Spermatogenic Failure 32: disease-characteristics research report

Spermatogenic failure 32 (SPGF32; MONDO:0020855; OMIM 618115) is a rare Mendelian male-infertility disorder associated with germline variation in the causal gene SOHLH1. Its canonical description is nonobstructive azoospermia (NOA) caused by severe failure of germ-cell development, with reported testicular germ-cell aplasia/Sertoli-cell-only histology. The evidence base is unusually small and centers on one recurrent splice-acceptor variant, NM_001101677.2:c.346-1G>A (rs140132974). Importantly, later human data and population frequency evidence challenge the original autosomal-dominant/de-novo interpretation: homozygosity can cause severe oligozoospermia, whereas heterozygotes may have azoospermia, oligoasthenoteratozoospermia, isolated teratozoospermia, or no recognized phenotype. Thus, the gene–disease association is credible, but penetrance, inheritance, and the pathogenicity of this particular allele remain incompletely resolved. [31][61][109]

Evidence cutoff: October 22, 2026. Disease-specific human literature through 2024 remained sparse; the most relevant 2023 publication is an expanded mouse knockout phenotyping study. A small 2025 human study is noted only where it materially updates the phenotype.

1. Disease information

1.1 Definition and scope

SPGF32 is a genetic form of primary testicular spermatogenic failure. The defining manifestation in the original disease record is male infertility from NOA, not obstruction of an otherwise normally functioning reproductive tract. The original patients had absence of spermatogenic cells and a Sertoli-cell-only pattern on biopsy. [24]

The record is an aggregated disease-level construct, assembled principally from OMIM, MedGen/MONDO, ClinVar and published cohorts—not an individual EHR phenotype. Individual-patient observations underpinning it include two Korean men in the 2010 discovery study, Japanese replication cases, and a later Chinese severe-oligozoospermia case. [114]

1.2 Identifiers and names

MedGen confirms MONDO:0020855, OMIM 618115, SOHLH1 at 9q34.3, and the two canonical synonyms. [31]

2. Etiology

2.1 Primary causal factor

The established initiating factor is a germline defect affecting SOHLH1, which encodes a germ-cell-specific basic helix-loop-helix transcription regulator. The best studied allele, c.346-1G>A, disrupts a splice acceptor, activates a cryptic splice site in exon 4, deletes 18 coding nucleotides, damages the bHLH domain, and reduces transcriptional activation of the KIT promoter. [61]

The discovery abstract’s key conclusion was:

“Our findings indicate that a splice-acceptor site mutation that probably causes a nonfunctional SOHLH1 protein results in nonobstructive azoospermia by the lack of normal spermatogenesis.”
— Choi et al., Human Mutation, July 2010, PMID: 20506135 [61]

2.2 Risk factors and evidence strength

The 2022 human study summarized its revised inheritance interpretation as:

“the heterozygous mutation of c.346-1G > A in SOHLH1 is responsible for teratozoospermia, and this homozygous mutation in SOHLH1 impairs spermatogenesis and further leads to the reduced sperm count.”
— Liu et al., Human Molecular Genetics, March 31, 2022, PMID: 34448846 [62]

That conclusion is not definitive: the homozygous patient’s father was non-carrier and maternal DNA was unavailable, so parentage, phase and full segregation were not established. [62]

2.3 Protective factors and gene–environment interaction

No disease-specific protective allele, modifier gene, diet, medication, or behavioral intervention has been demonstrated. Avoiding gonadotoxic exposures may preserve residual spermatogenesis in male infertility generally, but it cannot correct congenital loss of SOHLH1 transcriptional function.

No controlled human gene–environment interaction study exists for SPGF32. A reasonable but unproven model is that fever, testicular heat, chemotherapy, radiation, smoking or other oxidative insults could further reduce an already limited germ-cell reserve.

3. Phenotypes

Because only a handful of molecularly characterized patients exist, percentages would be misleading. Frequencies below are qualitative and evidence-specific rather than population estimates.

