👪

Inheritance

1

Autosomal recessive HP:0000007

Disease requires biallelic DNAH8 variants. Reported genotypes include homozygous missense, frameshift and splice-acceptor variants in consanguineous Chinese, French/North African and Pakistani families, and compound heterozygous missense variants in Chinese men.

Autosomal recessive inheritance

Show evidence (2 references)

PMID:32619401 SUPPORT Human Clinical

"bi-allelic deleterious DNAH8 variants lead to male infertility with MMAF"

Biallelic variants in the index cohorts establish recessive inheritance.

PMID:36308074 SUPPORT Human Clinical

"Sanger sequencing confirmed the patients' father and fertile brothers to be heterozygous carriers"

Heterozygous carriers in the family are fertile, consistent with recessive inheritance.

◈

Mechanistic Hypotheses

1

DNAH8 is the sperm-specific gamma heavy chain of the outer dynein arm, so its loss causes isolated male infertility rather than primary ciliary dyskinesia

sperm_restricted_dnah8_oda CANONICAL

Evidence balance 4 support

Sperm and respiratory cilia build their outer dynein arms from different heavy chains: DNAH8 and DNAH17 in sperm, DNAH5 with DNAH9 or DNAH11 in respiratory cilia. DNAH8 is therefore needed in the sperm flagellum but not in motile cilia. In patients the evidence is clinical (normal situs and no PCD symptoms), not a formal ciliary work-up such as nasal nitric oxide or ciliary beat analysis.

Pathograph links

Loss of the DNAH8 Outer-Arm Dynein Heavy Chain -> Outer Dynein Arm Loss in the Sperm Axoneme DIRECT DNAH8 is a structural heavy chain of the sperm ODA; without it, its partner heavy chain DNAH17 is also depleted from the flagellum.

Show evidence (4 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 of control sperm and respiratory cells shows the sperm-restricted ODA heavy-chain composition.

PMID:31178125 SUPPORT BACKGROUND Other

"the contribution of the different HCs (γ-type: DNAH5 and DNAH8 and β-type: DNAH9, DNAH11, and DNAH17) in ODAs from both organelles is unknown"

Places DNAH8 with DNAH5 as the two gamma-type ODA heavy chains.

PMID:36308074 SUPPORT Human Clinical

"the affected individuals exhibited a normal visceral position (Supplementary Figure 2), without any clinical symptoms of PCD"

DNAH8-null patients have normal situs and no PCD symptoms.

+ 1 more reference

⚙

Pathophysiology

4

Loss of the DNAH8 Outer-Arm Dynein Heavy Chain

Truncating, splice and missense alleles lead to absent or markedly reduced DNAH8 in patient sperm. A frameshift allele removes the transcript by nonsense-mediated decay, and a splice-acceptor allele skips exon 45 and truncates the protein within the motor domain.

DNAH8 is the sperm-specific gamma heavy chain of the outer dynein arm, so its loss causes isolated male infertility rather than primary ciliary dyskinesia

DNAH8 hgnc:2952

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

Downstream

Outer Dynein Arm Loss in the Sperm Axoneme DNAH8 is a structural heavy chain of the sperm ODA; without it, its partner heavy chain DNAH17 is also depleted from the flagellum.

Show evidence (3 references)

PMID:36308074 SUPPORT Human Clinical

"Endogenous DNAH8 transcripts were not detected in either patient, but a clear band was obtained for the fertile control"

The homozygous frameshift allele abolishes DNAH8 mRNA in patients.

PMID:33611675 SUPPORT In Vitro

"We found that the splicing variant led to the deletion of exon 45, which resulted in a frameshift and a predicted truncated protein (p.G2104Efs*19)"

Minigene assay shows the splice-acceptor allele truncates DNAH8.

PMID:33704367 SUPPORT Human Clinical

"Immunofluorescence assay showed that DNAH8 protein expression was significantly decreased in the sperm tail of the patients"

Compound heterozygous missense genotypes also reduce DNAH8 in sperm.

Outer Dynein Arm Loss in the Sperm Axoneme

The sperm ODA contains the heavy chains DNAH8 and DNAH17. Loss of DNAH8 depletes DNAH17 from patient sperm and ODAs are missing or disassembled on electron microscopy.

Outer dynein arm assembly GO:0036158 ↓ DECREASED

Outer dynein arm GO:0036157

Downstream

Sperm Axonemal Disorganization Loss of the ODA accompanies a wider breakdown of the axoneme, with missing doublets, outer dense fibers and central pair. How loss of an ODA heavy chain destabilizes these other structures is not established.

Show evidence (2 references)

PMID:36308074 SUPPORT Human Clinical

"expression of DNAH17 was dramatically reduced in the spermatozoa of the patients compared to healthy individuals"

An independent family confirms co-depletion of the partner ODA heavy chain DNAH17.

