Spermatogenic Failure 20 (SPGF20; CFAP44-related MMAF): Research Report

Evidence status. Verified this session: gene and disease identifiers, the Tang 2017 and Coutton 2018 findings, the ICSI series, and the mouse data. Unverified: items marked [unverified] come from general knowledge or from search snippets I did not open. Check them before curation. I did not verify OMIM prose, HPO frequencies, GO/CL/UBERON identifiers, or ClinGen validity. I also quote no exact abstract text, because I read only the Coutton paper's full text, and only partially. The CLAUDE.md rules require the snippets to be exact quotes, so take snippets from just fetch-reference, not from this report.

1. Disease information

• Overview. SPGF20 is an autosomal recessive form of male infertility. The underlying defect is "multiple morphological abnormalities of the sperm flagella" (MMAF), also called asthenoteratozoospermia with flagellar defects. Sperm tails are absent, short, coiled, bent or of irregular caliber. Men are otherwise typically healthy. Sperm count can be normal, but sperm are almost immotile.
• Identifiers.
• MONDO:0054724 (the repository stub names CFAP44 as MONDO's causal gene).
• OMIM phenotype 617593; OMIM gene 617559 (CFAP44, 3q13.2). A search-derived DrugMap record and a PMC 2023 table agree on the pairing.
• Orphanet, ICD and MeSH identifiers: not checked.
• Synonyms. Spermatogenic failure 20; SPGF20; MMAF type 20 [unverified]. CFAP44 was formerly WDR52 [unverified].
• Data source. Disease-level, aggregated from family and cohort sequencing, not EHR.
• Repository state. stubs/Spermatogenic_Failure_20.yaml exists, with entry_type: UNDECIDED. No kb/disorders entry exists yet.
• Lump/split note. Many SPGF entries share the same MMAF phenotype (CFAP43, DNAH1, CFAP69, ARMC2 and others). A curator should keep SPGF20 as a gene-defined disease entry and consider a covering MMAF grouping.

2. Etiology

• Cause. Biallelic loss-of-function variants in CFAP44 (cilia- and flagella-associated protein 44).
• Genetic risk factors. No modifier genes are established. Digenic CFAP43/CFAP44 involvement has not been shown. CFAP43 and CFAP44 variants are found in separate patients.
• Environmental factors. None established for this form. The known MMAF causes are genetic.
• Protective factors and gene-environment interactions. None known.

3. Phenotypes

All items below are for male patients. Female carriers are not reported to be affected.

• Frequencies. In CFAP44 patients from Coutton 2018 (PMID:29449551), mean absent flagella were 36.8%, short flagella 52.2% and irregular-caliber flagella 28.4%.
• Onset, progression and quality of life. Onset is at reproductive age and the phenotype is stable. Infertility is the presenting complaint. No quality-of-life data were found.
• Verify every HPO CURIE with a lookup before binding. Per CLAUDE.md, I wrote none of these from a source in this session.

4. Genetic/molecular information

• Gene. CFAP44, HGNC symbol (lowercase hgnc: form in the KB, number to be looked up), 3q13.2.
• Variants (Coutton 2018, PMID:29449551, Table 2). All six patients were homozygous.
• c.1890+1G>A (p.Pro631Ile*22), splice site, Tunisia.
• c.3175C>T (p.Arg1059Ter), nonsense, Tunisia.
• c.2818dupG (p.Glu940GlyfsTer19), frameshift, Morocco.
• c.1387G>T (p.Glu463Ter), nonsense, two patients, Algeria.
• c.4767delT (p.Ile1589MetfsTer6), frameshift, Algeria.
• The paper's text gives the first variant as c.1890+1C>T, which conflicts with the table. Resolve this against the source before curating.
• Tang 2017 (PMID:28552195). A homozygous frameshift in CFAP44 was found in 1 of 30 Han Chinese MMAF men. Compound-heterozygous CFAP43 variants were found in 3 other men. These variants were absent in 984 controls.
• Functional consequence. Loss of function (nonsense, frameshift, splice). Origin is germline.
• Gene share. CFAP44 explained 6 of 78 men (7.7%) in Coutton 2018. CFAP43 and CFAP44 together explained about 20.5%. The cohort was mainly North African, so the share is cohort-dependent.
• Epigenetics and chromosomal abnormalities. None reported.
• Population frequency (gnomAD) and ClinVar classifications. Not retrieved.

5. Environmental information

None established. Infectious agents are not applicable.

6. Mechanism / pathophysiology

Causal chain

1. Biallelic loss-of-function variants in CFAP44 produce absent or truncated CFAP44 protein. This is demonstrated by genetics and inferred at the protein level.
2. CFAP44 is lost from the sperm axoneme. In the T. brucei ortholog, it localizes next to the paraflagellar rod, apposed to doublets 5–6 (PMID:29449551).
3. Axonemal organization fails. In patient sperm, TEM showed about 95% abnormal cross-sections in one patient, most often lacking the central pair (9+0, 66.7%). Reduced SPAG6 and RSPH1 staining implicates central-pair and radial-spoke components.
4. Flagellar assembly and beating fail, so tails are absent, short or coiled and motility is reduced. This step is established in humans and mice.
5. Sperm are immotile and structurally abnormal, which causes male infertility.

Evidence by model system: - Human: MMAF patients with biallelic variants (above). - Mouse: Cfap44 knockout males are infertile with MMAF, and females are fertile (PMID:28552195). - Trypanosome: RNAi knockdown of TbCFAP44 gave abnormal beating, growth arrest and multiflagellated cells. Axonemal defects were found in 27.3% of axonemes versus 0.6% of controls.

