the ovary Severe ovarian dysgenesis in reported individuals manifests on imaging as absent bilateral ovaries.
Delayed puberty Hypoestrogenism from ovarian failure delays development of secondary sexual characteristics.
Delayed menarche Ovarian failure delays menarche in the reported affected girls.
Elevated follicle-stimulating hormone Loss of ovarian feedback leads to elevated circulating follicle-stimulating hormone.
Elevated luteinizing hormone Loss of ovarian feedback leads to elevated circulating luteinizing hormone.
Decreased anti-Mullerian hormone Ovarian follicle depletion is reflected by decreased circulating anti-Mullerian hormone.
Show evidence (2 references)
PMID:34707299 SUPPORT Human Clinical
"In silico analyses, combined with concordant mouse model phenotypes support these as new genetic causes of POI."
This supports HROB variants as a cause of primary ovarian insufficiency.
PMID:38105698 SUPPORT Human Clinical
"both girls were diagnosed with primary ovarian insufficiency."
This independently confirms primary ovarian insufficiency in a second HROB family.
Spermatogenic arrest (predicted male branch)
In male mice, HROB loss depletes germ cells with seminiferous tubules largely devoid of germ cells, predicting a spermatogenic-failure branch in 46,XY humans. No human male case has yet been reported, so this node rests on model-organism evidence only.
spermatocyte CL:0000017
male gamete generation GO:0048232 ↓ DECREASED
Show evidence (1 reference)
PMID:31467087 SUPPORT Model Organism
"Mice with targeted mutations in Hrob are infertile due to depletion of germ cells and display phenotypes consistent with a prophase I meiotic arrest."
Hrob-mutant male mice are infertile from germ-cell depletion, the basis for a predicted human male spermatogenic-failure branch.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for HROB-related gametogenic failure Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

8
Endocrine 3
Hypergonadotropic hypogonadism Hypergonadotropic hypogonadism HP:0000815
Show evidence (1 reference)
PMID:38105698 SUPPORT Human Clinical
"The laboratory test results indicated increased follicle-stimulating hormone and luteinizing hormone, decreased anti-Mullerian hormone, and pelvic ultrasound showed a cord-like uterus and absence of bilateral ovaries."
Elevated gonadotropins with low anti-Mullerian hormone support hypergonadotropic hypogonadism in affected individuals.
Context-specific annotations (1)
FEMALE
Show evidence (1 reference)
PMID:38105698 SUPPORT Human Clinical
"The laboratory test results indicated increased follicle-stimulating hormone and luteinizing hormone, decreased anti-Mullerian hormone, and pelvic ultrasound showed a cord-like uterus and absence of bilateral ovaries."
Elevated gonadotropins with low anti-Mullerian hormone and absent ovaries support hypergonadotropic hypogonadism.
Delayed puberty Delayed puberty HP:0000823
Show evidence (1 reference)
PMID:38105698 SUPPORT Human Clinical
"Oral estradiol valerate at an initial dose of 0.125 mg/d was given to the proband, and the secondary sexual characteristics began to develop after 6 months."
Development of secondary sexual characteristics only after estrogen therapy supports delayed puberty from ovarian failure.
Context-specific annotations (1)
FEMALE
Show evidence (1 reference)
PMID:38105698 SUPPORT Human Clinical
"Oral estradiol valerate at an initial dose of 0.125 mg/d was given to the proband, and the secondary sexual characteristics began to develop after 6 months."
Secondary sexual characteristics developed only after estrogen therapy, indicating delayed puberty.
Delayed menarche Delayed menarche HP:0012569
Show evidence (1 reference)
PMID:38105698 SUPPORT Human Clinical
"A 13-year and 6-month-old girl attended the Hunan Children's Hospital due to delayed menarche."
Delayed menarche was the presenting symptom in the proband with biallelic HROB variants.
Context-specific annotations (1)
FEMALE
Genitourinary 2
Premature ovarian insufficiency Premature ovarian insufficiency HP:0008209
Show evidence (1 reference)
PMID:34707299 SUPPORT Human Clinical
"propose HROB and REC8 variants as new genetic causes while exploring their link to pathogenesis."
This study proposes HROB as a genetic cause of premature ovarian insufficiency.
Context-specific annotations (1)
FEMALE
Reported in 46,XX individuals with biallelic HROB variants.
Show evidence (1 reference)
PMID:38105698 SUPPORT Human Clinical
"both girls were diagnosed with primary ovarian insufficiency."
