I'm still gathering primary-literature details on CFAP61 (the gene behind SPGF84). The PubMed and PMC pages are blocked, so I'm looking for PMIDs and abstracts elsewhere.

Spermatogenic Failure 84 (SPGF84): research report

Reliability note. This report comes from web searches only. PubMed, PMC and the Development PDF were blocked or rate-limited, so I read no abstract or full text directly. The facts below come from search-result summaries and aggregator pages.

• No quotes: I give no exact abstract quotes. Any snippet written for the KB must be taken from just fetch-reference output.
• PMIDs: only PMID 35387802 was seen in a search result. The other papers are cited by DOI or title, and their PMIDs still need to be fetched.
• Ontology IDs: I give only labels for HPO, GO, CL, UBERON and NCIT terms. Look up every CURIE with runoak or the cache before binding it.

1. Disease information

SPGF84 is an autosomal recessive form of male infertility caused by biallelic loss-of-function variants in CFAP61. The main feature is multiple morphological abnormalities of the sperm flagella (MMAF), which severely reduce motility. Some men also have reduced sperm counts.

• Identifiers (NCBI MedGen C5830562):
• OMIM #620409
• MONDO:0957301
• gene locus 20p11.23
• Ontology placement: MONDO places it under spermatogenic failure, as a reproductive system disorder (SAIL Concept Library).
• Other resources: KEGG spermatogenic failure H01282 and MalaCards list the entry.
• Synonyms and series: SPGF84; CFAP61-related MMAF; asthenoteratozoospermia due to CFAP61. It belongs to the numbered SPGF series, which is heterogeneous, and many of its members are flagellar or MMAF genes.
• Source type: disease-level and aggregated, built from small family and cohort studies.
• Not found: Orphanet and ICD identifiers. Check these directly.

2. Etiology

• Cause: homozygous or compound heterozygous CFAP61 variants (MalaCards via Disease Ontology).
• Environmental risk factors: none established. Other causes of male infertility must be excluded in the differential.
• Protective factors and gene-environment interactions: none reported.
• Possible modifiers: other axonemal genes, such as CFAP251, appear to be involved downstream. That is a mechanistic link, not a demonstrated modifier effect.

3. Phenotypes

Male-limited phenotypes (candidate HPO labels, all to be verified):

• Cohort observation: in the J Med Genet cohort, two of 325 men with oligoasthenoteratozoospermia (OAT), 0.62%, carried biallelic CFAP61 variants.
• Other organs: no primary ciliary dyskinesia (PCD) features are described. The mouse knockout lacks the usual PCD symptoms.
• Frequencies and quality of life: no per-phenotype frequencies or quality-of-life data are available. Infertility is expected to have psychosocial impact, but I found no study.

4. Genetic and molecular information

• Gene: CFAP61 (cilia and flagella associated protein 61, also C20orf26), 20p11.23. A homolog of the radial spoke protein Rsp19. HGNC ID not retrieved. Look it up and write it in lowercase hgnc: form.
• Reported variants:
• Pakistani families (Ma et al., Frontiers in Cell and Developmental Biology, DOI 10.3389/fcell.2021.803818):
  • 11 infertile men in three unrelated families.
  • c.451_452del (p.I151Nfs*4) in family 1.
  • c.847C>T (p.R283*) in families 2 and 3.
  • Both variants truncate the protein.
• Splice variant: c.143+5G>A causes exon skipping (Liu et al., Development 2021, DOI 10.1242/dev.199805).
• Later reports: a novel homozygous splicing variant (J Assist Reprod Genet 2024) and two of 325 OAT men in the J Med Genet cohort.
• Consequence: loss of function (truncation or exon skipping). No dominant-negative or gain-of-function mechanism is known.
• Origin: germline.
• Not retrieved: ClinVar and ClinGen classifications, gnomAD frequencies, ClinGen gene-disease validity, and epigenetic or chromosomal findings. Check just check-gene-validity and ClinGen before recording any tier.

5. Environmental information

None known. No infectious agents and no lifestyle factors are linked.

6. Mechanism and pathophysiology

1. Biallelic CFAP61 loss-of-function variants (truncating or splicing) reduce or abolish CFAP61 protein in the testis.
2. CFAP61 is a component of the calmodulin- and radial-spoke-associated complex (CSC) in the axoneme. This is a conserved role, described in a bioRxiv preprint of the Development paper.
3. Early in spermiogenesis, radial spoke assembly is impaired in Cfap61-/- mice (preprint, mouse data).
4. The axoneme becomes unstable and scatters. The distribution of intraflagellar transport (IFT) proteins is disrupted (preprint, mouse data).
5. In patient sperm, the central pair and radial spokes are missing and the axonemes are disorganized. CFAP61 and CFAP251 signals are absent from the tail (Frontiers 2021). The J Med Genet cohort also found missing central pair microtubules and mitochondrial sheath malformation.

6. The result is short, coiled or absent flagella with no progressive motility, which leads to male infertility. The step from structural defect to loss of motility is inferred, not separately demonstrated.

