HFM1-related gametogenic failure

Mendelian MONDO:0014322 Pathograph 7 Show in embeddings browser Primary ovarian insufficiency Male infertility Meiotic disorder

HFM1-related gametogenic failure is a recessive disorder of meiotic crossover formation caused by biallelic loss-of-function variants in HFM1 (helicase for meiosis 1). HFM1 encodes an evolutionarily conserved ATP-dependent DExH-box helicase that is essential for crossover formation and completion of meiotic prophase I. It acts in concert with the MutSγ complex (MSH4-MSH5) to process recombination intermediates and designate class I crossovers. Biallelic HFM1 loss impairs synapsis and crossover formation, leading to germ-cell arrest at meiotic metaphase I and subsequent apoptosis. The reported human spectrum is bisexual: 46,XX individuals present with primary ovarian insufficiency (premature ovarian failure 9, OMIM:615724) including poor ovarian response and recurrent implantation failure, while 46,XY individuals present with non-obstructive azoospermia (NOA) with spermatogenic arrest at metaphase I. The shared mechanistic theme is failed HFM1-dependent crossover resolution during meiosis, analogous to the related SYCE1-, STAG3-, MCM8-, and MCM9-linked gametogenic failure syndromes.

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1
Mappings
1
Inheritance
4
Pathophys.
3
Phenotypes
2
Gaps
7
Pathograph
1
Genes
2
Medical Actions
🔗

Mappings

MONDO
MONDO:0014322 premature ovarian failure 9
skos:exactMatch MONDO
MONDO:0014322 (premature ovarian failure 9; OMIM:615724) is the current MONDO anchor for biallelic HFM1-related gonadal failure. It captures the female ovarian-failure presentation; no dyadic "HFM1-related gametogenic failure" grouper has yet been minted.
👪

Inheritance

1
Autosomal recessive inheritance HP:0000007
All reported families carry biallelic (homozygous or compound-heterozygous) loss-of-function HFM1 variants segregating with disease in a recessive pattern, consistent with the POF9 OMIM assignment and mouse model data.
Autosomal recessive inheritance
Show evidence (2 references)
PMID:35526155 SUPPORT Human Clinical
"Six variants (homozygous or compound heterozygous) in HFM1 were identified in the three Chinese patients with NOA and two brothers with NOA from the Pakistani family."
Homozygous and compound-heterozygous HFM1 variants segregating with infertility in multiple independent families confirm recessive inheritance.
PMID:36864181 SUPPORT Human Clinical
"We identified a novel homozygous splicing variant in HFM1 (NM_001017975.6: c.1730-1G > T) in two siblings."
Homozygous HFM1 splicing variant in consanguineous siblings causing gametogenic failure in both sexes, confirming recessive transmission.
?

Discussions and Knowledge Gaps

2
The female phenotype of HFM1 deficiency ranges from complete POI to poor ovarian response and recurrent implantation failure — what determines severity, is residual HFM1 crossover activity the primary modifier, and can early ovarian reserve monitoring identify candidates for fertility preservation before complete failure occurs?
KNOWLEDGE GAP OPEN gap_hfm1_female_phenotype_severity
Attached to
pathophysiology#Ovarian follicle depletion and primary ovarian insufficiency
Does microTESE sperm retrieval success in biallelic HFM1 NOA correlate with variant predicted severity (null versus hypomorphic), and can pre-procedure genotype-phenotype scoring replace reliance on biopsy alone in predicting retrievability?
KNOWLEDGE GAP OPEN gap_hfm1_microtese_success_by_variant
Attached to
pathophysiology#Spermatogenic arrest and non-obstructive azoospermia
⚙

