Spermatogenic Failure 28

Mendelian MONDO:0054732 Pathograph 18 Show in embeddings browser Spermatogenic Failure Genetic Disease

Spermatogenic failure 28 (SPGF28) is autosomal recessive male infertility caused by biallelic loss-of-function variants in FANCM, a DNA translocase that works with the Fanconi anemia (FA) core complex and the Bloom helicase complex to keep replicating and recombining DNA stable. Most reported men have non-obstructive azoospermia, and testicular biopsy shows a Sertoli cell-only pattern with no germ cells. Men in one consanguineous Pakistani family had oligoasthenozoospermia instead, so the spermatogenic defect is variable. Patient lymphocytes break their chromosomes more often after exposure to the crosslinking agent mitomycin C, but the men reported with spermatogenic failure had no bone marrow failure or congenital malformations. In mice, Fancm loss depletes primordial germ cells and then spermatogonial stem cells, and arrests some spermatids. Biallelic FANCM truncating variants are also found in women with premature ovarian insufficiency and in people of both sexes with early-onset cancer and severe chemotherapy toxicity. ClinGen groups these presentations with SPGF28 as one autosomal recessive FANCM Fanconi-like genomic instability disorder, which is distinct from Fanconi anemia.

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1
Mappings
1
Inheritance
5
Pathophys.
8
Phenotypes
1
Hypotheses
18
Pathograph
1
Genes
4
Medical Actions
2
Models
1
Deep Research
🔗

Mappings

MONDO
MONDO:0100578 FANCM Fanconi-like genomic instability disorder Not Yet Curated
skos:broadMatch MONDO
ClinGen lumps spermatogenic failure 28 (OMIM 618086), premature ovarian failure 15 (OMIM 618096) and Fanconi-like syndrome (OMIM 227850) into one autosomal recessive FANCM disease, MONDO:0100578. This entry covers the male spermatogenic presentation of that broader disorder. MONDO does not currently place MONDO:0054732 beneath MONDO:0100578.
👪

Inheritance

1
Autosomal recessive HP:0000007
Disease requires biallelic FANCM loss-of-function variants: compound heterozygous frameshift and splice variants in Estonian brothers, homozygous nonsense variants in Estonian, Portuguese and Chinese men, and a homozygous frameshift in a consanguineous Pakistani family.
Autosomal recessive inheritance
Show evidence (2 references)
PMID:30075111 SUPPORT Human Clinical
"The study convincingly demonstrates that bi-allelic recessive LoF variants in FANCM cause azoospermia."
Recessive biallelic loss of function causes the disease.
PMID:29895858 SUPPORT Human Clinical
"A homozygous PV in FANCM (c.1946_1958del, p.P648Lfs*16) was found cosegregating with male infertility."
Homozygous variant segregating with infertility in a consanguineous family.
◈

Mechanistic Hypotheses

1
Men with SPGF28 may share the cancer and chemotoxicity risk of other biallelic FANCM carriers
fancm_infertility_cancer_spectrum EMERGING
Evidence balance 4 support 2 refute
The same biallelic FANCM truncating genotypes that cause SPGF28 cause premature ovarian insufficiency, early-onset cancer and severe chemotherapy toxicity in other carriers, and ClinGen treats these as one disease. A Finnish biobank study found high cancer risks in people homozygous for p.Gln1701*, one of the SPGF28 alleles. A systematic review, however, found that men carrying C-terminal truncating variants had only infertility, and the men reported with spermatogenic failure had no cancer when described. Whether men with SPGF28 carry a clinically meaningful cancer risk, and whether that depends on variant position, is unresolved.
Show evidence (6 references)
PMID:40642874 SUPPORT Human Clinical
"Homozygous c.5101C>T (N = 76) was associated with a high risk of breast, head and neck, gastrointestinal, gynecological, hematologic, skin, and lung cancer"
High cancer risk in homozygotes for an allele also reported in SPGF28 (p.Gln1701*).
PMID:28837157 SUPPORT Human Clinical
"Care should be taken with chemotherapy and radiation treatments in these patients due to expected acute toxicity."
Chemotoxicity in biallelic FANCM carriers with cancer.
PMID:28837162 SUPPORT Human Clinical
"They show a heterogeneous phenotype including cancer predisposition, toxicity to chemotherapy, early menopause, and possibly chromosome fragility."
Cancer, chemotoxicity and gonadal failure together in women homozygous for FANCM loss-of-function variants.
+ 3 more references
⚙

Pathophysiology

5
Loss of FANCM DNA Translocase Activity
Biallelic truncating variants remove full-length FANCM. FANCM is a structure-specific DNA translocase whose ATPase motor activity is needed to resist DNA crosslinkers; it remodels stalled replication forks and recombination intermediates. No full-length FANCM was detected in blood from the Pakistani patients.
FANCM hgnc:23168 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves FANCM (hgnc:23168). hgnc:23168 is a gene from the HUGO Gene Nomenclature Committee.
DNA translocase activity GO:0015616 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased DNA translocase activity (GO:0015616). GO:0015616 is a molecular function from the Gene Ontology.
Downstream
Defective DNA Interstrand Crosslink Repair
Loss of Meiotic Crossover Restraint Shown in Fancm-deficient mice; not studied in patients.
Show evidence (4 references)
PMID:30714416 SUPPORT REVIEW SYNTHESIS Other
"FANCM is a tumor suppressor gene that encodes a conserved and structure-specific DNA translocase."
Review stating the molecular function of FANCM.
PMID:19423727 SUPPORT In Vitro
"FANCM and a C-terminal deletion mutant rescued the cross-linker sensitivity of FANCM(-/-) cells, whereas a FANCM ATPase mutant did not."
The ATPase motor activity of FANCM is required for crosslinker resistance.
PMID:29895858 SUPPORT Human Clinical
"Western blot analysis using an antibody recognizing an epitope between FANCM amino acids 600 and 700 confirmed the absence of full-length FANCM protein from the blood samples of all three infertile brothers"
Patient blood lacks full-length FANCM.
+ 1 more reference
Loss of Meiotic Crossover Restraint
FANCM limits meiotic crossovers. Fancm-deficient mice have a genome-wide increase in crossover frequency. The authors propose that this anti-crossover role is separable from the germ cell loss, so it is not drawn as a cause of the infertility here.
Negative regulation of reciprocal meiotic recombination GO:0045128 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased Negative regulation of reciprocal meiotic recombination (GO:0045128). GO:0045128 is a biological process from the Gene Ontology.
Show evidence (2 references)
PMID:37601968 SUPPORT Model Organism
"identify a genome-wide increase in crossover frequencies in Fancm-deficient mice"
Mouse evidence for the anti-crossover role.
PMID:37601968 SUPPORT Model Organism
"We propose that the anti-crossover function and role in gametogenesis of Fancm are separable"
The authors separate this role from the gametogenesis defect.
Progressive Germ Cell Depletion
Germ cells are lost from the seminiferous tubules, leaving Sertoli cells only in the most severe cases. In mice, Fancm loss reduces primordial germ cells before birth and then progressively depletes spermatogonial stem cells with age. Human testis biopsies show the end state, Sertoli cell-only tubules; whether the human loss is also progressive is not known.
Spermatogonium CL:0000020 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Spermatogonium (CL:0000020). CL:0000020 is a cell type from the Cell Ontology. Primordial germ cell CL:0000670 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Primordial germ cell (CL:0000670). CL:0000670 is a cell type from the Cell Ontology.
Male germ-line stem cell population maintenance GO:0036098 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased Male germ-line stem cell population maintenance (GO:0036098). GO:0036098 is a biological process from the Gene Ontology.
Animal models
FancmΔC/ΔC mouse Mouse recapitulates The model reproduces germ cell loss and Sertoli cell-only tubules.
FancmΔ2/Δ2 knockout mouse Mouse partially recapitulates Gonadal hypoplasia in both sexes.
Downstream
Sertoli cell-only phenotype
Non-obstructive azoospermia
Oligozoospermia Partial germ cell loss reduces sperm output without abolishing it.
Decreased testicular size Germ cells make up most of the seminiferous epithelium.
Elevated circulating follicle stimulating hormone level Raised FSH accompanies the loss of germ cells; the feedback route was not studied in these patients.
Male infertility
Show evidence (3 references)
PMID:29895858 SUPPORT Model Organism
"suggesting an age-dependent progressive loss of SSCs in FancmΔC/ΔC mice"
Progressive spermatogonial stem cell loss in the mouse model of the patient variant.
PMID:37601968 SUPPORT BACKGROUND Model Organism
"It was previously reported that a reduction in the number of primordial germ cells occurs prior to birth in Fancm-mutant mice of both sexes."
Earlier mouse work showing primordial germ cell loss.
PMID:34976027 SUPPORT Human Clinical
"H&E staining and immunohistochemistry showed Sertoli cell-only Syndrome (SCOS) in the three patients with NOA."
Complete germ cell loss in patient testes.
Round Spermatid Maturation Arrest
In the FancmΔC/ΔC mouse, which carries a variant close to the Pakistani family's, 43.5% of tubules stop at the round spermatid stage. This was not reported in other Fanc mouse models. It may explain why some men produce a few, poorly motile sperm instead of none, but no testis histology is available from those men.
Spermatid CL:0000018 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Spermatid (CL:0000018). CL:0000018 is a cell type from the Cell Ontology.
Spermatid development GO:0007286 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased Spermatid development (GO:0007286). GO:0007286 is a biological process from the Gene Ontology.
Downstream
Oligozoospermia
Reduced sperm motility Proposed from the mouse arrest; the cause of the motility defect in patients was not studied.
Show evidence (1 reference)
PMID:29895858 SUPPORT Model Organism
"Adult FancmΔC/ΔC mice showed spermatogenic failure, with germ cell loss in 50.2% of testicular tubules and round-spermatid maturation arrest in 43.5% of tubules."
Round spermatid arrest in the mouse model.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Spermatogenic Failure 28 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 1
Elevated circulating follicle stimulating hormone level HP:0008232 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Elevated FSH, annotated with Elevated circulating follicle stimulating hormone level (HP:0008232). HP:0008232 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34976027 SUPPORT Human Clinical
"Laboratory examination revealed elevated FSH levels (14.29 IU/L and 12.85 IU/L versus 1.5–12.5 IU/L in normal)."
Raised FSH in two brothers.
Genitourinary 6
Male infertility HP:0003251 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Male infertility (HP:0003251). HP:0003251 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29895858 SUPPORT Human Clinical
"These findings revealed male infertility to be a novel phenotype of human patients with a biallelic FANCM PV."
Male infertility in biallelic FANCM carriers.
Non-obstructive azoospermia HP:0011961 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Non-obstructive azoospermia (HP:0011961). HP:0011961 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:30075111 SUPPORT Human Clinical
"we detected two additional NOA-affected case subjects with independent FANCM homozygous nonsense variants"
NOA in Estonian and Portuguese men with FANCM nonsense variants.
PMID:34976027 SUPPORT Human Clinical
"Routine semen analyses (three times) revealed normal volume but no sperm in the ejaculate, indicating complete azoospermia."
Azoospermia in Chinese brothers.
Sertoli cell-only phenotype HP:0034299 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sertoli cell-only syndrome, annotated with Sertoli cell-only phenotype (HP:0034299). HP:0034299 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:30075111 SUPPORT Human Clinical
"two Estonian brothers diagnosed with NOA and Sertoli cell-only syndrome (SCOS)"
SCOS in the first reported family.
PMID:34976027 SUPPORT Human Clinical
"H&E staining and immunohistochemistry showed Sertoli cell-only Syndrome (SCOS) in the three patients with NOA."
SCOS in three Chinese patients.
Oligozoospermia HP:0000798 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Oligozoospermia (HP:0000798). HP:0000798 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29895858 SUPPORT Human Clinical
"Two of the affected brothers, IV:1 (married for 21 years) and IV:3 (single) were diagnosed with mild and severe oligoasthenospermia, respectively."
Oligoasthenozoospermia in two homozygous brothers.
Reduced sperm motility HP:0012207 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Asthenozoospermia, annotated with Reduced sperm motility (HP:0012207). HP:0012207 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29895858 SUPPORT Human Clinical
"two manifesting oligoasthenospermia and one exhibiting azoospermia"
Oligoasthenozoospermia includes reduced motility.
Decreased testicular size HP:0008734 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Small testes, annotated with Decreased testicular size (HP:0008734). HP:0008734 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34976027 SUPPORT Human Clinical
"Physical examination showed the small size of the testis (10 ml in the proband, and 8 ml in the elder brother, both sides)."
Small testes in two patients.
Cellular 1
Chromosomal breakage induced by crosslinking agents HP:0003221 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Mitomycin C-induced chromosomal breakage, annotated with Chromosomal breakage induced by crosslinking agents (HP:0003221). HP:0003221 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:29895858 SUPPORT Human Clinical
"Moreover, consistent with previous reports,16,17 our patients show increased ICL sensitivity but do not have bone marrow failure."
Crosslink sensitivity without marrow failure in SPGF28 patients.
CGGV:assertion_28865445-bea0-42c1-8f50-fae94e93f1d8-2024-12-10T170000.000Z SUPPORT REVIEW SYNTHESIS Other
"humans with biallelic loss of function FANCM variants have not developed spontaneous bone marrow failure"
ClinGen's reason for refuting FANCM as a Fanconi anemia gene supports reading this cellular sign as distinct from Fanconi anemia.
🧬