PMID:31178125 SUPPORT Human Clinical

"these analyses indicated the absence of DNAH17 and DNAH8, whereas DNAH2 and DNALI, two inner dynein arm components, were present"

The reciprocal result in DNAH17-deficient sperm: DNAH8 is lost while inner-arm components are kept, showing that DNAH8 and DNAH17 assemble together into the sperm ODA.

Sperm Axonemal Disorganization

Most flagellar cross-sections show disorganized or missing peripheral doublets and outer dense fibers, missing ODAs and an absent central pair complex, so the 9+2 arrangement is lost.

Sperm CL:0000019

Axoneme GO:0005930 Sperm flagellum GO:0036126

Downstream

Multiple Morphological Abnormalities of the Sperm Flagella

Abnormal sperm axoneme morphology

Show evidence (2 references)

PMID:36308074 SUPPORT Human Clinical

"ultrastructural defects were observed in more than 80% of the sections of sperm flagella from the two patients, including disorganized or missing peripheral microtubule doublets and outer dense fibers, missing or disassembled outer dense arms (ODAs), and absent central pair complexes"

Ultrastructural demonstration of the axonemal lesion in patients.

PMID:32619401 SUPPORT Human Clinical

"Hematoxylin-eosin staining and electron microscopy analyses of the spermatozoa from men harboring bi-allelic DNAH8 variants showed a highly aberrant morphology and ultrastructure of the sperm flagella."

Aberrant flagellar ultrastructure in the index cohort.

Multiple Morphological Abnormalities of the Sperm Flagella

The defining semen phenotype: absent, short, coiled, angulated and irregular-caliber flagella in the same ejaculate, with severely reduced motility.

Sperm CL:0000019

Sperm flagellum assembly GO:0120316 ↓ DECREASED

Animal models

Dnah8 knockout mouse Mouse recapitulates The knockout reproduces the human MMAF phenotype and sterility.

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

Bent sperm flagella

Irregularly shaped sperm tail

Show evidence (2 references)

PMID:36308074 SUPPORT Human Clinical

"Morphologically, the abnormal sperm were characterized by coiled, absent, short, and angulation, with irregular sperm flagellar phenotypes"

Describes the MMAF mosaic in patient sperm.

CGGV:assertion_e740f4af-53fe-4c51-99f6-6111fe343d7f-2022-06-23T160000.000Z SUPPORT Other

"Spermatogenic failure 46 (SPGF46) is characterized by male infertility due to morphologic abnormalities of the flagella (MMAF), including flagella that are absent, short, coiled, angulated, and/or of irregular caliber"

ClinGen expert-panel summary of the disease phenotype across published probands.

⬡

Pathograph

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

●

Phenotypes

9

Male infertility Reproductive HP:0003251

Show evidence (1 reference)

PMID:32681648 SUPPORT Human Clinical

"a loss-of-function mutation in DNAH8 can cause male infertility with MMAF"

Independent report of male infertility with a DNAH8 loss-of-function allele.

Reduced sperm motility Reproductive HP:0012207

Show evidence (1 reference)

PMID:36308074 SUPPORT Human Clinical

"These results indicate that IV:1 and IV:3 exhibited severe asthenozoospermia due to MMAF."

Severe asthenozoospermia in both affected brothers.

Absent sperm flagella Reproductive HP:0032558

Show evidence (1 reference)

PMID:36308074 SUPPORT Human Clinical

"Morphologically, the abnormal sperm were characterized by coiled, absent, short, and angulation, with irregular sperm flagellar phenotypes"

Absent flagella reported in patient sperm.

Short sperm flagella Reproductive HP:0032559

Show evidence (1 reference)

PMID:36308074 SUPPORT Human Clinical

"Morphologically, the abnormal sperm were characterized by coiled, absent, short, and angulation, with irregular sperm flagellar phenotypes"

Short flagella reported in patient sperm.

Coiled sperm flagella Reproductive HP:0032560

Show evidence (1 reference)

PMID:36308074 SUPPORT Human Clinical

"Coiled flagella (%) | 29.2* | 35.2* | <17.0"

Coiled flagella well above the reference limit in both patients.

Bent sperm flagella Reproductive HP:0034811

Show evidence (1 reference)

PMID:36308074 SUPPORT Human Clinical

"Angulation (%) | 20.8* | 13.4* | <13.0"

Angulated flagella above the reference limit in both patients.

Irregularly shaped sperm tail Reproductive HP:0033393

Show evidence (1 reference)

PMID:36308074 SUPPORT Human Clinical

"Irregular caliber (%) | 21.7* | 29.7* | <2.0"

Irregular-caliber flagella far above the reference limit in both patients.

Abnormal sperm axoneme morphology Reproductive HP:0033524

Show evidence (1 reference)

PMID:36308074 SUPPORT Human Clinical

"Hence, these findings indicate that the homozygous frameshift mutation in DNAH8 causes severe ultrastructural flagellum defects."

Ultrastructural axonemal defects in patient sperm.

Abnormal sperm head morphology Reproductive HP:0012865

Show evidence (1 reference)

PMID:33611675 SUPPORT Human Clinical

"However, this patient showed a high percentage of sperm with abnormal heads rather than tail defects (Table 1)."