Pathophysiology

4
Impaired crossover formation at meiotic recombination intermediates
Biallelic HFM1 loss disables the helicase activity required to process recombination intermediates into designated crossovers during meiotic prophase I. HFM1 stabilizes the MutSγ complex (MSH4-MSH5) on Holliday junctions and promotes class I crossover formation. Its loss leads to varying reductions in HFM1 foci on chromosome axes and defects in synapsis and crossover formation, blocking meiotic progression.
HFM1 hgnc:20193
meiotic DNA repair synthesis GO:0000711 ↓ DECREASED reciprocal meiotic recombination GO:0007131 ↓ DECREASED
Downstream
Meiotic arrest and germ cell depletion Unresolved meiotic recombination intermediates block germ-cell progression through prophase I and trigger germ-cell apoptosis.
Show evidence (2 references)
PMID:35526155 SUPPORT Human Clinical
"Biallelic variants in HFM1 cause human male infertility owing to non-obstructive azoospermia (NOA) with impaired crossover formation and meiotic metaphase I (MMI) arrest."
Establishes impaired crossover formation as the direct consequence of biallelic HFM1 variants in human infertility.
PMID:35526155 SUPPORT Model Organism
"These Hfm1 variants led to various reductions of HFM1 foci on chromosome axes and resulted in varying degrees of synapsis and crossover formation defects in the mutant male mice."
Mouse models of patient HFM1 variants recapitulate synapsis and crossover defects, linking reduced HFM1 foci to defective meiotic recombination.
Meiotic arrest and germ cell depletion
Germ cells that cannot complete meiotic crossover formation arrest at meiotic metaphase I and are eliminated by apoptosis 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:35526155 SUPPORT Model Organism
"Hfm1 mutant female mice displayed infertility or subfertility with oogenesis variously affected."
Mouse models demonstrate germ-cell failure in both sexes on HFM1 loss, consistent with the pachytene/metaphase arrest and germ-cell depletion pathway.
Ovarian follicle depletion and primary ovarian insufficiency
Loss of oocytes during meiotic crossover failure depletes the ovarian reserve. 46,XX individuals present with primary ovarian insufficiency, poor ovarian response in IVF cycles, and/or recurrent implantation failure. The severity varies: some individuals have amenorrhea and ovarian dysgenesis while others have oligomenorrhea or subfertility.
oocyte CL:0000023
female gamete generation GO:0007292 ↓ DECREASED
Downstream
Premature ovarian insufficiency The female branch presents clinically as primary or premature ovarian insufficiency, with variable severity from poor ovarian response to complete ovarian failure.
Show evidence (2 references)
PMID:32962729 SUPPORT Human Clinical
"We recruited 24 patients with POI and identified variants in POI-related genes in 14 patients, including bi-allelic mutations in DNAH6, HFM1, EIF2B2, BNC, and LRPPRC."
WES cohort confirms biallelic HFM1 variants as a cause of primary ovarian insufficiency in 46,XX individuals.
PMID:36864181 SUPPORT Human Clinical
"Apart from NOA and POI, biallelic variants in HFM1 were also associated with recurrent implantation failure (RIF)."
Documents the full female phenotypic spectrum of HFM1 deficiency from POI to poor ovarian response and recurrent implantation failure.
Spermatogenic arrest and non-obstructive azoospermia
In 46,XY individuals, HFM1-dependent meiotic failure produces spermatogenic arrest at meiotic metaphase I. Testicular histology shows complete arrest of spermatogenesis; no retrievable spermatozoa are found on microTESE, and patients present with non-obstructive azoospermia (NOA) or, in some cases with hypomorphic variants, severe oligozoospermia amenable to ICSI.
spermatocyte CL:0000017
male gamete generation GO:0048232 ↓ DECREASED
Downstream
Azoospermia In 46,XY individuals, severe spermatogenic arrest manifests clinically as non-obstructive azoospermia.
Show evidence (2 references)
PMID:35526155 SUPPORT Human Clinical
"Testicular histological analysis revealed that spermatogenesis is arrested at MMI in patients carrying the variants."
Direct histological evidence of spermatogenic arrest at metaphase I in men with biallelic HFM1 variants, establishing the male phenotype.
PMID:37574498 SUPPORT Human Clinical
"Our results showed that a deleterious splicing variant in HFM1 was related to NOA in these two patients."
Additional independent NOA family with a splicing variant in HFM1 confirms the male infertility phenotype.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Referential integrity issues (1):
  • Target 'Azoospermia' (from 'Spermatogenic arrest and non-obstructive azoospermia') not found in named elements
Pathograph: causal mechanism network for HFM1-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

