Research Report: Spermatogenic Failure 51 (SPGF51; CFAP91/MAATS1-related MMAF)

Evidence base. I could check only a few sources: search snippets, the Disease Ontology entry as reported by a search, and MalaCards. The OMIM page returned 403 and the JMG full text returned 429. The report rests on one primary human study, one mouse knockout paper, and one Tetrahymena paper. Items marked [unverified] come from my background knowledge or from a search summary that I did not confirm against the source. I have no exact abstract quotes to offer. Before they are used as evidence snippets, quotes must be pulled with just fetch-reference.

1. Disease information

• Overview: SPGF51 is an autosomal recessive form of male infertility. It is a severe asthenoteratozoospermia of the "multiple morphological abnormalities of the sperm flagella" (MMAF) type. Flagellar defects reduce or abolish sperm motility. The causal gene is CFAP91 (alias MAATS1) at 3q13.33.
• Identifiers:
• OMIM #619177, per an MGI listing returned by search. I did not confirm it on OMIM.
• Disease Ontology DOID:0112273, with parents DOID:0050737 and DOID:0111910.
• MONDO:0030926, as given in the template. A search suggested this is SPGF51, but the mapping was not confirmed. Check it in the MONDO browser.
• Orphanet, ICD and MeSH identifiers were not retrieved. MalaCards lists a "Spermatogenic Failure 51 (SPGF51)" card.
• Synonyms: SPGF51; CFAP91-related asthenoteratozoospermia; MAATS1-related MMAF.
• Data origin: Disease-level, from research exome cohorts and OMIM/DO curation. It is not derived from EHR data.

2. Etiology

• Cause: Biallelic (homozygous or compound heterozygous) loss-of-function variants in CFAP91.
• Genetic risk factors: None known beyond the causal gene.
• Environmental risk factors, protective factors and gene-environment interactions: None documented in the sources I found.

3. Phenotypes

All data are from Martinez et al. 2020, J Med Genet 57(10):708 (PMID:32161152, per a bvsalud record). The study identified six unrelated men from a cohort of 167 MMAF cases.

• Onset and course: Not reported beyond manifesting at adult reproductive age. It is presumably stable. [unverified]
• Quality of life: No data. Impact is presumably limited to fertility. [unverified]
• Syndromic features: I found none. CFAP91 variants have not been tied to respiratory ciliary disease in the retrieved sources. I did not check this directly.
• Frequency: Six of 167 MMAF cases, about 3.6%. The cohort was pre-selected for MMAF.

4. Genetic and molecular information

• Gene: CFAP91 (MAATS1), 3q13.33. I did not retrieve the HGNC ID. Look it up in HGNC and use the lowercase hgnc: form.
• Variants: Homozygous deleterious variants, described as loss-of-function (the retrieved summaries did not list the specific variants). Specific variants, ClinVar classifications and gnomAD frequencies were not retrieved.
• Origin: Germline.
• Modifier genes, epigenetics and chromosomal abnormalities: None reported.
• Gene-disease validity: I did not check ClinGen or GenCC. Do not assign a tier without copying one from a source (CGGV:).

5. Environmental information

None known. No infectious agent applies.

6. Mechanism and pathophysiology

Causal chain: 1. Biallelic loss-of-function variants in CFAP91 remove the protein (shown by patient sperm immunostaining). 2. CFAP91 is a calmodulin- and spoke-associated complex (CSC) protein, and it forms a physical and functional partner pair with WDR66. Loss of CFAP91 disrupts CSC and radial spoke assembly. This was shown in humans and in Tetrahymena. 3. In mouse, CFAP91 scaffolds assembly of radial spoke 3 (RS3). Without it, the RS3 proteins CFAP251 and LRRC23 are mislocalized in sperm flagella. 4. Patient sperm show severe central pair complex (CPC) and radial spoke defects by electron microscopy. 5. The axoneme is structurally disorganized, so flagella are absent, short, bent or coiled, and sperm are immotile. This is inferred from the structural findings. 6. Immotile, morphologically abnormal sperm cannot achieve fertilization, which causes male infertility.

Evidence by system: - Human: Six patients, with patient sperm EM and immunostaining. WDR66 was confirmed as a partner. - Trypanosoma brucei: Knockdown of TbCFAP91 impaired flagellar movement and produced CPC defects, as in humans. - Tetrahymena (2022): CFAP91 sits at the base of RS2 and RS3. Knockout impairs RS3 docking and adjacent inner dynein arm assembly, and cilia beat in an uncoordinated manner at greatly reduced frequency. I did not retrieve the PMID. - Mouse (2025): Cfap91 knockout (Nat Commun 16:8238, PMC12423330) causes impaired sperm flagellum formation and male infertility. Proximity labeling identified EFCAB5, and Efcab5 knockout males show reduced sperm motility and fertility.

