MCM8-related gametogenic failure

Mendelian MONDO:0044776 Pathograph 9 Show in embeddings browser Primary ovarian insufficiency Ovarian dysgenesis Male infertility Disorder of sex development

MCM8-related gametogenic failure is a recessive meiotic DNA-repair disorder caused by biallelic loss-of-function variants in MCM8. MCM8 partners with MCM9 (and the loader HROB/MCM8IP) as a helicase that promotes RAD51-dependent homologous-recombination repair of DNA double-strand breaks, including the programmed breaks of meiotic prophase I. The reported human spectrum is bisexual: 46,XX individuals present with primary ovarian insufficiency / ovarian dysgenesis, primary amenorrhea, and hypergonadotropic hypogonadism (premature ovarian failure 10, OMIM:612885), while 46,XY individuals present with small testes, non-obstructive azoospermia, and Sertoli cell-only histology. A chromosomal-instability state is demonstrable as impaired repair of induced chromosome breaks, and biallelic carriers show an emerging predisposition to early-onset germ cell tumors. The shared mechanistic theme is failed MCM8-MCM9-dependent homologous recombination during meiosis with germ-cell loss, paralleling the related MCM9- and HROB-related disorders.

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1
Inheritance
5
Pathophys.
8
Phenotypes
9
Pathograph
1
Genes
3
Medical Actions
👪

Inheritance

1
Autosomal recessive inheritance HP:0000007
Reported families carry biallelic (homozygous or compound-heterozygous) loss-of-function MCM8 variants segregating with disease in a recessive pattern.
Autosomal recessive inheritance
Show evidence (2 references)
PMID:25437880 SUPPORT Human Clinical
"Our study identifies an autosomal recessive disorder caused by an MCM8 mutation that manifests with endocrine dysfunction and genomic instability."
This directly supports recessive inheritance of the core MCM8-related syndrome.
PMID:25873734 SUPPORT Human Clinical
"we identified two novel homozygous mutations in the MCM8 gene: a splice (c.1954-1G>A) and a frameshift (c.1469-1470insTA)."
Homozygous loss-of-function MCM8 variants segregating in consanguineous families establish recessive transmission.
⚙

Pathophysiology

5
Impaired homologous recombination
Biallelic MCM8 loss disables the MCM8-MCM9 helicase, reducing RAD51 recruitment and homologous-recombination repair of DNA double-strand breaks. This genome-maintenance defect is especially damaging during meiosis, where programmed double-strand breaks must be repaired by homologous recombination.
MCM8 hgnc:16147
double-strand break repair via homologous recombination GO:0000724 ↓ DECREASED
Downstream
Meiotic arrest and germ cell depletion Germline cells are highly sensitive to MCM8-dependent genome-maintenance failure: unresolved meiotic recombination intermediates block progression through prophase I.
Show evidence (3 references)
PMID:23401855 SUPPORT In Vitro
"Consistent with a role in the repair of ICLs by homologous recombination (HR), knockdown of MCM8 or MCM9 significantly reduces HR repair efficiency."
This directly supports reduced homologous-recombination repair after MCM8 loss.
PMID:23401855 SUPPORT In Vitro
"Chromatin immunoprecipitation analysis using human DR-GFP cells or Xenopus egg extract demonstrated that MCM8 and MCM9 proteins are rapidly recruited to DNA damage sites and promote RAD51 recruitment."
This places MCM8 upstream of RAD51 loading during homologous recombination.
PMID:22771120 SUPPORT Model Organism
"chromatin recruitment of HR factors like Rad51 and RPA is impaired and HR strongly reduced."
Mcm8-deficient cells fail to load RAD51, confirming the homologous- recombination defect in vivo.
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 in both sexes.
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.
Spermatogenic arrest and non-obstructive azoospermia In 46,XY individuals, the same germ-cell depletion produces spermatogenic failure presenting as non-obstructive azoospermia.
Show evidence (1 reference)
PMID:22771120 SUPPORT Model Organism
"MCM8(-/-) mice are sterile because spermatocytes are blocked in meiotic prophase I, and females have only arrested primary follicles and frequently develop ovarian tumors."
This documents prophase I arrest with germ-cell depletion in both sexes on MCM8 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, primary amenorrhea, 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.
Show evidence (1 reference)
PMID:25437880 SUPPORT Human Clinical
"Here, we studied 3 sisters with primary amenorrhea, hypothyroidism, and hypergonadotropic hypogonadism."
This documents ovarian failure with hypergonadotropic hypogonadism as the founding female phenotype of biallelic MCM8 deficiency.
Spermatogenic arrest and non-obstructive azoospermia
In 46,XY individuals, MCM8-dependent meiotic failure in spermatocytes produces spermatogenic arrest with small testes, non-obstructive azoospermia, and Sertoli cell-only histology.
spermatocyte CL:0000017
male gamete generation GO:0048232 ↓ DECREASED
Downstream
Azoospermia In 46,XY individuals severe spermatogenic failure manifests clinically as non-obstructive azoospermia.