3
Genitourinary 2
Premature ovarian insufficiency Premature ovarian insufficiency HP:0008209
Show evidence (1 reference)
PMID:32962729 SUPPORT Human Clinical
"We recruited 24 patients with POI and identified variants in POI-related genes in 14 patients, including bi-allelic mutations in DNAH6, HFM1, EIF2B2, BNC, and LRPPRC."
WES cohort identifies biallelic HFM1 as a cause of POI in 46,XX individuals.
Context-specific annotations (1)
FEMALE
Reported in 46,XX individuals with biallelic HFM1 variants.
Show evidence (1 reference)
PMID:36864181 SUPPORT Human Clinical
"Apart from NOA and POI, biallelic variants in HFM1 were also associated with recurrent implantation failure (RIF)."
Documents POI as the female arm of HFM1-related gametogenic failure.
Male infertility Male infertility HP:0003251
Show evidence (1 reference)
PMID:34429122 SUPPORT Human Clinical
"Histopathology of the testis showed that spermatogenesis was completely blocked at metaphase in these two patients carrying the HFM1 homozygous variants."
Histopathological demonstration of metaphase I arrest in patients with biallelic HFM1 variants.
Context-specific annotations (1)
MALE
Other 1
Non-obstructive azoospermia Non-obstructive azoospermia HP:0011961
Show evidence (1 reference)
PMID:34429122 SUPPORT Human Clinical
"This study identified novel homozygous variants of HFM1 that are responsible for spermatogenic failure and NOA, and microTESE did not aid in retrieving sperms from these patients."
Confirms NOA as a consequence of biallelic HFM1 loss, and notes that microTESE is not retrievable — relevant for clinical counseling.
Context-specific annotations (1)
MALE
Reported in 46,XY individuals with biallelic HFM1 variants.
Show evidence (1 reference)
PMID:35526155 SUPPORT Human Clinical
"Biallelic variants in HFM1 cause human male infertility owing to non-obstructive azoospermia (NOA) with impaired crossover formation and meiotic metaphase I (MMI) arrest."
Establishes NOA with metaphase I arrest as the male phenotype of HFM1 deficiency.
🧬

Genetic Associations

1
HFM1 (Causative (Primary))
Gene: HFM1 hgnc:20193
Autosomal recessive inheritance
💊

Medical Actions

2
Genetic counseling
Action: Genetic Counseling NCIT:C15240
Genetic counseling for couples with biallelic HFM1 variants. Assisted reproductive technology outcomes depend on residual HFM1 function: complete loss-of-function in 46,XY individuals typically makes microTESE unsuccessful (sperm retrieval rate is low); hypomorphic variants may allow ICSI with the few available spermatozoa. For 46,XX individuals, oocyte cryopreservation before complete ovarian failure may preserve fertility if the diagnosis is made early.
Hormone replacement therapy
Action: Pharmacotherapy NCIT:C15986
Estrogen-progestogen hormone replacement therapy is standard of care for 46,XX individuals with HFM1-related primary ovarian insufficiency, addressing bone density, cardiovascular risk, and menopausal symptoms.
{ }

