Spermatogenic Failure 39

1. Disease Information

Overview. SPGF39 is an autosomal recessive form of male infertility caused by biallelic variants in DNAH17. A disease-ontology description gives the phenotype as a spermatogenic failure "characterized by multiple morphologic anomalies of the sperm flagellum, lack of the outer dynein arms in the flagella, and asthenozoospermia" (drugmap disease page). It is isolated: the sources describe infertility without a syndromic or ciliary phenotype.

Identifiers | Resource | ID | |---|---| | MONDO | MONDO:0032845 | | OMIM | #618643 (SPGF39) | | Gene | DNAH17 (OMIM 610063), 17q25.3 | | MedGen | C5231438 | | LOVD disease entry | #06384 (LOVD) | | Orphanet, ICD-10/11, MeSH | not retrieved |

Synonyms. Spermatogenic failure 39; SPGF39; DNAH17-related MMAF or asthenozoospermia. This is the MMAF (multiple morphological abnormalities of the sperm flagella) / asthenoteratozoospermia spectrum.

Source type. The disease-level resources (OMIM, MONDO) aggregate the case literature. The primary papers are small patient series with sperm and genetic analysis.

2. Etiology

• Causal factor: homozygous or compound heterozygous DNAH17 variants. OMIM lists autosomal recessive inheritance with a phenotype-mapping key of 3, meaning the molecular basis is known (MedGen/OMIM mirror).
• Gene-disease validity: one gene-target database lists the association as "Definitive" (drugmap). Per the dismech rule, I did not use this as a ClinGen tier. It is not a CGGV record. Check the cached ClinGen data with just check-gene-validity before recording any tier.
• Risk, protective and gene-environment factors: none found. No environmental, lifestyle, modifier-gene or protective-variant data turned up for this monogenic disorder. These are gaps, not negatives.

3. Phenotypes

All items are male-limited. Frequencies were not retrieved. Suggested HPO terms are leads that need lookup and validation.

• Onset and course: onset is at reproductive age, when infertility is noticed. The condition is lifelong and non-progressive in the reports seen, which is inferred.
• Quality of life: not retrieved.

4. Genetic / Molecular Information

• Gene: DNAH17, axonemal dynein heavy chain 17, a sperm-specific outer dynein arm heavy chain. HGNC id: look up in cache. dismech uses lowercase hgnc: CURIEs.
• Variant types: the literature includes loss-of-function variants (nonsense, frameshift, splice) and missense variants.
• Whitfield et al. 2019 (Am J Hum Genet 105(1):198–212) is the foundational paper, "Mutations in DNAH17, encoding a sperm-specific axonemal outer dynein arm heavy chain, cause isolated male infertility due to asthenozoospermia".
• Zhang et al. 2020 (J Exp Med 217(2):e20182365) reports a DNAH17 missense variant causing flagella destabilization and asthenozoospermia (JEM).
• Sha et al. 2020 (Ann Hum Genet 84:271–9) reports biallelic variants in a patient with severe asthenozoospermia and MMAF, with DNAH17 protein nearly undetectable in sperm (Wiley).
• Zhang et al. 2021 (Clin Genet 99:176–86) reports novel loss-of-function variants causing MMAF in humans and mice (Mount Sinai record).
• Newer reports include a 2023 J Assist Reprod Genet paper (Springer), a 2025 Reprod Sci paper on splice-site variants truncating the AAA6 domain (Springer) and a recent Asian J Androl paper (PubMed 41549443).
• Cohort size: the 2023 paper says that, with its five new cases, the literature held 21 patients with DNAH17 mutations.
• Allele frequency, ACMG classifications, ClinVar counts, founder variants, modifier genes, epigenetics, chromosomal abnormalities: not retrieved.
• Functional consequence: loss of function, with loss of the outer dynein arms and of DNAH17 protein in sperm (Sha 2020).

5. Environmental Information

None found. There are no known toxin, lifestyle or infectious contributors for this monogenic form. Leave environmental: empty.

6. Mechanism / Pathophysiology

Causal chain (steps 1–3 and 5 follow the sources; step 4 is inferred from the DNAH17 and dynein-arm biology rather than shown directly):

1. Biallelic DNAH17 variants (loss of function, or destabilizing missense) are inherited from both parents.
2. These lead to loss or severe reduction of DNAH17 protein in sperm (Sha 2020).
3. This results in absent outer dynein arms in the sperm axoneme, seen by electron microscopy (MedGen mirror).
4. (Inferred) Without outer-arm dynein force generation, the flagellum cannot beat normally. This causes asthenozoospermia.
5. (Branch) In many men, flagellar assembly also fails and the tail becomes short, absent, coiled or irregular (MMAF). In the mouse, disorganized microtubules and outer dense fibers appear in developing spermatids (impaired flagellar assembly).
6. Sperm cannot reach or fertilize the oocyte, so the man is infertile.

Cell types and processes (suggested terms, to be looked up): - Cell types: spermatid (CL:0000018), spermatozoon (CL:0000019). - Processes: sperm flagellum assembly and axoneme assembly (GO:0007288), outer dynein arm assembly (GO:0036158, check), sperm motility (GO:0097722). - Compartments: motile cilium or sperm flagellum, axoneme. - Anatomy: testis (UBERON:0000473), seminiferous tubule, sperm flagellum. - Protein: a dynein heavy chain with ATPase (AAA) domains. The 2025 paper reports splice variants that truncate the AAA6 domain. Further structure-function detail was not retrieved.

