Spermatogenic Failure 41

1. Disease Information

• Overview. SPGF41 is an autosomal recessive form of male infertility caused by biallelic loss of function of CFAP70. It presents as oligo-astheno-teratozoospermia with multiple morphological abnormalities of the sperm flagella (MMAF). Affected men have no other reported symptoms. [Secondary: MGI/OMIM:618670, Disease Ontology DOID:0111912, MalaCards]
• Identifiers. MONDO:0032863. OMIM #618670, which two MGI pages agree on. One search result suggested OMIM:619515, but that came from a garbled page layout and is unresolved. DOID:0111912. The Disease Ontology lists it under "spermatogenic failure", which is_a "autosomal recessive disease".
• Synonyms. SPGF41; spermatogenic failure 41; CFAP70-related MMAF; male infertility due to CFAP70 deficiency.
• Source type. Aggregated, from case reports and small cohorts. These are not EHR-derived.
• Suggested classification. DISEASE (a gene-defined Mendelian entry). It is a candidate for the Spermatogenic_Failure / MMAF grouping, but check existing groupings first.

2. Etiology

• Causal factor. Biallelic loss-of-function variants in CFAP70 (10q22.2), which encodes an axonemal protein.
• Risk and protective factors. None known beyond genotype. No modifier genes, environmental risk factors, protective variants or gene-environment interactions are reported in what I retrieved.

3. Phenotypes

All items below come from the 2019 and 2023 human reports and the OMIM mirrors. Frequencies are not available. Both 2019 patients and the 2023 patient had the core features, and none had extra-genital findings.

• Onset and course. Lifelong, with presentation at the time of attempted conception. Course is stable. No source gave quality-of-life data.
• Not reported. No primary ciliary dyskinesia features (respiratory disease, situs inversus) in the retrieved sources. I did not search specifically for them, so treat "absent" as unconfirmed.

4. Genetic / Molecular Information

• Gene. CFAP70 (cilia- and flagella-associated protein 70), 10q22.2. Look up the HGNC ID with runoak before writing it; the repo uses lowercase hgnc:.
• Reported variants.
• Beurois et al. 2019 (PMID:31621862): two unrelated men from a 167-man MMAF exome cohort. Patient 1 had homozygous c.1723-1G>T, a splice-acceptor change at exon 16. Patient 2 had homozygous p.Phe60Ile in exon 3, a missense variant judged likely deleterious.
• Jin et al. 2023 (PMID:37352829): one Chinese man with homozygous nonsense c.2962C>T, p.R988X.
• Mechanism class. Loss of function. This is supported by the nonsense and splice variants and by the knockout mice.
• Gene–disease validity. I did not check ClinGen or GenCC. Check cache/clingen and just check-gene-validity before recording a tier. Do not assign one yourself.
• Not found. Allele frequencies, epigenetic data, chromosomal abnormalities and modifier genes.

5. Environmental Information

None identified. There are no infectious agents. No lifestyle or toxicant data were retrieved. Do not add environmental: entries from this report.

6. Mechanism / Pathophysiology

Causal chain (steps 1 to 3 are demonstrated in humans; steps 4 to 6 rest mainly on the mouse and Chlamydomonas work; the last step is inferred):

1. Biallelic loss-of-function variants (splice, nonsense, missense) in CFAP70 reduce or abolish CFAP70 protein. Demonstrated by immunofluorescence in the splice-variant patient, where CFAP70 was absent from the flagellum.
2. CFAP70 is lost from the sperm axoneme. In the 2019 report, outer-dynein-arm and central-pair markers were also absent from the same patient's sperm, so loss of CFAP70 co-occurs with loss of those structures. Whether this is cause or consequence is not settled.
3. CFAP70 normally sits at the base of the outer dynein arm and binds the axoneme (PMID:30158508; in Chlamydomonas it is placed at the C2a central-apparatus projection, PMID:33988244). It interacts with the outer-dynein-arm components DNAI1 and DNAI2 (PMID:37458246).
4. Without it, flagellum biogenesis and assembly fail during spermiogenesis, with reduced AKAP3 in the flagella (mouse, PMID:37458246). This leads to MMAF and loss of motility.
5. Spermiogenesis is also disturbed upstream of the flagellum. Cfap70-null mouse late spermatids have club-shaped heads and abnormal manchette disassembly (PMID:37458246), and sperm counts fall, which fits the oligozoospermia (PMID:37352829).

6. Result: severe asthenozoospermia, teratozoospermia and oligozoospermia, and male infertility. The branch between flagellar and head or manchette defects is shown in mice, and it is inferred that humans share it.

7. Suggested GO / CL / UBERON (verify each by lookup): GO sperm flagellum assembly / axonemal dynein complex assembly / cilium movement; CL spermatid (CL:0000018); UBERON testis (UBERON:0000473), epididymis semen/sperm flagellum as relevant. Do not write these IDs without a lookup.

8. Omics, immune, metabolic. None reported.

7. Anatomical Structures Affected

• Testis, specifically the post-meiotic germ cells (spermatids and spermatozoa).
• Subcellular: the sperm flagellar axoneme, the outer dynein arm and central apparatus, and the manchette.
• No other organs reported. Bilateral, as expected for a systemic germline genotype.

8. Temporal Development

Onset is lifelong, from puberty, and is detected in adulthood on infertility work-up. The course is non-progressive from the information available. No remission patterns are known.

9. Inheritance and Population

• Inheritance. Autosomal recessive (HP:0000007). Reported cases are homozygous, and OMIM also describes compound heterozygotes.
• Consanguinity. Homozygosity in unrelated patients suggests it may matter, but I did not retrieve the parental data.
• Epidemiology. Not available. There is no prevalence figure. Cases are described as rare, and the 2019 yield was 2 of 167 MMAF men (about 1%).
• Population. Cases came from a mainly North African/European MMAF cohort (2019) and a Chinese man (2023). Founder effects are not established.
• Sex. Male only in terms of phenotype, since the phenotype is infertility of spermatogenic origin.