Source YAML

click to show 
name: HFM1-related gametogenic failure
creation_date: "2026-06-23T14:00:00Z"
category: Mendelian
description: >-
  HFM1-related gametogenic failure is a recessive disorder of meiotic crossover
  formation caused by biallelic loss-of-function variants in HFM1 (helicase for
  meiosis 1). HFM1 encodes an evolutionarily conserved ATP-dependent DExH-box
  helicase that is essential for crossover formation and completion of meiotic
  prophase I. It acts in concert with the MutSγ complex (MSH4-MSH5) to process
  recombination intermediates and designate class I crossovers. Biallelic HFM1
  loss impairs synapsis and crossover formation, leading to germ-cell arrest at
  meiotic metaphase I and subsequent apoptosis. The reported human spectrum is
  bisexual: 46,XX individuals present with primary ovarian insufficiency
  (premature ovarian failure 9, OMIM:615724) including poor ovarian response and
  recurrent implantation failure, while 46,XY individuals present with
  non-obstructive azoospermia (NOA) with spermatogenic arrest at metaphase I.
  The shared mechanistic theme is failed HFM1-dependent crossover resolution
  during meiosis, analogous to the related SYCE1-, STAG3-, MCM8-, and
  MCM9-linked gametogenic failure syndromes.
disease_term:
  preferred_term: HFM1-related gametogenic failure
  term:
    id: MONDO:0014322
    label: premature ovarian failure 9
parents:
- Primary ovarian insufficiency
- Male infertility
- Meiotic disorder
synonyms:
- HFM1 deficiency
- HFM1-associated gametogenic failure
- premature ovarian failure 9
- POF9
- helicase for meiosis 1 deficiency
notes: >-
  The MONDO anchor available is MONDO:0014322 (premature ovarian failure 9;
  OMIM:615724), which captures the female ovarian-failure presentation first
  described. The broader preferred term "HFM1-related gametogenic failure"
  reflects the conserved meiotic-crossover mechanism and the bisexual germ-cell
  failure documented in humans: both 46,XX primary ovarian insufficiency and
  46,XY non-obstructive azoospermia / metaphase-I arrest arise from the same
  biallelic HFM1 loss. HFM1 is mechanistically distinct from the MCM8/MCM9
  helicase pair (which act at the DNA-damage resection step): HFM1 acts
  downstream at crossover designation and Holliday junction resolution. No cancer
  predisposition has been reported for biallelic HFM1 variants, distinguishing
  this entry from MCM8- and MCM9-related gametogenic failure. A dyadic
  "HFM1-related gametogenic failure" MONDO grouper class does not currently exist;
  re-anchoring to a future minted grouper is a one-line change. Some 46,XX
  individuals additionally present with recurrent implantation failure (RIF) in
  IVF cycles, likely reflecting oocyte meiotic errors from residual HFM1
  dysfunction.
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0014322
      label: premature ovarian failure 9
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: >-
      MONDO:0014322 (premature ovarian failure 9; OMIM:615724) is the current
      MONDO anchor for biallelic HFM1-related gonadal failure. It captures the
      female ovarian-failure presentation; no dyadic "HFM1-related gametogenic
      failure" grouper has yet been minted.
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    All reported families carry biallelic (homozygous or compound-heterozygous)
    loss-of-function HFM1 variants segregating with disease in a recessive
    pattern, consistent with the POF9 OMIM assignment and mouse model data.
  evidence:
  - reference: PMID:35526155
    reference_title: "Biallelic HFM1 variants cause non-obstructive azoospermia with meiotic arrest in humans by impairing crossover formation to varying degrees."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Six variants (homozygous or compound heterozygous) in HFM1 were identified
      in the three Chinese patients with NOA and two brothers with NOA from the
      Pakistani family.
    explanation: >-
      Homozygous and compound-heterozygous HFM1 variants segregating with
      infertility in multiple independent families confirm recessive inheritance.
  - reference: PMID:36864181
    reference_title: "Novel deleterious splicing variant in HFM1 causes gametogenesis defect and recurrent implantation failure: concerning the risk of chromosomal abnormalities in embryos."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified a novel homozygous splicing variant in HFM1
      (NM_001017975.6: c.1730-1G > T) in two siblings.
    explanation: >-
      Homozygous HFM1 splicing variant in consanguineous siblings causing
      gametogenic failure in both sexes, confirming recessive transmission.
pathophysiology:
- name: Impaired crossover formation at meiotic recombination intermediates
  conforms_to: "meiotic_prophase_failure#Homologous Recombination Repair of Meiotic DNA Breaks"
  description: >-
    Biallelic HFM1 loss disables the helicase activity required to process
    recombination intermediates into designated crossovers during meiotic prophase
    I. HFM1 stabilizes the MutSγ complex (MSH4-MSH5) on Holliday junctions and
    promotes class I crossover formation. Its loss leads to varying reductions in
    HFM1 foci on chromosome axes and defects in synapsis and crossover formation,
    blocking meiotic progression.
  genes:
  - preferred_term: HFM1
    term:
      id: hgnc:20193
      label: HFM1
  biological_processes:
  - preferred_term: meiotic DNA repair synthesis
    term:
      id: GO:0000711
      label: meiotic DNA repair synthesis
    modifier: DECREASED
  - preferred_term: reciprocal meiotic recombination
    term:
      id: GO:0007131
      label: reciprocal meiotic recombination
    modifier: DECREASED
  evidence:
  - reference: PMID:35526155
    reference_title: "Biallelic HFM1 variants cause non-obstructive azoospermia with meiotic arrest in humans by impairing crossover formation to varying degrees."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Biallelic variants in HFM1 cause human male infertility owing to
      non-obstructive azoospermia (NOA) with impaired crossover formation and
      meiotic metaphase I (MMI) arrest.
    explanation: >-
      Establishes impaired crossover formation as the direct consequence of
      biallelic HFM1 variants in human infertility.
  - reference: PMID:35526155
    reference_title: "Biallelic HFM1 variants cause non-obstructive azoospermia with meiotic arrest in humans by impairing crossover formation to varying degrees."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      These Hfm1 variants led to various reductions of HFM1 foci on chromosome
      axes and resulted in varying degrees of synapsis and crossover formation
      defects in the mutant male mice.
    explanation: >-
      Mouse models of patient HFM1 variants recapitulate synapsis and crossover
      defects, linking reduced HFM1 foci to defective meiotic recombination.
  downstream:
  - target: Meiotic arrest and germ cell depletion
    description: >-
      Unresolved meiotic recombination intermediates block germ-cell progression
      through prophase I and trigger germ-cell apoptosis.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - defective crossover designation
    - unresolved meiotic recombination intermediates
    - meiotic metaphase I arrest
    evidence:
    - reference: PMID:34429122
      reference_title: "Novel variants in helicase for meiosis 1 lead to male infertility due to non-obstructive azoospermia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Histopathology of the testis showed that spermatogenesis was completely
        blocked at metaphase in these two patients carrying the HFM1 homozygous
        variants.
      explanation: >-
        Testicular histopathology shows metaphase I arrest in patients with
        biallelic HFM1 variants, confirming the recombination failure to
        meiotic arrest to azoospermia pathway.
- 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 meiotic crossover formation arrest at
    meiotic metaphase I and are eliminated by apoptosis 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:35526155
    reference_title: "Biallelic HFM1 variants cause non-obstructive azoospermia with meiotic arrest in humans by impairing crossover formation to varying degrees."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Hfm1 mutant female mice displayed infertility or subfertility with oogenesis
      variously affected.
    explanation: >-
      Mouse models demonstrate germ-cell failure in both sexes on HFM1 loss,
      consistent with the pachytene/metaphase arrest and germ-cell depletion
      pathway.
  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 crossover failure depletes the ovarian
    reserve. 46,XX individuals present with primary ovarian insufficiency,
    poor ovarian response in IVF cycles, and/or recurrent implantation failure.
    The severity varies: some individuals have amenorrhea and ovarian dysgenesis
    while others have oligomenorrhea or subfertility.
  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:32962729
    reference_title: "Whole-exome sequencing in patients with premature ovarian insufficiency: early detection and early intervention."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We recruited 24 patients with POI and identified variants in POI-related
      genes in 14 patients, including bi-allelic mutations in DNAH6, HFM1,