Genetic Associations

1
FANCM (Causal)
Gene: FANCM hgnc:23168 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is FANCM (hgnc:23168). hgnc:23168 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (3 references)
PMID:30075111 SUPPORT Human Clinical
"Compound heterozygous loss-of-function (LoF) variants in FANCM (Fanconi anemia complementation group M) were detected as the most likely cause for their condition."
Primary gene-disease report.
PMID:29895858 SUPPORT Human Clinical
"A homozygous PV in FANCM (c.1946_1958del, p.P648Lfs*16) was found cosegregating with male infertility."
Independent replication in a Pakistani family.
PMID:34976027 SUPPORT Human Clinical
"Herein, we identified compound heterozygous variants in FANCM in two NOA-affected brothers (c. 1778delG:p. R593Qfs*76 and c. 1663G > T:p. V555F), and a homozygous variant in FANCM (c. 1972C > T:p. R658X) in a sporadic case with NOA, respectively."
Replication in Chinese patients.
💊

Medical Actions

4
Genetic Counseling
Action: Genetic CounselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Genetic Counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. NCIT:C15240
Platform: Other
Counseling on recessive inheritance and on the possible cancer and hematologic risks of biallelic FANCM variants, as recommended after a Sertoli cell-only case with an astrocytoma.
Show evidence (1 reference)
PMID:38927643 SUPPORT Human Clinical
"genetic counseling should be applied to azoospermia patients diagnosed with FANC mutations"
Authors' recommendation for men with FANC-gene azoospermia.
Cancer and Hematologic Surveillance
Action: cancer and hematologic surveillanceNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is cancer and hematologic surveillance, annotated with Cancer Screening (NCIT:C15406). NCIT:C15406 is a clinical intervention from the NCI Thesaurus. Ontology label: Cancer Screening NCIT:C15406
Platform: Other
Regular screening for cancer and hematologic abnormalities is proposed by the authors of two case series. It is expert opinion; no study has tested surveillance in men with SPGF28.
Show evidence (2 references)
PMID:38927643 SUPPORT Human Clinical
"with proposals for the multidisciplinary monitoring of these men in terms of regular screenings for cancer or hematologic abnormalities and other potential complications"
Recommendation for cancer and hematologic screening.
PMID:34976027 SUPPORT Human Clinical
"Thus, future cancer incidence of the patients should be monitored."
A second group recommends cancer monitoring.
Caution with Chemotherapy and Radiotherapy
Platform: Other
If a biallelic FANCM carrier develops cancer, crosslinking chemotherapy and radiotherapy may cause acute toxicity, so dose reduction or other regimens are suggested. This rests on carriers with cancer, not on men with SPGF28.
Mechanism Target:
Defective DNA Interstrand Crosslink Repair — Cells that repair crosslinks poorly are more sensitive to crosslinking chemotherapy, which is the reason for the caution.
Show evidence (1 reference)
PMID:28837157 SUPPORT Human Clinical
"Care should be taken with chemotherapy and radiation treatments in these patients due to expected acute toxicity."
Links the caution to the cellular crosslink defect seen in these patients.
Show evidence (1 reference)
PMID:38927643 SUPPORT Human Clinical
"such as dose reductions or alternative regimens of chemotherapy and/or radiotherapy"
Suggested adaptation of cancer treatment.
Microsurgical Testicular Sperm Extraction
Action: microsurgical testicular sperm extractionNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is microsurgical testicular sperm extraction, annotated with Sperm Retrieval (NCIT:C94427). NCIT:C94427 is a clinical intervention from the NCI Thesaurus. Ontology label: Sperm Retrieval NCIT:C94427
Platform: Surgery
The Chinese men with SPGF28 underwent micro-TESE. Their tissue showed Sertoli cell-only histology, and no sperm retrieval outcome is reported in the cached sources. The yield in SPGF28 is unknown.
Mechanism Target:
Non-obstructive azoospermia — Searches the testis for residual foci of spermatogenesis to bypass azoospermia.
Show evidence (1 reference)
PMID:34976027 SUPPORT Human Clinical
"The two brothers with NOA and the NOA-affected sporadic cases were subjected to microsurgical testicular sperm extraction (micro-TESE) operation"
Micro-TESE was performed in SPGF28 patients.
🔬

Diagnosis

5
Karyotype and Y-chromosome microdeletion analysis
Exclusion tests done before gene-level testing. Every reported man had a normal 46,XY karyotype and no Y-chromosome microdeletion.
karyotyping and Y-chromosome microdeletion analysis NCIT:C16768 NCI Thesaurus (NCIT)
Results: Normal 46,XY karyotype with no Y-chromosome microdeletion.
Show evidence (1 reference)
PMID:34976027 SUPPORT Human Clinical
"All patients have 46,XY karyotypes without microdeletions in the Y chromosome."
Chromosomal causes were excluded in the Chinese patients.
Semen analysis
Repeated semen analysis shows azoospermia with normal ejaculate volume, or oligoasthenozoospermia in milder cases.
semen analysis NCIT:C25294 NCI Thesaurus (NCIT)
Results: Azoospermia with normal volume, or oligoasthenozoospermia.
Show evidence (1 reference)
PMID:34976027 SUPPORT Human Clinical
"Routine semen analyses (three times) revealed normal volume but no sperm in the ejaculate, indicating complete azoospermia."
Repeated semen analysis establishes azoospermia.
Testicular biopsy histology
Histology and immunohistochemistry of testicular tissue, obtained at biopsy or micro-TESE, show Sertoli cell-only tubules.
testicular biopsy NCIT:C15189 NCI Thesaurus (NCIT)
Results: Sertoli cell-only tubules with no germ cells.
Show evidence (1 reference)
PMID:34976027 SUPPORT Human Clinical
"H&E staining and immunohistochemistry showed Sertoli cell-only Syndrome (SCOS) in the three patients with NOA."
Biopsy histology in three patients.
Exome sequencing
Exome sequencing finds the biallelic FANCM variants, confirmed by Sanger sequencing and segregation in the family.
exome sequencing NCIT:C101295 NCI Thesaurus (NCIT)
Results: Biallelic FANCM loss-of-function variants.
Show evidence (2 references)
PMID:30075111 SUPPORT Human Clinical
"whole-exome sequencing (WES) was applied to two Estonian brothers diagnosed with NOA and Sertoli cell-only syndrome (SCOS)"
Exome sequencing identified the first FANCM family.
PMID:29895858 SUPPORT Human Clinical
"Exome and Sanger sequencing were used for PV screening."
Exome plus Sanger confirmation in the Pakistani family.
Mitomycin C chromosomal breakage test
Lymphocytes cultured with mitomycin C show excess chromosomal breaks. This supports a loss-of-function effect, for example when a variant is of uncertain significance; it is not specific to FANCM.
chromosomal breakage analysis (mitomycin C) NCIT:C18280 NCI Thesaurus (NCIT)
Results: Dose-dependent increase in mitomycin C-induced chromosomal breaks.
Show evidence (1 reference)
PMID:29895858 SUPPORT Human Clinical
"lymphocytes from both IV:2 and IV:3 displayed a dose-dependent increase in MMC-induced chromosomal breaks per cell, which averaged 3 to 17 times those of the father"
Breakage test result in two affected brothers.
🐁

