Spermatogenic Failure 39

👪

Inheritance

1

Autosomal recessive HP:0000007

Disease requires biallelic DNAH17 variants: homozygous variants in consanguineous Pakistani, Chinese and other families, and compound heterozygous variants in non-consanguineous families. Heterozygous carriers are fertile.

Autosomal recessive inheritance

Show evidence (2 references)

PMID:40009974 SUPPORT Human Clinical

"These variants exhibited an autosomal-recessive inheritance pattern and caused deficiency of DNAH17 in spermatozoa."

Recessive segregation in five unrelated families.

PMID:31658987 SUPPORT Human Clinical

"Whole-exome sequencing identified a missense variant (c.G5408A, p.C1803Y) in DNAH17, a functionally uncharacterized gene, recessively cosegregating with asthenozoospermia in the family."

Recessive co-segregation in a consanguineous family.

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Mechanistic Hypotheses

2

DNAH17 is a sperm-specific outer dynein arm heavy chain, so its loss causes isolated male infertility rather than primary ciliary dyskinesia

sperm_specific_dnah17_oda CANONICAL

Evidence balance 3 support 2 refute

DNAH17 and DNAH8 are found along the sperm axoneme but not in respiratory cilia, which use DNAH5, DNAH9 and DNAH11 instead. Patients therefore keep respiratory ODAs and have no ciliary disease. Two small reports of DNAH17 variants in individuals with laterality defects are the only evidence against this, and neither includes functional data.

Show evidence (5 references)

PMID:31178125 SUPPORT In Vitro

"We show that DNAH17 and DNAH8, but not DNAH5, DNAH9, or DNAH11, colocalize with α-tubulin along the sperm axoneme, whereas the reverse picture is observed in respiratory cilia, thus explaining the phenotype restricted to sperm cells."

Immunostaining shows the distinct heavy-chain composition of sperm and ciliary ODAs.

PMID:31658987 SUPPORT Model Organism

"Using the antibody against DNAH17, we found that DNAH17 protein was indeed not detected in cilia from tracheae and was detected only in testes and epididymides of WT mice"

In wild-type mice DNAH17 protein is absent from tracheal cilia and restricted to testis and epididymis.

PMID:31658987 SUPPORT In Vitro

"Consistently, in humans, DNAH17 was detected only in testes, but not in various somatic cell lines"

Immunoblotting of human testis lysate and human somatic cell lines (including alveolar epithelial A549) shows the same testis-restricted expression in humans.

+ 2 more references

Null DNAH17 alleles cause MMAF, while a hypomorphic missense allele causes asthenozoospermia with normal flagellar morphology

dnah17_allelic_severity EMERGING

Evidence balance 2 support

Loss-of-function alleles remove DNAH17 and give MMAF with disorganized axonemes; the p.C1803Y allele keeps DNAH17 in the flagellum and gives normal morphology with motility loss from doublet 4-7 destabilization. The same split is seen in mice (Dnah17-/- versus Dnah17M/M). The evidence for the hypomorphic class rests on one family.

Pathograph links

Hypomorphic DNAH17 p.C1803Y Missense Allele -> Destabilization of Microtubule Doublets 4-7 During Epididymal Storage DIRECT Shown for the p.C1803Y allele in patients and knock-in mice, where the ODA heavy chain is present but doublets 4-7 are lost after the sperm are stored in the epididymis.

Show evidence (2 references)

PMID:37574497 SUPPORT Human Clinical

"DNAH17 has been associated with asthenozoospermia and male infertility, but different types of DNAH17 variants appear to be involved in different sperm phenotypes."

Literature review of 21 patients noting allele-dependent phenotypes.

PMID:31658987 SUPPORT Human Clinical

"In this study, we recruited three primary infertile patients from Pakistan, born to a consanguineous union and suffering from asthenozoospermia with no MMAF-like phenotype or ciliary-related symptoms."

The missense family lacks MMAF.

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Pathophysiology

6

Loss of the DNAH17 Outer-Arm Dynein Heavy Chain

Nonsense, frameshift, splice and many missense alleles abolish or sharply reduce DNAH17 protein in sperm. Splice-site alleles can delete exons encoding the AAA6 part of the motor domain. The p.C1803Y missense allele is an exception, in which DNAH17 is still made and localizes normally to the flagellum; it is a separate hypomorphic node.

DNAH17 hgnc:2946

minus-end-directed microtubule motor activity GO:0008569 ↓ DECREASED

Downstream

Outer Dynein Arm Loss in the Sperm Axoneme DNAH17 is a structural heavy chain of the sperm ODA; without it the partner heavy chain DNAH8 and the ODA docking and intermediate-chain proteins are also lost from sperm.

Show evidence (3 references)

PMID:31178125 SUPPORT Human Clinical

"We also demonstrate the loss of function associated with DNAH17 mutations in two unrelated individuals by performing immunoblot and immunofluorescence analyses on sperm cells"

Patient sperm lack DNAH17 protein.

PMID:33070343 SUPPORT Human Clinical

"Whole-exome sequencing identified novel homozygous DNAH17 variants, which led to loss of DNAH17 proteins, in the patients."

Independent confirmation of protein loss with homozygous loss-of-function alleles.

PMID:41258988 SUPPORT In Vitro

"Minigene assays confirmed exon 72 skipping, leading to a frameshift mutation (p.Asn3844Lysfs*13) that truncates the AAA6 domain."

Splice alleles truncate the motor domain.

Hypomorphic DNAH17 p.C1803Y Missense Allele

The homozygous p.C1803Y (c.G5408A) missense allele reported in one consanguineous Pakistani family. Unlike null alleles, it does not remove DNAH17: the protein is still made and localizes normally to the sperm flagellum, and ODAs remain visible on the surviving doublets in knock-in mice. Motor function is presumed reduced rather than lost, and flagella form normally but are destabilized later.

Null DNAH17 alleles cause MMAF, while a hypomorphic missense allele causes asthenozoospermia with normal flagellar morphology

DNAH17 hgnc:2946

minus-end-directed microtubule motor activity GO:0008569 ↓ DECREASED

Downstream

Destabilization of Microtubule Doublets 4-7 During Epididymal Storage Shown for the p.C1803Y allele in patients and knock-in mice, where the ODA heavy chain is present but doublets 4-7 are lost after the sperm are stored in the epididymis.

Show evidence (1 reference)

PMID:31658987 SUPPORT Human Clinical

"DNAH17, specifically expressed in testes, was localized to sperm flagella, and the mutation did not alter its localization."

In patient sperm the missense protein is still present and correctly localized.

Outer Dynein Arm Loss in the Sperm Axoneme

ODAs are absent along the sperm flagellum. Proteomics of patient sperm shows reduced DNAH8, the intermediate chain DNAI1 and the docking-complex proteins ODAD2 and ODAD4. Respiratory cilia keep their ODAs.

Outer dynein arm assembly GO:0036158 ↓ DECREASED

Outer dynein arm GO:0036157

Downstream

Sperm Axonemal Disorganization ODA loss accompanies loss of doublets 4-7, mitochondrial sheath defects and, with null alleles, complete axonemal disorganization. How loss of an ODA heavy chain destabilizes these other structures is not established.

Show evidence (3 references)

PMID:31178125 SUPPORT Human Clinical

"By analyzing five male individuals who consulted for isolated infertility and displayed a loss of ODAs in their sperm cells but not in their respiratory cells, we identified bi-allelic mutations in DNAH17."

ODA loss restricted to sperm in patients.

PMID:41549443 SUPPORT Human Clinical

"In addition to DNAH17, several proteins associated with ODA assembly, including ODAD4, ODAD2, DNAI1, and DNAH8, were among the top 10 downregulated proteins in DNAH17-mutant patients"

Proteomic evidence that the whole sperm ODA fails to assemble.

PMID:40009974 SUPPORT Human Clinical

"Comprehensive functional analysis revealed that DNAH17 deficiency impaired the assembly and docking of outer dynein arms, affected the acrosome reaction, and disrupted mitochondrial function."

Independent cohort confirming impaired ODA assembly and docking.

Destabilization of Microtubule Doublets 4-7 During Epididymal Storage

With the hypomorphic p.C1803Y allele, sperm are formed normally but lose doublets 4-7 at the principal and end pieces while stored in the epididymis. Sperm count and morphology stay normal, so the result is asthenozoospermia without MMAF. Doublet 4-7 loss is also frequent in patients with null alleles, alongside wider axonemal disorganization.