This documents primary ovarian insufficiency in two sisters with biallelic HROB variants.
Aplasia of the ovary Aplasia of the ovary HP:0010463
Show evidence (1 reference)
PMID:38105698 SUPPORT Human Clinical
"pelvic ultrasound showed a cord-like uterus and absence of bilateral ovaries."
Pelvic ultrasound documented absence of bilateral ovaries in the affected girls.
Context-specific annotations (1)
FEMALE
Reported as absence of bilateral ovaries on pelvic ultrasound.
Show evidence (1 reference)
PMID:38105698 SUPPORT Human Clinical
"pelvic ultrasound showed a cord-like uterus and absence of bilateral ovaries."
Non-visualized bilateral ovaries with a cord-like uterus support ovarian aplasia.
Other 3
Elevated follicle-stimulating hormone Elevated circulating follicle stimulating hormone level HP:0008232
Show evidence (1 reference)
PMID:38105698 SUPPORT Human Clinical
"The laboratory test results indicated increased follicle-stimulating hormone and luteinizing hormone, decreased anti-Mullerian hormone, and pelvic ultrasound showed a cord-like uterus and absence of bilateral ovaries."
The reported laboratory findings explicitly include increased follicle-stimulating hormone.
Context-specific annotations (1)
FEMALE
Elevated luteinizing hormone Elevated circulating luteinizing hormone level HP:0011969
Show evidence (1 reference)
PMID:38105698 SUPPORT Human Clinical
"The laboratory test results indicated increased follicle-stimulating hormone and luteinizing hormone, decreased anti-Mullerian hormone, and pelvic ultrasound showed a cord-like uterus and absence of bilateral ovaries."
The reported laboratory findings explicitly include increased luteinizing hormone.
Context-specific annotations (1)
FEMALE
Decreased anti-Mullerian hormone Decreased circulating antimullerian hormone circulation HP:0031103
Show evidence (1 reference)
PMID:38105698 SUPPORT Human Clinical
"The laboratory test results indicated increased follicle-stimulating hormone and luteinizing hormone, decreased anti-Mullerian hormone, and pelvic ultrasound showed a cord-like uterus and absence of bilateral ovaries."
The reported laboratory findings explicitly include decreased anti-Mullerian hormone.
Context-specific annotations (1)
FEMALE
🧬

Genetic Associations

1
HROB (Causative (Primary))
Autosomal recessive inheritance
Show evidence (2 references)
PMID:34707299 SUPPORT Human Clinical
"HROB encodes a factor that recruits MCM8/9 for DNA damage repair."
This establishes HROB as the causal gene and links it mechanistically to the MCM8-MCM9 DNA-repair complex.
PMID:38105698 SUPPORT Human Clinical
"carried heterozygous variants of HROB gene c.718C>T (p.Arg240*) and c.1351C>T (p.Arg451*), which were inherited from their parents respectively and consistent with autosomal recessive inheritance."
A second family with compound-heterozygous HROB nonsense variants supports the causal gene assignment.
💊

Medical Actions

1
Hormone replacement therapy
Action: hormone replacement therapy Ontology label: Pharmacotherapy NCIT:C15986
Agent: estradiol CHEBI:23965
Estrogen-based hormone replacement is used to treat hypoestrogenism, induce and maintain secondary sexual characteristics, and reduce long-term comorbidity in the ovarian-failure phenotype.
Show evidence (1 reference)
PMID:38105698 SUPPORT Human Clinical
"Oral estradiol valerate at an initial dose of 0.125 mg/d was given to the proband, and the secondary sexual characteristics began to develop after 6 months."
This documents estrogen replacement inducing pubertal development in an affected individual.
{ }

Source YAML

click to show 
name: HROB-related gametogenic failure
creation_date: "2026-06-05T12:00:00Z"
category: Mendelian
description: >-
  HROB-related gametogenic failure is a recessive meiotic DNA-repair disorder
  caused by biallelic loss-of-function variants in HROB (also known as C17orf53
  or MCM8IP). HROB encodes the OB-fold factor that recruits and activates the
  MCM8-MCM9 helicase during homologous-recombination repair of DNA breaks,
  including the programmed double-strand breaks of meiotic prophase I. The
  human spectrum reported to date is female: primary ovarian insufficiency,
  ovarian dysgenesis with hypergonadotropic hypogonadism, and delayed puberty
  (ovarian dysgenesis 11, OMIM:620897). Hrob-mutant mice are infertile in both
  sexes from germ-cell depletion with prophase I meiotic arrest, so an analogous
  male spermatogenic-failure branch is predicted but has not yet been reported in
  humans. The shared mechanistic theme is failed homologous recombination during
  meiosis with germ-cell loss.