Animal Models

2
FancmΔC/ΔC mouse
Males show spermatogenic failure with germ cell loss, Sertoli cell-only tubules and round spermatid arrest, and spermatogonia are hypersensitive to mitomycin C. No marrow failure or tumors were seen in adult mice.
Species
Mouse
Genotype
Fancm truncating variant nearly equivalent to human p.P648Lfs*16, homozygous
Publication
PMID:29895858
Pathograph links
Progressive Germ Cell Depletion recapitulates fidelity: moderate observes: tissue The model reproduces germ cell loss and Sertoli cell-only tubules.
Limitations: The mice are subfertile rather than sterile, and many tubules show round spermatid arrest, which has not been examined in patients.
Show evidence (1 reference)
PMID:29895858 SUPPORT Model Organism
"Hence, FancmΔC/ΔC mice phenocopied the clinical phenotypes in our patients (Table 1)."
Authors' statement that the mice reproduce the patient phenotype.
FancmΔ2/Δ2 knockout mouse
Fancm knockout mice have hypogonadism, crosslinker-sensitive embryonic fibroblasts and reduced tumor-free survival, without the full Fanconi anemia picture.
Species
Mouse
Genotype
Fancm exon 2 deletion, homozygous
Publication
PMID:19561169
Pathograph links
Progressive Germ Cell Depletion partially recapitulates fidelity: moderate Gonadal hypoplasia in both sexes.
Limitations: Reported as hypogonadism without a detailed testicular analysis in the abstract; the knockout removes exon 2 rather than modelling a patient allele.
Show evidence (1 reference)
PMID:19561169 SUPPORT Model Organism
"FANCM deficiency caused hypogonadism in mice and hypersensitivity to cross-linking agents in mouse embryonic fibroblasts (MEFs)"
Gonadal defect in the knockout.
{ }

