Spermatogenic Failure 45

Mendelian MONDO:0033671 Pathograph 15 Show in embeddings browser Spermatogenic Failure Genetic Disease

Spermatogenic failure 45 (SPGF45) is autosomal recessive male infertility caused by biallelic variants in DNAH2, which encodes an axonemal inner dynein arm heavy chain. Structural studies place DNAH2 in the double-headed inner dynein arm f (IDA f, also called I1) together with the heavy chains DNAH10 and DNAH12. Affected men have severe asthenoteratozoospermia with multiple morphological abnormalities of the sperm flagella (MMAF): most sperm have absent, short or coiled flagella, and some have mildly misshapen heads. Sperm count is normal to moderately reduced. Electron microscopy of patient sperm shows absent inner dynein arms, frequent loss of the central pair of microtubules, and a disorganized axoneme and mitochondrial sheath. In Dnah2 knockout mice, males but not females are infertile, sperm show the full MMAF spectrum, the inner-arm heavy chain DNAH1 and the radial spoke protein RSPH3 are lost from the flagellum, and basal body and annulus positioning during spermiogenesis is disturbed. Reported patients had no symptoms of primary ciliary dyskinesia, and the knockout mice had normal tracheal and oviductal cilia, so SPGF45 behaves as an isolated sperm flagellar disorder. ICSI with ejaculated sperm has given embryos, pregnancies and live births.

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1
Inheritance
5
Pathophys.
7
Phenotypes
1
Hypotheses
15
Pathograph
1
Genes
1
Medical Actions
1
Models
1
Deep Research
👪

Inheritance

1
Autosomal recessive HP:0000007
Disease requires biallelic DNAH2 variants. Reported genotypes are compound heterozygous or homozygous variants in Han Chinese men and a homozygous missense variant (p.W4240C) co-segregating in a consanguineous Pakistani family.
Autosomal recessive inheritance
Show evidence (2 references)
PMID:33771466 SUPPORT Human Clinical
"Three unrelated men with bi-allelic DNAH2 variants were identified. Sanger sequencing verified that the six novel variants originated from every parent."
Biallelic variants inherited one from each parent in three unrelated men.
PMID:33968937 SUPPORT Human Clinical
"we identified a novel recessive variant (NM_020877:c.12720G > T;p.W4240C) in DNAH2 by whole-exome sequencing, which fully co-segregated with the infertile male members in a consanguineous Pakistani family"
Recessive co-segregation in a consanguineous family.
◈

Mechanistic Hypotheses

1
Loss of DNAH2 disrupts the sperm flagellum but spares motile cilia, which is why SPGF45 is not primary ciliary dyskinesia
flagellum_specific_dnah2_requirement EMERGING
Evidence balance 2 support
Neither reported families nor knockout mice show motile cilia disease. The human evidence is the absence of reported symptoms, not systematic ciliary testing such as nasal nitric oxide or ciliary beat analysis, and DNAH2 partners in IDA f (DNAH10) can cause primary ciliary dyskinesia.
Show evidence (2 references)
PMID:33968937 SUPPORT Model Organism
"Histological analyses of ciliated epithelia of trachea and oviduct epithelia did not show significant morphological defects"
Normal tracheal and oviductal cilia in knockout mice.
PMID:33968937 SUPPORT Human Clinical
"No PCD-related symptoms were reported by the infertile males."
Affected men in the Pakistani family had no primary ciliary dyskinesia symptoms.
⚙