Head abnormalities predominate in one DNAH8 family.

🧬

Genetic Associations

1

DNAH8 (Causal)

Gene: DNAH8 hgnc:2952

Show evidence (4 references)

PMID:32619401 SUPPORT Human Clinical

"Two cases (2.2%) were identified as carrying bi-allelic missense DNAH8 variants"

Primary gene-disease report in a Chinese MMAF cohort.

PMID:32619401 SUPPORT Human Clinical

"permitted the identification of an additional male carrying a DNAH8 homozygous frameshift variant"

Replication in a second cohort from France, Iran and North Africa.

PMID:33704367 SUPPORT Human Clinical

"compound heterozygous mutations in DNAH8 (MIM:603337) may be responsible for multiple morphological abnormalities of the sperm flagella (MMAF)"

Compound heterozygous genotypes in two further patients.

+ 1 more reference

💊

Medical Actions

2

Intracytoplasmic Sperm Injection

Action: Intracytoplasmic Sperm Injection NCIT:C185482

Platform: Other

ICSI bypasses the motility and flagellar defect. A clinical pregnancy was reported for compound heterozygous patients, and a healthy child was born to a splice-variant proband. That proband's partner, however, had recurrent early embryonic arrest across seven ICSI attempts, with only two viable embryos, so a contribution of DNAH8 to early embryo development has been suggested but not established. ICSI with Dnah8 knockout sperm also gave good pregnancy outcomes in mice.

Mechanism Target:

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

Show evidence (1 reference)

PMID:33611675 SUPPORT Human Clinical

"intracytoplasmic sperm injection was able to overcome the inability of the spermatozoa to reach the ovum and thus produce a healthy child for the proband"

ICSI bypassed the motility defect and led to a live birth.

Show evidence (3 references)

PMID:33704367 SUPPORT Human Clinical

"clinical pregnancy could be achieved by intracytoplasmic sperm injection"

ICSI outcome in compound heterozygous patients.

PMID:33611675 SUPPORT Human Clinical

"the proband underwent seven ICSI attempts characterized by early embryonic arrest with only two viable embryos obtained, which led to a successful pregnancy"

Successful outcome but with recurrent embryonic arrest, a caveat for counselling.

PMID:32619401 SUPPORT Model Organism

"intracytoplasmic sperm injections using the spermatozoa from Dnah8-knockout male mice resulted in good pregnancy outcomes"

ICSI efficacy in the mouse model.

Genetic Counseling

Action: Genetic Counseling NCIT:C15240

Platform: Behavioral / lifestyle

Counselling for autosomal recessive recurrence and carrier testing of relatives once the familial DNAH8 alleles are known, including the reported variability of ICSI outcome.

Show evidence (1 reference)

PMID:36308074 SUPPORT Human Clinical

"The findings of this study improve our understanding of the genetic basis of MMAF and provide knowledge for genetic counseling of infertile men."

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

🔬

Diagnosis

4

Molecular Genetic Testing

Establishes the diagnosis. Probands have been identified by whole-exome sequencing of MMAF cohorts and families. Semen analysis and ultrastructure point to a flagellar gene but cannot name it, because MMAF is genetically heterogeneous.

Genetic Testing NCIT:C15709

Show evidence (1 reference)

PMID:32619401 SUPPORT Human Clinical

"To further define genetic factors underlying MMAF, we performed whole-exome sequencing in a cohort of 90 Chinese MMAF-affected men."

Whole-exome sequencing of an MMAF cohort identified the first DNAH8 probands.

Semen Analysis

Shows severe asthenozoospermia with MMAF; sperm concentration can be normal.

Show evidence (1 reference)

PMID:36308074 SUPPORT Human Clinical

"These results indicate that IV:1 and IV:3 exhibited severe asthenozoospermia due to MMAF."

Semen analysis findings in the affected brothers.

Transmission Electron Microscopy of Sperm Flagella

Flagellar cross-sections show disorganized or missing doublets and outer dense fibers, missing ODAs and absent central pair complexes.

Transmission Electron Microscopy NCIT:C18216

Show evidence (1 reference)

PMID:36308074 SUPPORT Human Clinical

"ultrastructural defects were observed in more than 80% of the sections of sperm flagella from the two patients, including disorganized or missing peripheral microtubule doublets and outer dense fibers, missing or disassembled outer dense arms (ODAs), and absent central pair complexes"

TEM findings in patient sperm.

Immunofluorescence of DNAH8 in Sperm

Absent or reduced DNAH8 and DNAH17 staining of sperm flagella supports pathogenicity of missense alleles.

Show evidence (1 reference)

PMID:32619401 SUPPORT Human Clinical

"Immunofluorescence assays performed on the spermatozoa from men harboring bi-allelic DNAH8 variants revealed the absent or markedly reduced staining of DNAH8 and its associated protein DNAH17."

Immunofluorescence of patient sperm demonstrates protein loss.