Sperm CL:0000019

Axoneme GO:0005930

Animal models

Dnah17 p.C1803Y knock-in mouse Mouse recapitulates The knock-in reproduces the patients' doublet 4-7 loss and asthenozoospermia.

Downstream

Reduced sperm motility

Abnormal sperm axoneme morphology

Show evidence (2 references)

PMID:31658987 SUPPORT Human Clinical

"However, spermatozoa of all three patients showed higher frequencies of microtubule doublet(s) 4-7 missing at principal piece and end piece than in controls."

Doublet 4-7 loss in patient sperm.

PMID:31658987 SUPPORT Model Organism

"Further examinations revealed that the doublets 4-7 were destabilized largely due to the storage of sperm in epididymis."

Knock-in mice locate the destabilization to epididymal storage.

Sperm Axonemal Disorganization

Flagellar cross-sections show missing ODAs, loss of doublets 4-7 at the principal and end pieces, mitochondrial sheath defects in the midpiece and, with null alleles, a completely disorganized axoneme. In Dnah17-/- mice clusters of disorganized microtubules and outer dense fibers appear already in developing spermatids, so flagellar assembly fails.

Sperm CL:0000019

Axoneme GO:0005930 Sperm flagellum GO:0036126

Animal models

Dnah17 knockout mouse Mouse recapitulates The knockout reproduces the human MMAF and axonemal disorganization.

Downstream

Multiple Morphological Abnormalities of the Sperm Flagella

Abnormal sperm axoneme morphology

Show evidence (3 references)

PMID:33070343 SUPPORT Human Clinical

"Transmission electron microscope analyses revealed completely disorganized axonemal structure as the predominant anomaly and increased frequencies of missings of microtubule doublet(s) 4-7 in sperm flagella of patients."

Axonemal disorganization in patients with loss-of-function alleles.

PMID:41549443 SUPPORT Human Clinical

"TEM further revealed multiple MS abnormalities in the midpiece; the absence of ODAs in the middle, principal, and end pieces; and the loss of DMTs 4–7 in the principal and end pieces of sperm flagella."

ODA, doublet and mitochondrial sheath defects in a further cohort.

PMID:33070343 SUPPORT Model Organism

"Clusters of disorganized microtubules and outer dense fibers were observed in developing spermatids, indicating impaired sperm flagellar assembly."

In knockout mice the defect begins during flagellar assembly in spermatids.

Multiple Morphological Abnormalities of the Sperm Flagella

The usual semen phenotype: short, coiled, absent and irregular-caliber flagella in the same ejaculate, with severely reduced motility and often abnormal heads and midpieces.

Sperm CL:0000019

Sperm flagellum assembly GO:0120316 ↓ DECREASED

Animal models

Dnah17 knockout mouse Mouse partially recapitulates MMAF is reproduced, but with a far more severe spermatogenic defect than in patients.

Swiss Large White boar with DNAH17 intronic deletion Pig recapitulates Spontaneous large-animal model of DNAH17-related MMAF.

Downstream

Reduced sperm motility

Male infertility Malformed, poorly motile sperm cannot reach or fertilize the oocyte in vivo.

Absent sperm flagella

Short sperm flagella

Coiled sperm flagella

Irregularly shaped sperm tail

Show evidence (2 references)

CGGV:assertion_ef0cbb29-220d-45ae-828c-ab233dcf4824-2022-09-08T110000.000Z SUPPORT Other

"Spermatogenic failure 39 (SPGF39) is characterized by male infertility due to morphologic abnormalities of the flagella (MMAF), including flagella that are short, absent, irregularly shaped, and coiled"

ClinGen expert-panel summary of the disease phenotype.

PMID:31841227 SUPPORT Human Clinical

"Spermatozoa sample from the patient showed severe asthenozoospermia and MMAF."

Independent compound heterozygous patient with MMAF.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

8

Male infertility Reproductive HP:0003251

Show evidence (1 reference)

PMID:31178125 SUPPORT Human Clinical

"Overall, this study demonstrates that mutations in DNAH17 are responsible for isolated male infertility"

Isolated male infertility is the disease presentation.

Reduced sperm motility Reproductive HP:0012207

Show evidence (2 references)

PMID:31658987 SUPPORT Human Clinical

"However, all three patients exhibited reduced sperm motility, with ≤25.0% of motile sperm and ≤17.5% progressively motile sperm."

Reduced motility with normal counts in the missense family.

PMID:41549443 SUPPORT Human Clinical

"Semen analysis revealed significant reductions in sperm motility and notable morphological changes."

Reduced motility in MMAF patients.

Absent sperm flagella Reproductive HP:0032558

Show evidence (1 reference)

CGGV:assertion_ef0cbb29-220d-45ae-828c-ab233dcf4824-2022-09-08T110000.000Z SUPPORT Other

"sperm cells from these patients present abnormal morphology and motility including absent, short, coiled, and irregular-caliber flagella"

ClinGen summary of patient sperm morphology.

Short sperm flagella Reproductive HP:0032559

Show evidence (1 reference)

PMID:41549443 SUPPORT Human Clinical

"SEM and Papanicolaou staining revealed multiple abnormalities in the sperm from proband-1, -3, and -4, including coiled and short tails, thickened and asymmetrical midpieces, and heads with vacuoles and abnormal acrosomes"

Short tails in patient sperm.

Coiled sperm flagella Reproductive HP:0032560

Show evidence (1 reference)

PMID:41549443 SUPPORT Human Clinical

"Coiled flagella (%) | 45.0±4.9 | 50.8±3.1 | 42.6±2.7 | 35.2±2.5 | 5.3±1.2 | <0.01"

Coiled flagella in four probands against 5.3% in controls.

Irregularly shaped sperm tail Reproductive HP:0033393

Show evidence (1 reference)

CGGV:assertion_ef0cbb29-220d-45ae-828c-ab233dcf4824-2022-09-08T110000.000Z SUPPORT Other

"sperm cells from these patients present abnormal morphology and motility including absent, short, coiled, and irregular-caliber flagella"

ClinGen summary of patient sperm morphology.

Abnormal sperm axoneme morphology Reproductive HP:0033524

Show evidence (1 reference)

PMID:41549443 SUPPORT Human Clinical

"In our study, we observed widespread loss of DMTs 4–7 and a complete absence of ODAs in both homozygous and compound heterozygous DNAH17 variant carriers, which is consistent with previous reports."

Axonemal ultrastructure defects in patients.

Abnormal sperm head morphology Reproductive HP:0012865

Show evidence (1 reference)

PMID:41549443 SUPPORT Human Clinical

"SEM and Papanicolaou staining revealed multiple abnormalities in the sperm from proband-1, -3, and -4, including coiled and short tails, thickened and asymmetrical midpieces, and heads with vacuoles and abnormal acrosomes"

Head and acrosome defects in patient sperm.

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Genetic Associations

1

DNAH17 (Causal)

Gene: DNAH17 hgnc:2946

Show evidence (5 references)

PMID:31178125 SUPPORT Human Clinical

"displayed a loss of ODAs in their sperm cells but not in their respiratory cells, we identified bi-allelic mutations in DNAH17"

Primary gene-disease report.

PMID:33070343 SUPPORT Human Clinical

"Here, we recruited two consanguineous families of Pakistani and Chinese origins, respectively, diagnosed with MMAF."

Replication in consanguineous families with knockout mouse support.

PMID:40009974 SUPPORT Human Clinical

"Ten novel variants in DNAH17 were identified in five unrelated families with five infertile male probands."

Further recessive families from a 75-patient MMAF cohort.

+ 2 more references

💊

Medical Actions

2

Intracytoplasmic Sperm Injection

Action: Intracytoplasmic Sperm Injection NCIT:C185482

Platform: Other

ICSI bypasses the motility defect, but outcomes are poorer than for many other MMAF genes. Total fertilization failure has been reported, and in a review of 11 couples only three achieved clinical pregnancy, all with ICSI combined with assisted oocyte activation (AOA). A 2025 series reported transferable embryos without AOA in four couples, and a later series reported pregnancies with ICSI plus AOA. The fertilization defect may reflect impaired acrosome reaction and reduced sperm PLCZ1, but this is not established.

Mechanism Target:

Multiple Morphological Abnormalities of the Sperm Flagella — Direct injection makes flagellar propulsion and form irrelevant to fertilization.