Pathophysiology

5
Loss of the DNAH2 Inner-Arm Dynein Heavy Chain
Missense, nonsense and other biallelic DNAH2 variants reduce or abolish DNAH2 protein in sperm flagella. DNAH2 is one of the three heavy chains of the double-headed inner dynein arm f (IDA f / I1), alongside DNAH10 and DNAH12.
DNAH2 hgnc:2948 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves DNAH2 (hgnc:2948). hgnc:2948 is a gene from the HUGO Gene Nomenclature Committee.
minus-end-directed microtubule motor activity GO:0008569 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased minus-end-directed microtubule motor activity (GO:0008569). GO:0008569 is a molecular function from the Gene Ontology.
Inner dynein arm GO:0036156 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves Inner dynein arm (GO:0036156). GO:0036156 is a cellular component from the Gene Ontology.
Downstream
Loss of Inner-Arm and Radial Spoke Partners from the Sperm Flagellum Without DNAH2, other inner-arm and radial spoke components fail to accumulate in the flagellum.
Disordered Flagellar Development During Spermiogenesis Shown only in knockout mice. How an axonemal dynein heavy chain influences basal body number and annulus migration is not known.
Show evidence (3 references)
PMID:30811583 SUPPORT Human Clinical
"The DNAH2 protein level was significantly decreased and inner dynein arms were absent in the spermatozoa of patients."
Reduced DNAH2 protein in patient sperm.
PMID:33771466 SUPPORT Human Clinical
"Immunofluorescence data further validated these findings, showing reduced DNAH2 protein expression in the spermatozoa with DNAH2 variants, compared with normal spermatozoa."
Independent confirmation of reduced DNAH2 protein in patient sperm.
PMID:40898283 SUPPORT Computational
"The IDAf complex comprises intermediate chains (DNAI3, DNAI4, DNAI7), light chains (DYNLRB1, DYNRB2, DYNLL1), and heavy chains (DNAH2, DNAH10, DNAH12)."
Analysis of published cryo-EM axoneme structures places DNAH2 as a heavy chain of IDA f.
Loss of Inner-Arm and Radial Spoke Partners from the Sperm Flagellum
In Dnah2 knockout sperm the inner-arm heavy chain DNAH1 and the radial spoke protein RSPH3 are absent from the flagellum, while the outer-arm heavy chain DNAH9 and acetylated tubulin remain. This has been shown in mice; the corresponding protein panel has not been reported for patient sperm.
Inner dynein arm assembly GO:0036159 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased Inner dynein arm assembly (GO:0036159). GO:0036159 is a biological process from the Gene Ontology.
Downstream
Inner Dynein Arm and Central Pair Loss with Axonemal Disorganization
Show evidence (1 reference)
PMID:33968937 SUPPORT Model Organism
"Dnah2Δ/Δ sperm do not express another IDA component (DNAH1, magenta) and a radial spoke protein (RSPH3, green) but an ODA protein (DNAH9, yellow)."
Selective loss of inner-arm and radial spoke proteins with outer arm retained.
Inner Dynein Arm and Central Pair Loss with Axonemal Disorganization
Patient sperm lack inner dynein arms, often lack the central pair, and have a disarranged axoneme and defective mitochondrial sheath, so the 9+2 arrangement is broken.
Sperm CL:0000019 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Sperm (CL:0000019). CL:0000019 is a cell type from the Cell Ontology.
Axoneme GO:0005930 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves Axoneme (GO:0005930). GO:0005930 is a cellular component from the Gene Ontology. Sperm mitochondrial sheath GO:0097226 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves Sperm mitochondrial sheath (GO:0097226). GO:0097226 is a cellular component from the Gene Ontology.
Animal models
Dnah2 exon 25-28 deletion mouse Mouse partially recapitulates The knockout axoneme is severely disorganized, but electron densities for the inner arms are still seen on the microtubule doublets.
Downstream
Multiple Morphological Abnormalities of the Sperm Flagella
Show evidence (3 references)
PMID:33771466 SUPPORT Human Clinical
"transmission electron microscopy revealed the obvious absence of a central pair of microtubules and inner dynein arms in the spermatozoa with mutated DNAH2"
Ultrastructural loss of inner dynein arms and central pair in patient sperm.
PMID:30811583 SUPPORT Human Clinical
"The spermatozoa with DNAH2 mutations showed severely disarranged axonemal structures with mitochondrial sheath defection."
Disorganized axoneme and mitochondrial sheath in patient sperm.
PMID:40592014 SUPPORT Human Clinical
"Transmission electron microscopy (TEM) revealed substantial loss of inner dynein arms and mitochondrial damage"
A further cohort, pooled with DNAH6 and DNAH10 patients, shows the same inner-arm loss.
Disordered Flagellar Development During Spermiogenesis
In Dnah2 knockout testis, elongating spermatids carry a variable number of centrioles, the annulus fails to migrate to its normal position, and mature sperm keep centriolar proteins at the connecting piece. Heads are mildly misshapen. These findings come from mice only.
Spermatid CL:0000018 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Spermatid (CL:0000018). CL:0000018 is a cell type from the Cell Ontology.
Spermatid development GO:0007286 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased Spermatid development (GO:0007286). GO:0007286 is a biological process from the Gene Ontology.
Sperm annulus GO:0097227 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves Sperm annulus (GO:0097227). GO:0097227 is a cellular component from the Gene Ontology.
Downstream
Multiple Morphological Abnormalities of the Sperm Flagella Misplaced basal body and annulus impair flagellar elongation and compartmentalization.
Abnormal sperm head morphology The authors infer a head-shaping defect during spermiogenesis from the mild head abnormalities; the intermediate steps are not shown.
Oligozoospermia Knockout testes release fewer sperm. Why disordered spermiogenesis lowers the count is not established, and the human count reduction is variable.
Show evidence (1 reference)
PMID:33968937 SUPPORT Model Organism
"We found misexpression of centriolar proteins and delocalization of annulus proteins in Dnah2-null spermatids and sperm, suggesting dysregulated flagella development in spermiogenesis."
Basal body and annulus defects in knockout spermatids.
Multiple Morphological Abnormalities of the Sperm Flagella
The defining semen phenotype: absent, short, coiled, bent and irregular-caliber flagella in the same ejaculate. In patient sperm, absent and short flagella predominate.
Sperm CL:0000019 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Sperm (CL:0000019). CL:0000019 is a cell type from the Cell Ontology.
Sperm axoneme assembly GO:0007288 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased Sperm axoneme assembly (GO:0007288). GO:0007288 is a biological process from the Gene Ontology.
Animal models
Dnah2 exon 25-28 deletion mouse Mouse recapitulates The knockout reproduces the human MMAF spectrum.
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
Show evidence (2 references)
PMID:33771466 SUPPORT Human Clinical
"spermatozoa harbouring DNAH2 variants displayed severely aberrant morphology mainly with absent and short flagella"
MMAF dominated by absent and short flagella in patients.
PMID:33968937 SUPPORT Human Clinical
"PAP staining revealed morphological abnormalities prominently in the tail, such as near-absent, short, curved, or coiled forms, which is similar to a representative MMAF phenotype"
MMAF in the Pakistani family.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Spermatogenic Failure 45 Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