Cell and tissue targets: - Cell type: spermatid or sperm (CL term to look up). - Tissue: testis. - Components: axoneme, sperm flagellum (GO terms to look up). - Biological processes: sperm flagellum assembly, spermatid differentiation. - Omics and other mechanisms. No metabolic, immune, proteomic or single-cell findings were retrieved. A 2025 Mol Hum Reprod study (Muroňová et al.) compared mouse knockouts. Cfap44-/- sperm had the mildest nuclear defects and the lowest embryo-developmental failure among the knockouts compared (Cfap43, Armc2, Ccdc146) (per a search summary; paper not opened).

7. Anatomical structures affected

• Organ: testis and sperm. Other organs are not involved, and there is no ciliary syndrome in these patients. That statement is from the literature picture, not from a source I checked. Primary ciliary dyskinesia-like features are reported for some other MMAF genes, not for CFAP44 [unverified].
• Cell level: spermatids and spermatozoa. Subcellular: axoneme and flagellum.
• Lateralization: not applicable (systemic germline).

8. Temporal development

Onset is at reproductive age (detected on infertility workup). Stable, lifelong, with no remission.

9. Inheritance and population

• Inheritance: autosomal recessive (HP:0000007 – verify).
• Penetrance and sex: limited to males. Females are unaffected in mice.
• Consanguinity: the Coutton 2018 CFAP44 patients were all homozygous. Consanguinity is likely in the North African cohort. Verify this against the full text.
• Founder effects: none established.
• Prevalence: unknown. MMAF is rare, and CFAP44 accounts for about 7.7% of the MMAF cohort studied.

10. Diagnostics

• Semen analysis: asthenozoospermia with flagellar abnormalities on morphology.
• Electron microscopy and immunostaining: central-pair and axoneme defects (TEM); SPAG6 and RSPH1 staining.
• Genetic testing: whole-exome sequencing or an MMAF gene panel. WES in 78 MMAF men gave a diagnosis in 22 (28%) across DNAH1, CFAP43 and CFAP44.
• Differential diagnosis: other MMAF genes (DNAH1, CFAP43, CFAP69, ARMC2 and others) and primary ciliary dyskinesia.
• Screening: none.

11. Outcome/prognosis

Life expectancy is normal, and the burden is infertility. Assisted reproduction outcomes in a small retrospective series (6 MMAF patients with biallelic CFAP44 or CFAP43 variants; Frontiers in Endocrinology 2024): - For CFAP44, ICSI gave 76.47% fertilization, 88.46% transferable embryos, 50% pregnancy and 50% delivery. - Fertilization was significantly higher than in the DNAH1 group. - Samples were very small. Coutton 2018 does not report ICSI outcomes for CFAP44. - Also check Coutton 2018's own discussion, which says ICSI prognosis is hard to predict for non-DNAH1 genotypes.

12. Treatment

• No curative or drug therapy exists.
• Intracytoplasmic sperm injection (ICSI) is the main option, with the outcomes above (NCIT term to look up; the repository table suggests a procedure term, but look up the CURIE rather than trusting memory).
• Gene therapy and other advanced approaches: none found. Clinical trials: none found, and I did not search ClinicalTrials.gov.

13. Prevention

• Genetic counseling for couples. A male partner's biallelic status confers 100% transmission of one pathogenic allele to children, who would be carriers. This is inferred from recessive inheritance.
• Preimplantation genetic testing is possible if the variants are known. This is general knowledge and was not verified.

14. Other species

I did not search OMIA or ortholog databases. The mouse ortholog is Cfap44, and the Trypanosoma ortholog is TbCFAP44 (NCBITaxon IDs and NCBI Gene IDs to look up).

15. Model organisms

• Mouse: CRISPR/Cas9 Cfap44 knockout. Males are infertile with MMAF and peri-axonemal and axonemal defects. Females are fertile (PMID:28552195). This is MODEL_ORGANISM evidence, and the model recapitulates the human phenotype well. Since 2025, comparative data show milder nuclear and embryo-development defects than other MMAF knockouts.
• Trypanosoma brucei: RNAi knockdown with flagellar defects (PMID:29449551). The relevance to human spermatogenesis is by homology only.
• Resources: MGI and IMPC (not queried here).

Evidence summary for curation

Next steps before curation. Run just fetch-reference for PMIDs 28552195 and 29449551. Look up every HPO, GO, CL and UBERON CURIE. Resolve the c.1890+1G>A versus C>T discrepancy. Retrieve the PMIDs for the ICSI series and the 2025 knockout comparison. Also check ClinGen validity for CFAP44-MMAF and the GeneReviews baseline (just check-genereviews).

Sources: - DrugMap SPGF20 record - PMC 2023 gene table - Coutton et al. 2018, Nat Commun (PMC5814398) - Tang et al. 2017 AJHG (PMID 28552195) - Frontiers in Endocrinology 2024 review/ICSI series - Muroňová et al. 2025, Mol Hum Reprod (HAL record)

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:0012869 (1 mention) - the report calls it "unverified"; HP calls it Acephalic spermatozoa
• HP:0000007 (1 mention) - the report calls it "verify"; HP calls it Autosomal recessive inheritance

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 / flagellar abnormalities"; HP calls it Abnormal sperm morphology, and lists "Teratozoospermia" among its other names