Show evidence (1 reference)

PMID:41549443 SUPPORT Human Clinical

"These findings demonstrate that ICSI combined with AOA effectively circumvents DNAH17-related flagellar dysfunction"

ICSI with AOA bypasses the flagellar defect.

Show evidence (4 references)

PMID:37574497 SUPPORT Human Clinical

"Only three men with DNAH17 variants ultimately achieved clinical pregnancy with their partners through ICSI combined with assisted oocyte activation (AOA)."

ICSI can succeed, but in this review only with AOA.

PMID:40009974 SUPPORT Human Clinical

"Four of the affected couples obtained transferable embryos following intracytoplasmic sperm injection without artificial oocyte activation."

ICSI alone produced transferable embryos in another cohort.

PMID:34126833 REFUTE Human Clinical

"A male patient with a three-year history of primary infertility presented with TFF after two failed cycles of intracytoplasmic sperm injection (ICSI)."

Total fertilization failure after ICSI in a compound heterozygous patient.

+ 1 more reference

Genetic Counseling

Action: Genetic Counseling NCIT:C15240

Platform: Behavioral / lifestyle

Counselling for autosomal recessive recurrence and carrier testing of relatives once the familial DNAH17 alleles are known. Allele class bears on the expected semen phenotype (MMAF with null alleles, isolated asthenozoospermia with the p.C1803Y hypomorph) and on the reported variability of ICSI outcome.

Show evidence (2 references)

PMID:35932098 SUPPORT Human Clinical

"Our findings expand upon the spectrum of pathogenic DNAH17 variants that are responsible for MMAF, and provide new knowledge for genetic counselling of male infertility due to MMAF."

The authors name genetic counselling as the application of the molecular diagnosis.

PMID:40009974 SUPPORT Human Clinical

"The study provided vital insights for genetic diagnosis and counselling in males affected by MMAF."

A second cohort drawing the same conclusion.

🔬

Diagnosis

4

Molecular Genetic Testing

Establishes the diagnosis. Probands have been identified by whole-exome sequencing with Sanger confirmation of biallelic status. Semen analysis and ultrastructure point to a flagellar gene but cannot name it, because MMAF and asthenozoospermia are genetically heterogeneous.

Genetic Testing NCIT:C15709

Show evidence (1 reference)

PMID:33070343 SUPPORT Human Clinical

"Whole-exome sequencing identified novel homozygous DNAH17 variants, which led to loss of DNAH17 proteins, in the patients."

Whole-exome sequencing identified the causal alleles.

Semen Analysis

Shows asthenozoospermia, usually with MMAF and often with normal sperm concentration. With the p.C1803Y allele, morphology is normal and only motility is reduced.

Show evidence (1 reference)

PMID:41549443 SUPPORT Human Clinical

"Semen analysis revealed significant reductions in sperm motility and notable morphological changes."

Semen analysis is the first finding in patients.

Transmission Electron Microscopy of Sperm Flagella

Flagellar cross-sections show missing ODAs, loss of doublets 4-7 and, with null alleles, disorganized axonemes. Respiratory cilia are normal, which distinguishes the disorder from primary ciliary dyskinesia.

Transmission Electron Microscopy NCIT:C18216

Show evidence (1 reference)

PMID:33070343 SUPPORT Human Clinical

"Transmission electron microscope analyses revealed completely disorganized axonemal structure as the predominant anomaly and increased frequencies of missings of microtubule doublet(s) 4-7 in sperm flagella of patients."

TEM findings in patient sperm.

Immunofluorescence of DNAH17 in Sperm

Absent DNAH17 (and DNAH8) staining of sperm flagella confirms loss of function of null and many missense alleles. It is uninformative for the p.C1803Y allele, in which DNAH17 still localizes normally.

Show evidence (1 reference)

PMID:31178125 SUPPORT Human Clinical

"We also demonstrate the loss of function associated with DNAH17 mutations in two unrelated individuals by performing immunoblot and immunofluorescence analyses on sperm cells"

Immunofluorescence of patient sperm demonstrates protein loss.

🐁

Animal Models

3

Dnah17 knockout mouse

Dnah17-/- males have MMAF with disorganized axonemes. They also have a sharp fall in sperm count, deformed elongating spermatid nuclei and spermiation failure with apoptosis, which are not reported in patients.

Species

Mouse

Genotype

Dnah17-/- (knockout), homozygous

Publication

PMID:33070343

Pathograph links

Sperm Axonemal Disorganization recapitulates fidelity: high The knockout reproduces the human MMAF and axonemal disorganization.

Show evidence (1 reference)

PMID:33070343 SUPPORT Model Organism

"Similar to those found in patients, Dnah17-/- mice also displayed MMAF phenotype along with completely disorganized axonemal structures."

The knockout recapitulates the human lesion.

Multiple Morphological Abnormalities of the Sperm Flagella partially recapitulates fidelity: moderate MMAF is reproduced, but with a far more severe spermatogenic defect than in patients.

Limitations: Knockout mice have drastically reduced sperm counts and spermiation failure, whereas most patients have normal sperm concentrations.

Show evidence (1 reference)

PMID:31658987 SUPPORT Model Organism

"Noticeably, knockout of Dnah17 drastically reduced sperm count and resulted in morphologically abnormal spermatozoa with a typical human MMAF phenotype"

Records both the MMAF phenotype and the mouse-specific count reduction.

Dnah17 p.C1803Y knock-in mouse

Mice homozygous for the mouse equivalent of p.C1803Y have normal sperm count and morphology but reduced motility and fewer pups, with doublet 4-7 loss in epididymal sperm.

Species

Mouse

Genotype

Dnah17 M/M (homozygous knock-in of the patient missense variant)

Publication

PMID:31658987

Pathograph links

Destabilization of Microtubule Doublets 4-7 During Epididymal Storage recapitulates fidelity: high The knock-in reproduces the patients' doublet 4-7 loss and asthenozoospermia.

Show evidence (1 reference)

PMID:31658987 SUPPORT Model Organism

"Mice carrying a homozygous mutation (Dnah17M/M) equivalent to that in patients recapitulated the defects in patients' sperm tails."

The authors' statement that the knock-in recapitulates the human defect.

Swiss Large White boar with DNAH17 intronic deletion

A naturally occurring recessive allele in an inbred pig line causes immotile sperm with MMAF and disorganized axonemes.

Species

Pig

Genotype

Homozygous 13-bp intronic deletion upstream of DNAH17 exon 56 (in-frame exon skipping)

Publication

PMID:33724408

Pathograph links

Multiple Morphological Abnormalities of the Sperm Flagella recapitulates fidelity: moderate Spontaneous large-animal model of DNAH17-related MMAF.

Limitations: Boar sperm are completely immotile, a more severe motility phenotype than in most patients.

Show evidence (1 reference)

PMID:33724408 SUPPORT Model Organism

"Disruption of DNAH17 impairs the assembly of the flagellar axoneme and manifests in multiple morphological abnormalities of the sperm flagella."

Naturally occurring porcine model.

{ }

Source YAML

click to show

name: Spermatogenic Failure 39
creation_date: "2026-10-14T00:00:00Z"
category: Mendelian
synonyms:
- SPGF39
- spermatogenic failure 39
- DNAH17-related asthenozoospermia
- DNAH17-related multiple morphological abnormalities of the sperm flagella
description: >-
  Spermatogenic failure 39 (SPGF39) is autosomal recessive male infertility
  caused by biallelic variants in DNAH17, which encodes a beta-type heavy
  chain of the axonemal outer dynein arm (ODA). DNAH17 is a sperm-specific ODA
  heavy chain: with DNAH8 it forms the ODA of the sperm flagellum, whereas
  respiratory cilia use DNAH5 with DNAH9 or DNAH11 and contain no DNAH17. Loss
  of DNAH17 therefore removes the ODA, and DNAH8 with it, from sperm while
  sparing motile cilia, and affected men have no respiratory disease.