Source YAML

click to show 
name: Spermatogenic Failure 28
creation_date: "2026-10-15T00:00:00Z"
category: Mendelian
synonyms:
- SPGF28
- spermatogenic failure 28
- FANCM-related non-obstructive azoospermia
description: >-
  Spermatogenic failure 28 (SPGF28) is autosomal recessive male infertility
  caused by biallelic loss-of-function variants in FANCM, a DNA translocase
  that works with the Fanconi anemia (FA) core complex and the Bloom helicase
  complex to keep replicating and recombining DNA stable. Most reported men
  have non-obstructive azoospermia, and testicular biopsy shows a Sertoli
  cell-only pattern with no germ cells. Men in one consanguineous Pakistani
  family had oligoasthenozoospermia instead, so the spermatogenic defect is
  variable. Patient lymphocytes break their chromosomes more often after
  exposure to the crosslinking agent mitomycin C, but the men reported with
  spermatogenic failure had no bone marrow failure or congenital
  malformations. In mice, Fancm loss depletes primordial germ cells and then
  spermatogonial stem cells, and arrests some spermatids. Biallelic FANCM
  truncating variants are also found in women with premature ovarian
  insufficiency and in people of both sexes with early-onset cancer and severe
  chemotherapy toxicity. ClinGen groups these presentations with SPGF28 as one
  autosomal recessive FANCM Fanconi-like genomic instability disorder, which
  is distinct from Fanconi anemia.
disease_term:
  preferred_term: spermatogenic failure 28
  term:
    id: MONDO:0054732
    label: spermatogenic failure 28
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0100578
      label: FANCM Fanconi-like genomic instability disorder
    mapping_predicate: skos:broadMatch
    mapping_source: MONDO
    mapping_justification: >-
      ClinGen lumps spermatogenic failure 28 (OMIM 618086), premature ovarian
      failure 15 (OMIM 618096) and Fanconi-like syndrome (OMIM 227850) into one
      autosomal recessive FANCM disease, MONDO:0100578. This entry covers the
      male spermatogenic presentation of that broader disorder. MONDO does not
      currently place MONDO:0054732 beneath MONDO:0100578.
parents:
- Spermatogenic Failure
- Genetic Disease
notes: >-
  MONDO cross-references this disease as OMIM 618086. The entry is kept at the
  MONDO spermatogenic failure 28 concept rather than at the broader ClinGen
  disease because MONDO keeps them as separate terms and the stub queue
  nominated this one. Female ovarian insufficiency and the cancer and
  chemotoxicity phenotypes are recorded only through the broadMatch mapping and
  the mechanistic hypothesis below, not as phenotypes of this entry. The
  Croatian man with Sertoli cell-only syndrome and a diffuse astrocytoma
  (PMID:38927643) carried two FANCM missense variants of uncertain
  significance, so he is not counted among the loss-of-function cases.
  Abstract-only caches: PMID:30075111, PMID:28837157, PMID:28837162,
  PMID:40642874, PMID:40818381, PMID:30714416, PMID:19561169.
inheritance:
- name: Autosomal recessive
  description: >-
    Disease requires biallelic FANCM loss-of-function variants: compound
    heterozygous frameshift and splice variants in Estonian brothers,
    homozygous nonsense variants in Estonian, Portuguese and Chinese men, and a
    homozygous frameshift in a consanguineous Pakistani family.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:30075111
    reference_title: "Bi-allelic Recessive Loss-of-Function Variants in FANCM Cause Non-obstructive Azoospermia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The study convincingly demonstrates that bi-allelic recessive LoF variants in FANCM cause azoospermia."
    explanation: Recessive biallelic loss of function causes the disease.
  - reference: PMID:29895858
    reference_title: "A homozygous FANCM frameshift pathogenic variant causes male infertility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A homozygous PV in FANCM (c.1946_1958del, p.P648Lfs*16) was found cosegregating with male infertility."
    explanation: Homozygous variant segregating with infertility in a consanguineous family.
pathophysiology:
- name: Loss of FANCM DNA Translocase Activity
  description: >-
    Biallelic truncating variants remove full-length FANCM. FANCM is a
    structure-specific DNA translocase whose ATPase motor activity is needed
    to resist DNA crosslinkers; it remodels stalled replication forks and
    recombination intermediates. No full-length FANCM was detected in blood
    from the Pakistani patients.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: FANCM
    term:
      id: hgnc:23168
      label: FANCM
  molecular_functions:
  - preferred_term: DNA translocase activity
    modifier: DECREASED
    term:
      id: GO:0015616
      label: DNA translocase activity
  downstream:
  - target: Defective DNA Interstrand Crosslink Repair
    causal_link_type: DIRECT
  - target: Loss of Meiotic Crossover Restraint
    causal_link_type: DIRECT
    description: Shown in Fancm-deficient mice; not studied in patients.
  evidence:
  - reference: PMID:30714416
    reference_title: "A tumor suppressive DNA translocase named FANCM."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "FANCM is a tumor suppressor gene that encodes a conserved and structure-specific DNA translocase."
    explanation: Review stating the molecular function of FANCM.
  - reference: PMID:19423727
    reference_title: "Impaired FANCD2 monoubiquitination and hypersensitivity to camptothecin uniquely characterize Fanconi anemia complementation group M."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "FANCM and a C-terminal deletion mutant rescued the cross-linker sensitivity of FANCM(-/-) cells, whereas a FANCM ATPase mutant did not."
    explanation: The ATPase motor activity of FANCM is required for crosslinker resistance.
  - reference: PMID:29895858
    reference_title: "A homozygous FANCM frameshift pathogenic variant causes male infertility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Western blot analysis using an antibody recognizing an epitope between FANCM amino acids 600 and 700 confirmed the absence of full-length FANCM protein from the blood samples of all three infertile brothers"
    explanation: Patient blood lacks full-length FANCM.
  - reference: PMID:30075111
    reference_title: "Bi-allelic Recessive Loss-of-Function Variants in FANCM Cause Non-obstructive Azoospermia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "introduce a premature STOP codon leading to a truncated protein"
    explanation: The Estonian compound heterozygous variants truncate FANCM.
- name: Defective DNA Interstrand Crosslink Repair
  description: >-
    Without FANCM, cells repair DNA interstrand crosslinks poorly. Patient
    lymphocytes accumulate dose-dependent chromosomal breaks after mitomycin
    C, and spermatogonia from the matching mouse model are also hypersensitive
    to mitomycin C.
  biological_scale: CELLULAR
  biological_processes:
  - preferred_term: Interstrand cross-link repair
    modifier: DECREASED
    term:
      id: GO:0036297
      label: interstrand cross-link repair
  downstream:
  - target: Chromosomal breakage induced by crosslinking agents
    causal_link_type: DIRECT
  - target: Progressive Germ Cell Depletion
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Proposed: unrepaired DNA damage in proliferating germ cells reduces
      their survival. The spermatogonial hypersensitivity is shown in mice;
      which lesions kill human germ cells is not known.
    evidence:
    - reference: PMID:29895858
      reference_title: "A homozygous FANCM frameshift pathogenic variant causes male infertility."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "The loss-of-function FANCM PV increased ICL sensitivity in lymphocytes of patients and FancmΔC/ΔC spermatogonia."
      explanation: Germ cells of the mouse model share the crosslink sensitivity seen in patient cells.
  evidence:
  - reference: PMID:29895858
    reference_title: "A homozygous FANCM frameshift pathogenic variant causes male infertility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "lymphocytes from both IV:2 and IV:3 displayed a dose-dependent increase in MMC-induced chromosomal breaks per cell, which averaged 3 to 17 times those of the father"
    explanation: Crosslink sensitivity in lymphocytes of men with SPGF28.
  - reference: PMID:28837157
    reference_title: "Biallelic truncating FANCM mutations cause early-onset cancer but not Fanconi anemia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Patient-derived cells exhibited chromosomal fragility, hypersensitivity to interstrand crosslinks, and impaired FANCD2 monoubiquitination."
    explanation: Fibroblasts from other biallelic FANCM carriers show the same crosslink repair defect.
- name: Loss of Meiotic Crossover Restraint
  description: >-
    FANCM limits meiotic crossovers. Fancm-deficient mice have a genome-wide
    increase in crossover frequency. The authors propose that this
    anti-crossover role is separable from the germ cell loss, so it is not
    drawn as a cause of the infertility here.
  biological_scale: CELLULAR
  biological_processes:
  - preferred_term: Negative regulation of reciprocal meiotic recombination
    modifier: DECREASED
    term:
      id: GO:0045128
      label: negative regulation of reciprocal meiotic recombination
  evidence:
  - reference: PMID:37601968
    reference_title: "Fancm has dual roles in the limiting of meiotic crossovers and germ cell maintenance in mammals."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "identify a genome-wide increase in crossover frequencies in Fancm-deficient mice"
    explanation: Mouse evidence for the anti-crossover role.
  - reference: PMID:37601968
    reference_title: "Fancm has dual roles in the limiting of meiotic crossovers and germ cell maintenance in mammals."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We propose that the anti-crossover function and role in gametogenesis of Fancm are separable"
    explanation: The authors separate this role from the gametogenesis defect.
- name: Progressive Germ Cell Depletion
  description: >-
    Germ cells are lost from the seminiferous tubules, leaving Sertoli cells
    only in the most severe cases. In mice, Fancm loss reduces primordial germ
    cells before birth and then progressively depletes spermatogonial stem
    cells with age. Human testis biopsies show the end state, Sertoli
    cell-only tubules; whether the human loss is also progressive is not
    known.
  biological_scale: TISSUE
  cell_types:
  - preferred_term: Spermatogonium
    term:
      id: CL:0000020
      label: spermatogonium
  - preferred_term: Primordial germ cell
    term:
      id: CL:0000670
      label: primordial germ cell
  biological_processes:
  - preferred_term: Male germ-line stem cell population maintenance
    modifier: DECREASED
    term:
      id: GO:0036098
      label: male germ-line stem cell population maintenance
  downstream:
  - target: Sertoli cell-only phenotype
    causal_link_type: DIRECT
  - target: Non-obstructive azoospermia
    causal_link_type: DIRECT
  - target: Oligozoospermia
    causal_link_type: DIRECT
    description: Partial germ cell loss reduces sperm output without abolishing it.
  - target: Decreased testicular size
    causal_link_type: DIRECT
    description: Germ cells make up most of the seminiferous epithelium.
  - target: Elevated circulating follicle stimulating hormone level
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Raised FSH accompanies the loss of germ cells; the feedback route was not studied in these patients.
  - target: Male infertility
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:29895858
    reference_title: "A homozygous FANCM frameshift pathogenic variant causes male infertility."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "suggesting an age-dependent progressive loss of SSCs in FancmΔC/ΔC mice"
    explanation: Progressive spermatogonial stem cell loss in the mouse model of the patient variant.
  - reference: PMID:37601968
    reference_title: "Fancm has dual roles in the limiting of meiotic crossovers and germ cell maintenance in mammals."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: BACKGROUND
    snippet: "It was previously reported that a reduction in the number of primordial germ cells occurs prior to birth in Fancm-mutant mice of both sexes."
    explanation: Earlier mouse work showing primordial germ cell loss.
  - reference: PMID:34976027
    reference_title: "Novel Bi-Allelic Variants of FANCM Cause Sertoli Cell-Only Syndrome and Non-Obstructive Azoospermia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "H&E staining and immunohistochemistry showed Sertoli cell-only Syndrome (SCOS) in the three patients with NOA."
    explanation: Complete germ cell loss in patient testes.
- name: Round Spermatid Maturation Arrest
  description: >-
    In the FancmΔC/ΔC mouse, which carries a variant close to the Pakistani
    family's, 43.5% of tubules stop at the round spermatid stage. This was
    not reported in other Fanc mouse models. It may explain why some men
    produce a few, poorly motile sperm instead of none, but no testis
    histology is available from those men.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: Spermatid
    term:
      id: CL:0000018
      label: spermatid
  biological_processes:
  - preferred_term: Spermatid development
    modifier: DECREASED
    term:
      id: GO:0007286
      label: spermatid development
  downstream:
  - target: Oligozoospermia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Reduced sperm motility
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Proposed from the mouse arrest; the cause of the motility defect in patients was not studied.
  evidence:
  - reference: PMID:29895858
    reference_title: "A homozygous FANCM frameshift pathogenic variant causes male infertility."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Adult FancmΔC/ΔC mice showed spermatogenic failure, with germ cell loss in 50.2% of testicular tubules and round-spermatid maturation arrest in 43.5% of tubules."
    explanation: Round spermatid arrest in the mouse model.
mechanistic_hypotheses:
- hypothesis_group_id: fancm_infertility_cancer_spectrum
  hypothesis_label: Men with SPGF28 may share the cancer and chemotoxicity risk of other biallelic FANCM carriers
  status: EMERGING
  description: >-
    The same biallelic FANCM truncating genotypes that cause SPGF28 cause
    premature ovarian insufficiency, early-onset cancer and severe
    chemotherapy toxicity in other carriers, and ClinGen treats these as one
    disease. A Finnish biobank study found high cancer risks in people
    homozygous for p.Gln1701*, one of the SPGF28 alleles. A systematic review,
    however, found that men carrying C-terminal truncating variants had only
    infertility, and the men reported with spermatogenic failure had no
    cancer when described. Whether men with SPGF28 carry a clinically
    meaningful cancer risk, and whether that depends on variant position, is
    unresolved.
  evidence:
  - reference: PMID:40642874
    reference_title: "Recessive FANCM cancer syndrome with high cancer risks, chemotherapy toxicity, chromosome fragility, and gonadal failure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Homozygous c.5101C>T (N = 76) was associated with a high risk of breast, head and neck, gastrointestinal, gynecological, hematologic, skin, and lung cancer"
    explanation: High cancer risk in homozygotes for an allele also reported in SPGF28 (p.Gln1701*).
  - reference: PMID:28837157
    reference_title: "Biallelic truncating FANCM mutations cause early-onset cancer but not Fanconi anemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Care should be taken with chemotherapy and radiation treatments in these patients due to expected acute toxicity."
    explanation: Chemotoxicity in biallelic FANCM carriers with cancer.
  - reference: PMID:28837162
    reference_title: "Individuals with FANCM biallelic mutations do not develop Fanconi anemia, but show risk for breast cancer, chemotherapy toxicity and may display chromosome fragility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "They show a heterogeneous phenotype including cancer predisposition, toxicity to chemotherapy, early menopause, and possibly chromosome fragility."
    explanation: Cancer, chemotoxicity and gonadal failure together in women homozygous for FANCM loss-of-function variants.
  - reference: PMID:40818381
    reference_title: "Genotype-phenotype correlations in biallelic carriers of FANCM protein truncating variants: A systematic literature review."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Men carrying the same PTVs combinations showed infertility only."
    explanation: Men with C-terminal truncating variants had infertility without cancer in the reviewed reports.
  - reference: PMID:29895858
    reference_title: "A homozygous FANCM frameshift pathogenic variant causes male infertility."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "neither bone marrow failure nor cancer/tumor was detected in all the patients or adult FancmΔC/ΔC mice"
    explanation: >-
      No cancer in the three Pakistani patients when reported. Only the human
      half of the sentence is used here; the mouse result is not counted.
  - reference: CGGV:assertion_abb231b6-1452-4f24-a8c1-ab45a791e73c-2024-11-12T170000.000Z
    reference_title: "FANCM / FANCM Fanconi-like genomic instability disorder (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "we found no difference in molecular mechanism, inheritance pattern or phenotypic variability for Fanconi-like syndrome (OMIM:227850), Premature ovarian failure 15 (OMIM:618096) and Spermatogenic failure 28 (OMIM:618086)"
    explanation: ClinGen lumps SPGF28 with the cancer-prone Fanconi-like syndrome.
phenotypes:
- category: Reproductive
  name: Male infertility
  description: Primary male infertility is the presenting complaint in every reported man.
  phenotype_term:
    preferred_term: Male infertility
    term:
      id: HP:0003251
      label: Male infertility
  evidence:
  - reference: PMID:29895858
    reference_title: "A homozygous FANCM frameshift pathogenic variant causes male infertility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These findings revealed male infertility to be a novel phenotype of human patients with a biallelic FANCM PV."
    explanation: Male infertility in biallelic FANCM carriers.
- category: Reproductive
  name: Non-obstructive azoospermia
  description: >-
    The most common presentation: no sperm in the ejaculate because of failed