Quality-of-life consequences

No SPGF32-specific patient-reported outcome study exists. Male infertility generally is associated with psychological distress, relationship burden, invasive fertility procedures and uncertainty about biological parenthood. A 2023 meta-analysis estimated depression in infertile men at 18.3%, while a 2024 systematic review found reported quality-of-life scores ranging from 55.15 ± 13.52 to 91.45 ± 13.66, most often 70–80%. These figures should be annotated as indirect male-infertility evidence, not SPGF32-specific estimates. [124][133]

4. Genetic and molecular information

4.1 Gene annotation

NCBI/HGNC-linked resources identify the gene as protein coding and provide HGNC:27845, NCBI Gene 402381 and ENSG00000165643. [2]

4.2 Reported variants

The recurrent allele has a ClinVar global minor allele frequency around 0.003, with reported database frequencies from 0.00031 to 0.00329 and a Finnish gnomAD frequency around 0.015; gnomAD homozygotes have been reported. Those observations are difficult to reconcile with a fully penetrant dominant cause of severe NOA. [107]

4.3 Variant origin and functional class

• Reported variants are germline, not somatic.
• The likely molecular mechanism is loss or marked reduction of transcription-factor function.
• The splice allele is not a classic whole-protein null: it creates an in-frame deletion that impairs the bHLH region and reduces, rather than necessarily abolishes, transactivation.
• There is no convincing evidence for gain of function or dominant-negative action.
• Large causal deletions, translocations, aneuploidies or repeat expansions specifically defining SPGF32 have not been established.
• No validated modifier gene has been identified; SOHLH2 is a biologically plausible compensatory partner but is not a proven human clinical modifier.

4.4 Epigenetics

SOHLH1 participates in a transcriptional differentiation network, but no reproducible SPGF32-specific DNA-methylation, histone-mark or chromatin signature has been established in patients. Epigenetic assays are therefore research tools, not diagnostic biomarkers.

5. Environmental and lifestyle information

The environmental distinction is clinically important: finding a SOHLH1 variant should not prevent assessment for reversible endocrine, toxic, infectious or obstructive contributors.

6. Mechanism and pathophysiology

6.1 Ordered causal chain

1. A damaging germline SOHLH1 allele leads to abnormal SOHLH1 RNA splicing or reduced functional SOHLH1 protein.
2. Loss of an intact bHLH DNA-binding/dimerization domain leads to reduced transcriptional regulation of spermatogonial differentiation genes.
3. Reduced SOHLH1 activity leads to failure to suppress stem-cell-maintenance programs and failure to activate differentiation programs including KIT, SOX3, NGN3/NEUROG3, LHX8 and meiotic genes.
4. Failure of that transcriptional switch leads to impaired transition of undifferentiated type-A spermatogonia into differentiating KIT-positive spermatogonia and spermatocytes.
5. The differentiation block leads to depletion, disorganization and/or apoptosis of developing germ cells; effects on apoptosis and meiotic synaptonemal-complex formation are principally demonstrated in mice and inferred in humans.
6. Germ-cell loss leads to hypospermatogenesis, severe oligozoospermia, maturation failure or, at the extreme, Sertoli-cell-only tubules.
7. Reduced or absent mature sperm leads to teratozoospermia/oligoasthenozoospermia or nonobstructive azoospermia.
8. The semen phenotype results in subfertility or male infertility.

