Spermatogenic Failure 33

1. Disease Information

Overview. SPGF33 is an autosomal recessive form of male infertility. It is caused by biallelic loss-of-function variants in CFAP251, formerly called WDR66. The defining finding is multiple morphological abnormalities of the sperm flagella (MMAF), which leave the spermatozoa immotile.

Identifiers - MONDO:0029147 - OMIM 618152 - MedGen C4748395

The identifiers come from MalaCards/LOVD, MedGen and MGI. - I did not verify Orphanet, ICD-10/11 or MeSH identifiers. They are unconfirmed here.

Synonyms: SPGF33; spermatogenic failure, type 33 (SPGF-33).

Gene naming. One search summary flagged a "gene conflict" between WDR66 and CFAP251. This is not a real conflict. They are the same gene under old and new HGNC symbols. Curators must bind by HGNC ID and confirm the current symbol, because the KB checks label and CURIE only for self-consistency.

Data source. The entry is disease-level and aggregated, drawn from case series. It is not derived from EHR data.

Parent term. The disease sits under the broader "spermatogenic failure" concept (MedGen).

2. Etiology

• Causal factor: biallelic loss of function of CFAP251 (12q24.31).
• Genetic risk factors: none beyond the recessive causal variants. I found no modifier genes.
• Environmental risk factors, protective factors and gene-environment interactions: none identified in what I retrieved.

3. Phenotypes

All items are from male patients with MMAF. Frequencies are not quantified in the sources I retrieved.

The HPO IDs in this table are unverified suggestions. I did not look any of them up. Per the CLAUDE.md rule, none may be bound until a lookup (OAK or cache/hp/terms.csv) confirms the CURIE and label.

• Onset: adult presentation, usually when a couple seeks fertility evaluation. This is inferred, not sourced.
• Quality of life: no data retrieved.
• Extra-gonadal features: none were reported in the sources I saw. Whether CFAP251 loss affects motile cilia elsewhere in humans is unresolved here. A 2026 paper title suggests ciliary defects in humans and mice (PMID:41943837), but I only saw the title.

4. Genetic / Molecular Information

• Gene: CFAP251 (WDR66), 12q24.31. HGNC ID not looked up. The KB uses the lowercase hgnc: form.
• Inheritance: autosomal recessive.
• Mechanism class: loss of function.

Reported variants

• Variant origin: germline.
• Allele frequency: the Li 2019 summary described the variants as extremely rare or absent in population databases. I did not query gnomAD.
• Chromosomal and epigenetic information: none retrieved.

5. Environmental Information

Not covered. I found no environmental, lifestyle or infectious contributors, and I did not search for them.

6. Mechanism / Pathophysiology

Causal chain

1. Biallelic loss-of-function variants (SVA-mediated exon deletion, frameshift, nonsense or splice variants) in CFAP251 abolish or truncate the protein. This is demonstrated by genetics. Reduced protein in a patient's sperm was shown by Western blot and immunofluorescence (PMID:35087568).
2. CFAP251 is an axonemal protein, described in the Auguste title as associated with calmodulin and the radial-spoke complex. Its loss disrupts axoneme assembly or stability in the developing sperm tail. The mechanism here is partly inferred.
3. Disrupted axoneme assembly produces the MMAF flagellar phenotype: short, absent, coiled and irregular tails.
4. Transmission electron microscopy suggested that CFAP251 loss affects mitochondrial sheath formation. Auguste's title describes the spermatozoa as "lacking mitochondria", but I only saw a summary. This step is from a small family series.
5. The abnormal flagella give immotile spermatozoa and male infertility.

Orthologue evidence - Kherraf 2018 localized the Trypanosoma brucei ortholog to the axoneme. Reproducing the human deletion there impaired flagellar movement. This is in vitro/model-organism evidence in a protist. - Auguste 2018 used a Tetrahymena ortholog to show a role in coordinated ciliary beating.

Suggested terms. These are leads only and none has been looked up. - GO terms for axoneme assembly, sperm flagellum assembly and motile cilium assembly. - CL spermatid, plus the UBERON/GO components flagellum and axoneme.

Not covered: omics, single-cell and functional-genomics findings. I did not search for them.

7. Anatomical Structures Affected

• Primary: testis, with the seminiferous epithelium and the developing spermatid flagellum. The sperm tail and mitochondrial sheath are the structures involved.
• Localization: bilateral, because the cause is systemic germline. This is inferred.
• Secondary organs: none documented in the sources I saw. See the caveat on cilia in Section 3.

8. Temporal Development

Adult-onset recognition at fertility evaluation. The condition is non-progressive and lifelong, since it is structural and genetic. Both statements are inferred and not directly sourced.