  Most patients, especially those with truncating alleles, have
  asthenoteratozoospermia with multiple morphological abnormalities of the
  sperm flagella (MMAF): short, coiled, absent and irregular-caliber flagella,
  often with mitochondrial sheath and sperm head defects. Electron microscopy
  shows missing ODAs, frequent loss of peripheral microtubule doublets 4-7 and,
  with null alleles, a completely disorganized axoneme. A homozygous missense
  variant in one family caused asthenozoospermia with normal sperm morphology
  instead, through loss of doublets 4-7 during epididymal storage. Fertility
  can be achieved by intracytoplasmic sperm injection (ICSI), but fertilization
  failure is common, and ICSI combined with assisted oocyte activation has
  given better results.
disease_term:
  preferred_term: spermatogenic failure 39
  term:
    id: MONDO:0032845
    label: spermatogenic failure 39
parents:
- Spermatogenic Failure
- Genetic Disease
notes: >-
  MONDO cross-references the phenotype as OMIM 618643; the DNAH17 gene entry
  is OMIM 610063. ClinGen classifies DNAH17 in SPGF39 as
  Definitive (2022). Two reports describe compound heterozygous DNAH17
  variants in individuals with laterality defects: two Han Chinese probands
  with left-right asymmetry disorders (PMID:35692830) and one male with situs
  inversus totalis from an exome study of cardiovascular laterality defects
  (PMID:35474353, which ClinGen counted among its SPGF39 publications). Both
  conflict with the absence of DNAH17 from respiratory cilia, neither has
  functional data, and the second proband was too young for fertility
  testing, so laterality defects are not recorded as a phenotype. A Dnah17 knockout rat generated in a myopia study showed male
  infertility but not myopia (PMID:33764336).
inheritance:
- name: Autosomal recessive
  description: >-
    Disease requires biallelic DNAH17 variants: homozygous variants in
    consanguineous Pakistani, Chinese and other families, and compound
    heterozygous variants in non-consanguineous families. Heterozygous
    carriers are fertile.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:40009974
    reference_title: "Novel variants in DNAH17 cause sperm flagellar outer dynein arm defects but not total fertilization failure after ICSI."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These variants exhibited an autosomal-recessive inheritance pattern and caused deficiency of DNAH17 in spermatozoa."
    explanation: Recessive segregation in five unrelated families.
  - reference: PMID:31658987
    reference_title: "A DNAH17 missense variant causes flagella destabilization and asthenozoospermia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Whole-exome sequencing identified a missense variant (c.G5408A, p.C1803Y) in DNAH17, a functionally uncharacterized gene, recessively cosegregating with asthenozoospermia in the family."
    explanation: Recessive co-segregation in a consanguineous family.
pathophysiology:
- name: Loss of the DNAH17 Outer-Arm Dynein Heavy Chain
  description: >-
    Nonsense, frameshift, splice and many missense alleles abolish or sharply
    reduce DNAH17 protein in sperm. Splice-site alleles can delete exons
    encoding the AAA6 part of the motor domain. The p.C1803Y missense allele is
    an exception, in which DNAH17 is still made and localizes normally to the
    flagellum; it is a separate hypomorphic node.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: DNAH17
    term:
      id: hgnc:2946
      label: DNAH17
  molecular_functions:
  - preferred_term: minus-end-directed microtubule motor activity
    modifier: DECREASED
    term:
      id: GO:0008569
      label: minus-end-directed microtubule motor activity
  downstream:
  - target: Outer Dynein Arm Loss in the Sperm Axoneme
    causal_link_type: DIRECT
    description: >-
      DNAH17 is a structural heavy chain of the sperm ODA; without it the
      partner heavy chain DNAH8 and the ODA docking and intermediate-chain
      proteins are also lost from sperm.
    evidence:
    - reference: PMID:31178125
      reference_title: "Mutations in DNAH17, Encoding a Sperm-Specific Axonemal Outer Dynein Arm Heavy Chain, Cause Isolated Male Infertility Due to Asthenozoospermia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "these analyses indicated the absence of DNAH17 and DNAH8, whereas DNAH2 and DNALI, two inner dynein arm components, were present"
      explanation: Loss of DNAH17 removes its ODA partner DNAH8 but leaves inner-arm components.
  evidence:
  - reference: PMID:31178125
    reference_title: "Mutations in DNAH17, Encoding a Sperm-Specific Axonemal Outer Dynein Arm Heavy Chain, Cause Isolated Male Infertility Due to Asthenozoospermia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We also demonstrate the loss of function associated with DNAH17 mutations in two unrelated individuals by performing immunoblot and immunofluorescence analyses on sperm cells"
    explanation: Patient sperm lack DNAH17 protein.
  - reference: PMID:33070343
    reference_title: "Novel loss-of-function variants in DNAH17 cause multiple morphological abnormalities of the sperm flagella in humans and mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Whole-exome sequencing identified novel homozygous DNAH17 variants, which led to loss of DNAH17 proteins, in the patients."
    explanation: Independent confirmation of protein loss with homozygous loss-of-function alleles.
  - reference: PMID:41258988
    reference_title: "Novel DNAH17 Splice-Site Mutations Truncating the AAA6 Domain Cause Asthenozoospermia with MMAF."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Minigene assays confirmed exon 72 skipping, leading to a frameshift mutation (p.Asn3844Lysfs*13) that truncates the AAA6 domain."
    explanation: Splice alleles truncate the motor domain.
- name: Hypomorphic DNAH17 p.C1803Y Missense Allele
  description: >-
    The homozygous p.C1803Y (c.G5408A) missense allele reported in one
    consanguineous Pakistani family. Unlike null alleles, it does not remove
    DNAH17: the protein is still made and localizes normally to the sperm
    flagellum, and ODAs remain visible on the surviving doublets in knock-in
    mice. Motor function is presumed reduced rather than lost, and flagella
    form normally but are destabilized later.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: DNAH17
    term:
      id: hgnc:2946
      label: DNAH17
  molecular_functions:
  - preferred_term: minus-end-directed microtubule motor activity
    modifier: DECREASED
    term:
      id: GO:0008569
      label: minus-end-directed microtubule motor activity
  downstream:
  - target: Destabilization of Microtubule Doublets 4-7 During Epididymal Storage
    causal_link_type: DIRECT
    hypothesis_groups:
    - dnah17_allelic_severity
    description: >-
      Shown for the p.C1803Y allele in patients and knock-in mice, where the
      ODA heavy chain is present but doublets 4-7 are lost after the sperm are
      stored in the epididymis.
    evidence:
    - reference: PMID:31658987
      reference_title: "A DNAH17 missense variant causes flagella destabilization and asthenozoospermia."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Together, these TEM findings in Dnah17M/M mice recapitulated the defects of patients' sperm tails, demonstrating that the DNAH17 variant was indeed responsible for the absence of MTD(s) 4-7 in our asthenozoospermic patients."
      explanation: >-
        Knock-in mice carrying the patient allele reproduce the doublet 4-7
        loss, tying it to the variant.
  evidence:
  - reference: PMID:31658987
    reference_title: "A DNAH17 missense variant causes flagella destabilization and asthenozoospermia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "DNAH17, specifically expressed in testes, was localized to sperm flagella, and the mutation did not alter its localization."
    explanation: In patient sperm the missense protein is still present and correctly localized.
- name: Outer Dynein Arm Loss in the Sperm Axoneme
  description: >-
    ODAs are absent along the sperm flagellum. Proteomics of patient sperm
    shows reduced DNAH8, the intermediate chain DNAI1 and the docking-complex
    proteins ODAD2 and ODAD4. Respiratory cilia keep their ODAs.
  biological_scale: MOLECULAR
  cellular_components:
  - preferred_term: Outer dynein arm
    term:
      id: GO:0036157
      label: outer dynein arm
  biological_processes:
  - preferred_term: Outer dynein arm assembly
    modifier: DECREASED
    term:
      id: GO:0036158
      label: outer dynein arm assembly
  downstream:
  - target: Sperm Axonemal Disorganization
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      ODA loss accompanies loss of doublets 4-7, mitochondrial sheath defects
      and, with null alleles, complete axonemal disorganization. How loss of
      an ODA heavy chain destabilizes these other structures is not
      established.
  evidence:
  - reference: PMID:31178125
    reference_title: "Mutations in DNAH17, Encoding a Sperm-Specific Axonemal Outer Dynein Arm Heavy Chain, Cause Isolated Male Infertility Due to Asthenozoospermia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "By analyzing five male individuals who consulted for isolated infertility and displayed a loss of ODAs in their sperm cells but not in their respiratory cells, we identified bi-allelic mutations in DNAH17."
    explanation: ODA loss restricted to sperm in patients.
  - reference: PMID:41549443
    reference_title: "Novel homozygous or compound heterozygous DNAH17 variants lead to male infertility characterized by multiple morphological abnormalities of the sperm flagella and asthenoteratozoospermia in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In addition to DNAH17, several proteins associated with ODA assembly, including ODAD4, ODAD2, DNAI1, and DNAH8, were among the top 10 downregulated proteins in DNAH17-mutant patients"
    explanation: Proteomic evidence that the whole sperm ODA fails to assemble.
  - reference: PMID:40009974
    reference_title: "Novel variants in DNAH17 cause sperm flagellar outer dynein arm defects but not total fertilization failure after ICSI."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Comprehensive functional analysis revealed that DNAH17 deficiency impaired the assembly and docking of outer dynein arms, affected the acrosome reaction, and disrupted mitochondrial function."
    explanation: Independent cohort confirming impaired ODA assembly and docking.
- name: Destabilization of Microtubule Doublets 4-7 During Epididymal Storage
  description: >-
    With the hypomorphic p.C1803Y allele, sperm are formed normally but lose
    doublets 4-7 at the principal and end pieces while stored in the
    epididymis. Sperm count and morphology stay normal, so the result is
    asthenozoospermia without MMAF. Doublet 4-7 loss is also frequent in