disease_term:
  preferred_term: HROB-related gametogenic failure
  term:
    id: MONDO:0971176
    label: ovarian dysgenesis 11
parents:
- Primary ovarian insufficiency
- Ovarian dysgenesis
- Female infertility
synonyms:
- HROB deficiency
- C17orf53-related ovarian dysgenesis
- MCM8IP-related primary ovarian insufficiency
- ovarian dysgenesis 11
- ODG11
notes: >-
  The exact human disease anchor available in MONDO is MONDO:0971176 (ovarian
  dysgenesis 11; OMIM:620897), which captures the female ovarian-dysgenesis /
  primary-ovarian-insufficiency presentation that is the only HROB phenotype
  reported in humans to date. The broader preferred term "HROB-related
  gametogenic failure" reflects the conserved meiotic-prophase mechanism and the
  bisexual germ-cell depletion seen in Hrob-mutant mice; the male
  spermatogenic-failure branch is therefore included as a model-organism-predicted
  node and is not asserted as a human phenotype. This entry conforms to the
  meiotic_prophase_failure module, placing HROB alongside the MCM8/MCM9 helicase
  it loads.
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Reported families carry biallelic (homozygous or compound-heterozygous)
    loss-of-function HROB variants segregating with disease in a recessive
    pattern.
  evidence:
  - reference: PMID:34707299
    reference_title: "Meiotic genes in premature ovarian insufficiency: variants in HROB and REC8 as likely genetic causes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      two genes, REC8 and HROB, not previously associated with autosomal
      recessive POI.
    explanation: >-
      This supports autosomal-recessive transmission of HROB-related primary
      ovarian insufficiency.
  - reference: PMID:38105698
    reference_title: "Genetic analysis of novel pathogenic gene HROB in a family with primary ovarian insufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      carried heterozygous variants of HROB gene c.718C>T (p.Arg240*) and
      c.1351C>T (p.Arg451*), which were inherited from their parents respectively
      and consistent with autosomal recessive inheritance.
    explanation: >-
      This family shows compound-heterozygous HROB nonsense variants segregating
      as autosomal recessive disease.
pathophysiology:
- name: Impaired homologous recombination
  conforms_to: "meiotic_prophase_failure#Homologous Recombination Repair of Meiotic DNA Breaks"
  description: >-
    HROB is the OB-fold factor that recruits and activates the MCM8-MCM9 helicase
    at sites of DNA damage to drive recombination-associated DNA synthesis.
    Biallelic HROB loss therefore disables MCM8-MCM9-dependent homologous
    recombination, leaving meiotic and repair-associated DNA breaks unresolved.
  genes:
  - preferred_term: HROB
    term:
      id: hgnc:28460
      label: HROB
  biological_processes:
  - preferred_term: double-strand break repair via homologous recombination
    term:
      id: GO:0000724
      label: double-strand break repair via homologous recombination
    modifier: DECREASED
  evidence:
  - reference: PMID:31467087
    reference_title: "Control of homologous recombination by the HROB-MCM8-MCM9 pathway."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      C17orf53/HROB is an OB-fold-containing factor involved in HR that acts by
      recruiting the MCM8-MCM9 helicase to sites of DNA damage to promote DNA
      synthesis.
    explanation: >-
      This places HROB upstream of the MCM8-MCM9 helicase in homologous
      recombination.
  - reference: PMID:32528060
    reference_title: "MCM8IP activates the MCM8-9 helicase to promote DNA synthesis and homologous recombination upon DNA damage."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      MCM8IP directly associates with MCM8-9, a helicase complex mutated in
      primary ovarian insufficiency, and RPA1.
    explanation: >-
      This links HROB/MCM8IP physically to the MCM8-9 helicase whose loss causes
      primary ovarian insufficiency.