      EIF2B2, BNC, and LRPPRC.
    explanation: >-
      WES cohort confirms biallelic HFM1 variants as a cause of primary ovarian
      insufficiency in 46,XX individuals.
  - reference: PMID:36864181
    reference_title: "Novel deleterious splicing variant in HFM1 causes gametogenesis defect and recurrent implantation failure: concerning the risk of chromosomal abnormalities in embryos."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Apart from NOA and POI, biallelic variants in HFM1 were also associated
      with recurrent implantation failure (RIF).
    explanation: >-
      Documents the full female phenotypic spectrum of HFM1 deficiency from
      POI to poor ovarian response and recurrent implantation failure.
  downstream:
  - target: Premature ovarian insufficiency
    description: >-
      The female branch presents clinically as primary or premature ovarian
      insufficiency, with variable severity from poor ovarian response to
      complete ovarian failure.
    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, HFM1-dependent meiotic failure produces spermatogenic
    arrest at meiotic metaphase I. Testicular histology shows complete arrest of
    spermatogenesis; no retrievable spermatozoa are found on microTESE, and
    patients present with non-obstructive azoospermia (NOA) or, in some cases
    with hypomorphic variants, severe oligozoospermia amenable to ICSI.
  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:35526155
    reference_title: "Biallelic HFM1 variants cause non-obstructive azoospermia with meiotic arrest in humans by impairing crossover formation to varying degrees."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Testicular histological analysis revealed that spermatogenesis is arrested
      at MMI in patients carrying the variants.
    explanation: >-
      Direct histological evidence of spermatogenic arrest at metaphase I in
      men with biallelic HFM1 variants, establishing the male phenotype.
  - reference: PMID:37574498
    reference_title: "A novel splicing mutation in helicase for meiosis 1 leads to non-obstructive azoospermia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our results showed that a deleterious splicing variant in HFM1 was related
      to NOA in these two patients.
    explanation: >-
      Additional independent NOA family with a splicing variant in HFM1
      confirms the male infertility phenotype.
  downstream:
  - target: Azoospermia
    description: >-
      In 46,XY individuals, severe spermatogenic arrest manifests clinically as
      non-obstructive azoospermia.
    causal_link_type: DIRECT
phenotypes:
- name: Premature ovarian insufficiency
  category: Reproductive
  description: >-
    Reported 46,XX individuals present with primary ovarian insufficiency,
    often with poor ovarian response, recurrent implantation failure, or
    complete amenorrhea.
  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 HFM1 variants.
    evidence:
    - reference: PMID:36864181
      reference_title: "Novel deleterious splicing variant in HFM1 causes gametogenesis defect and recurrent implantation failure: concerning the risk of chromosomal abnormalities in embryos."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Apart from NOA and POI, biallelic variants in HFM1 were also associated
        with recurrent implantation failure (RIF).
      explanation: >-
        Documents POI as the female arm of HFM1-related gametogenic failure.
  evidence:
  - reference: PMID:32962729
    reference_title: "Whole-exome sequencing in patients with premature ovarian insufficiency: early detection and early intervention."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We recruited 24 patients with POI and identified variants in POI-related
      genes in 14 patients, including bi-allelic mutations in DNAH6, HFM1,
      EIF2B2, BNC, and LRPPRC.
    explanation: >-
      WES cohort identifies biallelic HFM1 as a cause of POI in 46,XX
      individuals.
- name: Non-obstructive azoospermia
  category: Reproductive
  description: >-
    46,XY individuals present with non-obstructive azoospermia (NOA) as the
    primary infertility phenotype. Testicular histology shows spermatogenic
    arrest at metaphase I. MicroTESE typically fails to retrieve spermatozoa in
    complete loss-of-function variants; hypomorphic variants may permit
    severe oligozoospermia with some ICSI success.
  phenotype_term:
    preferred_term: Non-obstructive azoospermia
    term:
      id: HP:0011961
      label: Non-obstructive azoospermia
  phenotype_contexts:
  - sex: MALE
    notes: Reported in 46,XY individuals with biallelic HFM1 variants.
    evidence:
    - reference: PMID:35526155