    patients with null alleles, alongside wider axonemal disorganization.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: Sperm
    term:
      id: CL:0000019
      label: sperm
  cellular_components:
  - preferred_term: Axoneme
    term:
      id: GO:0005930
      label: axoneme
  downstream:
  - target: Reduced sperm motility
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:31658987
      reference_title: "A DNAH17 missense variant causes flagella destabilization and asthenozoospermia."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Hence, consistent with the findings in the patients (Table 1), Dnah17M/M mice displayed markedly diminished sperm motility, proving that the DNAH17 variant is indeed pathogenic for asthenozoospermia."
      explanation: The knock-in allele reduces motility without changing count or morphology.
  - target: Abnormal sperm axoneme morphology
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:31658987
    reference_title: "A DNAH17 missense variant causes flagella destabilization and asthenozoospermia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "However, spermatozoa of all three patients showed higher frequencies of microtubule doublet(s) 4-7 missing at principal piece and end piece than in controls."
    explanation: Doublet 4-7 loss in patient sperm.
  - reference: PMID:31658987
    reference_title: "A DNAH17 missense variant causes flagella destabilization and asthenozoospermia."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Further examinations revealed that the doublets 4-7 were destabilized largely due to the storage of sperm in epididymis."
    explanation: Knock-in mice locate the destabilization to epididymal storage.
- name: Sperm Axonemal Disorganization
  description: >-
    Flagellar cross-sections show missing ODAs, loss of doublets 4-7 at the
    principal and end pieces, mitochondrial sheath defects in the midpiece and,
    with null alleles, a completely disorganized axoneme. In Dnah17-/- mice
    clusters of disorganized microtubules and outer dense fibers appear
    already in developing spermatids, so flagellar assembly fails.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: Sperm
    term:
      id: CL:0000019
      label: sperm
  cellular_components:
  - preferred_term: Axoneme
    term:
      id: GO:0005930
      label: axoneme
  - preferred_term: Sperm flagellum
    term:
      id: GO:0036126
      label: sperm flagellum
  downstream:
  - target: Multiple Morphological Abnormalities of the Sperm Flagella
    causal_link_type: DIRECT
  - target: Abnormal sperm axoneme morphology
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:33070343
    reference_title: "Novel loss-of-function variants in DNAH17 cause multiple morphological abnormalities of the sperm flagella in humans and mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Transmission electron microscope analyses revealed completely disorganized axonemal structure as the predominant anomaly and increased frequencies of missings of microtubule doublet(s) 4-7 in sperm flagella of patients."
    explanation: Axonemal disorganization in patients with loss-of-function alleles.
  - reference: PMID:41549443
    reference_title: "Novel homozygous or compound heterozygous DNAH17 variants lead to male infertility characterized by multiple morphological abnormalities of the sperm flagella and asthenoteratozoospermia in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "TEM further revealed multiple MS abnormalities in the midpiece; the absence of ODAs in the middle, principal, and end pieces; and the loss of DMTs 4–7 in the principal and end pieces of sperm flagella."
    explanation: ODA, doublet and mitochondrial sheath defects in a further cohort.
  - reference: PMID:33070343
    reference_title: "Novel loss-of-function variants in DNAH17 cause multiple morphological abnormalities of the sperm flagella in humans and mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Clusters of disorganized microtubules and outer dense fibers were observed in developing spermatids, indicating impaired sperm flagellar assembly."
    explanation: In knockout mice the defect begins during flagellar assembly in spermatids.
- name: Multiple Morphological Abnormalities of the Sperm Flagella
  description: >-
    The usual semen phenotype: short, coiled, absent and irregular-caliber
    flagella in the same ejaculate, with severely reduced motility and often
    abnormal heads and midpieces.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: Sperm
    term:
      id: CL:0000019
      label: sperm
  biological_processes:
  - preferred_term: Sperm flagellum assembly
    modifier: DECREASED
    term:
      id: GO:0120316
      label: sperm flagellum assembly
  downstream:
  - target: Reduced sperm motility
    causal_link_type: DIRECT
  - target: Male infertility
    causal_link_type: DIRECT
    description: Malformed, poorly motile sperm cannot reach or fertilize the oocyte in vivo.
  - target: Absent sperm flagella
    causal_link_type: DIRECT
  - target: Short sperm flagella
    causal_link_type: DIRECT
  - target: Coiled sperm flagella
    causal_link_type: DIRECT
  - target: Irregularly shaped sperm tail
    causal_link_type: DIRECT
  evidence:
  - reference: CGGV:assertion_ef0cbb29-220d-45ae-828c-ab233dcf4824-2022-09-08T110000.000Z
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Spermatogenic failure 39 (SPGF39) is characterized by male infertility due to morphologic abnormalities of the flagella (MMAF), including flagella that are short, absent, irregularly shaped, and coiled"
    explanation: ClinGen expert-panel summary of the disease phenotype.
  - reference: PMID:31841227
    reference_title: "DNAH17 is associated with asthenozoospermia and multiple morphological abnormalities of sperm flagella."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Spermatozoa sample from the patient showed severe asthenozoospermia and MMAF."
    explanation: Independent compound heterozygous patient with MMAF.
mechanistic_hypotheses:
- hypothesis_group_id: sperm_specific_dnah17_oda
  hypothesis_label: DNAH17 is a sperm-specific outer dynein arm heavy chain, so its loss causes isolated male infertility rather than primary ciliary dyskinesia
  status: CANONICAL
  description: >-
    DNAH17 and DNAH8 are found along the sperm axoneme but not in respiratory
    cilia, which use DNAH5, DNAH9 and DNAH11 instead. Patients therefore keep
    respiratory ODAs and have no ciliary disease. Two small reports of DNAH17
    variants in individuals with laterality defects are the only evidence
    against this, and neither includes functional data.
  evidence:
  - reference: PMID:31178125
    reference_title: "Mutations in DNAH17, Encoding a Sperm-Specific Axonemal Outer Dynein Arm Heavy Chain, Cause Isolated Male Infertility Due to Asthenozoospermia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We show that DNAH17 and DNAH8, but not DNAH5, DNAH9, or DNAH11, colocalize with α-tubulin along the sperm axoneme, whereas the reverse picture is observed in respiratory cilia, thus explaining the phenotype restricted to sperm cells."
    explanation: Immunostaining shows the distinct heavy-chain composition of sperm and ciliary ODAs.
  - reference: PMID:31658987
    reference_title: "A DNAH17 missense variant causes flagella destabilization and asthenozoospermia."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Using the antibody against DNAH17, we found that DNAH17 protein was indeed not detected in cilia from tracheae and was detected only in testes and epididymides of WT mice"
    explanation: In wild-type mice DNAH17 protein is absent from tracheal cilia and restricted to testis and epididymis.
  - reference: PMID:31658987
    reference_title: "A DNAH17 missense variant causes flagella destabilization and asthenozoospermia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Consistently, in humans, DNAH17 was detected only in testes, but not in various somatic cell lines"
    explanation: >-
      Immunoblotting of human testis lysate and human somatic cell lines
      (including alveolar epithelial A549) shows the same testis-restricted
      expression in humans.
  - reference: PMID:35692830
    reference_title: "Identification of DNAH17 Variants in Han-Chinese Patients With Left-Right Asymmetry Disorders."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "We report for the first time a possible association between DNAH17 gene variants and left-right asymmetry disorders, which is known as a causal gene for asthenozoospermia."
    explanation: >-
      Compound heterozygous DNAH17 variants in two probands with laterality
      defects would imply a role outside sperm. The association is
      unreplicated and no functional data were reported.
  - reference: PMID:35474353
    reference_title: "Exome sequencing in individuals with cardiovascular laterality defects identifies potential candidate genes."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, in a male individual (HET22_501) with situs inversus totalis with PFO, rare compound heterozygous missense variants in exon 46 and exon 75 in DNAH17"
    explanation: >-
      A second laterality report proposing DNAH17 as a candidate gene. It is a
      single proband with missense variants of uncertain significance, no
      functional or ciliary ultrastructural abnormality, and no fertility
      assessment.
- hypothesis_group_id: dnah17_allelic_severity
  hypothesis_label: Null DNAH17 alleles cause MMAF, while a hypomorphic missense allele causes asthenozoospermia with normal flagellar morphology
  status: EMERGING
  description: >-
    Loss-of-function alleles remove DNAH17 and give MMAF with disorganized
    axonemes; the p.C1803Y allele keeps DNAH17 in the flagellum and gives
    normal morphology with motility loss from doublet 4-7 destabilization.
    The same split is seen in mice (Dnah17-/- versus Dnah17M/M). The evidence
    for the hypomorphic class rests on one family.
  evidence:
  - reference: PMID:37574497
    reference_title: "Novel mutations in DNAH17 cause sperm flagellum defects and their influence on ICSI outcome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "DNAH17 has been associated with asthenozoospermia and male infertility, but different types of DNAH17 variants appear to be involved in different sperm phenotypes."
    explanation: Literature review of 21 patients noting allele-dependent phenotypes.
  - reference: PMID:31658987
    reference_title: "A DNAH17 missense variant causes flagella destabilization and asthenozoospermia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In this study, we recruited three primary infertile patients from Pakistan, born to a consanguineous union and suffering from asthenozoospermia with no MMAF-like phenotype or ciliary-related symptoms."
    explanation: The missense family lacks MMAF.
phenotypes:
- category: Reproductive
  name: Male infertility
  description: Primary male infertility is the presenting complaint; affected men are otherwise well.
  phenotype_term:
    preferred_term: Male infertility
    term:
      id: HP:0003251
      label: Male infertility
  evidence:
  - reference: PMID:31178125
    reference_title: "Mutations in DNAH17, Encoding a Sperm-Specific Axonemal Outer Dynein Arm Heavy Chain, Cause Isolated Male Infertility Due to Asthenozoospermia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Overall, this study demonstrates that mutations in DNAH17 are responsible for isolated male infertility"
    explanation: Isolated male infertility is the disease presentation.
- category: Reproductive
  name: Reduced sperm motility
  description: >-
    Asthenozoospermia is present in every reported patient, including those
    without MMAF. Sperm concentration is usually normal.
  phenotype_term:
    preferred_term: Asthenozoospermia
    term:
      id: HP:0012207
      label: Reduced sperm motility
  evidence:
  - reference: PMID:31658987
    reference_title: "A DNAH17 missense variant causes flagella destabilization and asthenozoospermia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "However, all three patients exhibited reduced sperm motility, with ≤25.0% of motile sperm and ≤17.5% progressively motile sperm."
    explanation: Reduced motility with normal counts in the missense family.
  - reference: PMID:41549443
    reference_title: "Novel homozygous or compound heterozygous DNAH17 variants lead to male infertility characterized by multiple morphological abnormalities of the sperm flagella and asthenoteratozoospermia in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Semen analysis revealed significant reductions in sperm motility and notable morphological changes."
    explanation: Reduced motility in MMAF patients.
- category: Reproductive
  name: Absent sperm flagella
  description: Some sperm lack a flagellum, as part of the MMAF mosaic.
  phenotype_term:
    preferred_term: Absent sperm flagella
    term:
      id: HP:0032558
      label: Absent sperm flagella
  evidence:
  - reference: CGGV:assertion_ef0cbb29-220d-45ae-828c-ab233dcf4824-2022-09-08T110000.000Z
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "sperm cells from these patients present abnormal morphology and motility including absent, short, coiled, and irregular-caliber flagella"
    explanation: ClinGen summary of patient sperm morphology.
- category: Reproductive
  name: Short sperm flagella
  description: Shortened flagella are part of the MMAF mosaic.
  phenotype_term:
    preferred_term: Short sperm flagella
    term:
      id: HP:0032559
      label: Short sperm flagella
  evidence:
  - reference: PMID:41549443
    reference_title: "Novel homozygous or compound heterozygous DNAH17 variants lead to male infertility characterized by multiple morphological abnormalities of the sperm flagella and asthenoteratozoospermia in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "SEM and Papanicolaou staining revealed multiple abnormalities in the sperm from proband-1, -3, and -4, including coiled and short tails, thickened and asymmetrical midpieces, and heads with vacuoles and abnormal acrosomes"
    explanation: Short tails in patient sperm.
- category: Reproductive
  name: Coiled sperm flagella
  description: Coiled flagella are the most frequent single flagellar anomaly, reaching 35-51% of sperm in one cohort.
  phenotype_term:
    preferred_term: Coiled sperm flagella
    term:
      id: HP:0032560
      label: Coiled sperm flagella
  evidence:
  - reference: PMID:41549443
    reference_title: "Novel homozygous or compound heterozygous DNAH17 variants lead to male infertility characterized by multiple morphological abnormalities of the sperm flagella and asthenoteratozoospermia in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Coiled flagella (%) | 45.0±4.9 | 50.8±3.1 | 42.6±2.7 | 35.2±2.5 | 5.3±1.2 | <0.01"
    explanation: Coiled flagella in four probands against 5.3% in controls.
- category: Reproductive
  name: Irregularly shaped sperm tail
  description: Irregular-caliber flagella are part of the MMAF mosaic.
  phenotype_term:
    preferred_term: Irregular-caliber sperm flagella
    term:
      id: HP:0033393
      label: Irregularly shaped sperm tail
  evidence:
  - reference: CGGV:assertion_ef0cbb29-220d-45ae-828c-ab233dcf4824-2022-09-08T110000.000Z
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "sperm cells from these patients present abnormal morphology and motility including absent, short, coiled, and irregular-caliber flagella"
    explanation: ClinGen summary of patient sperm morphology.
- category: Reproductive
  name: Abnormal sperm axoneme morphology
  description: >-
    Electron microscopy shows absent ODAs, loss of doublets 4-7 and, with null
    alleles, completely disorganized axonemes.
  phenotype_term:
    preferred_term: Abnormal sperm axoneme morphology
    term:
      id: HP:0033524
      label: Abnormal sperm axoneme morphology
  evidence:
  - reference: PMID:41549443
    reference_title: "Novel homozygous or compound heterozygous DNAH17 variants lead to male infertility characterized by multiple morphological abnormalities of the sperm flagella and asthenoteratozoospermia in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In our study, we observed widespread loss of DMTs 4–7 and a complete absence of ODAs in both homozygous and compound heterozygous DNAH17 variant carriers, which is consistent with previous reports."
    explanation: Axonemal ultrastructure defects in patients.
- category: Reproductive
  name: Abnormal sperm head morphology
  description: >-
    Many sperm have vacuolated heads and abnormal acrosomes, and the
    acrosome reaction is impaired. No mechanism linking DNAH17 loss to the
    head defect is established, so this phenotype is not linked to the
    causal chain.
  phenotype_term:
    preferred_term: Abnormal sperm head morphology
    term:
      id: HP:0012865
      label: Abnormal sperm head morphology
  evidence:
  - reference: PMID:41549443
    reference_title: "Novel homozygous or compound heterozygous DNAH17 variants lead to male infertility characterized by multiple morphological abnormalities of the sperm flagella and asthenoteratozoospermia in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "SEM and Papanicolaou staining revealed multiple abnormalities in the sperm from proband-1, -3, and -4, including coiled and short tails, thickened and asymmetrical midpieces, and heads with vacuoles and abnormal acrosomes"
    explanation: Head and acrosome defects in patient sperm.
genetic:
- name: DNAH17
  association: Causal
  gene_term:
    preferred_term: DNAH17
    term:
      id: hgnc:2946
      label: DNAH17
  gene_disease_validity:
  - validity_classification: DEFINITIVE
    classified_by: CLINGEN
    external_id: CGGV:assertion_ef0cbb29-220d-45ae-828c-ab233dcf4824-2022-09-08T110000.000Z
    evidence:
    - reference: CGGV:assertion_ef0cbb29-220d-45ae-828c-ab233dcf4824-2022-09-08T110000.000Z
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "DNAH17 | HGNC:2946 | spermatogenic failure 39 | MONDO:0032845 | AR | Definitive"
      explanation: ClinGen gene-disease validity record classifying this gene-disease pair as Definitive.
  notes: >-
    Reported alleles include nonsense, frameshift, splice-site (including
    donor-site variants causing exon 72 skipping) and many missense variants,
    homozygous or compound heterozygous. ClinGen's 2022 curation counted 10
    probands in 5 publications and 15 unique variants: PMID:31178125,
    PMID:33423959 (Song 2020), PMID:33070343, PMID:35474353 (Breuer 2022, a
    laterality-defect proband; see the sperm-specific hypothesis) and
    PMID:35932098 (Liu 2022). No abstract or full text could be retrieved for
    Song 2020, so it is not cited as evidence here.
  evidence:
  - reference: PMID:31178125
    reference_title: "Mutations in DNAH17, Encoding a Sperm-Specific Axonemal Outer Dynein Arm Heavy Chain, Cause Isolated Male Infertility Due to Asthenozoospermia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "displayed a loss of ODAs in their sperm cells but not in their respiratory cells, we identified bi-allelic mutations in DNAH17"
    explanation: Primary gene-disease report.
  - reference: PMID:33070343
    reference_title: "Novel loss-of-function variants in DNAH17 cause multiple morphological abnormalities of the sperm flagella in humans and mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we recruited two consanguineous families of Pakistani and Chinese origins, respectively, diagnosed with MMAF."
    explanation: Replication in consanguineous families with knockout mouse support.
  - reference: PMID:40009974
    reference_title: "Novel variants in DNAH17 cause sperm flagellar outer dynein arm defects but not total fertilization failure after ICSI."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ten novel variants in DNAH17 were identified in five unrelated families with five infertile male probands."
    explanation: Further recessive families from a 75-patient MMAF cohort.
  - reference: PMID:41549443
    reference_title: "Novel homozygous or compound heterozygous DNAH17 variants lead to male infertility characterized by multiple morphological abnormalities of the sperm flagella and asthenoteratozoospermia in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In the present study, we identified one novel homozygous and three compound heterozygous DNAH17 variants in one consanguineous and three nonconsanguineous families."
    explanation: Further families.
  - reference: PMID:35932098
    reference_title: "Novel compound heterozygous variants of DNAH17 in a Chinese infertile man with multiple morphological abnormalities of sperm flagella."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Novel compound heterozygous variants (c.5368C > T, p.R1790C and c.13183C > T, p.R4395W) of the DNAH17 gene were identified in the patient, and showed autosomal recessive inheritance in this family."
    explanation: A further compound heterozygous MMAF proband counted by ClinGen.
animal_models:
- name: Dnah17 knockout mouse
  species: Mouse
  genotype: Dnah17-/- (knockout), homozygous
  publication: PMID:33070343
  description: >-
    Dnah17-/- males have MMAF with disorganized axonemes. They also have a
    sharp fall in sperm count, deformed elongating spermatid nuclei and
    spermiation failure with apoptosis, which are not reported in patients.
  modeled_mechanisms:
  - target: Sperm Axonemal Disorganization
    relationship: RECAPITULATES
    fidelity: HIGH
    description: The knockout reproduces the human MMAF and axonemal disorganization.
    evidence:
    - reference: PMID:33070343