  - reference: PMID:32528060
    reference_title: "MCM8IP activates the MCM8-9 helicase to promote DNA synthesis and homologous recombination upon DNA damage."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      MCM8IP stimulates the helicase activity of MCM8-9.
    explanation: >-
      This shows HROB/MCM8IP is required to activate the MCM8-9 helicase, so its
      loss impairs recombination-associated DNA synthesis.
  downstream:
  - target: Prophase I meiotic arrest and germ cell depletion
    description: >-
      Unresolved meiotic recombination intermediates block progression through
      prophase I, leading to germ-cell arrest and depletion.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - defective meiotic recombination
    - unresolved meiotic DNA double-strand breaks
    evidence:
    - reference: PMID:31467087
      reference_title: "Control of homologous recombination by the HROB-MCM8-MCM9 pathway."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Mice with targeted mutations in Hrob are infertile due to depletion of
        germ cells and display phenotypes consistent with a prophase I meiotic
        arrest.
      explanation: >-
        This mouse model links HROB loss to prophase I meiotic arrest and
        germ-cell depletion.
- name: Prophase I meiotic arrest and germ cell depletion
  conforms_to: "meiotic_prophase_failure#Pachytene Checkpoint Arrest and Germ Cell Apoptosis"
  description: >-
    Germ cells that cannot complete homologous recombination arrest during
    meiotic prophase I and are eliminated rather than maturing into functional
    gametes, depleting the germ-cell pool.
  cell_types:
  - preferred_term: germ cell
    term:
      id: CL:0000586
      label: germ cell
  biological_processes:
  - preferred_term: apoptotic process
    term:
      id: GO:0006915
      label: apoptotic process
    modifier: INCREASED
  evidence:
  - reference: PMID:31467087
    reference_title: "Control of homologous recombination by the HROB-MCM8-MCM9 pathway."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Mice with targeted mutations in Hrob are infertile due to depletion of
      germ cells and display phenotypes consistent with a prophase I meiotic
      arrest.
    explanation: >-
      This documents prophase I arrest with germ-cell depletion on HROB loss.
  downstream:
  - target: Ovarian follicle depletion and primary ovarian insufficiency
    description: >-
      In 46,XX individuals, germ-cell depletion exhausts the ovarian follicle
      pool and produces primary ovarian insufficiency / ovarian dysgenesis.
    causal_link_type: DIRECT
  - target: Spermatogenic arrest (predicted male branch)
    description: >-
      In male mice the same germ-cell depletion produces spermatogenic failure;
      an analogous male branch is predicted in humans but not yet reported.
    causal_link_type: UNKNOWN
- name: Ovarian follicle depletion and primary ovarian insufficiency
  conforms_to: "meiotic_prophase_failure#Ovarian Follicle Depletion and Primary Ovarian Insufficiency"
  description: >-
    Loss of oocytes during meiotic progression depletes the ovarian reserve,
    presenting clinically as primary ovarian insufficiency, ovarian dysgenesis,
    and hypergonadotropic hypogonadism in 46,XX individuals.
  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:34707299
    reference_title: "Meiotic genes in premature ovarian insufficiency: variants in HROB and REC8 as likely genetic causes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In silico analyses, combined with concordant mouse model phenotypes
      support these as new genetic causes of POI.
    explanation: >-
      This supports HROB variants as a cause of primary ovarian insufficiency.
  - reference: PMID:38105698
    reference_title: "Genetic analysis of novel pathogenic gene HROB in a family with primary ovarian insufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      both girls were diagnosed with primary ovarian insufficiency.
    explanation: >-
      This independently confirms primary ovarian insufficiency in a second
      HROB family.
  downstream:
  - target: Premature ovarian insufficiency
    description: >-
      The female branch presents clinically as primary / premature ovarian
      insufficiency.
    causal_link_type: DIRECT
  - target: Hypergonadotropic hypogonadism
    description: >-
      Ovarian failure produces hypergonadotropic hypogonadism with elevated
      gonadotropins and low anti-Mullerian hormone.
    causal_link_type: DIRECT
  - target: Aplasia of the ovary
    description: >-
      Severe ovarian dysgenesis in reported individuals manifests on imaging as
      absent bilateral ovaries.
    causal_link_type: DIRECT
  - target: Delayed puberty
    description: >-
      Hypoestrogenism from ovarian failure delays development of secondary
      sexual characteristics.
    causal_link_type: DIRECT
  - target: Delayed menarche
    description: >-
      Ovarian failure delays menarche in the reported affected girls.
    causal_link_type: DIRECT
  - target: Elevated follicle-stimulating hormone
    description: >-
      Loss of ovarian feedback leads to elevated circulating
      follicle-stimulating hormone.