Show evidence (2 references)
PMID:25873734 SUPPORT Human Clinical
"two consanguineous families presenting as primary amenorrhoea in the females and as small testes and azoospermia in a male."
This directly documents the male spermatogenic-failure branch as small testes with azoospermia.
PMID:40064807 SUPPORT Human Clinical
"The testes tissue sections in the male showed a Sertoli cell-only syndrome (SCOS)."
This adds Sertoli cell-only histology as the testicular correlate of the male MCM8 phenotype.
Somatic genome instability and germ cell tumor predisposition
Beyond the gonads, MCM8-dependent homologous-recombination failure produces a somatic genome-instability state. In humans this is associated with an emerging predisposition to early-onset germ cell tumors; murine Mcm8 loss likewise produces ovarian tumors. This cancer profile is narrower than the gastrointestinal polyposis / colorectal-cancer spectrum reported for MCM9.
double-strand break repair via homologous recombination GO:0000724 ↓ DECREASED
Downstream
Germ cell tumor The somatic instability state drives an early-onset neoplasia phenotype, especially gonadal germ cell tumors.
Show evidence (2 references)
PMID:40684266 SUPPORT Human Clinical
"both biallelic MCM8 and MCM9 variants are linked to hypogonadism and the early development of germ cell tumors."
This establishes early-onset germ cell tumors as the human cancer branch of biallelic MCM8 deficiency.
PMID:22771120 SUPPORT Model Organism
"MCM8(-/-) mice are sterile because spermatocytes are blocked in meiotic prophase I, and females have only arrested primary follicles and frequently develop ovarian tumors."
The ovarian tumors of Mcm8-null mice provide model-organism support for a gonadal tumor-predisposition branch.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for MCM8-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 2
Hypergonadotropic hypogonadism Hypergonadotropic hypogonadism HP:0000815
Show evidence (1 reference)
PMID:25437880 SUPPORT Human Clinical
"Here, we studied 3 sisters with primary amenorrhea, hypothyroidism, and hypergonadotropic hypogonadism."
This directly supports hypergonadotropic hypogonadism in the female MCM8 syndrome.
Context-specific annotations (1)
FEMALE
Hypothyroidism Hypothyroidism HP:0000821
Show evidence (1 reference)
PMID:25437880 SUPPORT Human Clinical
"Here, we studied 3 sisters with primary amenorrhea, hypothyroidism, and hypergonadotropic hypogonadism."
This reports hypothyroidism in the originally described MCM8 sibship.
Genitourinary 4
Premature ovarian insufficiency Premature ovarian insufficiency HP:0008209
Show evidence (1 reference)
PMID:25437880 SUPPORT Human Clinical
"Here, we studied 3 sisters with primary amenorrhea, hypothyroidism, and hypergonadotropic hypogonadism."
The founding family establishes the ovarian-failure phenotype tied to a biallelic MCM8 variant.
Context-specific annotations (1)
FEMALE
Reported in 46,XX individuals with biallelic MCM8 variants.
Show evidence (1 reference)
PMID:40064807 SUPPORT Human Clinical
"primary gonadal dysgenesis in a consanguineous family characterized by underdeveloped testes and non-obstructive azoospermia (NOA) in a male and primary amenorrhoea and primary ovarian insufficiency (POI) in a female."
This family report documents primary ovarian insufficiency as the female presentation of biallelic MCM8 loss.
Primary amenorrhea Primary amenorrhea HP:0000786
Show evidence (1 reference)
PMID:25437880 SUPPORT Human Clinical
"Here, we studied 3 sisters with primary amenorrhea, hypothyroidism, and hypergonadotropic hypogonadism."
This documents primary amenorrhea in the founding female MCM8 family.
Context-specific annotations (1)
FEMALE
Azoospermia Azoospermia HP:0000027
Context-specific annotations (1)
MALE
Reported as small testes with azoospermia / non-obstructive azoospermia in 46,XY individuals.
Show evidence (2 references)
PMID:25873734 SUPPORT Human Clinical
"two consanguineous families presenting as primary amenorrhoea in the females and as small testes and azoospermia in a male."
This documents the male azoospermia branch of MCM8-related gonadal failure.
PMID:40064807 SUPPORT Human Clinical
"underdeveloped testes and non-obstructive azoospermia (NOA) in a male"
A second family independently confirms non-obstructive azoospermia in a 46,XY individual with biallelic MCM8 loss.
Sertoli cell-only syndrome Male infertility HP:0003251
Context-specific annotations (1)
MALE
Current local HPO does not expose a specific SCOS term, so this entry is anchored to the closest available male-infertility ancestor while keeping the histopathologic preferred term explicit.
