I'm pulling the abstracts of the other DNAH8 papers to get variant details and ICSI outcomes. Then I'll write the report.

Spermatogenic Failure 46 (SPGF46; DNAH8-related MMAF): research report

Evidence limits. The OMIM entry returned HTTP 403, so I could not read it. Its details (phenotype description, HPO annotations, allelic variants) come from search-result snippets and PubMed abstracts. PMIDs below were confirmed through PubMed E-utilities. Quotes marked "snippet" come from search-result text, not from a PubMed record I read in full. Anything I did not find is marked "not found".

1. Disease information

Overview. SPGF46 is an autosomal recessive form of primary male infertility. It is caused by bi-allelic loss-of-function or missense variants in DNAH8, which encodes an axonemal outer-arm dynein heavy chain. Affected men have asthenoteratozoospermia with multiple morphological abnormalities of the sperm flagella (MMAF). The MMAF phenotype combines absent, short, coiled, angulated and irregular-caliber flagella. The defect is restricted to the sperm tail, and ICSI can bypass it.

Identifiers

Synonyms. SPGF46; spermatogenic failure, type 46; DNAH8-related MMAF; MMAF with DNAH8 variants.

Data source. The case reports are individual patients (exome sequencing plus semen and EM analysis). The OMIM, MONDO and LOVD entries are aggregated disease-level resources.

2. Etiology

• Cause. Bi-allelic DNAH8 variants. The discovery paper reported that "Two cases (2.2%) were identified as carrying bi-allelic missense DNAH8 variants" among 90 Chinese MMAF men (snippet, PMID:32619401, Liu et al., Am J Hum Genet 2020). It also found a homozygous frameshift in a second cohort of 167 men from France, Iran and North Africa.
• Gene-disease validity. DrugMap lists DNAH8 as "Strong" with autosomal recessive inheritance. The source of that tier is not stated; the label is consistent with a ClinGen-style classification. Check ClinGen directly before recording a gene_disease_validity entry. It must be copied from a source record and not assigned.
• Risk and protective factors. None identified. No modifier genes, gene-environment interactions or protective variants were found for male infertility. A 2026 paper links DNAH8 dysfunction and DEHP exposure to hypospadias (PMID:42480140). I read only its title, so I make no claim about its content. It concerns a different phenotype and should not be merged into SPGF46.

3. Phenotypes

All phenotypes below are male-limited and restricted to the reproductive system. Frequencies are not quantified in the sources I read. Every patient described had the sperm phenotype.

• There is no consistent respiratory, laterality or other ciliary phenotype in the reports I read. DNAH8 was initially proposed as a candidate primary ciliary dyskinesia gene, but later studies showed MMAF in infertile men (snippet from the follow-up abstract).
• Quality-of-life data were not found.
• HPO term IDs above are from memory. Per the project rules, confirm each one with a lookup before binding it.

4. Genetic and molecular information

• Gene. DNAH8, 6p21.2, encoding dynein axonemal heavy chain 8. Confirm the HGNC ID by lookup, in the lowercase hgnc: form. I did not retrieve it.
• Inheritance. Autosomal recessive.
• Reported variants (from the abstracts I read):

• Consequence. Loss of function. mRNA decay was shown for the frameshift in PMID:36308074, and DNAH8 protein is absent or reduced in patient sperm.
• Not found. ClinVar classifications, gnomAD allele frequencies, epigenetic data, chromosomal abnormalities. This is a germline monogenic disorder.

5. Environmental information

No environmental, lifestyle or infectious causes are established for SPGF46. The DEHP/hypospadias paper above is outside this phenotype.

6. Mechanism and pathophysiology

Causal chain

1. Bi-allelic loss-of-function or missense variants in DNAH8 are the initiating lesion (demonstrated, PMID:32619401).
2. These lead to reduced or absent DNAH8 protein in the sperm flagellum. The evidence is immunofluorescence plus mRNA decay (demonstrated, PMID:36308074, PMID:33704367).
3. Loss of DNAH8 also reduces DNAH17, an associated dynein heavy chain, in sperm. This points to destabilization of outer dynein arm components (demonstrated for the association, per the discovery abstract; the exact mechanism is inferred).
4. Axonemal and periaxonemal organization is disrupted during spermiogenesis, producing MMAF flagella (demonstrated by EM).
5. Sperm motility is lost, which causes asthenoteratozoospermia and male infertility.

Branching. There is no demonstrated branch. Whether DNAH8 loss also affects motile cilia is unresolved. The reports show no strong ciliary phenotype.

Ontology suggestions (look up before binding). GO: axonemal dynein complex / outer dynein arm; sperm flagellum assembly; sperm axoneme assembly. CL: spermatid, spermatozoon. Uberon: testis, sperm flagellum.