    causal_link_type: DIRECT
  - target: Elevated luteinizing hormone
    description: >-
      Loss of ovarian feedback leads to elevated circulating luteinizing
      hormone.
    causal_link_type: DIRECT
  - target: Decreased anti-Mullerian hormone
    description: >-
      Ovarian follicle depletion is reflected by decreased circulating
      anti-Mullerian hormone.
    causal_link_type: DIRECT
- name: Spermatogenic arrest (predicted male branch)
  conforms_to: "meiotic_prophase_failure#Spermatogenic Arrest and Non-Obstructive Azoospermia"
  description: >-
    In male mice, HROB loss depletes germ cells with seminiferous tubules
    largely devoid of germ cells, predicting a spermatogenic-failure branch in
    46,XY humans. No human male case has yet been reported, so this node rests on
    model-organism evidence only.
  cell_types:
  - preferred_term: spermatocyte
    term:
      id: CL:0000017
      label: spermatocyte
  biological_processes:
  - preferred_term: male gamete generation
    term:
      id: GO:0048232
      label: male gamete generation
    modifier: DECREASED
  evidence:
  - reference: PMID:31467087
    reference_title: "Control of homologous recombination by the HROB-MCM8-MCM9 pathway."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Mice with targeted mutations in Hrob are infertile due to depletion of
      germ cells and display phenotypes consistent with a prophase I meiotic
      arrest.
    explanation: >-
      Hrob-mutant male mice are infertile from germ-cell depletion, the basis for
      a predicted human male spermatogenic-failure branch.
phenotypes:
- name: Premature ovarian insufficiency
  category: Reproductive
  description: >-
    Affected 46,XX individuals present with primary / premature ovarian
    insufficiency.
  phenotype_term:
    preferred_term: Premature ovarian insufficiency
    term:
      id: HP:0008209
      label: Premature ovarian insufficiency
  phenotype_contexts:
  - sex: FEMALE
    notes: Reported in 46,XX individuals with biallelic HROB variants.
    evidence:
    - reference: PMID:38105698
      reference_title: "Genetic analysis of novel pathogenic gene HROB in a family with primary ovarian insufficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        both girls were diagnosed with primary ovarian insufficiency.
      explanation: >-
        This documents primary ovarian insufficiency in two sisters with
        biallelic HROB variants.
  evidence:
  - reference: PMID:34707299
    reference_title: "Meiotic genes in premature ovarian insufficiency: variants in HROB and REC8 as likely genetic causes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      propose HROB and REC8 variants as new genetic causes while exploring their
      link to pathogenesis.
    explanation: >-
      This study proposes HROB as a genetic cause of premature ovarian
      insufficiency.
- name: Hypergonadotropic hypogonadism
  category: Reproductive
  description: >-
    Ovarian failure is accompanied by hypergonadotropic hypogonadism with
    elevated follicle-stimulating and luteinizing hormone and low anti-Mullerian
    hormone.
  phenotype_term:
    preferred_term: Hypergonadotropic hypogonadism
    term:
      id: HP:0000815
      label: Hypergonadotropic hypogonadism
  phenotype_contexts:
  - sex: FEMALE
    evidence:
    - reference: PMID:38105698
      reference_title: "Genetic analysis of novel pathogenic gene HROB in a family with primary ovarian insufficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The laboratory test results indicated increased follicle-stimulating
        hormone and luteinizing hormone, decreased anti-Mullerian hormone, and
        pelvic ultrasound showed a cord-like uterus and absence of bilateral
        ovaries.
      explanation: >-
        Elevated gonadotropins with low anti-Mullerian hormone and absent
        ovaries support hypergonadotropic hypogonadism.
  evidence:
  - reference: PMID:38105698
    reference_title: "Genetic analysis of novel pathogenic gene HROB in a family with primary ovarian insufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The laboratory test results indicated increased follicle-stimulating
      hormone and luteinizing hormone, decreased anti-Mullerian hormone, and
      pelvic ultrasound showed a cord-like uterus and absence of bilateral
      ovaries.
    explanation: >-
      Elevated gonadotropins with low anti-Mullerian hormone support
      hypergonadotropic hypogonadism in affected individuals.