7
Male infertility Reproductive HP:0003251 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Male infertility (HP:0003251). HP:0003251 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33968937 SUPPORT Human Clinical
"All the infertile males in this study failed to conceive over 10 years of marriages and unprotected sex (Table 1)."
Long-standing primary infertility in affected men.
Reduced sperm motility Reproductive HP:0012207 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Severe asthenozoospermia, annotated with Reduced sperm motility (HP:0012207). HP:0012207 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:30811583 SUPPORT Human Clinical
"these data suggest that the DNAH2 mutation can cause severe sperm flagella defects that damage sperm motility"
Reduced motility in DNAH2 patients.
PMID:33771466 SUPPORT Human Clinical
"bi-allelic DNAH2 variants might induce MMAF-associated asthenoteratozoospermia"
Asthenoteratozoospermia in an independent cohort.
Oligozoospermia Reproductive HP:0000798 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Oligozoospermia (HP:0000798). HP:0000798 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33968937 SUPPORT Human Clinical
"Three affected members (IV-1, IV-3, and V-1) were subjected to clinical analyses and initially diagnosed with oligoasthenozoospermia (OAZ, Table 1)."
Oligoasthenozoospermia in affected family members.
Absent sperm flagella Reproductive HP:0032558 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Absent sperm flagella (HP:0032558). HP:0032558 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33771466 SUPPORT Human Clinical
"spermatozoa harbouring DNAH2 variants displayed severely aberrant morphology mainly with absent and short flagella"
Absent flagella in patient sperm.
Short sperm flagella Reproductive HP:0032559 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short sperm flagella (HP:0032559). HP:0032559 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33771466 SUPPORT Human Clinical
"spermatozoa harbouring DNAH2 variants displayed severely aberrant morphology mainly with absent and short flagella"
Short flagella in patient sperm.
Coiled sperm flagella Reproductive HP:0032560 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Coiled sperm flagella (HP:0032560). HP:0032560 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33968937 SUPPORT Human Clinical
"PAP staining revealed morphological abnormalities prominently in the tail, such as near-absent, short, curved, or coiled forms"
Coiled flagella in patient sperm.
Abnormal sperm head morphology Reproductive HP:0012865 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal sperm head morphology (HP:0012865). HP:0012865 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33968937 SUPPORT Human Clinical
"which is similar to a representative MMAF phenotype, and mild defects in the head shape"
Mild head shape defects in patient sperm.
🧬

Genetic Associations

1
DNAH2 (Causal)
Gene: DNAH2 hgnc:2948 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is DNAH2 (hgnc:2948). hgnc:2948 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (3 references)
PMID:30811583 SUPPORT Human Clinical
"we identified five novel mutation sites in the DNAH2 gene in three cases from three families"
First gene-disease report.
PMID:33771466 SUPPORT Human Clinical
"Three unrelated men with bi-allelic DNAH2 variants were identified."
Independent replication in a 90-patient MMAF cohort.
PMID:33968937 SUPPORT Human Clinical
"WES analysis identified three rare damaging variants but only homozygous non-synonymous variant (c.12720G > T;p.W4240C) in DNAH2 co-segregated with the phenotype"
Co-segregating variant in a family of a different ancestry.
💊

Medical Actions

1
Intracytoplasmic Sperm Injection
Action: Intracytoplasmic Sperm InjectionNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Intracytoplasmic Sperm Injection (NCIT:C185482). NCIT:C185482 is a clinical intervention from the NCI Thesaurus. NCIT:C185482
Platform: Other
ICSI with ejaculated sperm bypasses the motility and form defect. In two Chinese series, all ICSI cycles produced pregnancies or blastocysts, and a pooled DNAH2/DNAH6/DNAH10 cohort reported live births in five of six couples. Numbers are small.
Mechanism Target:
Multiple Morphological Abnormalities of the Sperm Flagella — Direct injection makes flagellar propulsion and form irrelevant to fertilization.
Show evidence (1 reference)
PMID:30811583 SUPPORT Human Clinical
"ICSI treatment was performed for two MMAF patients with DNAH2 mutations and the associated couples successfully achieved pregnancy, indicating good nuclear quality of the sperm from the DNAH2 mutant patients."
ICSI succeeds because the sperm nucleus is intact.
Show evidence (2 references)
PMID:33771466 SUPPORT Human Clinical
"Intracytoplasmic sperm injection using spermatozoa from the three men with mutated DNAH2 resulted in blastocyst formation in all cases. Embryo transfer was carried out in two couples, both resulting in clinical pregnancy."
ICSI outcomes in three DNAH2 couples.
PMID:40592014 SUPPORT Human Clinical
"Moreover, five out of six affected couples achieved a live birth via intracytoplasmic sperm injection (ICSI)."
Live births in a cohort pooling DNAH2, DNAH6 and DNAH10 patients.
🐁

Animal Models

1
Dnah2 exon 25-28 deletion mouse
CRISPR/Cas9 deletion of exons 25-28 predicted to cause a frameshift; no full-length DNAH2 is made. Homozygous males are sterile with MMAF sperm; females are fertile and airway and oviduct cilia look normal.
Species
Mouse
Genotype
Dnah2 exon 25-28 deletion (C57BL/6N-Dnah2em1(IMPC)Tcp), homozygous
Publication
PMID:33968937
Pathograph links
Multiple Morphological Abnormalities of the Sperm Flagella recapitulates fidelity: high The knockout reproduces the human MMAF spectrum.
Show evidence (1 reference)
PMID:33968937 SUPPORT Model Organism
"Dnah2-null sperm cells display absent, short, bent, coiled, and/or irregular flagella consistent with the MMAF phenotype."
MMAF in knockout sperm.
Inner Dynein Arm and Central Pair Loss with Axonemal Disorganization partially recapitulates fidelity: moderate The knockout axoneme is severely disorganized, but electron densities for the inner arms are still seen on the microtubule doublets.
Limitations: Patient sperm lack inner dynein arms by TEM, whereas knockout sperm retain inner-arm electron densities despite losing DNAH1 and DNAH2, so the mouse does not reproduce the human inner-arm loss exactly.
Show evidence (1 reference)
PMID:33968937 SUPPORT Model Organism
"Electron densities corresponding to both IDA and ODA were observed from the microtubule doublets when the 9+2 arrangement is incomplete"
Records the retained inner-arm densities behind the limitation.
{ }

