Research report: Spermatogenic Failure 56 (SPGF56)

Scope and verification. This report rests on a limited set of sources that I read directly. Those are the Tu et al. 2021 full text on PMC (the first ~100,000 of ~114,000 characters; the supplements were not available), the GenCC and LOVD records, and search-result summaries for the other pages. I did not open OMIM, Orphanet, ClinGen, ClinVar, gnomAD or MONDO. Items I could not verify are marked [unverified], and the many sections with no disease-specific data say so. Every CURIE below is a lead and must be looked up before it is bound, per the repository's term contract.

1. Disease information

• Overview. SPGF56 is an autosomal recessive male infertility disorder caused by bi-allelic variants in DNAH10 (12q24.31). It presents as asthenoteratozoospermia with multiple morphological abnormalities of the sperm flagella (MMAF) and severely reduced sperm motility (MalaCards; LOVD).
• Identifiers.
• OMIM:619515 (LOVD).
• MedGen C5561978.
• MONDO:0030430, as given in the search-result summary. [unverified] My direct search for this ID returned nothing, so confirm it in OLS.
• Orphanet, ICD-10/11 and MeSH identifiers were not retrieved.
• Synonyms. SPERMATOGENIC FAILURE 56; SPGF56; "DNAH10-related MMAF"; "asthenoteratozoospermia" in the paper title.
• Source type. The aggregate disease record (OMIM) is built from patient-level exome data in one report (Tu et al. 2021). No EHR-derived information was found.
• Gene-disease validity. GenCC lists a "Moderate" classification (submission SGC-106953.2, evaluated February 2025) (GenCC). A DrugMap/DisGeNET-linked page lists "Limited". Different sources disagree, so copy the tier from the specific source with its own classified_by, and never assign one.
• Check ClinGen directly (just check-gene-validity), because I did not read a ClinGen record.

2. Etiology

• Cause. Bi-allelic (homozygous or compound heterozygous) DNAH10 variants. No environmental or infectious cause is established.
• Genetic risk factors. Tu et al. found five affected men from four unrelated families among 643 Chinese MMAF men, a yield of about 0.78%. Because of the small numbers, no population-level risk estimate exists (PMC8387467).
• Modifier genes, protective factors, gene-environment interactions. None reported.

3. Phenotypes

Source: Tu et al. 2021 (PMID:34237282), human clinical. The cohort is five men from four families, so frequencies are qualitative and no per-phenotype percentages exist.

• Other features. The paper reports no other primary ciliary dyskinesia (PCD) symptoms in these men. Hormone profile and karyotype were not available to me.
• Onset and course. Presenting complaint is adult infertility. No progression data exist.
• Quality of life. No data.

A separate 2023 report in Frontiers of Medicine describes "DNAH10 deficiency causes primary ciliary dyskinesia in humans and mice" (link). I could not retrieve it. That title is a lead for a respiratory-cilia phenotype, and its authors, PMID and findings are [unverified]. Check it before deciding whether SPGF56 is purely male-limited.

4. Genetic and molecular information

• Gene. DNAH10 (dynein axonemal heavy chain 10, encoding an inner dynein arm (IDA) heavy chain). Look up the HGNC ID from cache/hgnc/terms.csv or with runoak, in lowercase hgnc: form.
• Variants (Tu et al. 2021, NM_207437.3, from the full text):

• Classification and frequency. The missense variants were absent from 1000 Genomes and East Asian gnomAD, or very rare overall. SIFT, PolyPhen-2 and MutationTaster predicted them damaging. ClinVar and ACMG classifications were not retrieved. All variants are germline.
• Consequence. Loss of function (truncating variants) or presumed hypomorphic function (missense). Patient sperm show absent or markedly reduced DNAH10.
• Epigenetic or chromosomal findings. None reported.

5. Environmental information

None reported. There are no environmental, lifestyle or infectious factors, and no ECTO or NCBITaxon terms apply.

6. Mechanism / pathophysiology

Causal chain (steps 1–3 and 5 are shown in the human and mouse data, and step 4 is partly inferred):

1. Bi-allelic germline DNAH10 variants lead to loss or marked reduction of DNAH10 protein in sperm (shown by immunostaining in patients).
2. Loss of DNAH10 results in loss of inner dynein arms. TEM showed absent IDAs in about 80% of axonemal cross-sections, with central-pair and doublet disorganization.
3. IDA loss leads to depletion of the co-assembled IDA components DNAH2 and DNAH6 (almost absent in patient sperm). AKAP4 is mislocalized. DNAH8, DNAH17, DNAI1 and SPAG6 were comparable to controls.
4. The axoneme then fails to assemble or stay stable during spermiogenesis in elongating spermatids. The authors also speculate about intraflagellar or intramanchette transport roles from STRING predictions, which is not experimentally shown.
5. Flagellar assembly fails, giving the MMAF morphology: disorganized mitochondrial sheath and outer dense fibers, and absent, short or coiled tails.
6. The result is severely reduced motility (asthenozoospermia) and male infertility.

Quote supporting the central claim (abstract, PMID:34237282): "DNAH10 encodes an axonemal IDA heavy chain component that is predominantly expressed in the testes" and "DNAH10 is essential for sperm flagellar assembly".