Show evidence (1 reference)
PMID:40064807 SUPPORT Human Clinical
"The testes tissue sections in the male showed a Sertoli cell-only syndrome (SCOS)."
This supports Sertoli cell-only histology as the male gonadal-failure correlate of MCM8 deficiency.
Other 2
Chromosome breakage Chromosome breakage HP:0040012
Show evidence (2 references)
PMID:25437880 SUPPORT Human Clinical
"chromosomal break repair was deficient in fibroblasts from the affected individuals, likely due to inhibited recruitment of MCM8 p.P149R to sites of DNA damage."
This directly supports a chromosome-breakage phenotype consistent with the chromosomal-instability state.
PMID:25873734 SUPPORT Human Clinical
"Chromosomal breakage following exposure to mitomcyin C was significantly increased in cells from homozygous individuals for c.1954-1G>A, as well as c.1469-1470insTA."
An independent family confirms increased induced chromosomal breakage in MCM8-deficient cells.
Germ cell tumor Germ cell neoplasia HP:0100728
Show evidence (1 reference)
PMID:40684266 SUPPORT Human Clinical
"both biallelic MCM8 and MCM9 variants are linked to hypogonadism and the early development of germ cell tumors."
This supports early-onset germ cell tumors as the cancer phenotype linked to biallelic MCM8 variants.
🧬

Genetic Associations

1
MCM8 (Causative (Primary))
Autosomal recessive inheritance
Show evidence (2 references)
PMID:25437880 SUPPORT Human Clinical
"SNP analysis and whole-exome sequencing revealed the presence of a pathogenic variant of the minichromosome maintenance 8 gene (MCM8, c.446C>G; p.P149R) located within a region of homozygosity"
This establishes MCM8 as the causal gene in the founding female family.
PMID:40064807 SUPPORT Human Clinical
"A homozygous frameshift mutation c.998delG (p. Gly333Glufs*50) in MCM8 was identified in the two siblings."
This extends the causal role of biallelic MCM8 loss-of-function variants to a bisexual gonadal-failure family.
💊

Medical Actions

3
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 in the ovarian-failure branch, support pubertal development, and reduce osteoporosis risk.
Show evidence (2 references)
PMID:25437880 PARTIAL Human Clinical
"Here, we studied 3 sisters with primary amenorrhea, hypothyroidism, and hypergonadotropic hypogonadism."
This anchors the ovarian-failure branch to the hypergonadotropic hypogonadism that drives hormone-replacement treatment.
PMID:41942077 SUPPORT Other
"This review outlines key diagnostic criteria, initial investigations, referral pathways and management options including hormone therapy, chronic disease risk reduction, fertility counselling and psychosocial support."
This provides condition-level management evidence that hormone therapy is part of standard care for primary ovarian insufficiency, the core female branch of MCM8-related disease.
Germ cell tumor and cancer surveillance
Action: surveillance for malignancies MAXO:0001492
Because biallelic MCM8 deficiency is associated with early-onset germ cell tumors, affected individuals may benefit from cancer surveillance, including imaging for gonadal or extragonadal germ cell tumors.
Show evidence (1 reference)
PMID:40684266 SUPPORT Human Clinical
"These findings underscore the importance of including MCM8/MCM9 in diagnostic gene panels for certain clinical contexts and suggest that biallelic carriers may benefit from cancer surveillance."
This supports cancer surveillance for biallelic MCM8 carriers given the germ cell tumor risk.
Genetic counseling
Action: Genetic Counseling NCIT:C15240
Genetic counseling is appropriate for affected families because the condition is recessive, causes infertility in both sexes, and carries implications for reproductive planning and cancer surveillance.
Show evidence (1 reference)
PMID:40064807 SUPPORT Human Clinical
"expands the mutational spectrum of MCM8 involved in male NOA and female POI and provides a new molecular marker for genetic counseling of infertility."
This directly supports genetic counseling as part of management for MCM8-associated gonadal failure.
{ }

Source YAML

click to show 
name: MCM8-related gametogenic failure
creation_date: "2026-06-07T12:00:00Z"
category: Mendelian
description: >-
  MCM8-related gametogenic failure is a recessive meiotic DNA-repair disorder
  caused by biallelic loss-of-function variants in MCM8. MCM8 partners with MCM9
  (and the loader HROB/MCM8IP) as a helicase that promotes RAD51-dependent
  homologous-recombination repair of DNA double-strand breaks, including the
  programmed breaks of meiotic prophase I. The reported human spectrum is
  bisexual: 46,XX individuals present with primary ovarian insufficiency /
  ovarian dysgenesis, primary amenorrhea, and hypergonadotropic hypogonadism
  (premature ovarian failure 10, OMIM:612885), while 46,XY individuals present
  with small testes, non-obstructive azoospermia, and Sertoli cell-only
  histology. A chromosomal-instability state is demonstrable as impaired repair
  of induced chromosome breaks, and biallelic carriers show an emerging
  predisposition to early-onset germ cell tumors. The shared mechanistic theme
  is failed MCM8-MCM9-dependent homologous recombination during meiosis with
  germ-cell loss, paralleling the related MCM9- and HROB-related disorders.
