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Spermatogenic Failure 24 (SPGF24): research report

Evidence limits. This report rests on web search summaries and the PubMed abstract summaries I retrieved. PMC full texts were blocked by a browser-verification page. I have no verbatim abstract text, so there are no exact snippets here. Every quote must be copied from the cache after just fetch-reference PMID:…, and none should be written from this report. The PMIDs below came from search results and are not verified against PubMed. Three of them (29606301, 30415212, 37392306) were each reported by a single search listing, and 30415212 was explicitly flagged as coming from "one listing". HP, GO, CL and UBERON terms are suggestions only. Do not write CURIEs into the KB from memory. Look each one up with runoak or the term cache.

1. Disease information

SPGF24 is an autosomal recessive form of male infertility caused by biallelic loss of function in CFAP69 (7q21.13). Affected men have asthenoteratozoospermia with "multiple morphological abnormalities of the sperm flagella" (MMAF). Flagella are absent, short, coiled, bent or of irregular caliber. Sperm heads are also malformed, and sperm counts are very low.

Identifiers - OMIM 617959 - MONDO:0054728 - MedGen 1646063 - UMLS C4693751 - DOID:0111929

Synonyms: SPGF24, "spermatogenic failure, type 24". LOVD lists the gene under the older name C7orf63.

Data source: Disease-level, aggregated from small case series. OMIM refers to SPGF1 (258150) for the general discussion of genetic heterogeneity.

Sources: - MalaCards - LOVD disease 05564 - DrugMap - MedGen - Disease Ontology

2. Etiology

• Cause: Homozygous or compound heterozygous loss-of-function variants in CFAP69.
• Environmental, protective and gene-environment factors: None reported. This is a monogenic recessive disorder, and I found no sources on these topics.
• Consanguinity: The index family in He et al. was consanguineous.

3. Phenotypes

All phenotypes are in men and are human clinical findings.

• Onset and course: Not described. Presumably stable, presenting at adult reproductive age.
• Quality-of-life data: Not found.
• Non-reproductive features: None reported in the sources I retrieved. This is a gap, and I did not verify that none exist.

4. Genetic and molecular information

• Gene: CFAP69 (cilia and flagella associated protein 69), HGNC ID to be looked up. Use the lowercase hgnc: form in the KB.
• Variants:
• Dong et al. 2018 (AJHG 102:636–648, PMID:29606301): exome sequencing of 78 MMAF men found biallelic truncating CFAP69 variants in two unrelated individuals.
• He et al. 2019 (J Med Genet 56:96–103, PMID:30415212): a homozygous frameshift, p.Leu357Hisfs11, in a consanguineous Han Chinese family. Sanger sequencing of 34 more MMAF men found a homozygous nonsense variant, p.Trp216. Neither variant was in population databases. CFAP69 accounted for 5.7% (2/35) of that cohort.
• Tang et al. 2023 (J Assist Reprod Genet 40:2175–2184, PMID:37392306): a novel frameshift, p.Pro688Thrfs5, found among 35 MMAF men. The authors' literature review puts biallelic CFAP69* variants at about 2.5–5.7% of studied MMAF cohorts.
• Mechanism class: Loss of function (truncating variants). All variants I found are germline.
• Not found: modifier genes, epigenetic data, chromosomal abnormalities, ClinGen validity tier. DrugMap lists the evidence level as "limited". Check ClinGen directly with just list-gene-validity.

5. Environmental information

None known.

6. Mechanism and pathophysiology

Causal chain 1. Biallelic truncating CFAP69 variants cause loss of CFAP69 protein. Tang et al. showed reduced CFAP69 immunofluorescence in patient sperm. 2. CFAP69 is highly expressed in testis and localizes mainly to the sperm midpiece (Dong 2018, human and mouse). Its loss disrupts flagellar assembly and stability. 3. This leads to disrupted flagellar ultrastructure during spermiogenesis (TEM in Tang 2023; mouse data in Dong 2018 and He 2019). Inferred: the precise structural role of CFAP69 is not established in what I read, and I did not find a source describing a mitochondrial sheath role. 4. The result is MMAF and malformed heads. 5. Sperm are immotile or poorly motile, and the man is infertile.

Where the defect sits: In knockout mice, all stages of the seminiferous epithelium are present. Meiosis and earlier spermatogenesis are therefore preserved, and the lesion is in spermiogenesis (post-meiotic flagellum biogenesis). This differs from the meiotic arrest seen in many other SPGF subtypes.