• Cell types and processes. Elongated spermatid (CL:0000399 [verify]) and spermatozoon (CL:0000019 [verify]). GO leads include sperm flagellum assembly (GO:0120316 [verify]), axoneme assembly (GO:0035082 [verify]) and inner dynein arm / axonemal dynein complex (GO:0005858 [verify]).
• Not available. Metabolic, immune, transcriptomic, proteomic, single-cell, multi-omic and functional-screen data for SPGF56. Expression: abundant in human testis (Human Protein Atlas), and in mouse predominantly testicular, rising from postnatal day 21 and localized to the cytoplasm of elongated spermatids. Mouse trachea and fallopian tube also express it.

7. Anatomical structures affected

• Primary. Testis (UBERON:0000473 [verify]), specifically seminiferous tubule germ cells at spermiogenesis, and the sperm flagellum.
• Subcellular. Axoneme, with inner dynein arms as the primary lesion, plus the mitochondrial sheath and outer dense fibers disturbed secondarily.
• Secondary organs and lateralization. None reported for the human male phenotype, and the condition is bilateral. Whether motile cilia elsewhere are affected is unresolved (see the 2023 report above).

8. Temporal development

• Onset. Adult, presenting as infertility (spermatogenesis begins at puberty).
• Course. No natural-history, remission or progression data.

9. Inheritance and population

• Inheritance. Autosomal recessive (HP:0000007 [verify]).
• Consanguinity. Two of the four families were consanguineous (homozygous variants).
• Prevalence and incidence. Not available. The only figure is 5/643 (0.78%) of Chinese MMAF men in one cohort, which is a case fraction, not a population frequency.
• Population effects. The cohort is Chinese. No founder effect, carrier frequency or sex-ratio data exist (the disease is male-limited by phenotype).
• Penetrance, expressivity, anticipation, germline mosaicism. No data.

10. Diagnostics

• Semen analysis. Asthenoteratozoospermia with MMAF morphology.
• Sperm ultrastructure. H&E and SEM show flagellar defects. TEM shows absent IDAs. Immunofluorescence shows absent or reduced DNAH10, DNAH2 and DNAH6.
• Genetic testing. Exome sequencing identified all cases. Include DNAH10 in MMAF or male-infertility gene panels. No dedicated testing guideline was found.
• Differential diagnosis. Other MMAF genes (e.g. DNAH1, CFAP family genes). Other genes in the same inner-dynein-arm family can produce overlapping sperm phenotypes.

11. Outcome / prognosis

• There are no survival or quality-of-life data. The condition is not life-limiting and is primarily a fertility disorder.
• Fertility prognosis. Natural conception is not expected (a knockout mouse is completely infertile). Assisted reproduction can work (see section 12).

12. Treatment

• Assisted reproduction (ICSI). In Tu et al., three of five men underwent ICSI and two had good outcomes (Table S7). One partner (H049 II-2) had a poor result: six low-quality oocytes yielded three poor-quality embryos.
• NCIT lead: Intracytoplasmic Sperm Injection. Look up the CURIE; I did not retrieve it.
• Evidence is anecdotal (n=3), and the pregnancy and live-birth details are not available to me.
• No drug, gene therapy or clinical trial is known for SPGF56, and I searched no trial registries.

13. Prevention

• No primary prevention exists. Genetic counseling for consanguineous couples, and for the partner's carrier status, is the relevant counseling. Preimplantation or prenatal testing is possible in principle once variants are known, but there is no source for it here.

14. Other species / natural disease

No naturally occurring disease in other species was found (OMIA not searched). The mouse ortholog is Dnah10.

15. Model organisms

Source: Tu et al. 2021 (model organism, in vivo).

• Fidelity. The knockout recapitulates MMAF and infertility. The authors describe it as more severe than the patients' phenotype, which is a limitation. The knock-in models a specific human missense allele.
• The 2023 Frontiers of Medicine knock-in and knockout study reported male infertility plus PCD features with flagellar ultrastructure and motility defects (as summarized by search results). I could not read it, so cite it only after verifying.
• Resources. MGI/IMPC were not searched, and a Cyagen mouse atlas entry exists for the gene.

Gaps for curation

• The OMIM clinical synopsis, ClinGen record, Orphanet entry and ClinVar classifications were not read.
• Verify the MONDO ID and all HPO, GO, CL and UBERON leads before binding.
• Resolve the "Moderate" (GenCC) versus "Limited" (DrugMap) validity discrepancy against the primary source.
• Identify and verify the 2023 PCD-related paper, and check whether any non-sperm phenotype belongs in the entry.

Sources

• Tu et al. 2021, AJHG (PMID:34237282), PMC8387467
• GenCC submission SGC-106953.2
• LOVD disease 06925
• MalaCards: Spermatogenic Failure 56
• Frontiers of Medicine 2023, DNAH10 and PCD (not read)
• Cyagen mouse atlas, Dnah10

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:

• HP:0012206 (1 mention) - the report calls it "Asthenozoospermia"; HP calls it Abnormal sperm motility

Obsolete terms

These terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:

• CL:0000399 (obsolete phloem element) (1 mention)

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:0000798 (1 mention) - the report calls it "Oligospermia"; HP calls it Oligozoospermia, and lists "Oligospermia" among its other names

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.