Still working: I'm looking up PMIDs for the key papers on Europe PMC, then I'll write the report.

Spermatogenic Failure 68 (SPGF68; MONDO:0030721; OMIM:619805): CATSPERT-related globozoospermia

Reliability. The human evidence for this disease is a single reported patient. I verified the mouse biology from search-result abstracts and snippets. I could not open OMIM, GeneCards or PubMed directly, because the proxy refused those connections. Quotes below are paraphrases of search-result text, not verified abstract quotes. Before any quote goes into a snippet, run just fetch-reference and check it against the cache. I did not confirm the PMID for Oud et al. 2020. I did not verify MONDO, HGNC, HPO, GO or UBERON identifiers, so look each one up before binding it.

1. Disease information

SPGF68 is an autosomal recessive male infertility disorder. It is caused by a homozygous missense variant in CATSPERT, the gene whose older symbols are C2CD6 and ALS2CR11. The gene encodes CatSperτ (tau), an auxiliary subunit of the sperm CatSper calcium channel. OMIM's gene entry is *619776 (C2CD6) (OMIM). The phenotype entry is #619805.

• Phenotype: normal sperm count but globozoospermia. The sperm are round-headed and lack an acrosome. Some patients have a mix of acrosomeless sperm and sperm with a small or detached acrosome (acrosomal hypoplasia) (MalaCards, GeneCards).
• Evidence base: OMIM and the Disease Ontology rest this entry on one Moroccan man. The Disease Ontology notes only one patient as of 2024. A 2025 Tunisian globozoospermia study lists C2CD6 only as a candidate gene needing functional confirmation (Springer).
• Synonym: SPGF68. A related GeneCards disease label is "male infertility due to globozoospermia".
• Data source: this is aggregated disease-level information. It does not come from EHR data.
• Naming trap: the SPGF serial number does not say which gene is involved, and this gene is not one of the other CATSPER genes. CATSPER1 and CATSPER2 variants cause different entries, such as CATSPER1-related nonsyndromic male infertility and the deafness-infertility syndrome from a CATSPER2–STRC deletion. They are not SPGF68 (MedlinePlus). Also keep it apart from the CATSPERθ (CATSPERTHETA) work (PNAS 2023, PMID 37725640).

2. Etiology

• Cause: a homozygous germline variant in CATSPERT/C2CD6 (human genomic location 2q33.1).
• Genetic risk and protective factors, and gene–environment interaction: none reported.
• Environmental factors: none reported for this entry.

3. Phenotypes

The report rests on one patient, so there are no frequencies. HPO suggestions (look each up before binding):

• Onset and course: onset is adult, at the age of attempted conception. Severity is infertility. The disorder is not progressive. No syndromic features are reported.
• Quality of life: not reported.

4. Genetic and molecular information

• Gene: CATSPERT (HGNC lowercase form in the KB; look up the ID). Old symbols are C2CD6 and ALS2CR11.
• Variant: NM_001168221.2:c.338A>G, p.His113Arg (H113R). It is homozygous and missense. ClinVar variation ID 1345025 (ClinVar).
• Site and frequency: the histidine is conserved, in the C2 domain. The variant is absent from gnomAD.
• Discovery: exome sequencing of a globozoospermia cohort (Oud et al., Hum Reprod 2020; 35(1):240–252, OUP).
• Segregation: not reported.
• Origin: germline.
• Mechanism class: presumed loss of function. This is an inference from the mouse knockout, not demonstrated for H113R. No functional study of H113R is known to me.
• Modifier genes, epigenetic changes, chromosomal abnormalities: none reported.

5. Environmental information

None reported. There are no infectious agents and no lifestyle factors.

6. Mechanism and pathophysiology

Causal chain (steps 3 to 6 come from mouse data, and step 2 is inferred):

1. A homozygous CATSPERT c.338A>G (p.His113Arg) variant changes a conserved residue in the C2 domain of CatSperτ.
2. This presumably impairs CatSperτ function or stability. This is not demonstrated for H113R.
3. In mouse, CatSperτ is a membrane-associating C2-domain protein that reaches the flagellum on its own. It targets the CatSper channel into the quadrilinear Ca²⁺-signaling nanodomains of the sperm flagellar membrane. It is not needed for the channel to assemble (Hwang et al., Cell Rep 2022, PMID 34998468).
4. Without CatSperτ, the knockout sperm form a functional CatSper channel only at significantly reduced levels. The sperm conduct Ca²⁺ but fail to hyperactivate (bioRxiv). A separate preprint reports C2CD6 as essential for CatSper complex assembly (Yang et al., bioRxiv). The two groups differ on whether the channel assembles.
5. Failed hyperactivation leads to failed fertilization in vitro and in vivo, so the male is infertile.
6. The mouse knockouts have no reported acrosome defect, but the human patient has globozoospermia. This is an unresolved mismatch.