disease_term:
  preferred_term: MCM8-related gametogenic failure
  term:
    id: MONDO:0044776
    label: premature ovarian failure 10
parents:
- Primary ovarian insufficiency
- Ovarian dysgenesis
- Male infertility
- Disorder of sex development
synonyms:
- MCM8 deficiency
- MCM8-associated gametogenic failure
- premature ovarian failure 10
- POF10
- MCM8-related primary gonadal failure
notes: >-
  The exact human disease anchor available in MONDO is MONDO:0044776 (premature
  ovarian failure 10; OMIM:612885), which captures the female ovarian-failure
  presentation first described for MCM8. The broader preferred term
  "MCM8-related gametogenic failure" reflects the conserved meiotic-prophase
  mechanism and the bisexual germ-cell failure now documented in humans: both
  46,XX primary ovarian insufficiency and 46,XY non-obstructive azoospermia /
  Sertoli cell-only syndrome arise from the same biallelic MCM8 loss. This entry
  conforms to the meiotic_prophase_failure module, placing MCM8 alongside its
  MCM9 helicase partner and the HROB loader. The cancer-predisposition branch of
  MCM8 is narrower than MCM9's: current human evidence associates biallelic MCM8
  variants with early-onset germ cell tumors rather than the gastrointestinal
  polyposis / colorectal-cancer profile reported for MCM9.
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 MCM8 variants segregating with disease in a recessive
    pattern.
  evidence:
  - reference: PMID:25437880
    reference_title: "Exome sequencing reveals MCM8 mutation underlies ovarian failure and chromosomal instability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our study identifies an autosomal recessive disorder caused by an MCM8
      mutation that manifests with endocrine dysfunction and genomic instability.
    explanation: >-
      This directly supports recessive inheritance of the core MCM8-related
      syndrome.
  - reference: PMID:25873734
    reference_title: "Minichromosome maintenance complex component 8 (MCM8) gene mutations result in primary gonadal failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we identified two novel homozygous mutations in the MCM8 gene: a splice
      (c.1954-1G>A) and a frameshift (c.1469-1470insTA).
    explanation: >-
      Homozygous loss-of-function MCM8 variants segregating in consanguineous
      families establish recessive transmission.
pathophysiology:
- name: Impaired homologous recombination
  conforms_to: "meiotic_prophase_failure#Homologous Recombination Repair of Meiotic DNA Breaks"
  description: >-
    Biallelic MCM8 loss disables the MCM8-MCM9 helicase, reducing RAD51
    recruitment and homologous-recombination repair of DNA double-strand breaks.
    This genome-maintenance defect is especially damaging during meiosis, where
    programmed double-strand breaks must be repaired by homologous recombination.
  genes:
  - preferred_term: MCM8
    term:
      id: hgnc:16147
      label: MCM8
  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:23401855
    reference_title: "The MCM8-MCM9 complex promotes RAD51 recruitment at DNA damage sites to facilitate homologous recombination."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Consistent with a role in the repair of ICLs by homologous recombination
      (HR), knockdown of MCM8 or MCM9 significantly reduces HR repair
      efficiency.
    explanation: >-
      This directly supports reduced homologous-recombination repair after MCM8
      loss.
  - reference: PMID:23401855
    reference_title: "The MCM8-MCM9 complex promotes RAD51 recruitment at DNA damage sites to facilitate homologous recombination."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Chromatin immunoprecipitation analysis using human DR-GFP cells or
      Xenopus egg extract demonstrated that MCM8 and MCM9 proteins are rapidly
      recruited to DNA damage sites and promote RAD51 recruitment.
    explanation: >-
      This places MCM8 upstream of RAD51 loading during homologous
      recombination.
  - reference: PMID:22771120
    reference_title: "MCM8- and MCM9-deficient mice reveal gametogenesis defects and genome instability due to impaired homologous recombination."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      chromatin recruitment of HR factors like Rad51 and RPA is impaired and HR
      strongly reduced.
    explanation: >-
      Mcm8-deficient cells fail to load RAD51, confirming the homologous-
      recombination defect in vivo.
  downstream:
  - target: Meiotic arrest and germ cell depletion
    description: >-
      Germline cells are highly sensitive to MCM8-dependent genome-maintenance
      failure: unresolved meiotic recombination intermediates block progression
      through prophase I.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - defective meiotic recombination
    - unresolved meiotic DNA double-strand breaks
    evidence:
    - reference: PMID:22771120
      reference_title: "MCM8- and MCM9-deficient mice reveal gametogenesis defects and genome instability due to impaired homologous recombination."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        deficiency for these genes impairs homologous recombination
        (HR)-mediated DNA repair during gametogenesis and somatic cells cycles.
      explanation: >-
        This links the recombination defect to failed gametogenesis in
        Mcm8-deficient animals.