    spermatogenesis, with normal karyotype and no Y-chromosome microdeletion.
  phenotype_term:
    preferred_term: Non-obstructive azoospermia
    term:
      id: HP:0011961
      label: Non-obstructive azoospermia
  evidence:
  - reference: PMID:30075111
    reference_title: "Bi-allelic Recessive Loss-of-Function Variants in FANCM Cause Non-obstructive Azoospermia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we detected two additional NOA-affected case subjects with independent FANCM homozygous nonsense variants"
    explanation: NOA in Estonian and Portuguese men with FANCM nonsense variants.
  - reference: PMID:34976027
    reference_title: "Novel Bi-Allelic Variants of FANCM Cause Sertoli Cell-Only Syndrome and Non-Obstructive Azoospermia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Routine semen analyses (three times) revealed normal volume but no sperm in the ejaculate, indicating complete azoospermia."
    explanation: Azoospermia in Chinese brothers.
- category: Reproductive
  name: Sertoli cell-only phenotype
  description: Testicular biopsy shows seminiferous tubules lined by Sertoli cells with no germ cells.
  phenotype_term:
    preferred_term: Sertoli cell-only syndrome
    term:
      id: HP:0034299
      label: Sertoli cell-only phenotype
  evidence:
  - reference: PMID:30075111
    reference_title: "Bi-allelic Recessive Loss-of-Function Variants in FANCM Cause Non-obstructive Azoospermia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "two Estonian brothers diagnosed with NOA and Sertoli cell-only syndrome (SCOS)"
    explanation: SCOS in the first reported family.
  - reference: PMID:34976027
    reference_title: "Novel Bi-Allelic Variants of FANCM Cause Sertoli Cell-Only Syndrome and Non-Obstructive Azoospermia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "H&E staining and immunohistochemistry showed Sertoli cell-only Syndrome (SCOS) in the three patients with NOA."
    explanation: SCOS in three Chinese patients.
- category: Reproductive
  name: Oligozoospermia
  description: >-
    Two of three affected brothers in a Pakistani family had mild or severe
    oligoasthenozoospermia rather than azoospermia.
  phenotype_term:
    preferred_term: Oligozoospermia
    term:
      id: HP:0000798
      label: Oligozoospermia
  evidence:
  - reference: PMID:29895858
    reference_title: "A homozygous FANCM frameshift pathogenic variant causes male infertility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Two of the affected brothers, IV:1 (married for 21 years) and IV:3 (single) were diagnosed with mild and severe oligoasthenospermia, respectively."
    explanation: Oligoasthenozoospermia in two homozygous brothers.
- category: Reproductive
  name: Reduced sperm motility
  description: The oligozoospermic brothers also had reduced sperm motility.
  phenotype_term:
    preferred_term: Asthenozoospermia
    term:
      id: HP:0012207
      label: Reduced sperm motility
  evidence:
  - reference: PMID:29895858
    reference_title: "A homozygous FANCM frameshift pathogenic variant causes male infertility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "two manifesting oligoasthenospermia and one exhibiting azoospermia"
    explanation: Oligoasthenozoospermia includes reduced motility.
- category: Reproductive
  name: Decreased testicular size
  description: Testicular volume was reduced in two Chinese brothers (8 and 10 mL) but normal in a third patient.
  phenotype_term:
    preferred_term: Small testes
    term:
      id: HP:0008734
      label: Decreased testicular size
  evidence:
  - reference: PMID:34976027
    reference_title: "Novel Bi-Allelic Variants of FANCM Cause Sertoli Cell-Only Syndrome and Non-Obstructive Azoospermia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Physical examination showed the small size of the testis (10 ml in the proband, and 8 ml in the elder brother, both sides)."
    explanation: Small testes in two patients.
- category: Endocrine
  name: Elevated circulating follicle stimulating hormone level
  description: FSH was raised in the three Chinese patients; testosterone and LH were largely normal in the Pakistani family.
  phenotype_term:
    preferred_term: Elevated FSH
    term:
      id: HP:0008232
      label: Elevated circulating follicle stimulating hormone level
  evidence:
  - reference: PMID:34976027
    reference_title: "Novel Bi-Allelic Variants of FANCM Cause Sertoli Cell-Only Syndrome and Non-Obstructive Azoospermia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Laboratory examination revealed elevated FSH levels (14.29 IU/L and 12.85 IU/L versus 1.5–12.5 IU/L in normal)."
    explanation: Raised FSH in two brothers.
- category: Laboratory
  name: Chromosomal breakage induced by crosslinking agents
  description: >-
    Lymphocytes from tested patients show excess chromosomal breaks after
    mitomycin C. This cellular sign is shared with Fanconi anemia, but the
    men had no bone marrow failure.
  phenotype_term:
    preferred_term: Mitomycin C-induced chromosomal breakage
    term:
      id: HP:0003221
      label: Chromosomal breakage induced by crosslinking agents
  evidence:
  - reference: PMID:29895858
    reference_title: "A homozygous FANCM frameshift pathogenic variant causes male infertility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Moreover, consistent with previous reports,16,17 our patients show increased ICL sensitivity but do not have bone marrow failure."
    explanation: Crosslink sensitivity without marrow failure in SPGF28 patients.
  - reference: CGGV:assertion_28865445-bea0-42c1-8f50-fae94e93f1d8-2024-12-10T170000.000Z
    reference_title: "FANCM / Fanconi anemia (Refuted)"
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "humans with biallelic loss of function FANCM variants have not developed spontaneous bone marrow failure"
    explanation: >-
      ClinGen's reason for refuting FANCM as a Fanconi anemia gene supports
      reading this cellular sign as distinct from Fanconi anemia.
genetic:
- name: FANCM
  association: Causal
  relationship_type: CAUSATIVE
  gene_term:
    preferred_term: FANCM
    term:
      id: hgnc:23168
      label: FANCM
  notes: >-
    Reported alleles in men with spermatogenic failure: compound heterozygous
    p.Gln498Thrfs*7 and c.4387-10A>G, homozygous p.Gln1701* and p.Arg1931*
    (PMID:30075111); homozygous p.Pro648Leufs*16 (PMID:29895858); compound
    heterozygous p.Arg593Glnfs*76 with p.Val555Phe, and homozygous p.Arg658*
    (PMID:34976027). ClinGen classifies FANCM and the broader FANCM
    Fanconi-like genomic instability disorder (MONDO:0100578) as Definitive,
    autosomal recessive, and FANCM and Fanconi anemia as Refuted. No ClinGen
    assertion names spermatogenic failure 28 itself, so no validity tier is
    recorded on this record.
  evidence:
  - reference: PMID:30075111
    reference_title: "Bi-allelic Recessive Loss-of-Function Variants in FANCM Cause Non-obstructive Azoospermia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Compound heterozygous loss-of-function (LoF) variants in FANCM (Fanconi anemia complementation group M) were detected as the most likely cause for their condition."
    explanation: Primary gene-disease report.
  - reference: PMID:29895858
    reference_title: "A homozygous FANCM frameshift pathogenic variant causes male infertility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A homozygous PV in FANCM (c.1946_1958del, p.P648Lfs*16) was found cosegregating with male infertility."
    explanation: Independent replication in a Pakistani family.
  - reference: PMID:34976027
    reference_title: "Novel Bi-Allelic Variants of FANCM Cause Sertoli Cell-Only Syndrome and Non-Obstructive Azoospermia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Herein, we identified compound heterozygous variants in FANCM in two NOA-affected brothers (c. 1778delG:p. R593Qfs*76 and c. 1663G > T:p. V555F), and a homozygous variant in FANCM (c. 1972C > T:p. R658X) in a sporadic case with NOA, respectively."
    explanation: Replication in Chinese patients.
animal_models:
- name: FancmΔC/ΔC mouse
  species: Mouse
  genotype: Fancm truncating variant nearly equivalent to human p.P648Lfs*16, homozygous
  publication: PMID:29895858
  description: >-
    Males show spermatogenic failure with germ cell loss, Sertoli cell-only
    tubules and round spermatid arrest, and spermatogonia are hypersensitive
    to mitomycin C. No marrow failure or tumors were seen in adult mice.
  modeled_mechanisms:
  - target: Progressive Germ Cell Depletion
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: The model reproduces germ cell loss and Sertoli cell-only tubules.
    limitations: >-
      The mice are subfertile rather than sterile, and many tubules show
      round spermatid arrest, which has not been examined in patients.
    evidence:
    - reference: PMID:29895858
      reference_title: "A homozygous FANCM frameshift pathogenic variant causes male infertility."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Hence, FancmΔC/ΔC mice phenocopied the clinical phenotypes in our patients (Table 1)."
      explanation: Authors' statement that the mice reproduce the patient phenotype.
- name: FancmΔ2/Δ2 knockout mouse
  species: Mouse
  genotype: Fancm exon 2 deletion, homozygous
  publication: PMID:19561169
  description: >-
    Fancm knockout mice have hypogonadism, crosslinker-sensitive embryonic
    fibroblasts and reduced tumor-free survival, without the full Fanconi
    anemia picture.
  modeled_mechanisms:
  - target: Progressive Germ Cell Depletion
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: Gonadal hypoplasia in both sexes.
    limitations: >-
      Reported as hypogonadism without a detailed testicular analysis in the
      abstract; the knockout removes exon 2 rather than modelling a patient
      allele.
    evidence:
    - reference: PMID:19561169
      reference_title: "Fancm-deficient mice reveal unique features of Fanconi anemia complementation group M."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "FANCM deficiency caused hypogonadism in mice and hypersensitivity to cross-linking agents in mouse embryonic fibroblasts (MEFs)"
      explanation: Gonadal defect in the knockout.
diagnosis:
- name: Karyotype and Y-chromosome microdeletion analysis
  description: >-
    Exclusion tests done before gene-level testing. Every reported man had a
    normal 46,XY karyotype and no Y-chromosome microdeletion.
  diagnosis_term:
    preferred_term: karyotyping and Y-chromosome microdeletion analysis
    term:
      id: NCIT:C16768
      label: Karyotyping
  results: Normal 46,XY karyotype with no Y-chromosome microdeletion.
  evidence:
  - reference: PMID:34976027
    reference_title: "Novel Bi-Allelic Variants of FANCM Cause Sertoli Cell-Only Syndrome and Non-Obstructive Azoospermia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All patients have 46,XY karyotypes without microdeletions in the Y chromosome."
    explanation: Chromosomal causes were excluded in the Chinese patients.
- name: Semen analysis
  description: >-
    Repeated semen analysis shows azoospermia with normal ejaculate volume,
    or oligoasthenozoospermia in milder cases.
  diagnosis_term:
    preferred_term: semen analysis
    term:
      id: NCIT:C25294
      label: Laboratory Procedure
  results: Azoospermia with normal volume, or oligoasthenozoospermia.
  evidence:
  - reference: PMID:34976027
    reference_title: "Novel Bi-Allelic Variants of FANCM Cause Sertoli Cell-Only Syndrome and Non-Obstructive Azoospermia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Routine semen analyses (three times) revealed normal volume but no sperm in the ejaculate, indicating complete azoospermia."
    explanation: Repeated semen analysis establishes azoospermia.
- name: Testicular biopsy histology
  description: >-
    Histology and immunohistochemistry of testicular tissue, obtained at
    biopsy or micro-TESE, show Sertoli cell-only tubules.
  diagnosis_term:
    preferred_term: testicular biopsy
    term:
      id: NCIT:C15189
      label: Biopsy Procedure
  results: Sertoli cell-only tubules with no germ cells.
  evidence:
  - reference: PMID:34976027
    reference_title: "Novel Bi-Allelic Variants of FANCM Cause Sertoli Cell-Only Syndrome and Non-Obstructive Azoospermia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "H&E staining and immunohistochemistry showed Sertoli cell-only Syndrome (SCOS) in the three patients with NOA."
    explanation: Biopsy histology in three patients.
- name: Exome sequencing
  description: >-
    Exome sequencing finds the biallelic FANCM variants, confirmed by Sanger
    sequencing and segregation in the family.
  diagnosis_term:
    preferred_term: exome sequencing
    term:
      id: NCIT:C101295
      label: Whole Exome Sequencing
  results: Biallelic FANCM loss-of-function variants.
  evidence:
  - reference: PMID:30075111
    reference_title: "Bi-allelic Recessive Loss-of-Function Variants in FANCM Cause Non-obstructive Azoospermia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "whole-exome sequencing (WES) was applied to two Estonian brothers diagnosed with NOA and Sertoli cell-only syndrome (SCOS)"
    explanation: Exome sequencing identified the first FANCM family.
  - reference: PMID:29895858
    reference_title: "A homozygous FANCM frameshift pathogenic variant causes male infertility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Exome and Sanger sequencing were used for PV screening."
    explanation: Exome plus Sanger confirmation in the Pakistani family.
- name: Mitomycin C chromosomal breakage test
  description: >-
    Lymphocytes cultured with mitomycin C show excess chromosomal breaks.
    This supports a loss-of-function effect, for example when a variant is of
    uncertain significance; it is not specific to FANCM.
  diagnosis_term:
    preferred_term: chromosomal breakage analysis (mitomycin C)
    term:
      id: NCIT:C18280
      label: Cytogenetic Analysis
  results: Dose-dependent increase in mitomycin C-induced chromosomal breaks.
  evidence:
  - reference: PMID:29895858
    reference_title: "A homozygous FANCM frameshift pathogenic variant causes male infertility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "lymphocytes from both IV:2 and IV:3 displayed a dose-dependent increase in MMC-induced chromosomal breaks per cell, which averaged 3 to 17 times those of the father"
    explanation: Breakage test result in two affected brothers.
treatments:
- name: Genetic Counseling
  description: >-
    Counseling on recessive inheritance and on the possible cancer and
    hematologic risks of biallelic FANCM variants, as recommended after a
    Sertoli cell-only case with an astrocytoma.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:38927643
    reference_title: "FANCM Gene Variants in a Male Diagnosed with Sertoli Cell-Only Syndrome and Diffuse Astrocytoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "genetic counseling should be applied to azoospermia patients diagnosed with FANC mutations"
    explanation: Authors' recommendation for men with FANC-gene azoospermia.
- name: Cancer and Hematologic Surveillance
  description: >-
    Regular screening for cancer and hematologic abnormalities is proposed by
    the authors of two case series. It is expert opinion; no study has tested
    surveillance in men with SPGF28.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: cancer and hematologic surveillance
    term:
      id: NCIT:C15406
      label: Cancer Screening
  evidence:
  - reference: PMID:38927643
    reference_title: "FANCM Gene Variants in a Male Diagnosed with Sertoli Cell-Only Syndrome and Diffuse Astrocytoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "with proposals for the multidisciplinary monitoring of these men in terms of regular screenings for cancer or hematologic abnormalities and other potential complications"
    explanation: Recommendation for cancer and hematologic screening.
  - reference: PMID:34976027
    reference_title: "Novel Bi-Allelic Variants of FANCM Cause Sertoli Cell-Only Syndrome and Non-Obstructive Azoospermia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Thus, future cancer incidence of the patients should be monitored."
    explanation: A second group recommends cancer monitoring.
- name: Caution with Chemotherapy and Radiotherapy
  description: >-
    If a biallelic FANCM carrier develops cancer, crosslinking chemotherapy
    and radiotherapy may cause acute toxicity, so dose reduction or other
    regimens are suggested. This rests on carriers with cancer, not on men
    with SPGF28.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: dose-adapted chemotherapy and radiotherapy
  target_mechanisms:
  - target: Defective DNA Interstrand Crosslink Repair
    description: >-
      Cells that repair crosslinks poorly are more sensitive to crosslinking
      chemotherapy, which is the reason for the caution.
    evidence:
    - reference: PMID:28837157
      reference_title: "Biallelic truncating FANCM mutations cause early-onset cancer but not Fanconi anemia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Care should be taken with chemotherapy and radiation treatments in these patients due to expected acute toxicity."
      explanation: Links the caution to the cellular crosslink defect seen in these patients.
  evidence:
  - reference: PMID:38927643
    reference_title: "FANCM Gene Variants in a Male Diagnosed with Sertoli Cell-Only Syndrome and Diffuse Astrocytoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "such as dose reductions or alternative regimens of chemotherapy and/or radiotherapy"
    explanation: Suggested adaptation of cancer treatment.
- name: Microsurgical Testicular Sperm Extraction
  description: >-
    The Chinese men with SPGF28 underwent micro-TESE. Their tissue showed
    Sertoli cell-only histology, and no sperm retrieval outcome is reported
    in the cached sources. The yield in SPGF28 is unknown.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: microsurgical testicular sperm extraction
    term:
      id: NCIT:C94427
      label: Sperm Retrieval
  target_mechanisms:
  - target: Non-obstructive azoospermia
    description: Searches the testis for residual foci of spermatogenesis to bypass azoospermia.
  evidence:
  - reference: PMID:34976027
    reference_title: "Novel Bi-Allelic Variants of FANCM Cause Sertoli Cell-Only Syndrome and Non-Obstructive Azoospermia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The two brothers with NOA and the NOA-affected sporadic cases were subjected to microsurgical testicular sperm extraction (micro-TESE) operation"
    explanation: Micro-TESE was performed in SPGF28 patients.
📚

