Spermatogenic Failure 95

1. Disease Information

Overview. SPGF95 is an autosomal recessive form of male infertility. It is caused by homozygous loss-of-function variants in CFAP57. Sperm show multiple morphological abnormalities of the flagella (MMAF): absent, short, coiled, bent and irregular-caliber tails. Progressive motility is markedly reduced. Female fertility appears unaffected. - The OMIM phenotype table lists it as 1p34.2, AR, MIM 620917, gene CFAP57 (MIM 614259), per a search-surfaced OMIM table. The same snippet carries the clinical description and the female-fertility note. - This is a single-gene Mendelian disease, a member of the numbered "spermatogenic failure" series. It is not a grouping.

Identifiers

• Not found: Orphanet, ICD-10/11 and MeSH identifiers.
• The data are disease-level (OMIM, literature), not derived from EHR.

Synonyms. The descriptive label "MMAF due to CFAP57 mutation" is a term in the literature. I did not find other alternative names.

2. Etiology

• Cause. Biallelic loss-of-function variants in CFAP57.
• Genetic risk factors. I found no susceptibility loci or modifier genes.
• Environmental risk factors and protective factors. None identified for this entity.
• Gene–environment interactions. None identified. Environmental and lifestyle sections are therefore "not available" for this disease.

3. Phenotypes

All human data below come from Ma et al. 2023 (PMID:36752199) unless noted.

Cohort. Seven infertile men from 3 consanguineous Pakistani families. - Four were asthenozoospermic (P2, P5, P6, P7) and one (P3) was azoospermic. - AZF microdeletions and abnormal karyotypes were excluded. - Semen values and MMAF percentages appear only in Table 1, which is an image I could not read.

• Onset, severity, progression. Not described beyond adult infertility. Infertility is a fixed defect, so there is no known progression.
• Frequency. The exact proportions in Table 1 were not retrieved.
• Ciliary or systemic symptoms. These were mostly absent. The authors report "no overt ciliary symptoms". The exception is P6, who reported a typhoid-like illness, headaches and occasional breathing difficulty. He declined further testing, so this is not an established PCD feature.
• Emirati family (2026). A Molecular Biology Reports abstract, seen only as a search summary, reports a proband with 63% immotile sperm, 4% normal morphology and no PCD signs.
• Quality of life. No data found.

4. Genetic/Molecular Information

• Gene. CFAP57 (cilia and flagella associated protein 57), 1p34.2, OMIM 614259. The HGNC ID was not retrieved. Look it up and bind it as lowercase hgnc: per KB convention.
• Variants (all homozygous stop-gain, all supporting an LoF mechanism):

• Classification (ACMG/ClinVar). Not retrieved.
• Allele frequency (gnomAD). Not retrieved.
• Origin. Germline.
• Functional consequence. Both Pakistani variants abolish the long-transcript CFAP57 protein in sperm. The short transcript is unaffected.
• Modifier genes, epigenetics, chromosomal abnormalities. None reported.

5. Environmental Information

No environmental, lifestyle or infectious-agent contributors are described.

6. Mechanism / Pathophysiology

Causal chain (steps 1–4 are demonstrated in humans and mouse; step 5 is partly inferred): 1. A homozygous nonsense variant in CFAP57 introduces a premature stop codon in the long transcript. (Demonstrated.) 2. This leads to loss of long-isoform CFAP57 protein in spermatozoa. (Demonstrated in patient sperm and in the mouse.) 3. Loss of CFAP57 results in failed inner dynein arm (IDA) assembly in the sperm axoneme. Single-headed IDAs (markers DNAH6, DNALI1) are most affected. The double-headed IDA marker DNAH10 is less affected. Outer dynein arms are present. (Demonstrated by immunofluorescence and by TEM in P7.) 4. Testis levels of IDA proteins (DNAH1, DNAH6, DNALI1) are normal, so the defect is in assembly or incorporation and not in synthesis. (Demonstrated in the mouse.) 5. Disorganized axonemes then produce the MMAF morphology and immotile or poorly motile sperm, which leads to asthenozoospermia or azoospermia and male infertility. (Demonstrated, but the link from IDA loss to the specific flagellar shape defects is inferred.)

Branch: why there is no motile-cilia disease. The authors propose that the unaffected short transcript preserves ciliary function. This is a hypothesis and is not demonstrated.

Supporting quote from the Discussion of PMID:36752199: "loss of the long transcript of Cfap57 disrupted IDA assembly in sperm flagella". Verify this against the full text before using it as a snippet.

Cell types and terms to check. - Cell types: spermatid (CL:0000018) and spermatozoon (CL:0000019). - GO terms: axonemal dynein complex assembly, inner dynein arm assembly, sperm flagellum assembly (all need lookup). - GO cellular component: sperm flagellum, axoneme.

Not found. I found no data on omics, single-cell, metabolic, immune or epigenetic changes. The Chlamydomonas ortholog FAP57 has a similar role in IDA assembly, per the discovery paper.

