Spermatogenic Failure 40

1. Disease Information

Overview. SPGF40 is an autosomal recessive male infertility disorder caused by biallelic variants in CFAP65 (2q35). It is a sperm-specific flagellar disorder, classically "multiple morphological abnormalities of the sperm flagella" (MMAF). Sperm tails are absent, short, bent, coiled or of irregular caliber, so sperm motility is severely reduced or absent. Some patients also have sperm-head defects, including acrosomal hypoplasia or aplasia. Sources: MalaCards and MedGen mirror.

• Synonyms. SPGF40; spermatogenic failure 40; CFAP65-related MMAF or asthenoteratozoospermia (informal).
• Data type. The knowledge is aggregated from case series and families, not from EHR data.
• Gene-disease validity. One aggregator lists "Limited" with AR inheritance. I did not confirm whether this is ClinGen, GenCC or another source, so do not record it as a ClinGen tier without checking the CGGV: record. Evidence has grown since the original 2019 reports, so a re-curated tier may differ.
• Related disorders. Other MMAF genes (CFAP43, CFAP44, CFAP61, CFAP69, DNAH1, ARMC2, CFAP58, TTC29) are separate OMIM spermatogenic failure entries (Tang 2017, PMID:28552195; Coutton 2019, PMID:30686508).

2. Etiology

• Causal factor. Biallelic loss-of-function variants in CFAP65 are the only established cause.
• Genetic risk and modifiers. None are described.
• Environmental risk, protective factors and gene-environment interactions. No evidence found; the relevant cohort papers did not report any.
• Heterogeneity. In the Chinese cohort reported by Li et al., biallelic CFAP-gene variants explained 15 of 80 MMAF cases (19%). Of these, 4 were in CFAP65, 7 in CFAP43, 2 in CFAP44 and 2 in CFAP69. This figure came from a search snippet and should be checked against the source.

3. Phenotypes

All phenotypes are male-specific unless stated.

Respiratory features are inconsistent across reports (summarized in Table 2 of the 2026 paper, PMC13383139): - Several compound heterozygotes had chronic cough, sinusitis or pneumonia (for example c.5341G>T, p.E1781X). - One patient with c.5341G>T plus c.1775_1776del had PCD-like features, nasosinusitis and tympanitis. - p.W892X and the 2026 frameshift were isolated MMAF with no PCD symptoms. - Whether the respiratory findings are caused by CFAP65 or are incidental is unresolved.

Characteristics. - Onset is at reproductive age, when infertility is detected. - The condition is stable, with no progression reported. - No quality-of-life data were found.

4. Genetic/Molecular Information

• Gene. CFAP65, NM_194302.3, 35 exons, encoding a 1,925-amino-acid protein with an ASH domain, an MSP domain, a transmembrane helix (aa 187–209) and a coiled-coil region (PMC13383139). The HGNC ID was not retrieved; look it up, and use lowercase hgnc: in this repository.
• Reported variants. The list below is from Table 2 of the 2026 paper, so check each against its original paper.
• c.5341G>T (p.E1781X)
• c.2284C>T (p.R762X) with c.1751delC (p.P584fs)
• c.3021C>A (p.N1007K) with c.5714_5721del (p.L1905fs)
• c.1775_1776del (p.P527Rfs*74)
• c.2675G>A (p.W892X)
• c.582_587delinsCG (p.Q194Hfs*4); homozygous; first cousins; absent from gnomAD and 1000 Genomes; "likely pathogenic" by the authors' tools.
• Types. Predominantly nonsense, frameshift and splice variants, with a few missense (p.N1007K). The mechanism is presumed loss of function.
• Somatic vs germline. Germline.
• Modifier genes, epigenetics and chromosomal abnormalities. None reported.
• Allele frequency. Not retrieved apart from the absence of the 2026 variant from gnomAD.