10. Diagnostics

• Semen analysis. Oligo-astheno-teratozoospermia with MMAF morphology, scored on sperm morphology.
• Genetic testing. Exome sequencing (it identified both 2019 cases), or a male infertility or MMAF gene panel that includes CFAP70. Biallelic variants confirm the diagnosis.
• Supportive. Immunofluorescence for CFAP70 and outer dynein arm markers on sperm. Electron microscopy of the axoneme was not confirmed in what I retrieved.
• Differential. Other MMAF genes (DNAH1, CFAP43, CFAP44, WDR66, ARMC2, FSIP2), which are other SPGF entries, and primary ciliary dyskinesia. Note that in the 2019 report, WDR66-mutated patients' sperm also lacked CFAP70 staining, while ARMC2, FSIP2 and CFAP43 mutants retained it.
• Screening. None established.

11. Outcome / Prognosis

No mortality or morbidity data. Reported patients have no symptoms besides sterility. Prognosis for natural fertility is poor. Prognosis for assisted reproduction is described as better than for natural conception. Per the 2023 report, ICSI may help affected couples, though that is a suggestion and I found no outcome series for CFAP70 specifically.

12. Treatment

• No disease-modifying therapy. The only measure indicated is assisted reproduction, namely ICSI with the patient's own sperm. Suggested NCIT: NCIT:C15986 is wrong here, because it is pharmacotherapy. Look up an ICSI or assisted-reproduction term (candidate: intracytoplasmic sperm injection) and bind only if one verifies. Otherwise leave term: off and use a free-text preferred_term.
• Genetic counselling. NCIT:C15240, which the repo lists.
• Trials. I did not search ClinicalTrials.gov. None known.
• Pharmacogenomics, gene therapy. None.

13. Prevention

There is no primary prevention. Carrier screening and genetic counselling for relatives are appropriate in principle, since this is autosomal recessive. Preimplantation genetic testing is possible after a diagnosis, though I found no literature specific to CFAP70. A transmissible risk is unlikely to apply to the offspring phenotype, so counselling needs a clear statement of carrier status.

14. Other Species / Natural Disease

I did not search OMIA. A GWAS in Holstein cattle listed CFAP70 as a candidate for sire fertility traits (PMID:35484513). That is association only, and it is not a naturally occurring Mendelian disease. A hybrid yellow catfish study reported lower CFAP70 expression in sterile hybrids (PMID:38891632); that is a correlation in a different context.

15. Model Organisms

• Mouse knockout (Cfap70-/-). Two independent reports.
• Jin et al. 2023 (PMID:37352829): sterile, mainly from oligo-astheno-teratozoospermia. A truncating mouse allele modelled the patient's R988X change and reproduced his features, which is the strongest model-to-human link in the set.
• Biol Reprod 2023 (PMID:37458246): MMAF, club-shaped heads, abnormal manchette disassembly, and reduced AKAP3.
• Fidelity. Good for the reproductive phenotype. A limitation is that mice show head and manchette defects, which are less prominent in the human reports I retrieved.
• Other systems. Chlamydomonas FAP70 mutants show impaired outer dynein arm activity and flagellar motility (PMID:30158508), and the central-apparatus placement is in PMID:33988244. Mouse cell knockdown reduced ciliary beating (PMID:30158508). Evidence source for the mouse and Chlamydomonas items is MODEL_ORGANISM; the cell data are IN_VITRO.
• Resources not checked. MGI, IMPC and ZFIN allele pages, beyond the MGI disease-association page above.

Curation Notes for the KB Entry

1. Decision. Record entry_type: DISEASE. Delete the stub in the curation PR, add a history/disorders/Spermatogenic_Failure_41/ record, and put the claim on a claim-labelled issue titled Curate spermatogenic failure 41 (MONDO:0032863).
2. Evidence work still needed. Run just fetch-reference for PMIDs 31621862, 37352829, 37458246, 30158508 and 33988244. Re-read each abstract and copy exact snippets. Quote the OMIM text from a cached source if one exists, since I could not access OMIM.
3. Terms to look up, not trust. Every HPO, GO, CL, UBERON and NCIT ID above is a suggestion that I did not verify. The HGNC ID for CFAP70 was not looked up.
4. Loose ends. Resolve the OMIM:618670 versus 619515 ambiguity. Check ClinGen for a CFAP70 gene-disease validity assertion. Search for a GeneReviews chapter with just check-genereviews. Search for additional CFAP70 case reports after 2023. The latest PubMed hits listed in my search (PMIDs 38891632 through 42417609) were not individually screened.
5. Lump/split. One gene, one phenotype, so keep it as a single entry. Compare it against the existing MMAF-gene SPGF entries for possible grouping membership.

Sources

• MGI disease page for OMIM:618670
• Disease Ontology DOID:0111912
• MalaCards: Spermatogenic Failure 41
• eBioMedicine 2023, CFAP70 diagnostic target (PMID:37352829)
• PubMed: Beurois et al., Hum Reprod 2019 (PMID:31621862)
• PubMed: Biol Reprod 2023, Cfap70 mouse (PMID:37458246)
• PubMed: Cells 2018, CFAP70 axoneme-binding (PMID:30158508)
• PubMed: J Cell Sci 2021, FAP70 C2a (PMID:33988244)

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:0012206 (1 mention) - the report calls it "Asthenozoospermia"; HP calls it Abnormal sperm motility
• HP:0012864 (1 mention) - the report calls it "multiple flagellar abnormalities"; HP calls it Abnormal sperm morphology

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.