References & Deep Research

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (1)

Create: Spermatogenic Failure 28 (FANCM) · 2026-10-15T15:54:30Z · View source

New entry for spermatogenic failure 28 (MONDO:0054732), autosomal recessive non-obstructive azoospermia from biallelic FANCM loss of function. Lump/split: kept as a DISEASE at the MONDO SPGF28 concept, with a skos:broadMatch to MONDO:0100578 (FANCM Fanconi-like genomic instability disorder), the broader disease into which ClinGen lumps SPGF28, POF15 and Fanconi-like syndrome. Pathograph: FANCM DNA translocase loss (GO:0015616) -> defective interstrand crosslink repair -> progressive germ cell depletion -> Sertoli cell-only, NOA, oligozoospermia, small testes, raised FSH, infertility; a mouse-derived round spermatid arrest branch; and a separate mouse-only meiotic crossover node not drawn as a cause of infertility. Cancer and chemotoxicity risk in men is recorded as an EMERGING mechanistic hypothesis with supporting and refuting evidence rather than as phenotypes. The falcon provider failed authentication; the claude_code deep-research report (research/Spermatogenic_Failure_28-deep-research-claude_code.md) was used as leads, and every snippet was taken from references fetched with just fetch-reference. preflight-dr was not run because no local MONDO build is available. Validated with validate-disorders, validate-terms, count-verified-snippets and the offline QC gates.

Claude Code ▸
Spermatogenic Failure 28 (SPGF28; FANCM-related male infertility): Research Report
claude-opus-5-5 2026-10-15T15:35:23.026995

Spermatogenic Failure 28 (SPGF28; FANCM-related male infertility): Research Report

Target: Spermatogenic failure 28, MONDO:0054732 · Category: Mendelian (autosomal recessive) · Report date: 2026-10-15

How this report was sourced. In this session PubMed (MCP) and outbound network calls (E-utilities, curl) were blocked. All quotes marked [cached ✔] were read word for word from the repository's references_cache/ and can be used as snippets as they stand. Identifiers or citations marked [unverified] come from background knowledge and were not checked this session. Before binding or citing them in kb/, look each one up (just fetch-reference PMID:…, OLS or runoak). This follows CLAUDE.md's rule that every CURIE must be read from a source in the same step it is written.

1. Disease Information

Overview. SPGF28 is an autosomal recessive form of male infertility caused by biallelic loss-of-function (LoF) variants in FANCM (FA complementation group M, a DNA translocase). Affected men have non-obstructive azoospermia (NOA). On testicular biopsy this is most often Sertoli cell-only syndrome (SCOS). Some men have severe oligoasthenozoospermia instead. Endocrine function is otherwise largely preserved, and there is no bone-marrow failure.

The defining paper:

"The study convincingly demonstrates that bi-allelic recessive LoF variants in FANCM cause azoospermia." — Kasak et al. 2018, Am J Hum Genet, PMID:30075111 [cached ✔]

"These findings revealed male infertility to be a novel phenotype of human patients with a biallelic FANCM PV." — Yin et al. 2019, Genet Med, PMID:29895858 [cached ✔]

Identifiers

Resource ID Status
MONDO MONDO:0054732 "spermatogenic failure 28" in draft entry; confirm with just validate-terms
OMIM (phenotype) 618086 [unverified]
OMIM (gene) FANCM 609644 [cached ✔] (PMID:34976027 cites "FANCM (MIM: 609644)")
HGNC hgnc:23168 FANCM already bound in kb/disorders/Fanconi_Anemia.yaml
Orphanet no SPGF28-specific entry known; falls under NOA due to genetic causes / SCOS [unverified]
ICD-10 / ICD-11 N46.0 azoospermia (generic) / GB04.0 [unverified]
MeSH Azoospermia (D053713); Sertoli Cell-Only Syndrome (D050291) [unverified]

Synonyms: SPGF28; FANCM-related non-obstructive azoospermia; FANCM-associated Sertoli cell-only syndrome.

Related allelic conditions (same gene, different MONDO concepts; keep them separate): - Premature ovarian failure 15 (POF15; OMIM 618096 [unverified]): FANCM biallelic LoF in women. - FANCM-biallelic "FA-like" cancer and chemotherapy-toxicity phenotype: early-onset cancer and chemotherapy sensitivity without bone-marrow failure (PMID:28837162 [cached ✔]). - Monoallelic FANCM truncating variants as moderate breast-cancer risk alleles.

Data provenance. Everything here is case-level: family and sporadic exome studies reported in the literature. There are no registries or EHR cohorts.

2. Etiology

Primary cause: biallelic germline LoF variants in FANCM (chromosome 14q21.2 [unverified locus]).

Genetic risk factors - Truncating variants: frameshift, nonsense and splice (see §4). - Possibly biallelic missense variants in the helicase/DEAH domain. This is lower confidence and rests on in-silico prediction only (PMID:34976027, PMID:38927643).

Environmental risk factors. None are established. Zhang et al. speculate that DNA interstrand-crosslink (ICL) burden from environmental agents might modify severity:

"the ICL repair pathway is indispensable in the DNA replication of germ cells, and can be affected by a variety of environmental agents, which have also been proposed as explanations for the clinical variability in male patients suffering from infertility." — PMID:34976027 [cached ✔]

This is hypothesis-level only.

Protective factors: none known.

Gene–environment interaction: not studied in humans. A plausible but untested axis is ICL-inducing exposures (alkylating chemotherapy, aldehydes) in FANCM-deficient germ cells. Affected individuals do show cellular hypersensitivity to mitomycin C (MMC) (PMID:29895858).

3. Phenotypes

Phenotype Suggested HPO [verify each] Type / onset Frequency (n ≈ 11 reported men) Key evidence
Non-obstructive azoospermia HP:0011961 Non-obstructive azoospermia Sign; post-pubertal / adult presentation Most cases (~9/11) PMID:30075111, 34976027, 38927643
Sertoli cell-only syndrome (testis histology) HP:0011962 Sertoli cell-only syndrome [unverified] Biopsy finding All biopsied cases (Estonian proband, 3 Chinese, 1 Croatian) PMID:30075111, 34976027, 38927643
Oligoasthenozoospermia / severe oligozoospermia HP:0000798 Oligospermia; HP:0012207 Reduced sperm motility [unverified] Sign 2/3 Pakistani brothers PMID:29895858
Male infertility HP:0003251 Male infertility Adult 100% all
Elevated FSH HP:0008232 Elevated circulating follicle stimulating hormone concentration [unverified] Lab Common but not universal (3/3 Chinese; borderline to elevated in the Pakistani family; normal in the Croatian case) PMID:34976027, 29895858, 38927643
Reduced testicular volume HP:0008734 Decreased testicular size [unverified] Sign Variable (8–10 mL in 2 brothers; 12 mL in another) PMID:34976027
Low/low-normal testosterone HP:0040171 Decreased serum testosterone concentration [unverified] Lab Occasional (1 Croatian case below range) PMID:38927643
Chromosomal breakage after MMC (lymphocytes) HP:0003221 Chromosomal breakage induced by crosslinking agents [unverified] Lab / cellular In tested patients (2/2) PMID:29895858
Cancer (variable; incomplete evidence) e.g., HP:0100843 Glioblastoma not appropriate; diffuse astrocytoma → MONDO-level comorbidity Adult 1 reported man (compound heterozygous missense) PMID:38927643 (case report; causality not shown)

Supporting quotes [cached ✔] - "Adult FancmΔC/ΔC mice showed spermatogenic failure, with germ cell loss in 50.2% of testicular tubules and round-spermatid maturation arrest in 43.5% of tubules." (PMID:29895858; mouse) - "H&E staining and immunohistochemistry showed Sertoli cell-only Syndrome (SCOS) in the three patients with NOA." (PMID:34976027) - "Two of the affected brothers, IV:1 (married for 21 years) and IV:3 (single) were diagnosed with mild and severe oligoasthenospermia, respectively. Both had largely normal plasma levels of testosterone and pituitary hormones." (PMID:29895858) - "The loss-of-function FANCM PV increased ICL sensitivity in lymphocytes of patients and FancmΔC/ΔC spermatogonia." (PMID:29895858)

Absent features:

"neither bone marrow failure nor cancer/tumor was detected in all the patients or adult FancmΔC/ΔC mice." (PMID:29895858) [cached ✔]

Karyotype was 46,XY with no AZF microdeletions in every reported case.