Source YAML

click to show 
name: Spermatogenic Failure 45
creation_date: "2026-10-14T00:00:00Z"
category: Mendelian
synonyms:
- SPGF45
- spermatogenic failure 45
- DNAH2-related asthenoteratozoospermia
- DNAH2-related multiple morphological abnormalities of the sperm flagella
description: >-
  Spermatogenic failure 45 (SPGF45) is autosomal recessive male infertility
  caused by biallelic variants in DNAH2, which encodes an axonemal inner
  dynein arm heavy chain. Structural studies place DNAH2 in the
  double-headed inner dynein arm f (IDA f, also called I1) together with the
  heavy chains DNAH10 and DNAH12. Affected men have severe
  asthenoteratozoospermia with multiple morphological abnormalities of the
  sperm flagella (MMAF): most sperm have absent, short or coiled flagella,
  and some have mildly misshapen heads. Sperm count is normal to moderately
  reduced. Electron microscopy of patient sperm shows absent inner dynein
  arms, frequent loss of the central pair of microtubules, and a disorganized
  axoneme and mitochondrial sheath.

  In Dnah2 knockout mice, males but not females are infertile, sperm show
  the full MMAF spectrum, the inner-arm heavy chain DNAH1 and the radial
  spoke protein RSPH3 are lost from the flagellum, and basal body and
  annulus positioning during spermiogenesis is disturbed. Reported patients
  had no symptoms of primary ciliary dyskinesia, and the knockout mice had
  normal tracheal and oviductal cilia, so SPGF45 behaves as an isolated sperm
  flagellar disorder. ICSI with ejaculated sperm has given embryos,
  pregnancies and live births.
disease_term:
  preferred_term: spermatogenic failure 45
  term:
    id: MONDO:0033671
    label: spermatogenic failure 45
parents:
- Spermatogenic Failure
- Genetic Disease
notes: >-
  MONDO cross-references this disease as OMIM 619094 (the DNAH2 gene entry is
  OMIM 603333). ClinGen has no gene-disease validity classification for DNAH2
  and spermatogenic failure (searched kb/genes/ingest/clingen_gene_validity.tsv
  for DNAH2, no row). PMID:40592014 reports DNAH2, DNAH6 and DNAH10 patients
  together, and its abstract does not separate their results by gene, so its
  ICSI figures are pooled across the three genes. Abstract-only caches:
  PMID:30811583, PMID:33771466 and PMID:40592014; PMID:33968937 is full text.
inheritance:
- name: Autosomal recessive
  description: >-
    Disease requires biallelic DNAH2 variants. Reported genotypes are
    compound heterozygous or homozygous variants in Han Chinese men and a
    homozygous missense variant (p.W4240C) co-segregating in a consanguineous
    Pakistani family.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:33771466
    reference_title: "Novel bi-allelic variants in DNAH2 cause severe asthenoteratozoospermia with multiple morphological abnormalities of the flagella."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Three unrelated men with bi-allelic DNAH2 variants were identified. Sanger sequencing verified that the six novel variants originated from every parent."
    explanation: Biallelic variants inherited one from each parent in three unrelated men.
  - reference: PMID:33968937
    reference_title: "Genetic Defects in DNAH2 Underlie Male Infertility With Multiple Morphological Abnormalities of the Sperm Flagella in Humans and Mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we identified a novel recessive variant (NM_020877:c.12720G > T;p.W4240C) in DNAH2 by whole-exome sequencing, which fully co-segregated with the infertile male members in a consanguineous Pakistani family"
    explanation: Recessive co-segregation in a consanguineous family.
pathophysiology:
- name: Loss of the DNAH2 Inner-Arm Dynein Heavy Chain
  description: >-
    Missense, nonsense and other biallelic DNAH2 variants reduce or abolish
    DNAH2 protein in sperm flagella. DNAH2 is one of the three heavy chains
    of the double-headed inner dynein arm f (IDA f / I1), alongside DNAH10
    and DNAH12.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: DNAH2
    term:
      id: hgnc:2948
      label: DNAH2
  molecular_functions:
  - preferred_term: minus-end-directed microtubule motor activity
    modifier: DECREASED
    term:
      id: GO:0008569
      label: minus-end-directed microtubule motor activity
  cellular_components:
  - preferred_term: Inner dynein arm
    term:
      id: GO:0036156
      label: inner dynein arm
  downstream:
  - target: Loss of Inner-Arm and Radial Spoke Partners from the Sperm Flagellum
    causal_link_type: DIRECT
    description: Without DNAH2, other inner-arm and radial spoke components fail to accumulate in the flagellum.
    evidence:
    - reference: PMID:33968937
      reference_title: "Genetic Defects in DNAH2 Underlie Male Infertility With Multiple Morphological Abnormalities of the Sperm Flagella in Humans and Mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Absence of DNAH2 compromises the expression of other axonemal components such as DNAH1 and RSPH3."
      explanation: Knockout mouse sperm lose DNAH1 and RSPH3 when DNAH2 is absent.
  - target: Disordered Flagellar Development During Spermiogenesis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Shown only in knockout mice. How an axonemal dynein heavy chain
      influences basal body number and annulus migration is not known.
  evidence:
  - reference: PMID:30811583
    reference_title: "DNAH2 is a novel candidate gene associated with multiple morphological abnormalities of the sperm flagella."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The DNAH2 protein level was significantly decreased and inner dynein arms were absent in the spermatozoa of patients."
    explanation: Reduced DNAH2 protein in patient sperm.
  - reference: PMID:33771466
    reference_title: "Novel bi-allelic variants in DNAH2 cause severe asthenoteratozoospermia with multiple morphological abnormalities of the flagella."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Immunofluorescence data further validated these findings, showing reduced DNAH2 protein expression in the spermatozoa with DNAH2 variants, compared with normal spermatozoa."
    explanation: Independent confirmation of reduced DNAH2 protein in patient sperm.
  - reference: PMID:40898283
    reference_title: "DNAH10 mutation cause primary ciliary dyskinesia with defects of IDAf complex assembly and lung fibrosis manifestation."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "The IDAf complex comprises intermediate chains (DNAI3, DNAI4, DNAI7), light chains (DYNLRB1, DYNRB2, DYNLL1), and heavy chains (DNAH2, DNAH10, DNAH12)."
    explanation: Analysis of published cryo-EM axoneme structures places DNAH2 as a heavy chain of IDA f.