Suggested terms: - GO: axoneme assembly (GO:0035082), sperm flagellum assembly, cilium movement. I did not verify these IDs. - GO cellular component: motile cilium / sperm flagellum axoneme. - CL: spermatid (CL:0000018), sperm (CL:0000019). I did not verify these IDs.

No omics findings were retrieved.

7. Anatomical structures affected

• Organ and tissue: Testis and seminiferous epithelium, where spermiogenesis occurs.
• Cells: Late spermatids and spermatozoa.
• Subcellular: The sperm flagellar axoneme, including the central pair complex and radial spokes.
• Lateralization: Bilateral, as expected for a germline disorder.
• Other systems: None reported.

8. Temporal development

• Onset: Manifests at adult reproductive age, when infertility is evaluated.
• Course: Presumably stable. Natural history data are not available.

9. Inheritance and population

• Inheritance: Autosomal recessive (HP:0000007), from the DO and MalaCards entries.
• Consanguinity, founder effects and population distribution: Not retrieved. Consanguinity is common in MMAF cohorts generally, but I did not confirm it for these six patients. I assume the condition is rare.
• Sex: Male-limited phenotype.
• Prevalence and carrier frequency: Not available. Derive carrier frequency from gnomAD only if a source states it.

10. Diagnostics

• Semen analysis: Severe asthenozoospermia with MMAF morphology.
• Electron microscopy of sperm: Shows the CPC and radial spoke defects.
• Immunostaining: CFAP91 and partners such as WDR66, in patient sperm.
• Genetic testing: Exome sequencing or an MMAF/male infertility gene panel including CFAP91. Confirm panel inclusion in GTR.
• Differential: Other MMAF genes, such as DNAH1, CFAP43, CFAP44, CFAP69, AK7 and WDR66, and primary ciliary dyskinesia. I did not check GeneReviews for a chapter.

11. Prognosis

Natural conception is not expected. Life expectancy is not reported as affected, and I found no mortality data.

12. Treatment

• Established treatment: None specific.
• ICSI: Intracytoplasmic sperm injection is the usual option for MMAF. Outcomes for CFAP91 patients are not in the retrieved sources.
• Experimental: I found no trials, gene therapy or drug options.
• Suggested NCIT: Intracytoplasmic Sperm Injection and Assisted Reproductive Technology terms. Look the CURIEs up with runoak; I have not looked them up.

13. Prevention

• Genetic counseling: Autosomal recessive risk. Carrier testing of partners and relatives is possible.
• Other prevention: No primary or environmental measures are known.
• Prenatal and preimplantation testing: An option once variants are identified. Offspring of an affected man who has ICSI are obligate carriers.

14. Other species and natural disease

• Orthologs: Mouse Cfap91 (ENSMUSG00000022805); Tetrahymena CFAP91; Trypanosoma TbCFAP91.
• Natural disease in animals: I found nothing in OMIA and did not search it.

15. Model organisms

• Fidelity: The mouse recapitulates the male infertility and flagellar defect. I did not retrieve whether it also has non-sperm ciliary phenotypes.
• Resources: MGI, IMPC and Alliance of Genome Resources entries were not checked.

Key sources

• Martinez et al., J Med Genet 2020 (MAATS1/CFAP91)
• JMG blog summary
• BVS record, PMID 32161152
• Proximity labeling of CFAP91 identifies EFCAB5 (Nat Commun 2025, PMC12423330)
• MalaCards: Spermatogenic Failure 51

Gaps to close before curation

1. Confirm OMIM #619177, MONDO:0030926 and the HGNC ID for CFAP91.
2. Get the exact variants and ClinVar classifications.
3. Find any additional patient reports and ICSI outcomes.
4. Fetch the Martinez 2020 abstract and the Tetrahymena paper with just fetch-reference, and take snippets from the cache.
5. Check ClinGen, GeneReviews and GenCC for a validity tier.

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:0012870 (1 mention) - the report calls it "Abnormal sperm flagella morphology"; HP calls it Vanishing testis

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:

• HP:0012864 (1 mention) - the report calls it "Teratozoospermia"; HP calls it Abnormal sperm morphology, and lists "Teratozoospermia" among its other names
• GO:0035082 (1 mention) - the report calls it "GO: axoneme assembly"; GO calls it axoneme assembly
• CL:0000018 (1 mention) - the report calls it "CL: spermatid"; CL calls it spermatid