- name: 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 in both sexes.
  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:22771120
    reference_title: "MCM8- and MCM9-deficient mice reveal gametogenesis defects and genome instability due to impaired homologous recombination."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      MCM8(-/-) mice are sterile because spermatocytes are blocked in meiotic
      prophase I, and females have only arrested primary follicles and
      frequently develop ovarian tumors.
    explanation: >-
      This documents prophase I arrest with germ-cell depletion in both sexes on
      MCM8 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.
    causal_link_type: DIRECT
  - target: Spermatogenic arrest and non-obstructive azoospermia
    description: >-
      In 46,XY individuals, the same germ-cell depletion produces spermatogenic
      failure presenting as non-obstructive azoospermia.
    causal_link_type: DIRECT
- 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,
    primary amenorrhea, 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:25437880
    reference_title: "Exome sequencing reveals MCM8 mutation underlies ovarian failure and chromosomal instability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we studied 3 sisters with primary amenorrhea, hypothyroidism, and
      hypergonadotropic hypogonadism.
    explanation: >-
      This documents ovarian failure with hypergonadotropic hypogonadism as the
      founding female phenotype of biallelic MCM8 deficiency.
  downstream:
  - target: Premature ovarian insufficiency
    description: >-
      The female branch presents clinically as primary / premature ovarian
      insufficiency.
    causal_link_type: DIRECT
- name: Spermatogenic arrest and non-obstructive azoospermia
  conforms_to: "meiotic_prophase_failure#Spermatogenic Arrest and Non-Obstructive Azoospermia"
  description: >-
    In 46,XY individuals, MCM8-dependent meiotic failure in spermatocytes
    produces spermatogenic arrest with small testes, non-obstructive
    azoospermia, and Sertoli cell-only histology.
  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:25873734
    reference_title: "Minichromosome maintenance complex component 8 (MCM8) gene mutations result in primary gonadal failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      two consanguineous families presenting as primary amenorrhoea in the
      females and as small testes and azoospermia in a male.
    explanation: >-
      This directly documents the male spermatogenic-failure branch as small
      testes with azoospermia.
  - reference: PMID:40064807
    reference_title: "A novel homozygous frameshift mutation in MCM8 causes primary gonadal dysgenesis in both genders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The testes tissue sections in the male showed a Sertoli cell-only
      syndrome (SCOS).
    explanation: >-
      This adds Sertoli cell-only histology as the testicular correlate of the
      male MCM8 phenotype.
  downstream:
  - target: Azoospermia
    description: >-
      In 46,XY individuals severe spermatogenic failure manifests clinically as
      non-obstructive azoospermia.
    causal_link_type: DIRECT
- name: Somatic genome instability and germ cell tumor predisposition
  conforms_to: "meiotic_prophase_failure#Somatic DNA Repair Deficiency and Cancer Predisposition"
  description: >-
    Beyond the gonads, MCM8-dependent homologous-recombination failure produces
    a somatic genome-instability state. In humans this is associated with an
    emerging predisposition to early-onset germ cell tumors; murine Mcm8 loss
    likewise produces ovarian tumors. This cancer profile is narrower than the
    gastrointestinal polyposis / colorectal-cancer spectrum reported for MCM9.
  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:40684266
    reference_title: "Clinical syndromes linked to biallelic germline variants in MCM8 and MCM9."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      both biallelic MCM8 and MCM9 variants are linked to hypogonadism and the
      early development of germ cell tumors.
    explanation: >-
      This establishes early-onset germ cell tumors as the human cancer branch
      of biallelic MCM8 deficiency.
  - reference: PMID:22771120
    reference_title: "MCM8- and MCM9-deficient mice reveal gametogenesis defects and genome instability due to impaired homologous recombination."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      MCM8(-/-) mice are sterile because spermatocytes are blocked in meiotic
      prophase I, and females have only arrested primary follicles and
      frequently develop ovarian tumors.
    explanation: >-
      The ovarian tumors of Mcm8-null mice provide model-organism support for a
      gonadal tumor-predisposition branch.
  downstream:
  - target: Germ cell tumor
    description: >-
      The somatic instability state drives an early-onset neoplasia phenotype,
      especially gonadal germ cell tumors.
    causal_link_type: DIRECT
phenotypes:
- name: Premature ovarian insufficiency
  category: Reproductive
  description: >-
    Reported 46,XX individuals present with primary ovarian insufficiency or
    ovarian dysgenesis, often with primary amenorrhea and hypergonadotropic
    hypogonadism.