- name: Aplasia of the ovary
  category: Reproductive
  description: >-
    Pelvic imaging in reported individuals showed absent bilateral ovaries with
    a cord-like uterus, consistent with ovarian dysgenesis.
  phenotype_term:
    preferred_term: Aplasia of the ovary
    term:
      id: HP:0010463
      label: Aplasia of the ovary
  phenotype_contexts:
  - sex: FEMALE
    notes: >-
      Reported as absence of bilateral ovaries on pelvic ultrasound.
    evidence:
    - reference: PMID:38105698
      reference_title: "Genetic analysis of novel pathogenic gene HROB in a family with primary ovarian insufficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        pelvic ultrasound showed a cord-like uterus and absence of bilateral
        ovaries.
      explanation: >-
        Non-visualized bilateral ovaries with a cord-like uterus support
        ovarian aplasia.
  evidence:
  - reference: PMID:38105698
    reference_title: "Genetic analysis of novel pathogenic gene HROB in a family with primary ovarian insufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      pelvic ultrasound showed a cord-like uterus and absence of bilateral
      ovaries.
    explanation: >-
      Pelvic ultrasound documented absence of bilateral ovaries in the affected
      girls.
- name: Delayed puberty
  category: Reproductive
  description: >-
    Affected girls presented with delayed menarche and absent secondary sexual
    characteristics until hormone replacement was started.
  phenotype_term:
    preferred_term: Delayed puberty
    term:
      id: HP:0000823
      label: Delayed puberty
  phenotype_contexts:
  - sex: FEMALE
    evidence:
    - reference: PMID:38105698
      reference_title: "Genetic analysis of novel pathogenic gene HROB in a family with primary ovarian insufficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Oral estradiol valerate at an initial dose of 0.125 mg/d was given to the
        proband, and the secondary sexual characteristics began to develop after
        6 months.
      explanation: >-
        Secondary sexual characteristics developed only after estrogen therapy,
        indicating delayed puberty.
  evidence:
  - reference: PMID:38105698
    reference_title: "Genetic analysis of novel pathogenic gene HROB in a family with primary ovarian insufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Oral estradiol valerate at an initial dose of 0.125 mg/d was given to the
      proband, and the secondary sexual characteristics began to develop after
      6 months.
    explanation: >-
      Development of secondary sexual characteristics only after estrogen
      therapy supports delayed puberty from ovarian failure.
- name: Delayed menarche
  category: Reproductive
  description: >-
    Delayed menarche was the presenting complaint in the reported HROB family.
  phenotype_term:
    preferred_term: Delayed menarche
    term:
      id: HP:0012569
      label: Delayed menarche
  phenotype_contexts:
  - sex: FEMALE
  evidence:
  - reference: PMID:38105698
    reference_title: "Genetic analysis of novel pathogenic gene HROB in a family with primary ovarian insufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A 13-year and 6-month-old girl attended the Hunan Children's Hospital due
      to delayed menarche.
    explanation: >-
      Delayed menarche was the presenting symptom in the proband with biallelic
      HROB variants.
- name: Elevated follicle-stimulating hormone
  category: Reproductive
  description: >-
    Affected girls had increased follicle-stimulating hormone, reflecting loss
    of ovarian feedback in primary ovarian insufficiency.
  phenotype_term:
    preferred_term: Elevated follicle-stimulating hormone
    term:
      id: HP:0008232
      label: Elevated circulating follicle stimulating hormone level
  phenotype_contexts:
  - sex: FEMALE
  evidence:
  - reference: PMID:38105698
    reference_title: "Genetic analysis of novel pathogenic gene HROB in a family with primary ovarian insufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The laboratory test results indicated increased follicle-stimulating
      hormone and luteinizing hormone, decreased anti-Mullerian hormone, and
      pelvic ultrasound showed a cord-like uterus and absence of bilateral
      ovaries.
    explanation: >-
      The reported laboratory findings explicitly include increased
      follicle-stimulating hormone.
- name: Elevated luteinizing hormone
  category: Reproductive
  description: >-
    Affected girls had increased luteinizing hormone, reflecting
    hypergonadotropic ovarian failure.
  phenotype_term:
    preferred_term: Elevated luteinizing hormone
    term:
      id: HP:0011969
      label: Elevated circulating luteinizing hormone level
  phenotype_contexts:
  - sex: FEMALE
  evidence:
  - reference: PMID:38105698
    reference_title: "Genetic analysis of novel pathogenic gene HROB in a family with primary ovarian insufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The laboratory test results indicated increased follicle-stimulating
      hormone and luteinizing hormone, decreased anti-Mullerian hormone, and
      pelvic ultrasound showed a cord-like uterus and absence of bilateral
      ovaries.
    explanation: >-
      The reported laboratory findings explicitly include increased luteinizing
      hormone.