Omics, single-cell and immune data were not retrieved. None are expected for this disorder.

7. Anatomical Structures Affected

The primary site is the testis, specifically the post-meiotic germ cells (spermatids) and the sperm flagellum. No extragonadal involvement is reported, in contrast to primary ciliary dyskinesia. That absence is inferred from the isolated-infertility framing, so confirm it in Whitfield 2019. Lateralization is not applicable.

8. Temporal Development

Onset is at reproductive age. Course is stable and lifelong, which is inferred. No natural-history or remission data were found.

9. Inheritance and Population

• Inheritance: autosomal recessive (OMIM). HPO term HP:0000007.
• Sex: males only are affected.
• Prevalence, carrier frequency, penetrance, founder effects and consanguinity: not retrieved. Many MMAF cohorts include consanguineous families, but I did not confirm that here.
• Populations: cases were reported from several cohorts, including Chinese, North African and Middle Eastern ones. I did not verify this, so check each paper.

10. Diagnostics

• Semen analysis: severe asthenozoospermia, often with MMAF sperm morphology.
• Electron microscopy: absent outer dynein arms and a disorganized axoneme.
• Immunofluorescence: reduced or absent DNAH17 staining in sperm (Sha 2020).
• Genetic testing: whole-exome or gene-panel sequencing for DNAH17 and other MMAF genes (DNAH1, CFAP43, CFAP44 and others). Single-gene testing is feasible once the pattern is known. Panel contents were not retrieved.
• Differential diagnosis: other causes of asthenozoospermia and MMAF, and primary ciliary dyskinesia.
• Screening and clinical criteria: none.

11. Outcome / Prognosis

The disorder is not life-limiting. Fertility is the main outcome. - A pooled 2023 analysis reported worse pregnancy outcomes after ICSI in men with MMAF-type DNAH17 mutations. Only three men achieved a clinical pregnancy, with ICSI plus assisted oocyte activation (AOA) (Springer). - A newer report of two probands who had ICSI with AOA reported fertilization rates of 90.9–100.0% and blastocyst rates of 66.7–85.7% (PMC13423380). Its authors recommend ICSI with AOA over conventional IVF. Treat this as a small, conflicting data point, not a settled result.

12. Treatment

• No curative therapy.
• Assisted reproduction: ICSI, possibly with AOA, as above. Suggested NCIT leads, not verified: intracytoplasmic sperm injection and assisted reproductive technology. Look up the IDs before binding them. Per dismech rules, omit the term: if no suitable NCIT clinical-intervention term exists.
• Genetic counseling: NCIT:C15240 (listed in CLAUDE.md).
• Pharmacotherapy, gene therapy, trials (NCT): none found.

13. Prevention

Genetic counseling and carrier testing of partners in affected families. Preimplantation or prenatal testing is possible in principle, but I found no source on it. No primary-prevention measures exist.

14. Other Species / Natural Disease

No natural disease in other species was found. OMIA and breed data were not checked.

15. Model Organisms

• Mouse: Dnah17−/− mice showed an MMAF phenotype with completely disorganized axonemal structures, and disorganized microtubules and outer dense fibers in spermatids (Zhang et al. 2021, Mount Sinai record). The mouse phenocopies the human sperm phenotype. This is MODEL_ORGANISM evidence.
• ICSI in knockout mice: a ResearchGate summary says ICSI was performed in patients and KO mice with offspring monitored. I could not retrieve the results.
• Resources: an MGI/IMPC page for Dnah17 appeared in an earlier search, but I did not confirm the gene symbol mapping.
• Limitations: not retrieved.

Gaps for Curators

1. Fetch Whitfield 2019, Zhang 2020 (JEM), Sha 2020 and Zhang 2021 with just fetch-reference to get PMIDs and abstracts, then quote exact snippets from those.
2. Check GeneReviews and Orphanet for a baseline, using just check-genereviews.
3. Look up every HP, GO, CL, UBERON, NCIT and hgnc: identifier above in the same step you write it. The ones I gave are leads, not bindings.
4. Frequencies, prevalence, variant spectrum and the ICSI evidence need primary-source reading.

Sources: - OMIM-derived gene table search results - DrugMap SPGF39 page - LOVD disease #06384 - Sha et al. 2020, Ann Hum Genet - Zhang et al., JEM - Zhang et al. 2021, Clin Genet (Mount Sinai record) - J Assist Reprod Genet 2023 - Reprod Sci 2025 - Asian J Androl, PubMed 41549443 - PMC13423380

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:0032845 (1 mention) - the report calls it "MONDO"; MONDO calls it spermatogenic failure 39
• HP:0012206 (1 mention) - the report calls it "Asthenozoospermia"; HP calls it Abnormal sperm motility
• HP:0012864 (2 mentions) - the report calls it "check"; HP calls it Abnormal sperm morphology
• HP:0012862 (1 mention) - the report calls it "check"; HP calls it Abnormal germ cell morphology
• NCIT:C15240 (1 mention) - the report calls it "listed in CLAUDE.md"; NCIT calls it Genetic Counseling

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
• GO:0007288 (1 mention) - the report calls it "Processes: sperm flagellum assembly and axoneme assembly"; GO calls it sperm axoneme assembly
• UBERON:0000473 (1 mention) - the report calls it "Anatomy: testis"; UBERON calls it testis