  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 MCM8 variants.
    evidence:
    - reference: PMID:40064807
      reference_title: "A novel homozygous frameshift mutation in MCM8 causes primary gonadal dysgenesis in both genders."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        primary gonadal dysgenesis in a consanguineous family characterized by
        underdeveloped testes and non-obstructive azoospermia (NOA) in a male
        and primary amenorrhoea and primary ovarian insufficiency (POI) in a
        female.
      explanation: >-
        This family report documents primary ovarian insufficiency as the female
        presentation of biallelic MCM8 loss.
  evidence:
  - reference: PMID:25437880
    reference_title: "Exome sequencing reveals MCM8 mutation underlies ovarian failure and chromosomal instability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we studied 3 sisters with primary amenorrhea, hypothyroidism, and
      hypergonadotropic hypogonadism.
    explanation: >-
      The founding family establishes the ovarian-failure phenotype tied to a
      biallelic MCM8 variant.
- name: Primary amenorrhea
  category: Reproductive
  description: >-
    Affected 46,XX individuals commonly present with primary amenorrhea as the
    presenting feature of ovarian failure.
  phenotype_term:
    preferred_term: Primary amenorrhea
    term:
      id: HP:0000786
      label: Primary amenorrhea
  phenotype_contexts:
  - sex: FEMALE
  evidence:
  - reference: PMID:25437880
    reference_title: "Exome sequencing reveals MCM8 mutation underlies ovarian failure and chromosomal instability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we studied 3 sisters with primary amenorrhea, hypothyroidism, and
      hypergonadotropic hypogonadism.
    explanation: >-
      This documents primary amenorrhea in the founding female MCM8 family.
- name: Hypergonadotropic hypogonadism
  category: Reproductive
  description: >-
    Gonadal failure in affected 46,XX individuals is accompanied by
    hypergonadotropic hypogonadism.
  phenotype_term:
    preferred_term: Hypergonadotropic hypogonadism
    term:
      id: HP:0000815
      label: Hypergonadotropic hypogonadism
  phenotype_contexts:
  - sex: FEMALE
  evidence:
  - reference: PMID:25437880
    reference_title: "Exome sequencing reveals MCM8 mutation underlies ovarian failure and chromosomal instability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we studied 3 sisters with primary amenorrhea, hypothyroidism, and
      hypergonadotropic hypogonadism.
    explanation: >-
      This directly supports hypergonadotropic hypogonadism in the female MCM8
      syndrome.
- name: Hypothyroidism
  category: Endocrine
  description: >-
    Hypothyroidism was reported in the founding 46,XX MCM8 family, although it
    is not established as an obligate feature across later cohorts.
  phenotype_term:
    preferred_term: Hypothyroidism
    term:
      id: HP:0000821
      label: Hypothyroidism
  evidence:
  - reference: PMID:25437880
    reference_title: "Exome sequencing reveals MCM8 mutation underlies ovarian failure and chromosomal instability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we studied 3 sisters with primary amenorrhea, hypothyroidism, and
      hypergonadotropic hypogonadism.
    explanation: >-
      This reports hypothyroidism in the originally described MCM8 sibship.
- name: Chromosome breakage
  category: Laboratory
  description: >-
    Affected individuals show impaired repair of induced chromosome breaks,
    capturing the chromosomal-instability component of the syndrome.
  phenotype_term:
    preferred_term: Chromosome breakage
    term:
      id: HP:0040012
      label: Chromosome breakage
  evidence:
  - reference: PMID:25437880
    reference_title: "Exome sequencing reveals MCM8 mutation underlies ovarian failure and chromosomal instability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      chromosomal break repair was deficient in fibroblasts from the affected
      individuals, likely due to inhibited recruitment of MCM8 p.P149R to sites
      of DNA damage.
    explanation: >-
      This directly supports a chromosome-breakage phenotype consistent with the
      chromosomal-instability state.
  - reference: PMID:25873734
    reference_title: "Minichromosome maintenance complex component 8 (MCM8) gene mutations result in primary gonadal failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Chromosomal breakage following exposure to mitomcyin C was significantly
      increased in cells from homozygous individuals for c.1954-1G>A, as well as
      c.1469-1470insTA.
    explanation: >-
      An independent family confirms increased induced chromosomal breakage in
      MCM8-deficient cells.
- name: Azoospermia
  category: Reproductive
  description: >-
    In 46,XY individuals the disorder manifests as severe non-obstructive
    azoospermia, frequently with small testes.
  phenotype_term:
    preferred_term: Azoospermia
    term:
      id: HP:0000027
      label: Azoospermia
  phenotype_contexts:
  - sex: MALE
    notes: Reported as small testes with azoospermia / non-obstructive azoospermia in 46,XY individuals.
    evidence:
    - reference: PMID:25873734
      reference_title: "Minichromosome maintenance complex component 8 (MCM8) gene mutations result in primary gonadal failure."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        two consanguineous families presenting as primary amenorrhoea in the
        females and as small testes and azoospermia in a male.
      explanation: >-
        This documents the male azoospermia branch of MCM8-related gonadal
        failure.