- name: Loss of Inner-Arm and Radial Spoke Partners from the Sperm Flagellum
  description: >-
    In Dnah2 knockout sperm the inner-arm heavy chain DNAH1 and the radial
    spoke protein RSPH3 are absent from the flagellum, while the outer-arm
    heavy chain DNAH9 and acetylated tubulin remain. This has been shown in
    mice; the corresponding protein panel has not been reported for patient
    sperm.
  biological_scale: MOLECULAR
  biological_processes:
  - preferred_term: Inner dynein arm assembly
    term:
      id: GO:0036159
      label: inner dynein arm assembly
    modifier: DECREASED
  downstream:
  - target: Inner Dynein Arm and Central Pair Loss with Axonemal Disorganization
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:33968937
    reference_title: "Genetic Defects in DNAH2 Underlie Male Infertility With Multiple Morphological Abnormalities of the Sperm Flagella in Humans and Mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Dnah2Δ/Δ sperm do not express another IDA component (DNAH1, magenta) and a radial spoke protein (RSPH3, green) but an ODA protein (DNAH9, yellow)."
    explanation: Selective loss of inner-arm and radial spoke proteins with outer arm retained.
- name: Inner Dynein Arm and Central Pair Loss with Axonemal Disorganization
  description: >-
    Patient sperm lack inner dynein arms, often lack the central pair, and
    have a disarranged axoneme and defective mitochondrial sheath, so the
    9+2 arrangement is broken.
  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 mitochondrial sheath
    term:
      id: GO:0097226
      label: sperm mitochondrial sheath
  downstream:
  - target: Multiple Morphological Abnormalities of the Sperm Flagella
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:33771466
    reference_title: "Novel bi-allelic variants in DNAH2 cause severe asthenoteratozoospermia with multiple morphological abnormalities of the flagella."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "transmission electron microscopy revealed the obvious absence of a central pair of microtubules and inner dynein arms in the spermatozoa with mutated DNAH2"
    explanation: Ultrastructural loss of inner dynein arms and central pair in patient sperm.
  - reference: PMID:30811583
    reference_title: "DNAH2 is a novel candidate gene associated with multiple morphological abnormalities of the sperm flagella."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The spermatozoa with DNAH2 mutations showed severely disarranged axonemal structures with mitochondrial sheath defection."
    explanation: Disorganized axoneme and mitochondrial sheath in patient sperm.
  - reference: PMID:40592014
    reference_title: "Patients with mutations in DNAH2, DNAH6 and DNAH10 causing multiple morphological abnormalities of human sperm flagella achieve good ICSI outcomes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Transmission electron microscopy (TEM) revealed substantial loss of inner dynein arms and mitochondrial damage"
    explanation: A further cohort, pooled with DNAH6 and DNAH10 patients, shows the same inner-arm loss.
- name: Disordered Flagellar Development During Spermiogenesis
  description: >-
    In Dnah2 knockout testis, elongating spermatids carry a variable number
    of centrioles, the annulus fails to migrate to its normal position, and
    mature sperm keep centriolar proteins at the connecting piece. Heads are
    mildly misshapen. These findings come from mice only.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: Spermatid
    term:
      id: CL:0000018
      label: spermatid
  cellular_components:
  - preferred_term: Sperm annulus
    term:
      id: GO:0097227
      label: sperm annulus
  biological_processes:
  - preferred_term: Spermatid development
    term:
      id: GO:0007286
      label: spermatid development
    modifier: DECREASED
  downstream:
  - target: Multiple Morphological Abnormalities of the Sperm Flagella
    causal_link_type: DIRECT
    description: Misplaced basal body and annulus impair flagellar elongation and compartmentalization.
  - target: Abnormal sperm head morphology
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The authors infer a head-shaping defect during spermiogenesis from the
      mild head abnormalities; the intermediate steps are not shown.
    evidence:
    - reference: PMID:33968937
      reference_title: "Genetic Defects in DNAH2 Underlie Male Infertility With Multiple Morphological Abnormalities of the Sperm Flagella in Humans and Mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "We found DNAH2 deficiency in mice causes MMAF phenotypes and mildly abnormal heads"
      explanation: Mouse evidence pairing the spermiogenesis defect with abnormal heads.
  - target: Oligozoospermia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Knockout testes release fewer sperm. Why disordered spermiogenesis
      lowers the count is not established, and the human count reduction is
      variable.
    evidence:
    - reference: PMID:33968937
      reference_title: "Genetic Defects in DNAH2 Underlie Male Infertility With Multiple Morphological Abnormalities of the Sperm Flagella in Humans and Mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Compared to heterozygous mutants, homozygous Dnah2 mutants had fewer sperm cells in the lumen of seminiferous tubules and epididymis"
      explanation: Reduced sperm output in knockout mice.
  evidence:
  - reference: PMID:33968937
    reference_title: "Genetic Defects in DNAH2 Underlie Male Infertility With Multiple Morphological Abnormalities of the Sperm Flagella in Humans and Mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We found misexpression of centriolar proteins and delocalization of annulus proteins in Dnah2-null spermatids and sperm, suggesting dysregulated flagella development in spermiogenesis."
    explanation: Basal body and annulus defects in knockout spermatids.
- name: Multiple Morphological Abnormalities of the Sperm Flagella
  description: >-
    The defining semen phenotype: absent, short, coiled, bent and
    irregular-caliber flagella in the same ejaculate. In patient sperm,
    absent and short flagella predominate.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: Sperm
    term:
      id: CL:0000019
      label: sperm
  biological_processes:
  - preferred_term: Sperm axoneme assembly
    term:
      id: GO:0007288
      label: sperm axoneme assembly
    modifier: DECREASED
  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
  evidence:
  - reference: PMID:33771466