🐁

Animal Models

1

Dnah8 knockout mouse

CRISPR-generated Dnah8 knockout males are sterile with MMAF. ICSI with their sperm gave good pregnancy outcomes.

Species

Mouse

Genotype

Dnah8-/- (knockout), homozygous

Publication

PMID:32619401

Pathograph links

Multiple Morphological Abnormalities of the Sperm Flagella recapitulates fidelity: high The knockout reproduces the human MMAF phenotype and sterility.

Show evidence (1 reference)

PMID:32619401 SUPPORT Model Organism

"Dnah8-knockout male mice also presented typical MMAF phenotypes and sterility."

The mouse knockout recapitulates the human phenotype.

{ }

Source YAML

click to show

name: Spermatogenic Failure 46
creation_date: "2026-10-14T00:00:00Z"
category: Mendelian
synonyms:
- SPGF46
- spermatogenic failure 46
- DNAH8-related asthenoteratozoospermia
- DNAH8-related multiple morphological abnormalities of the sperm flagella
description: >-
  Spermatogenic failure 46 (SPGF46) is autosomal recessive male infertility
  caused by biallelic variants in DNAH8. DNAH8 encodes a gamma-type heavy chain
  of the axonemal outer dynein arm (ODA), the paralogue of the respiratory
  ciliary heavy chain DNAH5. Unlike DNAH5, DNAH8 is found along the sperm
  axoneme but not in respiratory cilia, where DNAH5 takes its place. Affected
  men have severe asthenoteratozoospermia with multiple morphological
  abnormalities of the sperm flagella (MMAF): absent, short, coiled, angulated
  and irregular-caliber flagella. Electron microscopy shows disorganized or
  missing peripheral microtubule doublets and outer dense fibers, missing outer
  dynein arms and loss of the central pair.