7. Anatomical Structures Affected

• Primary organ: testis, where spermiogenesis takes place (UBERON:0000473, verify).
• Sperm flagellum axoneme: 9+2 structure retained, IDAs absent.
• Laterality: not applicable (bilateral male reproductive phenotype).
• Secondary involvement: none established. Respiratory or other ciliated tissue is not clearly affected.

8. Temporal Development

• Onset: adult, presenting as infertility. It is lifelong and congenital in origin.
• Progression, remission, critical periods: no data.

9. Inheritance and Population

• Inheritance: autosomal recessive (OMIM). The Pakistani and Emirati families were consanguineous. The heterozygous parents in the Emirati family were unaffected carriers.
• Founder effect: R913* was found in two families, which may suggest a recurrent or founder variant. This is my inference and the paper's text does not state it.
• Not found: prevalence, incidence, carrier frequency, penetrance, sex ratio and geographic distribution beyond the Pakistani and Emirati families. Disease expression is male-limited by definition.

10. Diagnostics

• Semen analysis shows asthenozoospermia, or azoospermia in rare cases. Morphology shows MMAF.
• Genetic testing: WES identified the variants, confirmed by Sanger sequencing. A CFAP57 gene should be included in MMAF or male-infertility panels. I did not retrieve GTR or GeneReviews panel data.
• Excluded in workup: karyotype and AZF microdeletions.
• Research tools: TEM (IDA absence) and immunofluorescence (DNAH6, DNALI1).
• Differential: other MMAF genes (not enumerated here from sources), and primary ciliary dyskinesia, which is notably absent.
• No screening program applies.

11. Outcome/Prognosis

No survival or mortality effect is reported. The manifestation is infertility. I found no ICSI outcome data for CFAP57 patients. The discovery paper does not report ICSI results.

12. Treatment

No disease-specific treatment was found. - ICSI is the generally used route for MMAF infertility, but I found no CFAP57-specific outcome data. A relevant NCIT term to verify would be assisted reproductive technology. - No gene therapy, drugs or clinical trials were identified, and I did not search ClinicalTrials.gov directly. - Genetic counselling (NCIT:C15240, from the project's CLAUDE.md list) is appropriate for the consanguineous families and for carrier-parent counselling.

13. Prevention

No primary or secondary prevention applies. Genetic counselling and carrier testing in consanguineous families is the relevant tertiary and reproductive measure. This is general practice and not a CFAP57-specific source finding.

14. Other Species / Natural Disease

No natural veterinary disease was found, and I did not search OMIA. The mouse and Chlamydomonas orthologs are covered below.

15. Model Organisms

Mouse knock-in (Cfap57^M/M). From PMID:36752199. - Allele: c.2865-2871del, p.Lys956Phefs4, modelling the family 1 variant. - Normal growth, development and testis size. - Males infertile, with epididymal sperm counts about 5% of heterozygous controls. - All sperm morphologically abnormal (MMAF-like) and immotile by CASA. - No CFAP57 signal in the sperm tail, and disorganized axonemes in all analyzed cross-sections. - Fidelity. This recapitulates the human sperm phenotype and the lack of overt ciliary disease. The model has one allele, and the human long/short transcript logic is shared, so the mouse cannot independently test the short-transcript hypothesis. - Chlamydomonas FAP57* has a similar IDA-assembly role per the paper. - Not found: MGI or IMPC records, zebrafish or other models, and the mouse gene's NCBI ID.

Key Gaps for Curation

1. Confirm the MONDO ID (the header's MONDO:0975747 is unverified) and the HGNC ID for CFAP57.
2. Read OMIM #620917 for its clinical synopsis and the cited PMIDs.
3. Retrieve Table 1 of PMID:36752199 for semen parameters.
4. Check ClinVar and ClinGen for variant classifications and gene–disease validity. The ClinGen tier must be copied from a source and not assigned.
5. Evidence strength is thin. The human data are 3 families plus one 2026 abstract, and the mouse model is a single allele.

Sources

• Ma et al. 2023, JCI Insight (PMC9977434), PMID:36752199
• OMIM phenotype table snippet (PMC10042652)
• Alliance of Genome Resources, DOID:0070594
• MGI disease page, OMIM:620917
• UroToday abstract: Emirati CFAP57 nonsense variant
• DrugMAP spermatogenic failure parent term
• PomBase MONDO:0971000 (SPGF93)

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:

• DOID:0070594 (5 mentions) - the report calls it "Disease Ontology"; DOID calls it spermatogenic failure 95
• MONDO:0971000 (5 mentions) - the report calls it "SPGF93"; MONDO calls it spermatogenic failure 93
• HP:0012206 (1 mention) - the report calls it "Asthenozoospermia / reduced progressive motility"; HP calls it Abnormal sperm motility
• HP:0012864 (1 mention) - the report calls it "Abnormal sperm flagellum morphology (MMAF: absent, short, coiled, bent, irregular-caliber flagella)"; HP calls it Abnormal sperm morphology

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:

• CL:0000018 (1 mention) - the report calls it "Cell types: spermatid"; CL calls it spermatid

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.