Key primary papers (all human unless noted): 1. Wang W et al. 2019, J Med Genet, PMID:31413122. Whole-exome sequencing of 47 men with severe asthenozoospermia found CFAP65 variants in three. EM and immunostaining showed acrosome hypoplasia, mitochondrial sheath disruption and missing central pairs. 2. Li W et al. 2020, J Med Genet, PMID:31501240. Of 88 MMAF men, six families carried biallelic CFAP65 variants. A Cfap65 frameshift mouse reproduced MMAF. 3. Zhang X et al. 2019, Clin Genet, PMID:31571197. A homozygous nonsense variant in one MMAF patient. 4. 2026, Basic Clin Androl, PMID:42477516. A Pakistani consanguineous family with the p.Q194Hfs*4 variant.

5. Environmental Information

No environmental, lifestyle or infectious contributors were identified.

6. Mechanism / Pathophysiology

Causal chain (steps 1 and 2 are demonstrated in patients and mouse; steps 3 to 5 are partly inferred): 1. Biallelic loss-of-function variants in CFAP65 lead to loss of functional CFAP65 protein. 2. Loss of CFAP65 leads to axonemal defects. The mouse model shows loss of the C2a projection of the central apparatus (per the 2025 Cell Mol Life Sci abstract and the 2026 paper's citation of it); in patients, EM shows missing central pair or doublet microtubules and a disorganized fibrous sheath or outer dense fibers. 3. Axonemal disorganization results in short, absent, bent and coiled flagella (MMAF), which leads to severely impaired or absent sperm motility. This step is inferred rather than shown directly. 4. In a subset of patients, defective acrosome biogenesis causes head abnormalities. The knockout-mouse abstract also mentions manchette defects. The mechanism is not established, and CFAP65 localization (acrosome, midpiece or whole flagellum) is reported inconsistently across studies. 5. Sperm that cannot swim cannot reach or fertilize the oocyte, which results in male infertility.

Branch: motile cilia. The mouse data show hydrocephalus (ependymal cilia) but no significant respiratory cilia impairment. The human respiratory findings are inconsistent, so involvement of other motile cilia is unresolved.

Suggested terms (verify before binding): - GO: sperm flagellum assembly, axoneme assembly, acrosome assembly, cilium movement (GO:0003341 or similar). - CL: spermatid (CL:0000018), sperm (CL:0000019). - GO CC: sperm flagellum, axoneme, motile cilium.

Molecular profiling, single-cell, spatial and multi-omics data. None found. Expression is reported in the 2025 paper only in the context of localization, so I cannot cite it.

7. Anatomical Structures Affected

• Organs. Testis (spermatogenesis, spermiogenesis); sperm.
• Cells. Elongating spermatids and spermatozoa.
• Subcellular. Sperm flagellum axoneme (central pair, C2a projection, doublet microtubules), fibrous sheath, outer dense fibers, mitochondrial sheath, acrosome.
• Lateralization. Bilateral; this is a systemic germ-cell defect.
• Possible secondary involvement. Respiratory epithelium and ependyma, which are unproven in humans.

8. Temporal Development

Onset is at puberty or adulthood and is usually detected through a fertility evaluation. The course is lifelong and non-progressive. No remission is reported. No critical periods are described.

9. Inheritance and Population

• Inheritance. Autosomal recessive, with homozygous and compound heterozygous cases.
• Consanguinity. Present in the Pakistani family and in other homozygous cases.
• Sex. Affects males; female carriers are unaffected.
• Prevalence, incidence, carrier frequency, founder effects and geography. Not retrieved. Cases are reported from Chinese, Pakistani and North African cohorts, but this is not a systematic distribution. MMAF overall is rare.
• Penetrance, anticipation and germline mosaicism. Not reported.

10. Diagnostics

• Semen analysis. Asthenoteratozoospermia with MMAF morphology; sperm concentration can be normal.
• EM of sperm. Axonemal disorganization, missing central pair or doublets, and fibrous sheath disorganization.
• Genetic testing. Whole-exome sequencing or an MMAF/male-infertility gene panel including CFAP65; confirm with Sanger sequencing and segregation.
• Exclusions. Karyotype (46,XY) and Y microdeletion testing; assess for PCD symptoms.
• Differential diagnosis. Other MMAF genes (DNAH1, CFAP43, CFAP44, CFAP69, CFAP61, ARMC2) and PCD.
• Screening. No population screening exists. Cascade testing of relatives is reasonable in consanguineous families.
• LOINC. None retrieved.