6.2 Mechanistic detail

SOHLH1 and SOHLH2 are germ-cell-specific bHLH factors that form homo-/heterodimeric regulatory complexes. In mouse spermatogonia they directly regulate Gfra1, Sox3, Sohlh1, Sohlh2 and Kit, suppressing spermatogonial stem-cell maintenance while activating differentiation. [51]

The direct KIT link is especially relevant to the human splice allele. Deletion of either factor in male mice causes loss of KIT-positive spermatogonia, and promoter studies show that SOHLH1/SOHLH2 stimulate Kit transcription during postnatal spermatogonial differentiation. [50]

The landmark mouse abstract states:

“Loss of Sohlh1 causes infertility by disrupting spermatogonial differentiation into spermatocytes.”
— Ballow et al., Developmental Biology, June 2006, PMID: 16564520 [47]

In the original human minigene assay, c.346-1G>A produced a shortened transcript and impaired KIT-promoter activation, whereas p.Arg37Gln and p.Pro269Ser did not. This is direct in-vitro evidence for the splice defect but not proof of its penetrance in vivo. [61]

6.3 Pathways, processes and cell types

6.4 Metabolic, immune and tissue-damage findings

No characteristic human metabolomic, lipidomic, inflammatory or immune signature is known. The 2023 knockout study detected sex-specific metabolite changes and altered immune-cell profiles, behavior and cognition in mice, despite the apparently gonad-restricted infertility phenotype. These are hypothesis-generating model findings, not established manifestations of human SPGF32. [16]

6.5 Molecular profiling and advanced technologies

• Transcriptomics: mouse knockout/target studies show decreased differentiation genes and persistence of stem-cell programs; GEO GSE24816 contains relevant Sohlh1/Sohlh2 germ-cell transcription data. [149]
• Single-cell analysis: single-cell RNA sequencing has helped place Sohlh1 in differentiating spermatogonia and identify upstream regulators such as Dec2, but no patient-specific SPGF32 single-cell atlas has been published. [59]
• Proteomics/metabolomics: no validated human diagnostic profile.
• Spatial transcriptomics/multi-omics: no disease-specific clinical implementation.
• CRISPR/RNAi screens: no clinically actionable SPGF32 result.
• Organoids/iPSCs: no validated patient-derived diagnostic or therapeutic platform.

7. Anatomical structures affected

The process is expected to affect both testes because it is a constitutional germline disorder; unilateral disease is not characteristic. No reproducible secondary-organ involvement has been documented in human males.

8. Temporal development

• Biological onset: developmental, during establishment and postnatal differentiation of the male germ line.
• Clinical onset: usually post-pubertal/adult, when semen is assessed because of infertility.
• Pattern: insidious and chronic rather than acute or episodic.
• Course: generally stable infertility; sperm count may vary between analyses, particularly with severe oligo-/cryptozoospermia.
• Remission: spontaneous restoration of a normal sperm output has not been documented.
• Critical window: germ-cell differentiation before and after puberty. In adulthood, the main opportunity is identification and cryopreservation of rare ejaculated or surgically retrieved sperm—not restoration of the missing developmental transcription program.
• Stages: a formal SPGF32 staging system does not exist. Phenotypic severity can be described as abnormal morphology → oligoasthenoteratozoospermia → severe oligo-/cryptozoospermia → NOA/Sertoli-cell-only histology.

9. Inheritance and population

9.1 Inheritance

GenCC lists a strong SOHLH1–SPGF32 association and its submitted disease record labels the mode autosomal dominant. [106][32] Nevertheless, current variant-level evidence supports a more cautious entry:

Inheritance: unresolved/possibly semidominant or dosage-sensitive; autosomal-recessive loss of function is strongly plausible, while heterozygous c.346-1G>A may confer variably penetrant sperm abnormalities.

Reasons for caution include:

1. the original heterozygous NOA cases;
2. later heterozygous carriers with normal sperm concentration but abnormal morphology;
3. a homozygous patient with severe quantitative failure;
4. population homozygotes and a relatively high allele frequency;
5. ClinVar’s current conflicting classification. [107]

Penetrance is therefore incomplete or unknown, expressivity is clearly variable, and anticipation has not been reported. Germline mosaicism remains theoretically possible but unreported. No robust founder effect or carrier frequency has been established.