- name: Decreased anti-Mullerian hormone
  category: Reproductive
  description: >-
    Circulating anti-Mullerian hormone was decreased, consistent with depleted
    ovarian reserve in primary ovarian insufficiency.
  phenotype_term:
    preferred_term: Decreased anti-Mullerian hormone
    term:
      id: HP:0031103
      label: Decreased circulating antimullerian hormone circulation
  phenotype_contexts:
  - sex: FEMALE
  evidence:
  - reference: PMID:38105698
    reference_title: "Genetic analysis of novel pathogenic gene HROB in a family with primary ovarian insufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The laboratory test results indicated increased follicle-stimulating
      hormone and luteinizing hormone, decreased anti-Mullerian hormone, and
      pelvic ultrasound showed a cord-like uterus and absence of bilateral
      ovaries.
    explanation: >-
      The reported laboratory findings explicitly include decreased
      anti-Mullerian hormone.
genetic:
- name: HROB
  association: Causative (Primary)
  inheritance:
  - name: Autosomal recessive inheritance
    evidence:
    - reference: PMID:34707299
      reference_title: "Meiotic genes in premature ovarian insufficiency: variants in HROB and REC8 as likely genetic causes."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        two genes, REC8 and HROB, not previously associated with autosomal
        recessive POI.
      explanation: >-
        This supports recessive transmission at the gene level.
  evidence:
  - reference: PMID:34707299
    reference_title: "Meiotic genes in premature ovarian insufficiency: variants in HROB and REC8 as likely genetic causes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      HROB encodes a factor that recruits MCM8/9 for DNA damage repair.
    explanation: >-
      This establishes HROB as the causal gene and links it mechanistically to
      the MCM8-MCM9 DNA-repair complex.
  - reference: PMID:38105698
    reference_title: "Genetic analysis of novel pathogenic gene HROB in a family with primary ovarian insufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      carried heterozygous variants of HROB gene c.718C>T (p.Arg240*) and
      c.1351C>T (p.Arg451*), which were inherited from their parents respectively
      and consistent with autosomal recessive inheritance.
    explanation: >-
      A second family with compound-heterozygous HROB nonsense variants supports
      the causal gene assignment.
  notes: >-
    HROB (C17orf53 / MCM8IP) encodes the homologous-recombination OB-fold factor
    that loads and activates the MCM8-MCM9 helicase during DNA double-strand
    break repair and meiotic recombination.
treatments:
- name: Hormone replacement therapy
  description: >-
    Estrogen-based hormone replacement is used to treat hypoestrogenism, induce
    and maintain secondary sexual characteristics, and reduce long-term
    comorbidity in the ovarian-failure phenotype.
  treatment_term:
    preferred_term: hormone replacement therapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: estradiol
      term:
        id: CHEBI:23965
        label: estradiol
  evidence:
  - reference: PMID:38105698
    reference_title: "Genetic analysis of novel pathogenic gene HROB in a family with primary ovarian insufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Oral estradiol valerate at an initial dose of 0.125 mg/d was given to the
      proband, and the secondary sexual characteristics began to develop after
      6 months.
    explanation: >-
      This documents estrogen replacement inducing pubertal development in an
      affected individual.
diagnosis:
- name: Targeted molecular testing
  description: >-
    Exome or panel-based sequencing confirms the diagnosis by identifying
    biallelic pathogenic HROB variants in individuals with primary ovarian
    insufficiency or ovarian dysgenesis.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: MAXO:0000127
      label: genetic testing
  evidence:
  - reference: PMID:34707299
    reference_title: "Meiotic genes in premature ovarian insufficiency: variants in HROB and REC8 as likely genetic causes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We used whole exome sequencing to identify the genetic cause of POI in
      seven women.
    explanation: >-
      Whole-exome sequencing is the diagnostic approach that identified HROB as a
      POI gene.
  - reference: PMID:38105698
    reference_title: "Genetic analysis of novel pathogenic gene HROB in a family with primary ovarian insufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Whole exome sequencing and Sanger sequencing confirmed that the proband
      and her sister carried heterozygous variants of HROB gene
    explanation: >-
      This shows exome plus Sanger confirmation of biallelic HROB variants as the
      molecular diagnosis.