      reference_title: "Biallelic HFM1 variants cause non-obstructive azoospermia with meiotic arrest in humans by impairing crossover formation to varying degrees."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Biallelic variants in HFM1 cause human male infertility owing to
        non-obstructive azoospermia (NOA) with impaired crossover formation and
        meiotic metaphase I (MMI) arrest.
      explanation: >-
        Establishes NOA with metaphase I arrest as the male phenotype of HFM1
        deficiency.
  evidence:
  - reference: PMID:34429122
    reference_title: "Novel variants in helicase for meiosis 1 lead to male infertility due to non-obstructive azoospermia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This study identified novel homozygous variants of HFM1 that are
      responsible for spermatogenic failure and NOA, and microTESE did not aid
      in retrieving sperms from these patients.
    explanation: >-
      Confirms NOA as a consequence of biallelic HFM1 loss, and notes that
      microTESE is not retrievable — relevant for clinical counseling.
- name: Male infertility
  category: Reproductive
  description: >-
    Testicular biopsies from affected 46,XY individuals show spermatogenesis
    blocked at meiotic metaphase I, without progression to round spermatids
    or mature spermatozoa.
  phenotype_term:
    preferred_term: Male infertility
    term:
      id: HP:0003251
      label: Male infertility
  phenotype_contexts:
  - sex: MALE
  evidence:
  - reference: PMID:34429122
    reference_title: "Novel variants in helicase for meiosis 1 lead to male infertility due to non-obstructive azoospermia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Histopathology of the testis showed that spermatogenesis was completely
      blocked at metaphase in these two patients carrying the HFM1 homozygous
      variants.
    explanation: >-
      Histopathological demonstration of metaphase I arrest in patients with
      biallelic HFM1 variants.
genetic:
- name: HFM1
  association: Causative (Primary)
  inheritance:
  - name: Autosomal recessive inheritance
    evidence:
    - reference: PMID:35526155
      reference_title: "Biallelic HFM1 variants cause non-obstructive azoospermia with meiotic arrest in humans by impairing crossover formation to varying degrees."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Six variants (homozygous or compound heterozygous) in HFM1 were
        identified in the three Chinese patients with NOA and two brothers with
        NOA from the Pakistani family.
      explanation: >-
        Multiple independent families with biallelic HFM1 loss-of-function
        variants establish autosomal recessive inheritance.
  gene_term:
    preferred_term: HFM1
    term:
      id: hgnc:20193
      label: HFM1
treatments:
- name: Genetic counseling
  description: >-
    Genetic counseling for couples with biallelic HFM1 variants. Assisted
    reproductive technology outcomes depend on residual HFM1 function: complete
    loss-of-function in 46,XY individuals typically makes microTESE unsuccessful
    (sperm retrieval rate is low); hypomorphic variants may allow ICSI with
    the few available spermatozoa. For 46,XX individuals, oocyte cryopreservation
    before complete ovarian failure may preserve fertility if the diagnosis is
    made early.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
- name: Hormone replacement therapy
  description: >-
    Estrogen-progestogen hormone replacement therapy is standard of care for
    46,XX individuals with HFM1-related primary ovarian insufficiency, addressing
    bone density, cardiovascular risk, and menopausal symptoms.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
discussions:
- discussion_id: gap_hfm1_female_phenotype_severity
  prompt: >-
    The female phenotype of HFM1 deficiency ranges from complete POI to poor
    ovarian response and recurrent implantation failure — what determines severity,
    is residual HFM1 crossover activity the primary modifier, and can early
    ovarian reserve monitoring identify candidates for fertility preservation
    before complete failure occurs?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Ovarian follicle depletion and primary ovarian insufficiency
- discussion_id: gap_hfm1_microtese_success_by_variant
  prompt: >-
    Does microTESE sperm retrieval success in biallelic HFM1 NOA correlate
    with variant predicted severity (null versus hypomorphic), and can
    pre-procedure genotype-phenotype scoring replace reliance on biopsy alone
    in predicting retrievability?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Spermatogenic arrest and non-obstructive azoospermia