Omics, single-cell and functional screens. Not found.

7. Anatomical structures affected

• Organ. Testis and male reproductive tract. Spermatogenesis proceeds, but the sperm are defective.
• Cells. Late spermatids and spermatozoa.
• Subcellular. Sperm flagellum axoneme, outer dynein arms, periaxonemal structures.
• Lateralization. Not applicable (bilateral germ-cell phenotype).

8. Temporal development

• Onset. Presents in adulthood as infertility. Congenital cause, with no childhood manifestations reported.
• Progression. Not described as progressive. Longitudinal data were not found.
• Remission. None reported.

9. Inheritance and population

• Inheritance. Autosomal recessive. Both homozygous variants (in consanguineous families) and compound heterozygous variants are reported.
• Consanguinity. Two of the reported families were consanguineous (PMID:33611675, PMID:36308074).
• Population. Chinese, Pakistani and North African/Iranian/French cohorts. About 2.2% of the Chinese MMAF cohort carried bi-allelic missense variants. Prevalence, carrier frequency, founder effects and the share of MMAF explained by DNAH8 were not established in what I read.
• Sex. Males only.

10. Diagnostics

• Semen analysis. Asthenoteratozoospermia with an MMAF pattern.
• Electron microscopy. Disorganized axoneme and periaxonemal structures.
• Immunofluorescence. Absent or reduced DNAH8 and DNAH17 in sperm.
• Genetic testing. Exome sequencing found the variants in the cohort studies. A male-infertility or MMAF gene panel that includes DNAH8, or targeted sequencing, would be the practical approach. Specific panels and GTR listings were not retrieved.
• Differential diagnosis. Other MMAF genes (the search results name DNAH2, DNAH6, DNAH11 and CFAP61) and primary ciliary dyskinesia.
• Screening. None.

11. Prognosis

Fertility is not spontaneously restored. The disorder appears to cause no systemic disease in the reports I read, but long-term follow-up data were not found.

12. Treatment

• ICSI works. PMID:33611675 reports that ICSI produced a healthy child for the proband. PMID:33704367 reports a clinical pregnancy with ICSI. Per the discovery abstract, ICSI with sperm from Dnah8-knockout mice "resulted in good pregnancy outcomes".
• Suggested NCIT terms (verify by lookup): assisted reproductive technology / intracytoplasmic sperm injection. Choose the most specific NCIT term under the clinical-intervention root, and if none fits, keep a free-text preferred_term.
• Not found. Drug therapy, gene therapy, clinical trials, pharmacogenomics. No evidence-based medical therapy exists in what I read.
• Counseling. Genetic counseling is appropriate. This is my inference from recessive inheritance and not a cited guideline.

13. Prevention

There is no primary prevention. Genetic counseling and carrier testing in relatives of known families are the relevant measures, again as inference. I found no guideline source.

14. Other species

Not found: OMIA entries, breeds, NCBI Taxon or Gene IDs for natural disease in other species.

15. Model organisms

• Mouse. The Dnah8 knockout shows MMAF and male sterility, and ICSI with its sperm gives good pregnancy outcomes (PMID:32619401, MODEL_ORGANISM evidence). It closely recapitulates the human sperm phenotype.
• Limitations. I did not retrieve the knockout design, MGI or IMPC records, or any data on non-reproductive phenotypes.
• A caution for evidence grading. The mouse ICSI result is model-organism evidence. It should not be used as the only support for the human ICSI claim, which has its own human reports above.

Open items before curation

• Look up HGNC, HPO, GO, CL and NCIT identifiers. I recalled the HPO IDs above from memory.
• Fetch the references with just fetch-reference and quote snippets from the cache. The snippets in this report come from search-result text, and I did not read the abstracts verbatim.
• Check MONDO:0033673 directly in MONDO.
• Check the ClinGen validity record for DNAH8.

Sources: - LOVD disease entry SPGF46 - DrugMap disease record - Liu et al. 2020, AJHG (PMID 32619401) - Weng et al. 2021 (PMID 33704367) - Dil et al. 2023 (PMID 36308074) - Yang et al. 2020 (PMID 32681648) - Zhou et al. 2021 (PMID 33611675) - Li et al. 2026 (PMID 42480140)

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:0033673 (2 mentions) - the report calls it "MONDO"; MONDO calls it spermatogenic failure 46
• HP:0012206 (2 mentions) - the report calls it "Asthenozoospermia"; HP calls it Abnormal sperm motility

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 (2 mentions) - the report calls it "teratozoospermia"; HP calls it Abnormal sperm morphology, and lists "Teratozoospermia" among its other names