    - reference: PMID:40064807
      reference_title: "A novel homozygous frameshift mutation in MCM8 causes primary gonadal dysgenesis in both genders."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        underdeveloped testes and non-obstructive azoospermia (NOA) in a male
      explanation: >-
        A second family independently confirms non-obstructive azoospermia in a
        46,XY individual with biallelic MCM8 loss.
- name: Sertoli cell-only syndrome
  category: Reproductive
  description: >-
    Testicular histopathology in a reported male case showed Sertoli cell-only
    syndrome, consistent with severe germ-cell depletion.
  phenotype_term:
    preferred_term: Sertoli cell-only syndrome
    term:
      id: HP:0003251
      label: Male infertility
  phenotype_contexts:
  - sex: MALE
    notes: >-
      Current local HPO does not expose a specific SCOS term, so this entry is
      anchored to the closest available male-infertility ancestor while keeping
      the histopathologic preferred term explicit.
    evidence:
    - reference: PMID:40064807
      reference_title: "A novel homozygous frameshift mutation in MCM8 causes primary gonadal dysgenesis in both genders."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The testes tissue sections in the male showed a Sertoli cell-only
        syndrome (SCOS).
      explanation: >-
        This supports Sertoli cell-only histology as the male gonadal-failure
        correlate of MCM8 deficiency.
- name: Germ cell tumor
  category: Oncology
  description: >-
    Biallelic MCM8 variant carriers show an association with early-onset germ
    cell tumors, a narrower cancer spectrum than the gastrointestinal
    malignancy reported for MCM9.
  phenotype_term:
    preferred_term: Germ cell tumor
    term:
      id: HP:0100728
      label: Germ cell neoplasia
  evidence:
  - reference: PMID:40684266
    reference_title: "Clinical syndromes linked to biallelic germline variants in MCM8 and MCM9."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      both biallelic MCM8 and MCM9 variants are linked to hypogonadism and the
      early development of germ cell tumors.
    explanation: >-
      This supports early-onset germ cell tumors as the cancer phenotype linked
      to biallelic MCM8 variants.
genetic:
- name: MCM8
  association: Causative (Primary)
  inheritance:
  - name: Autosomal recessive inheritance
    evidence:
    - reference: PMID:25437880
      reference_title: "Exome sequencing reveals MCM8 mutation underlies ovarian failure and chromosomal instability."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Our study identifies an autosomal recessive disorder caused by an MCM8
        mutation that manifests with endocrine dysfunction and genomic
        instability.
      explanation: >-
        This supports recessive transmission at the gene level.
  evidence:
  - reference: PMID:25437880
    reference_title: "Exome sequencing reveals MCM8 mutation underlies ovarian failure and chromosomal instability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      SNP analysis and whole-exome sequencing revealed the presence of a
      pathogenic variant of the minichromosome maintenance 8 gene (MCM8,
      c.446C>G; p.P149R) located within a region of homozygosity
    explanation: >-
      This establishes MCM8 as the causal gene in the founding female family.
  - reference: PMID:40064807
    reference_title: "A novel homozygous frameshift mutation in MCM8 causes primary gonadal dysgenesis in both genders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A homozygous frameshift mutation c.998delG (p. Gly333Glufs*50) in MCM8 was
      identified in the two siblings.
    explanation: >-
      This extends the causal role of biallelic MCM8 loss-of-function variants to
      a bisexual gonadal-failure family.
  notes: >-
    MCM8 encodes minichromosome maintenance 8 homologous recombination repair
    factor, which partners with MCM9 as a helicase that promotes RAD51-dependent
    homologous recombination.
treatments:
- name: Hormone replacement therapy
  description: >-
    Estrogen-based hormone replacement is used to treat hypoestrogenism in the
    ovarian-failure branch, support pubertal development, and reduce
    osteoporosis risk.
  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:25437880
    reference_title: "Exome sequencing reveals MCM8 mutation underlies ovarian failure and chromosomal instability."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we studied 3 sisters with primary amenorrhea, hypothyroidism, and
      hypergonadotropic hypogonadism.
    explanation: >-
      This anchors the ovarian-failure branch to the hypergonadotropic
      hypogonadism that drives hormone-replacement treatment.
  - reference: PMID:41942077
    reference_title: >-
      Premature ovarian insufficiency diagnosis and management in general
      practice: A review based on the 2024 international guideline.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      This review outlines key diagnostic criteria, initial investigations,
      referral pathways and management options including hormone therapy,
      chronic disease risk reduction, fertility counselling and psychosocial
      support.
    explanation: >-
      This provides condition-level management evidence that hormone therapy is
      part of standard care for primary ovarian insufficiency, the core female
      branch of MCM8-related disease.