Not found: pathway, transcriptomic, proteomic, immune or metabolic data.

Suggested ontology terms (to be looked up): - GO: sperm flagellum assembly; spermatid differentiation; cilium organization - CL: spermatid; spermatozoon - UBERON: testis; seminiferous tubule - GO CC: sperm midpiece; sperm flagellum

7. Anatomical structures affected

• Organ and tissue: Testis and seminiferous epithelium. Spermatogenesis is otherwise preserved.
• Cells: Elongating spermatids and spermatozoa.
• Subcellular: Sperm flagellum, mainly the midpiece.
• Laterality: Bilateral, as expected for a systemic germline defect, though sources do not state it.

8. Temporal development

Not described in the sources I retrieved. No data on onset, progression, remission or critical periods.

9. Inheritance and population

• Inheritance: Autosomal recessive (LOVD; DrugMap). The HPO mode-of-inheritance term for autosomal recessive is to be looked up.
• Expressivity: The disorder is male-limited. Carrier parents are presumably unaffected.
• Prevalence: Not available. CFAP69 explains about 2.5–5.7% of MMAF cohorts (Tang 2023 review; He 2019: 2/35).
• Population: Cases reported so far are largely Chinese cohorts.
• Founder effect, carrier frequency, anticipation, mosaicism: Not found.

10. Diagnostics

• Semen analysis: Severe asthenoteratozoospermia with MMAF morphology.
• Electron microscopy: TEM shows aberrant axonemal and midpiece ultrastructure.
• Immunofluorescence: Reduced or absent CFAP69 in sperm.
• Genetic testing: Whole-exome sequencing or an MMAF gene panel, which is how all reported cases were found. Sanger sequencing confirms the variant.
• Differential diagnosis: Other MMAF genes (e.g. DNAH1, CFAP43, CFAP44), primary ciliary dyskinesia, and other genes causing spermatogenic failure.
• Not applicable or not found: screening programs, imaging, and any LOINC mapping. Search LOINC before binding any measurement.

11. Outcome and prognosis

• Fertility: Natural conception is not expected.
• Systemic outcomes: Not reported. No evidence of reduced life expectancy or other organ involvement in the sources I found.

12. Treatment

• ICSI: The only evidence is a single couple in Tang 2023, who had a healthy girl by ICSI. The authors conclude ICSI is effective for affected couples. This is one case, not a rate, and should be curated that way.
• Other: No pharmacotherapy, gene therapy or clinical trials found. Pharmacogenomics is not applicable.
• Suggested NCIT terms (to be looked up):
• An intracytoplasmic sperm injection or assisted reproduction term, if one exists in NCIT under Clinical Intervention or Procedure.
• Genetic Counseling (NCIT:C15240, listed in CLAUDE.md).

13. Prevention

• Genetic counseling and carrier testing of relatives (autosomal recessive).
• Preimplantation or prenatal testing is theoretically available. I found no SPGF24-specific literature on it.

14. Other species

I found no OMIA entry or natural disease in other species.

15. Model organisms

• Mouse: Two independent Cfap69 knockout lines, in Dong 2018 and He 2019 (CRISPR-Cas9). Males are sterile with MMAF-like flagellar defects. All stages of spermatogenesis are present, so the defect is in spermiogenesis.
• Fidelity: Reported as recapitulating the human MMAF phenotype. Female phenotype and non-reproductive organs are not described in what I read. Per CLAUDE.md, this belongs in animal_models: with modeled_mechanisms.
• Other resources: The Cyagen mouse atlas lists a knockout, and the Male Fertility Gene Atlas indexes the gene. I did not review IMPC or MGI.

Curation notes

• Tier before curating: Three case reports plus two mouse knockouts is a thin evidence base. Check the ClinGen tier first.
• Summaries only: I only saw summaries of the three key papers. The curator must confirm exact variant nomenclature, the Dong 2018 variants (not retrieved), semen parameters, and snippets from the cached abstracts.
• Grading: Grade evidence_source by what each quote describes. Mouse knockout statements are MODEL_ORGANISM, even though the papers also contain human data.

Sources

• Malacards SPGF24
• LOVD
• MedGen
• DrugMap
• Disease Ontology
• Dong 2018, PMC5985338
• He 2019, JMG
• Tang 2023, PMC10440328
• Tang 2023, Springer
• Cyagen mouse atlas
• Male Fertility Gene Atlas

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.

Every term resolved, and every label the report gave matched.