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

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

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)

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.

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

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.

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.

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