- name: Germ cell tumor and cancer surveillance
  description: >-
    Because biallelic MCM8 deficiency is associated with early-onset germ cell
    tumors, affected individuals may benefit from cancer surveillance, including
    imaging for gonadal or extragonadal germ cell tumors.
  treatment_term:
    preferred_term: surveillance for malignancies
    term:
      id: MAXO:0001492
      label: surveillance for malignancies
  evidence:
  - reference: PMID:40684266
    reference_title: "Clinical syndromes linked to biallelic germline variants in MCM8 and MCM9."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These findings underscore the importance of including MCM8/MCM9 in
      diagnostic gene panels for certain clinical contexts and suggest that
      biallelic carriers may benefit from cancer surveillance.
    explanation: >-
      This supports cancer surveillance for biallelic MCM8 carriers given the
      germ cell tumor risk.
- name: Genetic counseling
  description: >-
    Genetic counseling is appropriate for affected families because the
    condition is recessive, causes infertility in both sexes, and carries
    implications for reproductive planning and cancer surveillance.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:40064807
    reference_title: "A novel homozygous frameshift mutation in MCM8 causes primary gonadal dysgenesis in both genders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      expands the mutational spectrum of MCM8 involved in male NOA and female
      POI and provides a new molecular marker for genetic counseling of
      infertility.
    explanation: >-
      This directly supports genetic counseling as part of management for
      MCM8-associated gonadal failure.
diagnosis:
- name: Targeted molecular testing
  description: >-
    Exome or panel-based molecular testing can confirm the diagnosis by
    identifying biallelic pathogenic MCM8 variants in patients with primary
    gonadal failure.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: MAXO:0000127
      label: genetic testing
  evidence:
  - reference: PMID:25873734
    reference_title: "Minichromosome maintenance complex component 8 (MCM8) gene mutations result in primary gonadal failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we identified two novel homozygous mutations in the MCM8 gene: a splice
      (c.1954-1G>A) and a frameshift (c.1469-1470insTA).
    explanation: >-
      This supports molecular confirmation through gene-level sequencing.
- name: Chromosome breakage assessment
  description: >-
    Functional assessment of induced chromosome-break repair (e.g., after
    mitomycin C exposure) can help demonstrate the chromosomal-instability
    component of the disorder.
  diagnosis_term:
    preferred_term: clinical assessment
    term:
      id: MAXO:0000487
      label: clinical assessment
  evidence:
  - reference: PMID:25873734
    reference_title: "Minichromosome maintenance complex component 8 (MCM8) gene mutations result in primary gonadal failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Chromosomal breakage following exposure to mitomcyin C was significantly
      increased in cells from homozygous individuals for c.1954-1G>A, as well as
      c.1469-1470insTA.
    explanation: >-
      Increased induced chromosomal breakage supports a disease-relevant
      functional diagnostic assay.
- name: Hormonal and gonadal evaluation
  description: >-
    Serum gonadotropins (FSH, LH) and sex-hormone levels characterize the
    endocrine phenotype. In 46,XX individuals, elevated FSH and LH with low
    estradiol confirm hypergonadotropic hypogonadism; in 46,XY individuals,
    semen analysis is required because severe spermatogenic failure can occur
    despite otherwise unremarkable findings.
  diagnosis_term:
    preferred_term: hormonal evaluation
    term:
      id: MAXO:0000487
      label: clinical assessment
  evidence:
  - reference: PMID:25437880
    reference_title: "Exome sequencing reveals MCM8 mutation underlies ovarian failure and chromosomal instability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we studied 3 sisters with primary amenorrhea, hypothyroidism, and
      hypergonadotropic hypogonadism.
    explanation: >-
      Hypergonadotropic hypogonadism is the endocrine hallmark that FSH/LH
      testing reveals in 46,XX individuals with MCM8 deficiency.
- name: Andrological evaluation
  description: >-
    Male patients should undergo semen analysis as the primary assessment for
    spermatogenic failure; non-obstructive azoospermia is the expected finding.
    Testicular biopsy can confirm Sertoli cell-only syndrome histology when
    sperm retrieval is considered.
  diagnosis_term:
    preferred_term: clinical assessment
    term:
      id: MAXO:0000487
      label: clinical assessment
  evidence:
  - reference: PMID:40064807
    reference_title: "A novel homozygous frameshift mutation in MCM8 causes primary gonadal dysgenesis in both genders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The testes tissue sections in the male showed a Sertoli cell-only
      syndrome (SCOS).
    explanation: >-
      Testicular histology demonstrating Sertoli cell-only syndrome is part of
      the andrological evaluation of the male MCM8 branch.