    reference_title: "Novel bi-allelic variants in DNAH2 cause severe asthenoteratozoospermia with multiple morphological abnormalities of the flagella."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "spermatozoa harbouring DNAH2 variants displayed severely aberrant morphology mainly with absent and short flagella"
    explanation: MMAF dominated by absent and short flagella in patients.
  - reference: PMID:33968937
    reference_title: "Genetic Defects in DNAH2 Underlie Male Infertility With Multiple Morphological Abnormalities of the Sperm Flagella in Humans and Mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "PAP staining revealed morphological abnormalities prominently in the tail, such as near-absent, short, curved, or coiled forms, which is similar to a representative MMAF phenotype"
    explanation: MMAF in the Pakistani family.
mechanistic_hypotheses:
- hypothesis_group_id: flagellum_specific_dnah2_requirement
  hypothesis_label: Loss of DNAH2 disrupts the sperm flagellum but spares motile cilia, which is why SPGF45 is not primary ciliary dyskinesia
  status: EMERGING
  description: >-
    Neither reported families nor knockout mice show motile cilia disease.
    The human evidence is the absence of reported symptoms, not systematic
    ciliary testing such as nasal nitric oxide or ciliary beat analysis, and
    DNAH2 partners in IDA f (DNAH10) can cause primary ciliary dyskinesia.
  evidence:
  - reference: PMID:33968937
    reference_title: "Genetic Defects in DNAH2 Underlie Male Infertility With Multiple Morphological Abnormalities of the Sperm Flagella in Humans and Mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Histological analyses of ciliated epithelia of trachea and oviduct epithelia did not show significant morphological defects"
    explanation: Normal tracheal and oviductal cilia in knockout mice.
  - reference: PMID:33968937
    reference_title: "Genetic Defects in DNAH2 Underlie Male Infertility With Multiple Morphological Abnormalities of the Sperm Flagella in Humans and Mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "No PCD-related symptoms were reported by the infertile males."
    explanation: Affected men in the Pakistani family had no primary ciliary dyskinesia symptoms.
phenotypes:
- category: Reproductive
  name: Male infertility
  description: Primary male infertility is the presenting complaint; hormones, karyotype and Y-chromosome studies are normal.
  phenotype_term:
    preferred_term: Male infertility
    term:
      id: HP:0003251
      label: Male infertility
  evidence:
  - reference: PMID:33968937
    reference_title: "Genetic Defects in DNAH2 Underlie Male Infertility With Multiple Morphological Abnormalities of the Sperm Flagella in Humans and Mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All the infertile males in this study failed to conceive over 10 years of marriages and unprotected sex (Table 1)."
    explanation: Long-standing primary infertility in affected men.
- category: Reproductive
  name: Reduced sperm motility
  description: >-
    Severe asthenozoospermia. In the Pakistani family 80-90% of sperm were
    immotile and progressive motility was 0-7%.
  phenotype_term:
    preferred_term: Severe asthenozoospermia
    term:
      id: HP:0012207
      label: Reduced sperm motility
  evidence:
  - reference: PMID:30811583
    reference_title: "DNAH2 is a novel candidate gene associated with multiple morphological abnormalities of the sperm flagella."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "these data suggest that the DNAH2 mutation can cause severe sperm flagella defects that damage sperm motility"
    explanation: Reduced motility in DNAH2 patients.
  - reference: PMID:33771466
    reference_title: "Novel bi-allelic variants in DNAH2 cause severe asthenoteratozoospermia with multiple morphological abnormalities of the flagella."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "bi-allelic DNAH2 variants might induce MMAF-associated asthenoteratozoospermia"
    explanation: Asthenoteratozoospermia in an independent cohort.
- category: Reproductive
  name: Oligozoospermia
  description: >-
    Variable. The three examined men of the Pakistani family had sperm
    concentrations of 7-10 x10^6/ml, below the WHO limit of 15 x10^6/ml.
    Counts were not reported in the cached abstracts of the Chinese cohorts.
  phenotype_term:
    preferred_term: Oligozoospermia
    term:
      id: HP:0000798
      label: Oligozoospermia
  evidence:
  - reference: PMID:33968937
    reference_title: "Genetic Defects in DNAH2 Underlie Male Infertility With Multiple Morphological Abnormalities of the Sperm Flagella in Humans and Mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Three affected members (IV-1, IV-3, and V-1) were subjected to clinical analyses and initially diagnosed with oligoasthenozoospermia (OAZ, Table 1)."
    explanation: Oligoasthenozoospermia in affected family members.
- category: Reproductive
  name: Absent sperm flagella
  description: Flagellum-less sperm are among the commonest forms in the MMAF mosaic.
  phenotype_term:
    preferred_term: Absent sperm flagella
    term:
      id: HP:0032558
      label: Absent sperm flagella
  evidence:
  - reference: PMID:33771466
    reference_title: "Novel bi-allelic variants in DNAH2 cause severe asthenoteratozoospermia with multiple morphological abnormalities of the flagella."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "spermatozoa harbouring DNAH2 variants displayed severely aberrant morphology mainly with absent and short flagella"
    explanation: Absent flagella in patient sperm.
- category: Reproductive
  name: Short sperm flagella
  description: Short flagella are among the commonest forms in the MMAF mosaic.
  phenotype_term:
    preferred_term: Short sperm flagella
    term:
      id: HP:0032559
      label: Short sperm flagella
  evidence:
  - reference: PMID:33771466
    reference_title: "Novel bi-allelic variants in DNAH2 cause severe asthenoteratozoospermia with multiple morphological abnormalities of the flagella."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "spermatozoa harbouring DNAH2 variants displayed severely aberrant morphology mainly with absent and short flagella"
    explanation: Short flagella in patient sperm.
- category: Reproductive
  name: Coiled sperm flagella
  description: Coiled flagella occur in patients and in knockout mice.
  phenotype_term:
    preferred_term: Coiled sperm flagella
    term:
      id: HP:0032560
      label: Coiled sperm flagella
  evidence:
  - reference: PMID:33968937