9.2 Epidemiology and demographics

The c.346-1G>A population frequency varies by ancestry and may be particularly high in Finns, arguing against a simple fully penetrant dominant model. [107]

10. Diagnostics

10.1 Clinical diagnostic workflow

1. Confirm azoospermia or quantify severe oligozoospermia with at least two semen analyses using WHO-standard methods and examination of the centrifuged pellet. EAU guidance defines NOA by no sperm after centrifugation and recommends confirmation in two consecutive samples. [85]
2. Differentiate NOA from obstruction using history, physical examination, semen volume and pH, testicular size, and serum FSH; AUA/ASRM recommends this initial combination. [77]
3. Hormonal assessment: FSH, LH and morning total testosterone; add prolactin/estradiol when indicated.
4. Scrotal examination and ultrasound to assess testicular volume, varicocele or masses; ultrasound is supportive, not diagnostic of SPGF32.
5. First-tier standard genetics for severe spermatogenic failure: karyotype and Y-chromosome AZF deletion testing according to sperm-count and guideline thresholds.
6. Sequence-based testing: use a validated NOA/severe-oligozoospermia panel or exome/genome analysis that includes SOHLH1 and other established spermatogenic-failure genes.
7. Confirm and phase variants by Sanger or equivalent testing and test parents/siblings where available.
8. Interpret c.346-1G>A cautiously, explicitly acknowledging ClinVar conflict and population homozygotes.
9. Testicular tissue evaluation should generally accompany therapeutic sperm retrieval rather than be performed solely as a diagnostic biopsy; AUA/ASRM advises against routine diagnostic biopsy to distinguish obstruction from NOA. [76]

10.2 Genetic testing modalities

10.3 Pathology and biomarkers

The characteristic reported pathology is Sertoli-cell-only seminiferous tubules with absent germ cells. Other possible SOHLH1-associated patterns include sharply reduced and disorganized germ-cell stages. There is no validated serum protein, metabolite or imaging biomarker specific to SPGF32.

10.4 Differential diagnosis

10.5 Screening

There is no newborn or population screening. Appropriate strategies are cascade testing of adult relatives, reproductive counseling, and carrier/partner testing when a likely causal familial allele is found. Because c.346-1G>A classification is contested, irreversible reproductive decisions should not rely on that allele without expert re-evaluation.

11. Outcome and prognosis

• Survival/life expectancy: no evidence of reduced survival or disease-specific mortality in humans.
• Primary morbidity: infertility and associated psychosocial burden.
• Endocrine health: canonical SPGF32 is primarily germ-cell failure; testosterone may be preserved, but all NOA patients require endocrine assessment.
• Natural recovery: unlikely for Sertoli-cell-only histology; no curative restoration of spermatogenesis is established.
• Residual sperm: genotype alone cannot reliably predict whether focal sperm production will permit retrieval.
• Prognostic biomarkers: testicular histology, testis volume, FSH and testosterone may inform general NOA counseling but do not reliably determine individual micro-TESE success; no SOHLH1-specific biomarker exists.
• Complications: emotional distress, repeated invasive procedures, and possible transmission of a pathogenic allele through ICSI.

Across heterogeneous NOA—not specifically SPGF32—systematic-review evidence suggests surgical sperm retrieval up to about 50% and live birth up to 28% after use of retrieved sperm. These aggregate rates should not be presented as a genotype-specific prognosis. [155]

12. Treatment

There is no approved drug, gene therapy, RNA therapy or cell therapy that restores SOHLH1 function. Management is reproductive rather than disease-modifying.

AUA/ASRM recommends microdissection TESE for men with NOA undergoing retrieval and permits fresh or cryopreserved sperm for ICSI. [83]

Patient-specific published outcomes

In the 2022 series, ICSI was attempted in one homozygous severe-oligozoospermia patient and two heterozygous teratozoospermia patients; pregnancies and successful deliveries were reported. In the homozygous case, 7/10 injected oocytes fertilized and transfer of a later 4AB embryo produced a healthy baby. These are uncontrolled individual outcomes, not a response rate. [62]

Experimental treatment status

No SPGF32-specific ClinicalTrials.gov intervention, gene therapy, ASO, siRNA, stem-cell transplantation or CRISPR trial was identified. Germline editing is not an acceptable clinical prevention or treatment strategy.