Severity and course. Infertility is the presenting problem and appears stable once established. The mouse data suggest progressive spermatogonial stem cell (SSC) loss (see §6). That fits a spectrum from oligozoospermia to SCOS that may be age-dependent, but this has not been shown in humans.

Quality of life. No disease-specific data exist. The burden is infertility-related psychosocial distress, plus the possible downstream cancer-surveillance burden.

4. Genetic / Molecular Information

Causal gene: FANCM (hgnc:23168; MIM 609644). This is a DEAH-box DNA translocase of the FA core complex, with the domains PIP-box, DEAH (aa 77–590), MHF-binding (661–800), MM1 (826–967), MM2 (1218–1251) and ERCC4 (1818–1956). Domain boundaries are as listed in PMID:34976027 [cached ✔].

Reported variants in SPGF28 (RefSeq NM_020937)

Variant Protein Zygosity Population Phenotype Source
c.1491dupA p.Gln498Thrfs*7 (rs761250416) compound het (maternal) Estonian brothers NOA/SCOS PMID:30075111
c.4387-10A>G splice → premature stop (p.Arg1436_Ser1437insLeuLeu*) compound het (paternal) same family NOA/SCOS PMID:30075111
c.5101C>T p.Gln1701* (rs147021911) homozygous Estonian NOA PMID:30075111
c.5791C>T p.Arg1931* (rs144567652) homozygous Portuguese NOA PMID:30075111
c.1946_1958del p.Pro648Leufs*16 homozygous Pakistani (consanguineous), 3 brothers 1 azoospermia, 2 oligoasthenozoospermia PMID:29895858
c.1778delG + c.1663G>T p.Arg593Glnfs*76 + p.Val555Phe compound het Chinese brothers NOA/SCOS PMID:34976027
c.1972C>T p.Arg658* homozygous Chinese (sporadic, 1/479 NOA) NOA/SCOS PMID:34976027
c.170C>T? / c.950A>G? (p.Leu57Phe rs142007602 + p.Gln317Arg rs375644492) missense compound het Croatian SCOS (+ diffuse astrocytoma) PMID:38927643 (both VUS/conflicting in ClinVar)

The cDNA notation for the Croatian missense variants is not given in the cached text. Only the protein changes and rsIDs are reliable.

Classification. Truncating alleles behave as LoF and are pathogenic or likely pathogenic for SPGF28 in ClinVar [unverified ClinVar status]. The missense alleles are VUS. Per PMID:38927643, rs142007602 is "probably benign regarding Fanconi anemia, but in relation to spermatogenic failure… of uncertain significance".

Allele frequency. The Arg658* and Gln1701* alleles also recur in breast-cancer cohorts (e.g., p.Arg658* has a carrier frequency of about 0.1–0.5% in Finnish and European populations [unverified]). p.Leu57Phe has MAF 0.0017 and p.Gln317Arg has MAF 0.000016 (gnomAD v2.1.1, PMID:38927643 [cached ✔]).

Origin and mechanism. All variants are germline, and the functional consequence is LoF. Yin et al. showed no detectable full-length protein in blood, impaired FANCD2 monoubiquitination and foci in FANCM⁻/⁻ HEK293T cells re-expressing the mutant, and increased γH2AX (PMID:29895858, IN_VITRO).

Modifier genes: none established. Domain position has been proposed to shape the phenotype:

"Phenotype severity might correlate with mutation position in the gene." (PMID:28837162) [cached ✔]

Epigenetic / chromosomal: none. A normal karyotype is required to make the diagnosis.

ClinGen gene–disease validity: not checked this session. Run just list-gene-validity or just fetch-reference CGGV:… before recording any tier. Do not assign a tier.

5. Environmental Information

No environmental, lifestyle or infectious causes are known. The reported patients had no history of smoking, alcohol, cryptorchidism or varicocele (PMID:29895858, PMID:34976027). This is relevant if the entry later records an exposure; otherwise leave environmental: empty.

6. Mechanism / Pathophysiology

Ordered causal chain

  1. Biallelic FANCM LoF variants (truncating, or rarely missense in the DEAH/helicase domain) lead to absent or truncated FANCM protein. This is demonstrated in blood by western blot (PMID:29895858). Testis IHC shows absent or faint staining in Sertoli cells (PMID:30075111, PMID:38927643).
  2. Loss of FANCM produces loss of stalled-replication-fork recognition and of FA core complex recruitment. As a result, FANCD2–FANCI monoubiquitination fails and ICL repair is defective. This is demonstrated in vitro in PMID:29895858.
  3. "FANCM is the only protein within the FA core complex that can recognize and bind to stalled replication forks." (PMID:29895858) [cached ✔]
  4. Defective ICL repair and replication-fork protection cause genomic instability and DNA damage accumulation in proliferating germ cells. Measured readouts are MMC hypersensitivity in patient lymphocytes and in mouse spermatogonia, and increased γH2AX.
  5. Branch A: mitotic germline compartment (dominant branch in humans). DNA damage in primordial germ cells (PGCs) and SSCs leads to apoptosis and reduced proliferation, which causes progressive SSC depletion.
  6. Mouse: GFRA1⁺/SOX9⁺ ratio halved at 10 weeks and below one quarter at 70 weeks (PMID:29895858).
  7. Earlier Fancm mice: reduced PGC proliferation (Bakker et al. 2009 [unverified PMID]).
  8. The chain then runs: germ-cell loss → Sertoli cell-only tubules → non-obstructive azoospermia.
  9. The human SCOS endpoint is demonstrated. That the human SCOS arises through progressive loss is inferred from mice.
  10. Branch B: meiotic and post-meiotic compartment (model-derived). FANCM is an anti-crossover helicase with the MHF and BTR (BLM–TOP3A–RMI) complexes, so its loss dysregulates meiotic recombination/crossover control. This was established first in Arabidopsis (Crismani et al. 2012, Science [unverified PMID]), and loss in mice affects crossover number (cited in PMID:38927643). In the mouse model the result is partial round-spermatid maturation arrest (43.5% of tubules), which leads to oligoasthenozoospermia with abnormal morphology. This may explain the milder oligozoospermic presentations in the Pakistani family. It is inferred; human testis histology was not available for that family.
  11. Systemic consequence (variable; not part of SPGF28 core): somatic genomic instability may confer cancer predisposition and chemotherapy or radiotherapy toxicity. This is shown in biallelic FANCM women (PMID:28837162) and suggested in one SCOS man with astrocytoma (PMID:38927643, case-level only).

The germ-cell-specific emphasis is supported by expression data:

"FANCM exhibits enhanced testicular expression… localized FANCM to the Sertoli and spermatogenic cells of seminiferous tubules with increasing intensity through germ cell development. This is consistent with its role in maintaining genomic stability in meiosis and mitosis." (PMID:30075111) [cached ✔]

FANCM is functionally distinct from the canonical FA genes:

"biallelic FANCM mutations do not cause classical FA, providing proof that FANCM is not a canonical FA gene." (PMID:28837162) [cached ✔]

Yin et al. add that the round-spermatid arrest "has not been mentioned in Fancm mutant mice… suggesting that this role of FANCM could be independent of the canonical FA pathway" (PMID:29895858) [cached ✔].

Suggested ontology terms (all [unverified]; look each one up before binding)

GO biological processes - interstrand cross-link repair GO:0036297 - replication fork processing GO:0031297 - negative regulation of reciprocal meiotic recombination / meiotic crossover regulation (search "crossover") - spermatogenesis GO:0007283 - male germ-line stem cell population maintenance GO:0036098 - germ cell proliferation GO:0036093 - apoptotic process GO:0006915 - double-strand break repair via homologous recombination GO:0000724

GO molecular function / complex - ATP-dependent DNA/DNA annealing or translocase activity: check "ATP-dependent activity, acting on DNA" GO:0008094 - Fanconi anaemia nuclear complex GO:0043240 (already used in the FA entry) - FANCM-MHF complex GO:0071821

CL cell types - spermatogonial stem cell CL:0000020 (or "male germline stem cell") - spermatogonium CL:0000020 — confirm which label applies - primordial germ cell CL:0000670 - Sertoli cell CL:0000216 - round spermatid CL:0000018 / spermatid - spermatocyte CL:0000017

Modifiers: use LOSS_OF_FUNCTION for functional_impact_category on the variant node, and DECREASED for the process-level modifier values.

Molecular profiling. No transcriptomic, proteomic or single-cell datasets specific to FANCM-NOA are known. The Pakistani-family exome data are deposited as ArrayExpress E-MTAB-6090 (PMID:29895858 [cached ✔]). That is an exome dataset, not an expression dataset, and is a candidate for datasets: after just verify-datasets.

7. Anatomical Structures Affected

  • Primary organ: testis (UBERON:0000473 [unverified]), specifically the seminiferous tubule epithelium (UBERON:0001343 seminiferous tubule of testis [unverified]).
  • Secondary: none established. Some biopsies show tubular fibrosis ("tubular shadows") and mononuclear infiltrates (PMID:38927643).
  • Body system: male reproductive system.
  • Cells: germ cells, which are lost; Sertoli cells, which remain; Leydig cells, which appear normal (PMID:38927643).
  • Subcellular: nucleus, at replication forks and chromatin (GO:0005634 nucleus). IHC in human testis shows predominantly cytoplasmic FANCM staining (PMID:38927643 [cached ✔]), with Golgi localization reported in earlier work.
  • Laterality: bilateral (both testes SCOS in PMID:38927643; bilateral volumes in PMID:34976027).

8. Temporal Development

  • Onset: the defect is likely congenital or developmental, since mouse PGC defects arise in the embryo. Clinically it presents in adulthood at infertility evaluation; reported ages range from 23 to 48 years.
  • Course: stable infertility. The mouse model shows age-dependent progressive SSC loss (PMID:29895858), which suggests a possible window for early sperm cryopreservation in genotype-positive oligozoospermic men. This is an extrapolation, not established practice.
  • Remission: none.