    reference_title: "Genetic Defects in DNAH2 Underlie Male Infertility With Multiple Morphological Abnormalities of the Sperm Flagella in Humans and Mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "PAP staining revealed morphological abnormalities prominently in the tail, such as near-absent, short, curved, or coiled forms"
    explanation: Coiled flagella in patient sperm.
- category: Reproductive
  name: Abnormal sperm head morphology
  description: >-
    Mild head defects, including some spherical heads, accompany the tail
    defects. The nucleus is functional enough for ICSI to succeed.
  phenotype_term:
    preferred_term: Abnormal sperm head morphology
    term:
      id: HP:0012865
      label: Abnormal sperm head morphology
  evidence:
  - reference: PMID:33968937
    reference_title: "Genetic Defects in DNAH2 Underlie Male Infertility With Multiple Morphological Abnormalities of the Sperm Flagella in Humans and Mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "which is similar to a representative MMAF phenotype, and mild defects in the head shape"
    explanation: Mild head shape defects in patient sperm.
genetic:
- name: DNAH2
  association: Causal
  gene_term:
    preferred_term: DNAH2
    term:
      id: hgnc:2948
      label: DNAH2
  notes: >-
    Reported alleles include missense and nonsense variants located in the
    AAA ATPase and C-terminal dynein heavy chain domains: p.R1924C, p.S3835P
    and p.R3834Ter in the first Chinese report (as summarized in
    PMID:33968937), six further variants in three Chinese men
    (PMID:33771466), and homozygous p.W4240C (NM_020877 c.12720G>T) in a
    Pakistani family. No ClinGen gene-disease validity classification exists.
  evidence:
  - reference: PMID:30811583
    reference_title: "DNAH2 is a novel candidate gene associated with multiple morphological abnormalities of the sperm flagella."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we identified five novel mutation sites in the DNAH2 gene in three cases from three families"
    explanation: First gene-disease report.
  - reference: PMID:33771466
    reference_title: "Novel bi-allelic variants in DNAH2 cause severe asthenoteratozoospermia with multiple morphological abnormalities of the flagella."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Three unrelated men with bi-allelic DNAH2 variants were identified."
    explanation: Independent replication in a 90-patient MMAF cohort.
  - reference: PMID:33968937
    reference_title: "Genetic Defects in DNAH2 Underlie Male Infertility With Multiple Morphological Abnormalities of the Sperm Flagella in Humans and Mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "WES analysis identified three rare damaging variants but only homozygous non-synonymous variant (c.12720G > T;p.W4240C) in DNAH2 co-segregated with the phenotype"
    explanation: Co-segregating variant in a family of a different ancestry.
animal_models:
- name: Dnah2 exon 25-28 deletion mouse
  species: Mouse
  genotype: Dnah2 exon 25-28 deletion (C57BL/6N-Dnah2em1(IMPC)Tcp), homozygous
  publication: PMID:33968937
  description: >-
    CRISPR/Cas9 deletion of exons 25-28 predicted to cause a frameshift; no
    full-length DNAH2 is made. Homozygous males are sterile with MMAF sperm;
    females are fertile and airway and oviduct cilia look normal.
  modeled_mechanisms:
  - target: Multiple Morphological Abnormalities of the Sperm Flagella
    relationship: RECAPITULATES
    fidelity: HIGH
    description: The knockout reproduces the human MMAF spectrum.
    evidence:
    - reference: PMID:33968937
      reference_title: "Genetic Defects in DNAH2 Underlie Male Infertility With Multiple Morphological Abnormalities of the Sperm Flagella in Humans and Mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Dnah2-null sperm cells display absent, short, bent, coiled, and/or irregular flagella consistent with the MMAF phenotype."
      explanation: MMAF in knockout sperm.
  - target: Inner Dynein Arm and Central Pair Loss with Axonemal Disorganization
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >-
      The knockout axoneme is severely disorganized, but electron densities
      for the inner arms are still seen on the microtubule doublets.
    limitations: >-
      Patient sperm lack inner dynein arms by TEM, whereas knockout sperm
      retain inner-arm electron densities despite losing DNAH1 and DNAH2, so
      the mouse does not reproduce the human inner-arm loss exactly.
    evidence:
    - reference: PMID:33968937
      reference_title: "Genetic Defects in DNAH2 Underlie Male Infertility With Multiple Morphological Abnormalities of the Sperm Flagella in Humans and Mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Electron densities corresponding to both IDA and ODA were observed from the microtubule doublets when the 9+2 arrangement is incomplete"
      explanation: Records the retained inner-arm densities behind the limitation.
treatments:
- name: Intracytoplasmic Sperm Injection
  description: >-
    ICSI with ejaculated sperm bypasses the motility and form defect. In two
    Chinese series, all ICSI cycles produced pregnancies or blastocysts, and
    a pooled DNAH2/DNAH6/DNAH10 cohort reported live births in five of six
    couples. Numbers are small.
  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:30811583
      reference_title: "DNAH2 is a novel candidate gene associated with multiple morphological abnormalities of the sperm flagella."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "ICSI treatment was performed for two MMAF patients with DNAH2 mutations and the associated couples successfully achieved pregnancy, indicating good nuclear quality of the sperm from the DNAH2 mutant patients."
      explanation: ICSI succeeds because the sperm nucleus is intact.
  evidence:
  - reference: PMID:33771466
    reference_title: "Novel bi-allelic variants in DNAH2 cause severe asthenoteratozoospermia with multiple morphological abnormalities of the flagella."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Intracytoplasmic sperm injection using spermatozoa from the three men with mutated DNAH2 resulted in blastocyst formation in all cases. Embryo transfer was carried out in two couples, both resulting in clinical pregnancy."
    explanation: ICSI outcomes in three DNAH2 couples.
  - reference: PMID:40592014
    reference_title: "Patients with mutations in DNAH2, DNAH6 and DNAH10 causing multiple morphological abnormalities of human sperm flagella achieve good ICSI outcomes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Moreover, five out of six affected couples achieved a live birth via intracytoplasmic sperm injection (ICSI)."
    explanation: Live births in a cohort pooling DNAH2, DNAH6 and DNAH10 patients.
📚