  Loss of DNAH8 also depletes its ODA partner DNAH17 from the sperm flagellum,
  so the sperm ODA is lost as a unit. Reported patients have normal situs and
  no respiratory disease, consistent with the sperm-restricted expression of
  DNAH8. Dnah8 knockout mice reproduce MMAF and sterility. Fertility can be
  achieved by intracytoplasmic sperm injection (ICSI), although one family
  had repeated early embryonic arrest after ICSI.
disease_term:
  preferred_term: spermatogenic failure 46
  term:
    id: MONDO:0033673
    label: spermatogenic failure 46
parents:
- Spermatogenic Failure
- Genetic Disease
notes: >-
  MONDO cross-references the phenotype as OMIM 619095; the DNAH8 gene entry is
  OMIM 603337. ClinGen classifies DNAH8 in SPGF46 as Strong (2022) and DNAH8 in
  primary ciliary dyskinesia as Disputed, because the only PCD report
  (PMID:24307375, one patient with a homozygous nonsense variant) lacked
  clinical detail and DNAH8 is not expressed in respiratory cilia. That PCD
  claim is therefore not recorded here as a phenotype or subtype. One
  splice-variant family (PMID:33611675) had mainly sperm-head rather than tail
  abnormalities, so the morphological spectrum is variable.
inheritance:
- name: Autosomal recessive
  description: >-
    Disease requires biallelic DNAH8 variants. Reported genotypes include
    homozygous missense, frameshift and splice-acceptor variants in
    consanguineous Chinese, French/North African and Pakistani families, and
    compound heterozygous missense variants in Chinese men.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:32619401
    reference_title: "Bi-allelic DNAH8 Variants Lead to Multiple Morphological Abnormalities of the Sperm Flagella and Primary Male Infertility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "bi-allelic deleterious DNAH8 variants lead to male infertility with MMAF"
    explanation: Biallelic variants in the index cohorts establish recessive inheritance.
  - reference: PMID:36308074
    reference_title: "A novel homozygous frameshift variant in DNAH8 causes multiple morphological abnormalities of the sperm flagella in a consanguineous Pakistani family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sanger sequencing confirmed the patients' father and fertile brothers to be heterozygous carriers"
    explanation: Heterozygous carriers in the family are fertile, consistent with recessive inheritance.
pathophysiology:
- name: Loss of the DNAH8 Outer-Arm Dynein Heavy Chain
  description: >-
    Truncating, splice and missense alleles lead to absent or markedly reduced
    DNAH8 in patient sperm. A frameshift allele removes the transcript by
    nonsense-mediated decay, and a splice-acceptor allele skips exon 45 and
    truncates the protein within the motor domain.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: DNAH8
    term:
      id: hgnc:2952
      label: DNAH8
  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
    hypothesis_groups:
    - sperm_restricted_dnah8_oda
    description: >-
      DNAH8 is a structural heavy chain of the sperm ODA; without it, its
      partner heavy chain DNAH17 is also depleted from the flagellum.
    evidence:
    - reference: PMID:32619401
      reference_title: "Bi-allelic DNAH8 Variants Lead to Multiple Morphological Abnormalities of the Sperm Flagella and Primary Male Infertility."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Immunofluorescence assays performed on the spermatozoa from men harboring bi-allelic DNAH8 variants revealed the absent or markedly reduced staining of DNAH8 and its associated protein DNAH17."
      explanation: Loss of DNAH8 is accompanied by loss of the partner ODA heavy chain DNAH17.
  evidence:
  - reference: PMID:36308074
    reference_title: "A novel homozygous frameshift variant in DNAH8 causes multiple morphological abnormalities of the sperm flagella in a consanguineous Pakistani family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Endogenous DNAH8 transcripts were not detected in either patient, but a clear band was obtained for the fertile control"
    explanation: The homozygous frameshift allele abolishes DNAH8 mRNA in patients.
  - reference: PMID:33611675
    reference_title: "A novel splicing variant in DNAH8 causes asthenozoospermia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We found that the splicing variant led to the deletion of exon 45, which resulted in a frameshift and a predicted truncated protein (p.G2104Efs*19)"
    explanation: Minigene assay shows the splice-acceptor allele truncates DNAH8.
  - reference: PMID:33704367
    reference_title: "Mutations in DNAH8 contribute to multiple morphological abnormalities of sperm flagella and male infertility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Immunofluorescence assay showed that DNAH8 protein expression was significantly decreased in the sperm tail of the patients"
    explanation: Compound heterozygous missense genotypes also reduce DNAH8 in sperm.
- name: Outer Dynein Arm Loss in the Sperm Axoneme
  description: >-
    The sperm ODA contains the heavy chains DNAH8 and DNAH17. Loss of DNAH8
    depletes DNAH17 from patient sperm and ODAs are missing or disassembled on
    electron microscopy.
  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: >-
      Loss of the ODA accompanies a wider breakdown of the axoneme, with
      missing doublets, outer dense fibers and central pair. How loss of an
      ODA heavy chain destabilizes these other structures is not established.
  evidence:
  - reference: PMID:36308074
    reference_title: "A novel homozygous frameshift variant in DNAH8 causes multiple morphological abnormalities of the sperm flagella in a consanguineous Pakistani family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "expression of DNAH17 was dramatically reduced in the spermatozoa of the patients compared to healthy individuals"
    explanation: An independent family confirms co-depletion of the partner ODA heavy chain DNAH17.
  - 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: >-
      The reciprocal result in DNAH17-deficient sperm: DNAH8 is lost while
      inner-arm components are kept, showing that DNAH8 and DNAH17 assemble
      together into the sperm ODA.
- name: Sperm Axonemal Disorganization
  description: >-
    Most flagellar cross-sections show disorganized or missing peripheral
    doublets and outer dense fibers, missing ODAs and an absent central pair
    complex, so the 9+2 arrangement is lost.