9. Inheritance and Population

  • Inheritance: autosomal recessive (HP:0000007 [unverified]).
  • Penetrance: apparently complete for male infertility in biallelic-LoF men reported so far. Ascertainment bias is strong, since cases were identified through infertility clinics.
  • Expressivity: variable, ranging from mild oligoasthenozoospermia to SCOS (PMID:29895858 vs PMID:30075111).
  • Consanguinity: the Pakistani family was first-cousin (PMID:29895858). The other families were non-consanguineous.
  • Founder effects: p.Gln1701* and p.Arg658* recur in Northern European populations. p.Arg658* is also recurrent in Chinese NOA (1/479 in PMID:34976027). A formal founder analysis has not been done.
  • Prevalence: unknown. FANCM accounts for a small fraction of idiopathic NOA: about 1 in 479 Chinese NOA cases from one centre (PMID:34976027). Use measure_type: CASES_IN_LITERATURE. Roughly 11 men have been reported across 5 publications (2018–2024).
  • Sex: this MONDO concept is male-only. Biallelic women have POI or early menopause (POF15; PMID:28837162 mentions "early menopause").
  • Geography: Estonia, Portugal, Pakistan, China and Croatia.

10. Diagnostics

  • Semen analysis (WHO criteria): azoospermia confirmed on at least two centrifuged samples, or severe oligoasthenozoospermia.
  • Hormones: FSH (often raised), LH, testosterone. LOINC codes for FSH and testosterone must come from just loinc-seed-cache; do not type them.
  • Exclusions: karyotype (46,XY), Y-chromosome AZF microdeletion testing, CFTR testing if obstruction is suspected. All were normal in the reported cases.
  • Testicular biopsy / micro-TESE histology: SCOS. IHC shows absent DDX4 and UCHL1 germ-cell markers with retained SOX9 and AR (PMID:34976027 [cached ✔]).
  • Genetic testing: exome sequencing or an NOA gene panel including FANCM. Interpret under a recessive model and check for CNV on the second allele. PMID:34976027 ran a WES-based CNV analysis to exclude a hemizygous deletion.
  • Functional cytogenetics: an MMC or DEB chromosomal-breakage test on lymphocytes shows increased breaks (PMID:29895858). This supports pathogenicity of VUS. Note that it overlaps the FA diagnostic test (PMID:25827349, DEB analysis).
  • Differential diagnosis: other monogenic NOA (TEX11, TEX14, TEX15, MEIOB, STAG3, SYCE1, DMC1, SHOC1, HFM1, XRCC2; PMID:34976027, 34429122); Klinefelter syndrome; AZF deletions; classical Fanconi anemia, which differs by marrow failure and malformations; and post-chemotherapy azoospermia.
  • Screening: no population screening. Cascade testing of sisters is relevant because of POI risk, and of relatives because of breast-cancer risk.

11. Outcome / Prognosis

  • Survival: not reduced by SPGF28 itself, as far as is known. A death in the Pakistani family from valvular heart disease was attributed by the authors to another cause, since a heterozygous brother was also affected (PMID:29895858).
  • Fertility prognosis: poor in the SCOS presentations. No sperm retrieval was reported in the Chinese micro-TESE cases (PMID:34976027 reports SCOS histology; sperm-retrieval outcome not stated).
  • Long-term risk:
  • Possible cancer predisposition, extrapolated from biallelic FANCM women and monoallelic breast-cancer data (PMID:28837162) and from one astrocytoma case (PMID:38927643).
  • Possible hypersensitivity to chemotherapy and radiotherapy, which matters if cancer develops.
  • Zhang et al. recommend that "future cancer incidence of the patients should be monitored" (PMID:34976027) [cached ✔].

12. Treatment

No disease-modifying therapy exists. Management is reproductive and preventive.

Intervention Suggested NCIT [unverified] Notes
Micro-TESE + ICSI Surgical Procedure NCIT:C15329; ICSI (search NCIT "Intracytoplasmic Sperm Injection") Low yield expected in SCOS; ICSI possible in oligozoospermic men
Sperm cryopreservation search NCIT "Sperm Banking" Possibly time-sensitive (mouse SSC loss)
Donor sperm / adoption — Counselling
Genetic counselling NCIT:C15240 Genetic Counseling Recessive transmission, sister POI risk, cancer-risk discussion
Cancer surveillance / dose-adapted chemo-radiotherapy if cancer arises Supportive Care NCIT:C15747 Expert opinion: PMID:38927643 recommends "regular screenings for cancer or hematologic abnormalities" and "dose reductions or alternative regimens" [cached ✔]

Pharmacogenomics: FANCM deficiency may predict sensitivity to ICL agents and PARP inhibitors. This is preclinical or theoretical for SPGF28.

Gene or cell therapy: none. There are no clinical trials specific to FANCM-related NOA [unverified search].

13. Prevention

  • Primary: none.
  • Reproductive and genetic: carrier testing of partners. PGT-M is relevant if the offspring of an affected man via ICSI could be at risk (offspring are obligate carriers, and are affected only if the partner is a carrier).
  • Cascade testing: sisters (POF15 risk) and female relatives (breast-cancer risk, monoallelic).
  • Tertiary: cancer surveillance, and avoiding unnecessary ICL-agent exposure (expert opinion).

14. Other Species / Natural Disease

  • No naturally occurring FANCM infertility in domestic animals is recorded in OMIA [unverified].
  • FANCM is conserved from yeast (Mph1) to plants. In Arabidopsis thaliana, FANCM loss increases meiotic crossovers (Crismani et al. 2012 [unverified]), which is the basis for the anti-crossover role.
  • Mouse ortholog: Fancm (MGI ID to look up).

15. Model Organisms

Model Phenotype Fidelity / limitation Source
Fancm^ΔC/ΔC^ mouse (p.R638Rfs*8; mimics human p.P648Lfs*16) Subfertile males; testes ~47% smaller; epididymal sperm count reduced 97-fold; SCO (7.6%), germ-cell loss (42.6%) and round-spermatid arrest (43.5%) tubules; progressive SSC loss; spermatogonial MMC hypersensitivity; no marrow failure or tumours to 1 year MODERATE–HIGH; mice are subfertile rather than sterile, so milder than human SCOS PMID:29895858 [cached ✔]
Fancm^Δ2/Δ2^ knockout mouse Hypogonadism in both sexes; reduced PGC proliferation; tumour predisposition; non-Mendelian transmission in females Bakker et al. 2009, Hum Mol Genet [unverified PMID]
Fancm^C4/C4^ (helicase-domain missense) mouse Progressive germ-cell depletion approaching SCOS; elevated SCE; tumour susceptibility Luo et al. 2014 [unverified PMID]; summarized in PMID:38927643
FANCM⁻/⁻ HEK293T + mutant re-expression Impaired FANCD2 monoubiquitination and foci; increased γH2AX and MMC breaks IN_VITRO, PMID:29895858
Arabidopsis fancm Increased meiotic crossovers Crismani 2012 [unverified]

Key quote:

"Hence, FancmΔC/ΔC mice phenocopied the clinical phenotypes in our patients" (PMID:29895858) [cached ✔]

The model is reported as MODEL_ORGANISM evidence and should not be the sole support for any human phenotype.

Curation notes for the dismech entry

  1. Cached and quotable now: PMID:30075111, 29895858, 34976027, 38927643, 28837162 (plus the background references PMID:34429122 and 25827349). Run just count-verified-snippets after drafting.
  2. To fetch before citing:
  3. Bogliolo et al. 2018 (biallelic truncating FANCM → early-onset cancer, not FA)
  4. Fouquet et al. 2017 / Yang et al. 2020 (FANCM POI)
  5. Bakker et al. 2009 and Luo et al. 2014 (Fancm mice)
  6. Crismani et al. 2012
  7. Kasak & Laan review(s)
  8. GeneReviews: no SPGF28 chapter is expected; check with just check-genereviews.
  9. Scope: keep POF15 and the FA-like cancer phenotype out of this entry's core phenotypes. Mention them in notes or as cross-references, because this MONDO concept is the male spermatogenic failure.
  10. Pathograph wiring: variant LoF → defective ICL repair / replication fork protection → germ-cell genomic instability → SSC/PGC depletion (→ SCOS → NOA), plus a parallel meiotic crossover / round-spermatid arrest branch (→ oligoasthenozoospermia). Connect each phenotype with a downstream edge so it is not stranded (see just list-disconnected-phenotypes).
  11. Gene validity: do not assign a ClinGen tier unless a cached CGGV: record exists.

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome Count
References checked 7
Resolved 7
Unresolved (possible confabulation) 0
Unverifiable 0
Quoted claims checked 12
Quoted claims found in source 10
Quoted claims not found in source 2
References weighed for topical relevance 7
On topic 7
Off topic 0

Quotes not found in the cited source

Searched the abstract, any retrieved full text, and the title. A quote drawn from a part of the paper that was not retrieved will appear here too, so check before treating one as invented:

1 of these was searched against an abstract alone, with no full text retrieved - marked abstract only below. Where full text can be fetched, re-running with it will settle them; where the source publishes only a summary to PubMed, as GeneReviews chapters do, it will not, and the quote has to be checked by hand against the chapter itself.

  • PMID:30075111 (abstract only): "FANCM exhibits enhanced testicular expression… localized FANCM to the Sertoli and spermatogenic cells of seminiferous tubules with increasing intensity through germ cell development. This is consistent with its role in maintaining genomic stability in meiosis and mitosis."
  • closest text in source: "In control subjects, immunohistochemical staining localized FANCM to the Sertoli and spermatogenic cells of seminiferous tubules with increasing intensity through germ cell development"
  • PMID:29895858: "has not been mentioned in Fancm mutant mice… suggesting that this role of FANCM could be independent of the canonical FA pathway"
  • closest text in source: "Notably, 43.5% of seminiferous tubules displayed maturation arrest at round spermatid stage in FancmΔC/ΔC mice, which has not been mentioned in Fancm mutant mice18,19 or reported in any other FA mouse models,19–22 suggesting that this role of FANCM could be independent of the canonical FA pathway"

Term Validation

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

Outcome Count
Terms checked 33
Resolved 32
Unresolved (possible confabulation) 0
Obsolete 1
Unverifiable 0
Terms whose name was checked 4
Terms named correctly 0
Terms named as a different term 4

Terms the report names something else

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

  • GO:0043240 (1 mention) - the report calls it "already used in the FA entry"; GO calls it Fanconi anaemia nuclear complex
  • CL:0000020 (2 mentions) - the report calls it "confirm which label applies"; CL calls it spermatogonium
  • UBERON:0000473 (1 mention) - the report calls it "unverified"; UBERON calls it testis
  • HP:0000007 (1 mention) - the report calls it "unverified"; HP calls it Autosomal recessive inheritance

Obsolete terms

These terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:

  • HP:0100843 (obsolete Glioblastoma) (1 mention) - replaced by HP:0012174