Terms to consider (verify before binding): - GO: sperm flagellum, cation channel complex, sperm hyperactivation, calcium ion transmembrane transport. - CL: spermatozoon, spermatid. - UBERON: testis, sperm flagellum principal piece. - CatSper is a principal piece protein complex.

Immune, metabolic and omics findings: none reported.

7. Anatomical structures affected

• Organ: testis (spermatogenesis and sperm morphology).
• Cells: spermatids and spermatozoa.
• Subcellular: acrosome, sperm head and flagellar membrane.
• Lateralization: not applicable.
• Other organs: none. No syndromic features are reported.

8. Temporal development

The disease is congenital as a genetic condition but is detected in adulthood, through male factor infertility. It is stable and lifelong. No remission is reported.

9. Inheritance and population

• Inheritance: autosomal recessive. The one patient was homozygous.
• Population: one Moroccan man. Consanguinity, founder effect, penetrance, expressivity, prevalence and carrier frequency are not reported.
• Sex and age: male only. Adults.

10. Diagnostics

• Semen analysis: normal sperm count with globozoospermia. Acrosomeless sperm can be confirmed by Papanicolaou staining or acrosome-marker staining, and by electron microscopy.
• Genetic testing: exome sequencing or a globozoospermia or male-infertility gene panel. Panel inclusion of CATSPERT varies, so check with the laboratory.
• Differential diagnosis: DPY19L2-related globozoospermia is the main genetic cause. Others include GGN and further candidate genes (Celse et al., Hum Genet 2021, PMID 33108537). Also exclude other CatSper-gene disorders.
• Functional tests: CatSper function can be assessed in patient sperm. One preprint argues that defective CatSper function is a frequent cause of unexplained infertility (medRxiv 2023), but it is not peer-reviewed.

11. Prognosis

Natural fertility is unlikely. Other health is not reported to be affected. Prognosis for conception depends on assisted reproduction, below.

12. Treatment

No treatment is specific to SPGF68. No clinical trials are known to me.

• Standard care for globozoospermia: intracytoplasmic sperm injection (ICSI), sometimes with assisted oocyte activation. For this gene there is no outcome data. For globozoospermia in general, ICSI results are often poor because of fertilization failure. Check the systematic review (Crafa et al., World J Mens Health 2023, PMID 36047070) before citing.
• Mouse rescue: OMIM's gene entry says sterility was transiently rescued with a calcium ionophore, starvation, or both. I did not verify this directly.
• Counseling: genetic counseling.
• NCIT terms: look up the terms for intracytoplasmic sperm injection and genetic counseling. The CLAUDE.md lists NCIT:C15240 for genetic counseling.

13. Prevention

• Prevention levels: primary and secondary prevention do not apply, since the disease is recessive and congenital.
• Screening: carrier screening is not established.
• Reproductive options: genetic counseling and family testing if the variant is known.

14. Other species and natural disease

No natural disease is documented. The mouse ortholog is Catspert (MGI:1920713 per search results; verify), with NCBI Taxon 10090 for mouse. OMIA coverage was not checked.

15. Model organisms

• Mouse knockouts: male C2cd6/Catspert knockout mice are sterile. They show defective hyperactivation and fail fertilization in vitro and in vivo. OMIM attributes this to two groups, Yang et al. and Hwang et al. (Cell Rep 2022, PMID 34998468; Yang et al. bioRxiv). I did not find a published journal version of the Yang paper.
• Evidence type: MODEL_ORGANISM.
• Fidelity: male infertility is reproduced. Globozoospermia (the human hallmark) was not described in the mouse results I saw. Suggest a HUMAN_MODEL_MISMATCH discussion, with PARTIALLY_RECAPITULATES.
• Related CatSper knockouts: Catsper1, Catsper2, Catsper3 and Catsper4 knockouts also cause infertility with impaired hyperactivation (PubMed 14657366; Biol Reprod 2007). Reviews: Hwang & Chung, Physiology 2023, PMID 36512352.

Gaps to resolve before curating

1. Fetch Oud et al. 2020, find its PMID, and quote the CATSPERT/C2CD6 patient description (genotype, semen findings, ICSI history).
2. Confirm the gene symbol and HGNC ID, and check whether OMIM #619805 now cites more patients.
3. Resolve why a human acrosome defect appears with a mouse hyperactivation defect, and look for any functional data on H113R.
4. Check the GeneReviews and ClinGen baselines. I did not search either, and I did not find a GeneReviews chapter.

Sources

• OMIM 619776 (C2CD6)
• MalaCards SPGF68
• GeneCards CATSPERT
• Oud et al., Hum Reprod 2020
• ClinVar 1345025
• Hwang et al., Cell Rep 2022
• Yang et al., bioRxiv 2021
• Celse et al., Hum Genet 2021
• Crafa et al., World J Mens Health 2023
• Hwang & Chung, Physiology 2023

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:

• HP:0034307 (1 mention) - the report calls it "Globozoospermia"; HP calls it Elevated left ventricular end-diastolic diameter

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: OMIM, MGI.