  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:36308074
    reference_title: "A novel homozygous frameshift variant in DNAH8 causes multiple morphological abnormalities of the sperm flagella in a consanguineous Pakistani family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ultrastructural defects were observed in more than 80% of the sections of sperm flagella from the two patients, including disorganized or missing peripheral microtubule doublets and outer dense fibers, missing or disassembled outer dense arms (ODAs), and absent central pair complexes"
    explanation: Ultrastructural demonstration of the axonemal lesion in patients.
  - reference: PMID:32619401
    reference_title: "Bi-allelic DNAH8 Variants Lead to Multiple Morphological Abnormalities of the Sperm Flagella and Primary Male Infertility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hematoxylin-eosin staining and electron microscopy analyses of the spermatozoa from men harboring bi-allelic DNAH8 variants showed a highly aberrant morphology and ultrastructure of the sperm flagella."
    explanation: Aberrant flagellar ultrastructure in the index cohort.
- name: Multiple Morphological Abnormalities of the Sperm Flagella
  description: >-
    The defining semen phenotype: absent, short, coiled, angulated and
    irregular-caliber flagella in the same ejaculate, with severely reduced
    motility.
  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: Bent sperm flagella
    causal_link_type: DIRECT
  - target: Irregularly shaped sperm tail
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:36308074
    reference_title: "A novel homozygous frameshift variant in DNAH8 causes multiple morphological abnormalities of the sperm flagella in a consanguineous Pakistani family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Morphologically, the abnormal sperm were characterized by coiled, absent, short, and angulation, with irregular sperm flagellar phenotypes"
    explanation: Describes the MMAF mosaic in patient sperm.
  - reference: CGGV:assertion_e740f4af-53fe-4c51-99f6-6111fe343d7f-2022-06-23T160000.000Z
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Spermatogenic failure 46 (SPGF46) is characterized by male infertility due to morphologic abnormalities of the flagella (MMAF), including flagella that are absent, short, coiled, angulated, and/or of irregular caliber"
    explanation: ClinGen expert-panel summary of the disease phenotype across published probands.
mechanistic_hypotheses:
- hypothesis_group_id: sperm_restricted_dnah8_oda
  hypothesis_label: DNAH8 is the sperm-specific gamma heavy chain of the outer dynein arm, so its loss causes isolated male infertility rather than primary ciliary dyskinesia
  status: CANONICAL
  description: >-
    Sperm and respiratory cilia build their outer dynein arms from different
    heavy chains: DNAH8 and DNAH17 in sperm, DNAH5 with DNAH9 or DNAH11 in
    respiratory cilia. DNAH8 is therefore needed in the sperm flagellum but not
    in motile cilia. In patients the evidence is clinical (normal situs and no
    PCD symptoms), not a formal ciliary work-up such as nasal nitric oxide or
    ciliary beat analysis.
  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 of control sperm and respiratory cells shows the sperm-restricted ODA heavy-chain composition.
  - 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: OTHER
    quote_role: BACKGROUND
    snippet: "the contribution of the different HCs (γ-type: DNAH5 and DNAH8 and β-type: DNAH9, DNAH11, and DNAH17) in ODAs from both organelles is unknown"
    explanation: Places DNAH8 with DNAH5 as the two gamma-type ODA heavy chains.
  - reference: PMID:36308074
    reference_title: "A novel homozygous frameshift variant in DNAH8 causes multiple morphological abnormalities of the sperm flagella in a consanguineous Pakistani family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the affected individuals exhibited a normal visceral position (Supplementary Figure 2), without any clinical symptoms of PCD"
    explanation: DNAH8-null patients have normal situs and no PCD symptoms.
  - reference: CGGV:assertion_0c98a44d-6d43-48fc-8286-9e499bf04a1b-2022-06-23T160000.000Z
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "In summary, the evidence supporting the relationship between DNAH8 and autosomal recessive Primary Ciliary Dyskinesia has been disputed and no valid evidence remains to support the claim."
    explanation: ClinGen disputes the single earlier DNAH8-PCD report.
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:32681648
    reference_title: "Loss-of-function mutation in DNAH8 induces asthenoteratospermia associated with multiple morphological abnormalities of the sperm flagella."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a loss-of-function mutation in DNAH8 can cause male infertility with MMAF"
    explanation: Independent report of male infertility with a DNAH8 loss-of-function allele.
- category: Reproductive
  name: Reduced sperm motility
  description: >-
    Severe asthenozoospermia is present in all reported patients. Sperm
    concentration can be normal: both Pakistani brothers had counts above the
    WHO reference limit.
  phenotype_term:
    preferred_term: Severe asthenozoospermia
    term:
      id: HP:0012207
      label: Reduced sperm motility
  evidence:
  - reference: PMID:36308074
    reference_title: "A novel homozygous frameshift variant in DNAH8 causes multiple morphological abnormalities of the sperm flagella in a consanguineous Pakistani family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These results indicate that IV:1 and IV:3 exhibited severe asthenozoospermia due to MMAF."
    explanation: Severe asthenozoospermia in both affected brothers.
- 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: PMID:36308074
    reference_title: "A novel homozygous frameshift variant in DNAH8 causes multiple morphological abnormalities of the sperm flagella in a consanguineous Pakistani family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Morphologically, the abnormal sperm were characterized by coiled, absent, short, and angulation, with irregular sperm flagellar phenotypes"
    explanation: Absent flagella reported in patient sperm.
- 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:36308074
    reference_title: "A novel homozygous frameshift variant in DNAH8 causes multiple morphological abnormalities of the sperm flagella in a consanguineous Pakistani family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Morphologically, the abnormal sperm were characterized by coiled, absent, short, and angulation, with irregular sperm flagellar phenotypes"