References & Deep Research

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (1)

Create: Spermatogenic_Failure_45 · 2026-10-14T20:20:47Z · View source

New entry for MONDO:0033671 (DNAH2-related SPGF45, OMIM 619094), curated from the open stub, which is deleted. Two just research-disorder falcon runs failed with a 503 Edison authentication error (deep-research-client providers --check reported falcon UNREACHABLE), and a run with dr_fallback='--fallback' failed the same way without falling back, so the report used is research/Spermatogenic_Failure_45-deep-research-claude_code.md from just research-disorder claude_code. preflight-dr returned PASS (DNAH2 mentioned 21 times). The report cites few primary sources, so curation rests on PubMed-found papers fetched with just fetch-reference: PMID:30811583, PMID:33771466 and PMID:40592014 (abstracts) and PMID:33968937 (full text, human family plus Dnah2 deletion mouse); PMID:40898283 supplies the cryo-EM-based placement of DNAH2, DNAH10 and DNAH12 as IDA f heavy chains. Causal chain: DNAH2 protein loss, loss of DNAH1 and RSPH3 from the flagellum (mouse), inner dynein arm and central pair loss with axonemal and mitochondrial-sheath disorganization, MMAF, phenotypes; a mouse-only spermiogenesis node (basal body and annulus mispositioning) links to head defects and oligozoospermia. The mouse link records that knockout sperm retain inner-arm electron densities, unlike patient sperm. No ClinGen classification exists for DNAH2. Validated with just validate (all snippets verified), count-verified-snippets, validate-terms, check-entity-refs, check-causal-targets, check-duplicate-keys, check-enum-values and check-genereviews (NO_CHAPTER).

Claude Code ▸
Research report: Spermatogenic Failure 45 (SPGF45)
claude-haiku-5-5, claude-sonnet-5-5 5 citations 2026-10-14T20:11:06.282372

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

Research report: Spermatogenic Failure 45 (SPGF45)

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

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

1. Disease information

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

2. Etiology

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

3. Phenotypes

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

Phenotype Suggested HPO Evidence
Male infertility HP:0003251 Verified
Asthenozoospermia HP:0012206 Verified
Teratozoospermia / abnormal sperm flagellar morphology HP:0012864 or HP:0012207 Verified
Oligozoospermia HP:0000798 Verified, family-level
Normal FSH, LH, testosterone, prolactin n/a Verified
  • Sperm findings in the family. Sperm were 80%, 82% and 92% morphologically abnormal in three affected males. Defects were mainly in the tail, with mild head defects [Verified, PMC8103034].
  • Other findings. Karyotype and Y-microdeletion screening were normal. No extra-testicular phenotype was described; the mouse had no trachea or oviduct defects.
  • Quality of life. Not available.

4. Genetic and molecular information

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

5. Environmental information

None reported. No infectious agent is involved.

6. Mechanism and pathophysiology

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

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

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

7. Anatomical structures affected

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

8. Temporal development

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

9. Inheritance and population

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

10. Diagnostics

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

11. Outcome and prognosis

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

12. Treatment

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

13. Prevention

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

14. Other species and natural disease

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

15. Model organisms

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

Evidence gaps to close before curation

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

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

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome Count
References checked 3
Resolved 3
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 3
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 10
Resolved 9
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 1
Terms whose name was checked 5
Terms named correctly 2
Terms named as a different term 2
Terms whose name is worth a second look 1

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

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

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

  • CL:0000018 (1 mention) - the report calls it "Cell types: spermatid"; CL calls it spermatid

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: MGI.