11. Outcome/Prognosis

No survival effect is reported. The main outcome is infertility. No quality-of-life, complication or prognostic-factor data were found apart from the unresolved respiratory question.

12. Treatment

No curative or disease-specific therapy exists. In the sources I read, the 2026 paper reports no ICSI outcomes for CFAP65 carriers. - Assisted reproduction. ICSI is the usual approach for MMAF. In a CFAP43/CFAP44 context, ICSI outcomes were discussed (ref. 4 in PMC13383139), but I could not verify success rates for CFAP65, so none are stated here. - Gene therapy and others. None. - Counseling. Genetic counseling is appropriate. - Suggested NCIT terms (verify). Assisted reproductive technology and genetic counseling (the CLAUDE.md list gives NCIT:C15240 for Genetic Counseling). - Clinical trials. None identified.

13. Prevention

• Primary and secondary prevention. None.
• Genetic counseling and reproductive options. These include carrier testing of partners in consanguineous families and preimplantation genetic testing where applicable.
• Lifestyle measures. None are evidence-based for this condition.

14. Other Species / Natural Disease

• Natural disease. I found no OMIA entry. This was not checked directly.
• Comparative biology. The 2026 paper's discussion says chicken CFAP65 is related to sperm motility (also noted in the Zhang 2019 summary). This is unverified.
• Zoonotic aspects. Not applicable.

15. Model Organisms

• Mouse. Two sources describe a Cfap65 knockout or frameshift mouse:
• Li et al. 2020 (PMID:31501240) reported a frameshift mutant that reproduced MMAF.
• The 2025 Cell Mol Life Sci paper (DOI 10.1007/s00018-025-05583-2) reports C2a projection loss, severe MMAF and hydrocephalus. It also describes acrosome malformation, abnormal head shape, manchette defects and disorganized axonemes.
• Fidelity. The mouse reproduces MMAF and, to a variable extent, head defects. It additionally shows hydrocephalus and no clear respiratory phenotype, which differs from the mixed human respiratory findings. This difference justifies a HUMAN_MODEL_MISMATCH discussion in the KB if the entry is curated.
• Database resources. MGI, IMPC and the Alliance of Genome Resources were not checked.

Gaps for curators

1. Fetch and quote the four primary papers (PMIDs 31413122, 31501240, 31571197, 42477516) from references_cache/.
2. Look up the current ClinGen/GenCC record for CFAP65 / SPGF40 and copy the tier. The "Limited" tier I found may be out of date.
3. Resolve every suggested HPO, GO, CL and NCIT term by lookup. None is verified.
4. Find the PMID for the 2025 mouse paper in PubMed.
5. Check GeneReviews and Orphanet for an MMAF chapter or entry, and run just check-genereviews.

Sources

• MalaCards: Spermatogenic Failure 40
• MedGen C5231451 mirror
• PMC13383139: novel homozygous CFAP65 frameshift, Pakistani family (2026)
• PMID:31413122, Wang 2019
• PMID:31501240, Li 2020
• PMID:31571197, Zhang 2019
• PMID:28552195, Tang 2017
• PMID:30686508, Coutton 2019
• Springer CMLS 2025, CFAP65 and the C2a projection
• Diverse monogenic subforms of human spermatogenic failure (PMC9792524)

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:0032859 (2 mentions) - the report calls it "MONDO"; MONDO calls it spermatogenic failure 40

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:0012206 (1 mention) - the report calls it "Asthenozoospermia / absent motility"; HP calls it Abnormal sperm motility
• HP:0012864 (1 mention) - the report calls it "Teratozoospermia, MMAF"; HP calls it Abnormal sperm morphology, and lists "Teratozoospermia" among its other names
• CL:0000018 (1 mention) - the report calls it "CL: spermatid"; CL calls it spermatid