      reference_title: "Novel loss-of-function variants in DNAH17 cause multiple morphological abnormalities of the sperm flagella in humans and mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Similar to those found in patients, Dnah17-/- mice also displayed MMAF phenotype along with completely disorganized axonemal structures."
      explanation: The knockout recapitulates the human lesion.
  - target: Multiple Morphological Abnormalities of the Sperm Flagella
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: MMAF is reproduced, but with a far more severe spermatogenic defect than in patients.
    limitations: >-
      Knockout mice have drastically reduced sperm counts and spermiation
      failure, whereas most patients have normal sperm concentrations.
    evidence:
    - reference: PMID:31658987
      reference_title: "A DNAH17 missense variant causes flagella destabilization and asthenozoospermia."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Noticeably, knockout of Dnah17 drastically reduced sperm count and resulted in morphologically abnormal spermatozoa with a typical human MMAF phenotype"
      explanation: Records both the MMAF phenotype and the mouse-specific count reduction.
- name: Dnah17 p.C1803Y knock-in mouse
  species: Mouse
  genotype: Dnah17 M/M (homozygous knock-in of the patient missense variant)
  publication: PMID:31658987
  description: >-
    Mice homozygous for the mouse equivalent of p.C1803Y have normal sperm
    count and morphology but reduced motility and fewer pups, with doublet 4-7
    loss in epididymal sperm.
  modeled_mechanisms:
  - target: Destabilization of Microtubule Doublets 4-7 During Epididymal Storage
    relationship: RECAPITULATES
    fidelity: HIGH
    description: The knock-in reproduces the patients' doublet 4-7 loss and asthenozoospermia.
    evidence:
    - reference: PMID:31658987
      reference_title: "A DNAH17 missense variant causes flagella destabilization and asthenozoospermia."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Mice carrying a homozygous mutation (Dnah17M/M) equivalent to that in patients recapitulated the defects in patients' sperm tails."
      explanation: The authors' statement that the knock-in recapitulates the human defect.
- name: Swiss Large White boar with DNAH17 intronic deletion
  species: Pig
  genotype: Homozygous 13-bp intronic deletion upstream of DNAH17 exon 56 (in-frame exon skipping)
  publication: PMID:33724408
  description: >-
    A naturally occurring recessive allele in an inbred pig line causes
    immotile sperm with MMAF and disorganized axonemes.
  modeled_mechanisms:
  - target: Multiple Morphological Abnormalities of the Sperm Flagella
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: Spontaneous large-animal model of DNAH17-related MMAF.
    limitations: >-
      Boar sperm are completely immotile, a more severe motility phenotype
      than in most patients.
    evidence:
    - reference: PMID:33724408
      reference_title: "Infertility due to defective sperm flagella caused by an intronic deletion in DNAH17 that perturbs splicing."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Disruption of DNAH17 impairs the assembly of the flagellar axoneme and manifests in multiple morphological abnormalities of the sperm flagella."
      explanation: Naturally occurring porcine model.
treatments:
- name: Intracytoplasmic Sperm Injection
  description: >-
    ICSI bypasses the motility defect, but outcomes are poorer than for many
    other MMAF genes. Total fertilization failure has been reported, and in a
    review of 11 couples only three achieved clinical pregnancy, all with ICSI
    combined with assisted oocyte activation (AOA). A 2025 series reported
    transferable embryos without AOA in four couples, and a later series
    reported pregnancies with ICSI plus AOA. The fertilization defect may
    reflect impaired acrosome reaction and reduced sperm PLCZ1, but this is
    not established.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Intracytoplasmic Sperm Injection
    term:
      id: NCIT:C185482
      label: Intracytoplasmic Sperm Injection
  target_mechanisms:
  - target: Multiple Morphological Abnormalities of the Sperm Flagella
    description: Direct injection makes flagellar propulsion and form irrelevant to fertilization.
    evidence:
    - reference: PMID:41549443
      reference_title: "Novel homozygous or compound heterozygous DNAH17 variants lead to male infertility characterized by multiple morphological abnormalities of the sperm flagella and asthenoteratozoospermia in humans."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "These findings demonstrate that ICSI combined with AOA effectively circumvents DNAH17-related flagellar dysfunction"
      explanation: ICSI with AOA bypasses the flagellar defect.
  evidence:
  - reference: PMID:37574497
    reference_title: "Novel mutations in DNAH17 cause sperm flagellum defects and their influence on ICSI outcome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Only three men with DNAH17 variants ultimately achieved clinical pregnancy with their partners through ICSI combined with assisted oocyte activation (AOA)."
    explanation: ICSI can succeed, but in this review only with AOA.
  - reference: PMID:40009974
    reference_title: "Novel variants in DNAH17 cause sperm flagellar outer dynein arm defects but not total fertilization failure after ICSI."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Four of the affected couples obtained transferable embryos following intracytoplasmic sperm injection without artificial oocyte activation."
    explanation: ICSI alone produced transferable embryos in another cohort.
  - reference: PMID:34126833
    reference_title: "Novel DNAH17 mutations associated with fertilization failures after ICSI."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "A male patient with a three-year history of primary infertility presented with TFF after two failed cycles of intracytoplasmic sperm injection (ICSI)."
    explanation: Total fertilization failure after ICSI in a compound heterozygous patient.
  - reference: PMID:34373205
    reference_title: "A novel mutation in DNAH17 is present in a patient with multiple morphological abnormalities of the flagella."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Moreover, the outcome of ICSI in the patient was unsuccessful."
    explanation: Unsuccessful ICSI in a homozygous missense patient.
- name: Genetic Counseling
  description: >-
    Counselling for autosomal recessive recurrence and carrier testing of
    relatives once the familial DNAH17 alleles are known. Allele class bears on
    the expected semen phenotype (MMAF with null alleles, isolated
    asthenozoospermia with the p.C1803Y hypomorph) and on the reported
    variability of ICSI outcome.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:35932098
    reference_title: "Novel compound heterozygous variants of DNAH17 in a Chinese infertile man with multiple morphological abnormalities of sperm flagella."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our findings expand upon the spectrum of pathogenic DNAH17 variants that are responsible for MMAF, and provide new knowledge for genetic counselling of male infertility due to MMAF."
    explanation: The authors name genetic counselling as the application of the molecular diagnosis.
  - reference: PMID:40009974
    reference_title: "Novel variants in DNAH17 cause sperm flagellar outer dynein arm defects but not total fertilization failure after ICSI."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The study provided vital insights for genetic diagnosis and counselling in males affected by MMAF."
    explanation: A second cohort drawing the same conclusion.
diagnosis:
- name: Molecular Genetic Testing
  description: >-
    Establishes the diagnosis. Probands have been identified by whole-exome
    sequencing with Sanger confirmation of biallelic status. Semen analysis and
    ultrastructure point to a flagellar gene but cannot name it, because MMAF
    and asthenozoospermia are genetically heterogeneous.
  diagnosis_term:
    preferred_term: Genetic Testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:33070343
    reference_title: "Novel loss-of-function variants in DNAH17 cause multiple morphological abnormalities of the sperm flagella in humans and mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Whole-exome sequencing identified novel homozygous DNAH17 variants, which led to loss of DNAH17 proteins, in the patients."
    explanation: Whole-exome sequencing identified the causal alleles.
- name: Semen Analysis
  description: >-
    Shows asthenozoospermia, usually with MMAF and often with normal sperm
    concentration. With the p.C1803Y allele, morphology is normal and only
    motility is reduced.
  evidence:
  - reference: PMID:41549443
    reference_title: "Novel homozygous or compound heterozygous DNAH17 variants lead to male infertility characterized by multiple morphological abnormalities of the sperm flagella and asthenoteratozoospermia in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Semen analysis revealed significant reductions in sperm motility and notable morphological changes."
    explanation: Semen analysis is the first finding in patients.
- name: Transmission Electron Microscopy of Sperm Flagella
  description: >-
    Flagellar cross-sections show missing ODAs, loss of doublets 4-7 and, with
    null alleles, disorganized axonemes. Respiratory cilia are normal, which
    distinguishes the disorder from primary ciliary dyskinesia.
  diagnosis_term:
    preferred_term: Transmission Electron Microscopy
    term:
      id: NCIT:C18216
      label: Transmission Electron Microscopy
  evidence:
  - reference: PMID:33070343
    reference_title: "Novel loss-of-function variants in DNAH17 cause multiple morphological abnormalities of the sperm flagella in humans and mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Transmission electron microscope analyses revealed completely disorganized axonemal structure as the predominant anomaly and increased frequencies of missings of microtubule doublet(s) 4-7 in sperm flagella of patients."
    explanation: TEM findings in patient sperm.
- name: Immunofluorescence of DNAH17 in Sperm
  description: >-
    Absent DNAH17 (and DNAH8) staining of sperm flagella confirms loss of
    function of null and many missense alleles. It is uninformative for the
    p.C1803Y allele, in which DNAH17 still localizes normally.
  evidence:
  - reference: PMID:31178125
    reference_title: "Mutations in DNAH17, Encoding a Sperm-Specific Axonemal Outer Dynein Arm Heavy Chain, Cause Isolated Male Infertility Due to Asthenozoospermia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We also demonstrate the loss of function associated with DNAH17 mutations in two unrelated individuals by performing immunoblot and immunofluorescence analyses on sperm cells"
    explanation: Immunofluorescence of patient sperm demonstrates protein loss.

