I'm gathering primary-literature details (PMIDs, variants, ICSI outcomes) on DNAH2 and SPGF45 before I write the report.

Research report: Spermatogenic Failure 45 (SPGF45)

Evidence caveat. OMIM (403) and PubMed (cookie wall) blocked direct fetching, and LOVD was blocked too. Statements are therefore tagged: - [Verified] means I read it in a fetched page or search result. - [Secondary] means it came from a search-result summary only. - [Not verified] means I could not confirm it. I have not invented PMIDs, so those items are marked for checking.

Repo note. stubs/Spermatogenic_Failure_45.yaml and a 14-line kb/disorders/Spermatogenic_Failure_45.yaml already exist in this checkout. This report is a research input, and nothing in the repo was edited.

1. Disease information

• Overview. SPGF45 is an autosomal recessive form of male infertility. It is caused by biallelic variants in DNAH2, which encodes an axonemal inner-arm dynein heavy chain. The sperm phenotype is asthenoteratozoospermia, typically multiple morphological abnormalities of the sperm flagella (MMAF). Sperm tails are absent, short, bent, coiled or of irregular caliber.
• Identifiers.
• OMIM #619094 (SPGF45), LOVD disease 06934 [Secondary].
• MONDO:0033671 (from the repo stub and a DrugMap record).
• The gene-disease link is rated "Moderate" in the DrugMap record [Secondary].
• Parent term: spermatogenic failure, MONDO:0004983 [Secondary].
• Orphanet, ICD and MeSH IDs: [Not verified].
• Synonyms. SPGF45; DNAH2-related MMAF; DNAH2-related asthenoteratozoospermia.
• Data source. The disease is defined at the aggregate gene-disease level. The supporting studies are small patient cohorts and families, not EHR data.

2. Etiology

• Causal factor. Biallelic loss-of-function or deleterious missense variants in DNAH2 (MIM 603333). All reported cases are genetic.
• Genetic risk and modifiers. None established. In the Pakistani family, two other rare variants (FZD3 p.F201S and MYDGF c.174+1G>T) did not co-segregate with infertility [Verified, PMC8103034].
• Environmental risk, protective factors and gene-environment interactions. None reported.

3. Phenotypes

Phenotype frequencies are not given in the sources I could read. The HPO terms below are suggestions to look up before binding.

• Sperm findings in the family. Sperm were 80%, 82% and 92% morphologically abnormal in three affected males. Defects were mainly in the tail, with mild head defects [Verified, PMC8103034].
• Other findings. Karyotype and Y-microdeletion screening were normal. No extra-testicular phenotype was described; the mouse had no trachea or oviduct defects.
• Quality of life. Not available.

4. Genetic and molecular information

• Gene. DNAH2 (17p13.1). The HGNC ID should be looked up in the repo's hgnc: form and not typed from memory.
• Inheritance. Autosomal recessive [Secondary].
• Reported variants.
• NM_020877:c.12720G>T (p.W4240C), homozygous, in a consanguineous Pakistani family. It was found by exome sequencing, co-segregated with infertility, is absent from gnomAD and Bravo, and has CADD 31 [Verified, PMID:33968937].
• Chinese MMAF cohorts: Li et al. 2019 (Clin Genet) is cited as the original DNAH2-MMAF report, and Gao et al. 2021 (Reprod Biomed Online 42(5):963-72) reported three unrelated men with biallelic DNAH2 variants [Secondary; PMIDs not verified].
• A 2025 cohort of 75 MMAF men found DNAH2, DNAH6 and DNAH10 variants in six unrelated men [Secondary, PMID:40592014].
• Functional consequence. Loss of function. DNAH2 protein is absent from mutant mouse sperm.
• Epigenetics and chromosomal abnormalities. None reported.

5. Environmental information

None reported. No infectious agent is involved.

6. Mechanism and pathophysiology

Causal chain (steps 1-2 are demonstrated in human families, steps 3-6 come from the mouse model, and step 7 is inferred): 1. Biallelic DNAH2 variants (human: p.W4240C; mouse: deletion of exons 25-28) lead to loss of functional DNAH2 protein. 2. DNAH2 is lost from sperm flagella, along with DNAH1 (another inner-arm dynein) and the radial spoke protein RSPH3. Acetylated tubulin and the outer-arm dynein DNAH9 are retained. 3. This disrupts flagellar assembly during spermiogenesis: an incomplete 9+2 axoneme, misaligned outer dense fibers and doublets, an unfused or missing fibrous sheath, and midpiece/mitochondrial disorganization. 4. Centriolar proteins (CENTRIN1, γ-tubulin) end up near the connecting piece, and annulus proteins (SEPTIN4, SEPTIN12) are mislocalized. The authors propose that basal body and annulus positioning is also disrupted. 5. Sperm tails come out absent, short, bent, coiled or irregular. The mouse proportions were absent 31%, short 9%, bent 11%, coiled 16% and irregular caliber 28%. 6. Reduced sperm number and motility result in asthenozoospermia or oligoasthenozoospermia. 7. Infertility follows (inferred from step 6).

Source for steps 2-6: PMC8103034 [Verified]. Quote from it: "Our results demonstrate that DNAH2 is essential for multiple steps in sperm flagella formation."