9. Inheritance and Population

• Inheritance: autosomal recessive.
• Prevalence: not retrieved. Penetrance and expressivity are not characterized in what I saw.
• Frequency among MMAF cohorts: about 9% (7 of 78) in the Kherraf cohort and about 5% (3 of 65) in the Li Han Chinese cohort.
• Founder effect: Kherraf describes the SVA-mediated deletion as "ancestral". The seven men carried the same deletion type, which is consistent with a founder allele. I did not retrieve population details, so confirm before asserting one. Kherraf's cohort included North African patients. This is from the author list and the Tunisian clinical centres, not from a stated cohort description.
• Consanguinity: not described in the sources I saw. The Wang 2022 case was nonconsanguineous.
• Sex ratio: affects males only. Female carriers are presumed unaffected, though I did not verify this.

10. Diagnostics

• Semen analysis shows immotile spermatozoa and MMAF morphology. Count and morphology details were not retrieved.
• Genetic testing: whole-exome sequencing identified the variants in all the cited studies. Note that Kherraf's deletion is a structural variant, so copy-number-aware analysis is needed, and a standard SNV/indel pipeline may miss it. This is an inference from the mechanism.
• Electron microscopy and immunofluorescence can show the axonemal and mitochondrial sheath defects.
• Differential diagnosis: other MMAF genes such as DNAH1, CFAP43, CFAP44 and CFAP69. These are from general knowledge and were not verified. A review of spermatogenic failure genetics is at PMID:30656449.

11. Outcome / Prognosis

No survival or life-expectancy effect is expected. The disease is confined to fertility, as far as the retrieved sources show. Reproductive prognosis is addressed in Section 12.

12. Treatment

• No curative treatment is documented.
• Assisted reproduction: intracytoplasmic sperm injection (ICSI) is the reported route. Wang 2022 reports a successful pregnancy after ICSI in a man with a CFAP251 splice variant (PMID:35087568).
• A 2026 case report describes sperm selection by hypo-osmotic swelling before ICSI in two men with flagellar defects, one involving CFAP251 (PMID:42871648). I saw only the title.
• Suggested NCIT term: an assisted-reproduction or ICSI term. None has been looked up. Per the CLAUDE.md rules, search for it and omit the binding if none is suitable.
• Pharmacotherapy, gene therapy and clinical trials: none found. I did not search ClinicalTrials.gov.
• The Wang 2022 pregnancy is a single case. Overall ICSI success rates in CFAP251 MMAF are unknown here.

13. Prevention

Not covered, apart from genetic counseling for recurrence risk. The inheritance is autosomal recessive, so a carrier couple has a 25% risk per pregnancy. A male child of two carriers would be affected. I did not search for guidelines.

14. Other Species / Natural Disease

Not covered. I did not check OMIA, so I make no claim about naturally occurring disease in other species.

15. Model Organisms

• Protists: T. brucei ortholog (axonemal localization, motility impairment with the human deletion) and Tetrahymena ortholog (coordinated ciliary beating). See Section 6.
• Mouse: I found no mouse knockout data for Cfap251/Wdr66. The searches did not turn up any. A 2026 paper title mentions "humans and mice" (PMID:41943837), which may include a mouse model. Check this paper directly, along with MGI and IMPC.
• Model limitations: protist models carry the axoneme but not mammalian spermiogenesis or the mitochondrial sheath. This is a likely HUMAN_MODEL_MISMATCH or KNOWLEDGE_GAP candidate until a mouse model is confirmed.

Curation Notes and Open Items

1. Retracted papers. The WDR66 literature includes cancer papers unrelated to SPGF33. PMID:29717028 is retracted (PMID:36861483) and has an expression of concern (PMID:33870408). Do not cite any of them for this disease.
2. Verify before binding: all HPO, GO, CL, UBERON and NCIT suggestions above, the HGNC ID for CFAP251, and the Orphanet, ICD and MeSH identifiers.
3. Exact snippets: none are given. Fetch the references for PMIDs 30122540, 30122541, 30310178 and 35087568, and copy quotes from the cached text.
4. Evidence source: the case series are HUMAN_CLINICAL. The T. brucei and Tetrahymena results are MODEL_ORGANISM, and the CFAP251 localization is IN_VITRO or MODEL_ORGANISM, depending on how the paper is graded.
5. Gaps to close: a mouse model, ICSI success rates, the HPO frequency of each phenotype, and the Orphanet and GeneReviews status (use just check-genereviews).

Sources

• LOVD disease record 05565 (SPGF33, OMIM:618152)
• MedGen C4748395 (mirror)
• MGI disease page OMIM:618152
• Kherraf et al. 2018, Am J Hum Genet, PMID:30122540
• Auguste et al. 2018, Am J Hum Genet, PMID:30122541
• Li et al. 2019, J Hum Genet, PMID:30310178
• Wang et al. 2022, Front Genet, PMID:35087568
• Review of spermatogenic failure genetics, PMID:30656449
• 2026 papers seen by title only: PMID:41943837, PMID:42871648

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:0012864 (1 mention) - the report calls it "? verify"; 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.