13. Prevention

Primary prevention

The inherited molecular lesion cannot be prevented by diet, vaccination or lifestyle. Avoiding unnecessary testicular heat, tobacco, anabolic steroids, gonadotoxic chemicals and radiation is reasonable for general fertility preservation but is not proven to prevent SPGF32.

Secondary prevention

• Early evaluation of men from affected families.
• Semen analysis after puberty when clinically appropriate.
• Cryopreservation if sperm are present.
• Cascade genetic testing after expert variant interpretation.
• Partner testing if a recessive pathogenic allele is confirmed.

Tertiary prevention

• Avoid prolonged empiric therapies that delay retrieval when residual spermatogenesis may decline.
• Offer fertility-preservation and ART counseling.
• Monitor endocrine and psychological health.
• Provide reproductive genetic counseling before ICSI.

Reproductive prevention options

For a well-established pathogenic familial genotype, options include natural conception with prenatal diagnosis, IVF with PGT-M, donor gametes or adoption. With c.346-1G>A, counseling must emphasize conflicting pathogenicity and unresolved heterozygous penetrance. No immunization, medication prophylaxis or public-health control program is applicable.

14. Other species and naturally occurring disease

No breed-associated OMIA disorder, cross-species transmission or zoonotic potential applies. This is a constitutional genetic disorder, not an infectious disease.

15. Model organisms

15.1 Mouse models

The 2023 mouse study’s abstract states:

“The Sohlh1 knockout mouse model… presents with… impaired spermatogenesis in males,” but extragonadal phenotyping also found “abnormal immune profiles… sex-specific alterations of metabolites, and behavior and cognition changes.”
— Rodríguez-Escribà et al., Biology of Reproduction, April 2023, PMID: 36723967 [16]

15.2 Model validity

Strengths

• Recapitulates germ-cell differentiation failure and infertility.
• Establishes temporal order from transcription-factor loss to spermatogonial arrest.
• Permits testicular histology, cell sorting, ChIP, transcriptomics and fertility studies.
• Demonstrates biologic plausibility for human splice-variant findings.

Limitations

• Complete knockout is not equivalent to partial-function c.346-1G>A.
• Human heterozygous penetrance is much less clear than mouse homozygous-null penetrance.
• Mouse spermatogenic timing and genetic background differ from humans.
• Human Sertoli-cell-only pathology and ICSI outcomes cannot be fully modeled.
• Reported systemic mouse phenotypes should not be entered as human SPGF32 manifestations without clinical corroboration.

Overall evidence assessment

The principal knowledge-base caution is therefore to retain SOHLH1 as the causal gene for MONDO:0020855, but not encode c.346-1G>A as an unquestionably fully penetrant dominant pathogenic allele. Its molecular effect is well supported; its clinical penetrance and mode of inheritance are not.

Reference Validation

Checked with linkml-reference-validator 0.3.0.

All extracted references resolved successfully.

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:

• MONDO:0020855 (4 mentions) - the report calls it "MONDO"; MONDO calls it spermatogenic failure 32

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:

• GO:0007126 (GO_0007126) (1 mention) - replaced by GO:0051321

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

• CL:0000019 (2 mentions) - the report calls it "Spermatozoon", "Spermatozoa"; CL calls it sperm, and lists "spermatozoid" among its other names
• UBERON:0001343 (1 mention) - the report calls it "Seminiferous tubule"; UBERON calls it seminiferous tubule of testis, and lists "seminiferous tubule" among its other names

Terms named inconsistently

The report gives these identifiers more than one name of its own:

• CL:0000019 - called "Spermatozoon", "Spermatozoa"
• CL:0000216 - called "Sertoli cell", "Sertoli cells"

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA, MGI.