📚

References & Deep Research

Deep Research

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Evaluations and curation notes (1)

Create: Spermatogenic_Failure_39 · 2026-10-14T20:20:14Z · View source

New entry for MONDO:0032845 (DNAH17-related SPGF39), curated from the open stub, which was deleted. Evidence comes from the full texts of PMID:31658987, PMID:41549443 and PMID:35692830, the abstracts of PMID:31178125, PMID:31841227, PMID:33070343, PMID:33724408, PMID:34126833, PMID:34373205, PMID:37574497, PMID:40009974 and PMID:41258988, and the ClinGen DNAH17/SPGF39 record (Definitive, copied into gene_disease_validity), all fetched with just fetch-reference. The causal chain runs from DNAH17 loss, to sperm outer dynein arm loss (with DNAH8, DNAI1, ODAD2 and ODAD4 depletion), to doublet 4-7 destabilization and axonemal disorganization, to MMAF and the phenotypes. Two hypotheses: sperm-specific ODA heavy chain (CANONICAL, with the unreplicated laterality report PMID:35692830 recorded as REFUTE) and allele-dependent severity, null alleles giving MMAF and the p.C1803Y hypomorph giving asthenozoospermia without MMAF (EMERGING). Mouse knockout, p.C1803Y knock-in mouse and Swiss Large White boar models are linked. ICSI outcomes are mixed and recorded with SUPPORT and REFUTE items. Deep research: just research-disorder falcon failed repeatedly with Edison 503 'Failed to authenticate' over about 40 minutes, including with --fallback and --fallback-provider claude_code; just research-disorder claude_code produced research/Spermatogenic_Failure_39-deep-research-claude_code.md. just preflight-dr returned WARN only because the report cites the gene OMIM 610063 rather than the phenotype OMIM 618643; both are now in notes. Validated with just validate, count-verified-snippets, validate-disorders (both files, 80/80 snippets), check-entity-refs, check-causal-targets, check-duplicate-keys, check-enum-values and check-genereviews (NO_CHAPTER).

Claude Code ▸

1. Disease Information

claude-haiku-5-5, claude-sonnet-5-5 10 citations 2026-10-14T20:32:27.798745

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.

Phenotype	Suggested HPO lead	Notes
Male infertility	HP:0003251	Presenting feature
Asthenozoospermia	HP:0012206	Core feature; sperm motility is severely reduced
Abnormal sperm flagellum morphology (MMAF: short, absent, coiled, irregular tails)	HP:0012864 (check)	Per MedGen summary
Abnormal sperm head and midpiece morphology	HP:0012862 (check)	Reported in some men
Teratozoospermia / asthenoteratozoospermia	HP:0012864 (check)	Used in the 2025 AJA title
Oligozoospermia	HP:0000798	Listed in a mouse-phenotype mirror; unconfirmed in humans
Absent outer dynein arms on EM	no HPO term likely	Ultrastructural finding

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):

Biallelic DNAH17 variants (loss of function, or destabilizing missense) are inherited from both parents.
These lead to loss or severe reduction of DNAH17 protein in sperm (Sha 2020).
This results in absent outer dynein arms in the sperm axoneme, seen by electron microscopy (MedGen mirror).
(Inferred) Without outer-arm dynein force generation, the flagellum cannot beat normally. This causes asthenozoospermia.
(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).
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

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.
Check GeneReviews and Orphanet for a baseline, using just check-genereviews.
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.
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.

Outcome	Count
References checked	5
Resolved	5
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	5
On topic	3
Off topic	0

All extracted references resolved successfully.

Term Validation

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

Outcome	Count
Terms checked	14
Resolved	14
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	0
Terms whose name was checked	10
Terms named correctly	2
Terms named as a different term	5
Terms whose name is worth a second look	3

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

Spermatogenic Failure 39

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References & Deep Research

Deep Research

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic / Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome / Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Gaps for Curators

Reference Validation

Term Validation

Terms the report names something else

Terms whose name is worth a second look