• Suggested terms.
• GO biological processes: sperm flagellum assembly, spermatid differentiation, cilium movement.
• GO cellular components: axonemal dynein complex, sperm flagellum.
• Cell types: spermatid (CL:0000018), spermatozoon (CL:0000019).
• Omics, single-cell, metabolic and immune findings. None found.

7. Anatomical structures affected

• Primary site. The testis (seminiferous epithelium), with the defect expressed in elongating spermatids and the mature sperm flagellum.
• Subcellular structures. Axoneme, outer dense fibers, fibrous sheath, midpiece mitochondria, connecting piece and annulus.
• Other organs. No respiratory-cilia or oviduct phenotype was seen in the mouse. In humans, no primary ciliary dyskinesia is reported in the sources I read, but I did not search for this specifically.
• Laterality. Bilateral and systemic to the male germline.

8. Temporal development

• Onset. Congenital genotype, with manifestation at reproductive age. Infertility is usually the presenting complaint.
• Course. Stable and non-progressive, with no remission pattern reported.

9. Inheritance and population

• Inheritance. Autosomal recessive. Consanguinity was present in the Pakistani family. Expressivity in mice is complete in males, and heterozygous carriers are fertile.
• Prevalence. Not documented. MMAF is rare among infertile men, and DNAH2 is one of several genes.
• Sex. Affects males only, because the mouse nulls show female fertility.
• Populations. Cases are reported from Pakistan and China. Founder effects and carrier frequency are [Not verified].

10. Diagnostics

• Semen analysis. Asthenozoospermia or oligoasthenozoospermia, with more than 80% abnormal forms mainly in the tail.
• Imaging. Electron microscopy of sperm shows the axonemal and fibrous sheath defects.
• Immunofluorescence. Absent DNAH2, DNAH1 and RSPH3 in sperm.
• Genetic testing. Exome sequencing or an infertility gene panel including DNAH2. Normal karyotype and Y-chromosome microdeletion screening are the usual prerequisites.
• Differential. Other MMAF genes (DNAH1, CFAP43, CFAP44, DNAH6, DNAH8, DNAH10, DNAH11, FSIP2) and primary ciliary dyskinesia.
• Screening, LOINC and criteria. [Not verified]; no validated screening exists.

11. Outcome and prognosis

• Life expectancy. Normal, since there is no systemic disease described.
• Fertility. Natural conception is unlikely.
• Assisted reproduction. Several reports describe good ICSI outcomes. In a 2025 cohort including DNAH2, DNAH6 and DNAH10 patients, five of six couples achieved a live birth [Secondary, PMID:40592014]. An earlier DNAH2 study also reported pregnancies in two couples [Secondary]. These are small series.

12. Treatment

• Established treatment. ICSI, using ejaculated sperm. Suggested NCIT term: Intracytoplasmic Sperm Injection (look up the CURIE).
• Drugs. No effective pharmacotherapy. Hormones are normal, so gonadotropin therapy has no rationale.
• Gene therapy, other advanced therapy and trials. None found.
• Counseling. Genetic counseling is appropriate. Sons conceived by ICSI would be obligate carriers if the partner is not a carrier.

13. Prevention

Primary prevention is not applicable. Carrier or cascade testing of relatives is possible in affected families. Preimplantation genetic testing is theoretically available, but no source I read describes it for DNAH2.

14. Other species and natural disease

• Orthologs. Mouse Dnah2 (MGI:95543, see the IMPC gene page).
• Natural disease in animals. None found in OMIA; I did not search it.

15. Model organisms

• Mouse. A Dnah2 CRISPR/Cas9 deletion (exons 25-28) [Verified, PMC8103034].
• Homozygous males are infertile.
• Heterozygous males and females of both genotypes are fertile.
• Seminiferous tubules and epididymis have fewer sperm.
• Flagella are absent, short, bent, coiled or of irregular caliber, with mild head defects.
• Midpiece and mitochondrial defects are present.
• The model recapitulates the human MMAF phenotype well. Its limitation is that human ICSI outcomes cannot be tested in it.
• Related suggested relationship values for the KB: RECAPITULATES, HIGH fidelity, evidence_source: MODEL_ORGANISM.
• Other models. Not found.

Evidence gaps to close before curation

1. Fetch OMIM #619094 through an authorized route to confirm the gene, inheritance and clinical synopsis.
2. Run just fetch-reference on PMID:33968937 and PMID:40592014, then pull exact snippets from the cached files.
3. Find and verify the PMIDs for Li et al. 2019 and Gao et al. 2021, and check GeneReviews and ClinGen for DNAH2 gene-disease validity (the "Moderate" rating above is from DrugMap only).
4. Look up every HPO, GO, CL and NCIT CURIE with runoak or the cache; none above are verified.

Sources: - Hwang et al. 2021, PMC8103034 - PMID 40592014 (DNAH2/DNAH6/DNAH10 ICSI outcomes) - LOVD SPGF45 - DrugMap disease record - IMPC Dnah2

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:0004983 (1 mention) - the report calls it "Secondary"; MONDO calls it spermatogenic failure
• HP:0012206 (1 mention) - 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:

• 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: MGI.