7. Cells: spermatid and spermatozoon, in the seminiferous epithelium of the testis.

8. Cell component: the sperm flagellar axoneme, radial spoke and central pair (GO labels to verify).
9. Not available: omics, single-cell, metabolomic and CRISPR screen data.
10. Possible Leydig cell link: one paper reports that CFAP61 knockdown reduced Leydig cell testosterone via the MAPK/COX-2 pathway (Funct Integr Genomics 2023). This is a cell-line finding that needs corroboration.

7. Anatomical structures affected

Testis and seminiferous tubules, with spermatids as the target cells. The sperm flagellum (axoneme, mitochondrial sheath) is the affected structure. The condition is male-limited and systemic involvement is not described.

8. Temporal development

Congenital genotype. Infertility presents in adulthood, during attempts to conceive. It does not progress and is lifelong. No remission is reported.

9. Inheritance and population

• Inheritance: autosomal recessive.
• Consanguinity: the Pakistani families suggest a role for consanguinity (homozygous variants), but I did not verify this in the paper.
• Population: Pakistani families, Chinese cohorts and others.
• Prevalence: not established. About 0.6% of OAT men in one cohort.
• Sex ratio: affects males only.
• Not retrieved: carrier frequency, founder effects, penetrance and expressivity.

10. Diagnostics

• Semen analysis: severe asthenoteratozoospermia, with a high proportion of MMAF flagella. Counts vary.
• Electron microscopy: disorganized axonemes. Findings in the cohorts include missing central pair, radial spokes and inner dynein arms.
• Immunofluorescence: absent CFAP61 and CFAP251 signals in sperm tails.
• Genetic testing: exome or MMAF/asthenoteratozoospermia gene panel with CFAP61 included. Confirm biallelic variants. A sample report from Arcensus Diagnostics notes ICSI is likely to be effective. It is a commercial sample, not primary evidence.
• Differential:
• Other MMAF genes (DNAH1, CFAP43, CFAP44, CFAP69, CFAP251 and others).
• PCD (check for respiratory symptoms).
• Acquired causes of OAT.

11. Outcome and prognosis

Fertility is impaired, but general health is not affected as far as is known. Natural fertilization is unlikely. No survival or mortality data are available.

12. Treatment

• ICSI (intracytoplasmic sperm injection; NCIT term to look up) is the main option. One affected man fathered a healthy baby by ICSI in the J Med Genet cohort (PMID 35387802). The Arcensus report cites 100% fertilization in treated probands, which is a weak source.
• Genetic counseling. There is no drug, gene or cell therapy and no clinical trial that I found.
• Possible concern: whether sperm quality can support ICSI success depends on the individual. The outcomes cited are from very small numbers.

13. Prevention

There is no primary prevention. Options are genetic counseling and carrier testing of relatives. For couples using ICSI, preimplantation or prenatal testing is possible, though the heritable risk to a child is that of a carrier (recessive), and a male child homozygous for the variant would also be infertile.

14. Other species and natural disease

I found no natural disease report (not checked in OMIA). The mouse ortholog is Cfap61 (NCBI Gene IDs not retrieved).

15. Model organisms

• Mouse knockout (Cfap61-/-):
• Male sterility with MMAF (Liu et al., Development 2021, DOI 10.1242/dev.199805; preprint).
• An earlier knockout paper (ScienceDirect, "Absence of murine CFAP61 causes male infertility due to MMAF").
• The J Med Genet cohort paper used knockout mice with an OAT phenotype.
• The preprint says the mice lack the PCD symptoms usually seen with cilia genes.
• Fidelity: the mouse reproduces the male-infertility MMAF phenotype well. It is a loss-of-function model and does not cover human genotype-specific variation.
• Not checked: MGI or IMPC records, zebrafish and other models, and organoids.

Suggested KB follow-ups

1. Run just fetch-reference for each paper (PMID 35387802 first, then look up the PMIDs of the Ma 2021/2022, Liu 2021 and 2024 splice-variant papers).
2. Quote evidence snippets only from the cached text.
3. Look up every ontology CURIE (MONDO:0957301 is from MedGen and MONDO's own listing) and the lowercase hgnc: ID for CFAP61.
4. Check ClinGen, GeneReviews and Orphanet before adding gene validity or a baseline phenotype.

Sources

• NCBI MedGen C5830562
• SAIL Concept Library: MONDO:0957301
• MalaCards: SPGF84
• KEGG H01282
• Ma et al. 2021, Frontiers (PMC8841411)
• Liu et al. 2021, Development and its bioRxiv preprint
• J Med Genet, PMID 35387802
• Splice variant report, J Assist Reprod Genet 2024
• CFAP61 knockdown and Leydig cells, 2023
• Murine CFAP61 knockout, ScienceDirect
• Arcensus sample WGS report

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Unresolved references

These identifiers did not resolve to a record and may be fabricated. A lookup that failed for transport reasons is indistinguishable from one that failed because the record does not exist, so spot-check before acting on them:

• DOI:10.1242/dev.199805/2120252/dev199805.pdf (4 mentions) - Identifier did not resolve to a record

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

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