    explanation: Short flagella reported in patient sperm.
- category: Reproductive
  name: Coiled sperm flagella
  description: Coiled flagella are the most frequent single flagellar anomaly in the Pakistani brothers.
  phenotype_term:
    preferred_term: Coiled sperm flagella
    term:
      id: HP:0032560
      label: Coiled sperm flagella
  evidence:
  - reference: PMID:36308074
    reference_title: "A novel homozygous frameshift variant in DNAH8 causes multiple morphological abnormalities of the sperm flagella in a consanguineous Pakistani family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Coiled flagella (%) | 29.2* | 35.2* | <17.0"
    explanation: Coiled flagella well above the reference limit in both patients.
- category: Reproductive
  name: Bent sperm flagella
  description: Angulated (bent) flagella are part of the MMAF mosaic.
  phenotype_term:
    preferred_term: Angulated sperm flagella
    term:
      id: HP:0034811
      label: Bent sperm flagella
  evidence:
  - reference: PMID:36308074
    reference_title: "A novel homozygous frameshift variant in DNAH8 causes multiple morphological abnormalities of the sperm flagella in a consanguineous Pakistani family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Angulation (%) | 20.8* | 13.4* | <13.0"
    explanation: Angulated flagella above the reference limit in both patients.
- 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: PMID:36308074
    reference_title: "A novel homozygous frameshift variant in DNAH8 causes multiple morphological abnormalities of the sperm flagella in a consanguineous Pakistani family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Irregular caliber (%) | 21.7* | 29.7* | <2.0"
    explanation: Irregular-caliber flagella far above the reference limit in both patients.
- category: Reproductive
  name: Abnormal sperm axoneme morphology
  description: >-
    Electron microscopy shows missing or disorganized doublets, missing outer
    dynein arms and absent central pair complexes.
  phenotype_term:
    preferred_term: Abnormal sperm axoneme morphology
    term:
      id: HP:0033524
      label: Abnormal sperm axoneme morphology
  evidence:
  - reference: PMID:36308074
    reference_title: "A novel homozygous frameshift variant in DNAH8 causes multiple morphological abnormalities of the sperm flagella in a consanguineous Pakistani family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hence, these findings indicate that the homozygous frameshift mutation in DNAH8 causes severe ultrastructural flagellum defects."
    explanation: Ultrastructural axonemal defects in patient sperm.
- category: Reproductive
  name: Abnormal sperm head morphology
  description: >-
    Variable. In one family with a homozygous splice-acceptor variant most
    sperm had abnormal heads rather than tail defects, whereas head morphometry
    was normal in the Pakistani frameshift family. No mechanism for 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:33611675
    reference_title: "A novel splicing variant in DNAH8 causes asthenozoospermia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "However, this patient showed a high percentage of sperm with abnormal heads rather than tail defects (Table 1)."
    explanation: Head abnormalities predominate in one DNAH8 family.
genetic:
- name: DNAH8
  association: Causal
  gene_term:
    preferred_term: DNAH8
    term:
      id: hgnc:2952
      label: DNAH8
  gene_disease_validity:
  - validity_classification: STRONG
    classified_by: CLINGEN
    external_id: CGGV:assertion_e740f4af-53fe-4c51-99f6-6111fe343d7f-2022-06-23T160000.000Z
    evidence:
    - reference: CGGV:assertion_e740f4af-53fe-4c51-99f6-6111fe343d7f-2022-06-23T160000.000Z
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "DNAH8 | HGNC:2952 | spermatogenic failure 46 | MONDO:0033673 | AR | Strong"
      explanation: ClinGen gene-disease validity record classifying this gene-disease pair as Strong.
  notes: >-
    Reported alleles include missense, frameshift (c.6158_6159insT,
    p.Gly2054Trpfs*50) and splice-acceptor (c.6311-2A>G, exon 45 skipping)
    variants. ClinGen's 2022 curation counted 7 probands in 4 publications and
    reached the genetic-evidence maximum; it holds the classification at Strong
    only because three years had not yet passed since the first report.
  evidence:
  - reference: PMID:32619401
    reference_title: "Bi-allelic DNAH8 Variants Lead to Multiple Morphological Abnormalities of the Sperm Flagella and Primary Male Infertility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Two cases (2.2%) were identified as carrying bi-allelic missense DNAH8 variants"
    explanation: Primary gene-disease report in a Chinese MMAF cohort.
  - reference: PMID:32619401
    reference_title: "Bi-allelic DNAH8 Variants Lead to Multiple Morphological Abnormalities of the Sperm Flagella and Primary Male Infertility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "permitted the identification of an additional male carrying a DNAH8 homozygous frameshift variant"
    explanation: Replication in a second cohort from France, Iran and North Africa.
  - reference: PMID:33704367
    reference_title: "Mutations in DNAH8 contribute to multiple morphological abnormalities of sperm flagella and male infertility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "compound heterozygous mutations in DNAH8 (MIM:603337) may be responsible for multiple morphological abnormalities of the sperm flagella (MMAF)"
    explanation: Compound heterozygous genotypes in two further patients.
  - reference: PMID:36308074
    reference_title: "A novel homozygous frameshift variant in DNAH8 causes multiple morphological abnormalities of the sperm flagella in a consanguineous Pakistani family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a novel homozygous frameshift variant (c.6158_6159insT) in dynein axonemal heavy chain 8 (DNAH8) from two infertile brothers with MMAF in a consanguineous Pakistani family was identified by WES"
    explanation: Further loss-of-function allele in a different population.
animal_models:
- name: Dnah8 knockout mouse
  species: Mouse
  genotype: Dnah8-/- (knockout), homozygous
  publication: PMID:32619401
  description: >-
    CRISPR-generated Dnah8 knockout males are sterile with MMAF. ICSI with
    their sperm gave good pregnancy outcomes.
  modeled_mechanisms:
  - target: Multiple Morphological Abnormalities of the Sperm Flagella
    relationship: RECAPITULATES
    fidelity: HIGH
    description: The knockout reproduces the human MMAF phenotype and sterility.
    evidence:
    - reference: PMID:32619401
      reference_title: "Bi-allelic DNAH8 Variants Lead to Multiple Morphological Abnormalities of the Sperm Flagella and Primary Male Infertility."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Dnah8-knockout male mice also presented typical MMAF phenotypes and sterility."
      explanation: The mouse knockout recapitulates the human phenotype.
treatments:
- name: Intracytoplasmic Sperm Injection
  description: >-
    ICSI bypasses the motility and flagellar defect. A clinical pregnancy was
    reported for compound heterozygous patients, and a healthy child was born
    to a splice-variant proband. That proband's partner, however, had
    recurrent early embryonic arrest across seven ICSI attempts, with only two
    viable embryos, so a contribution of DNAH8 to early embryo development has
    been suggested but not established. ICSI with Dnah8 knockout sperm also
    gave good pregnancy outcomes in mice.
  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:33611675
      reference_title: "A novel splicing variant in DNAH8 causes asthenozoospermia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "intracytoplasmic sperm injection was able to overcome the inability of the spermatozoa to reach the ovum and thus produce a healthy child for the proband"
      explanation: ICSI bypassed the motility defect and led to a live birth.
  evidence:
  - reference: PMID:33704367
    reference_title: "Mutations in DNAH8 contribute to multiple morphological abnormalities of sperm flagella and male infertility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "clinical pregnancy could be achieved by intracytoplasmic sperm injection"
    explanation: ICSI outcome in compound heterozygous patients.
  - reference: PMID:33611675
    reference_title: "A novel splicing variant in DNAH8 causes asthenozoospermia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the proband underwent seven ICSI attempts characterized by early embryonic arrest with only two viable embryos obtained, which led to a successful pregnancy"
    explanation: Successful outcome but with recurrent embryonic arrest, a caveat for counselling.
  - reference: PMID:32619401
    reference_title: "Bi-allelic DNAH8 Variants Lead to Multiple Morphological Abnormalities of the Sperm Flagella and Primary Male Infertility."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "intracytoplasmic sperm injections using the spermatozoa from Dnah8-knockout male mice resulted in good pregnancy outcomes"
    explanation: ICSI efficacy in the mouse model.
- name: Genetic Counseling
  description: >-
    Counselling for autosomal recessive recurrence and carrier testing of
    relatives once the familial DNAH8 alleles are known, including 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:36308074
    reference_title: "A novel homozygous frameshift variant in DNAH8 causes multiple morphological abnormalities of the sperm flagella in a consanguineous Pakistani family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The findings of this study improve our understanding of the genetic basis of MMAF and provide knowledge for genetic counseling of infertile men."
    explanation: The authors name genetic counselling as the application of the molecular diagnosis.
diagnosis:
- name: Molecular Genetic Testing
  description: >-
    Establishes the diagnosis. Probands have been identified by whole-exome
    sequencing of MMAF cohorts and families. Semen analysis and ultrastructure
    point to a flagellar gene but cannot name it, because MMAF is genetically
    heterogeneous.
  diagnosis_term:
    preferred_term: Genetic Testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:32619401
    reference_title: "Bi-allelic DNAH8 Variants Lead to Multiple Morphological Abnormalities of the Sperm Flagella and Primary Male Infertility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "To further define genetic factors underlying MMAF, we performed whole-exome sequencing in a cohort of 90 Chinese MMAF-affected men."
    explanation: Whole-exome sequencing of an MMAF cohort identified the first DNAH8 probands.
- name: Semen Analysis
  description: >-
    Shows severe asthenozoospermia with MMAF; sperm concentration can be
    normal.
  evidence:
  - reference: PMID:36308074
    reference_title: "A novel homozygous frameshift variant in DNAH8 causes multiple morphological abnormalities of the sperm flagella in a consanguineous Pakistani family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These results indicate that IV:1 and IV:3 exhibited severe asthenozoospermia due to MMAF."
    explanation: Semen analysis findings in the affected brothers.
- name: Transmission Electron Microscopy of Sperm Flagella
  description: >-
    Flagellar cross-sections show disorganized or missing doublets and outer
    dense fibers, missing ODAs and absent central pair complexes.
  diagnosis_term:
    preferred_term: Transmission Electron Microscopy
    term:
      id: NCIT:C18216
      label: Transmission Electron Microscopy
  evidence:
  - reference: PMID:36308074
    reference_title: "A novel homozygous frameshift variant in DNAH8 causes multiple morphological abnormalities of the sperm flagella in a consanguineous Pakistani family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ultrastructural defects were observed in more than 80% of the sections of sperm flagella from the two patients, including disorganized or missing peripheral microtubule doublets and outer dense fibers, missing or disassembled outer dense arms (ODAs), and absent central pair complexes"
    explanation: TEM findings in patient sperm.
- name: Immunofluorescence of DNAH8 in Sperm
  description: >-
    Absent or reduced DNAH8 and DNAH17 staining of sperm flagella supports
    pathogenicity of missense alleles.
  evidence:
  - reference: PMID:32619401
    reference_title: "Bi-allelic DNAH8 Variants Lead to Multiple Morphological Abnormalities of the Sperm Flagella and Primary Male Infertility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Immunofluorescence assays performed on the spermatozoa from men harboring bi-allelic DNAH8 variants revealed the absent or markedly reduced staining of DNAH8 and its associated protein DNAH17."
    explanation: Immunofluorescence of patient sperm demonstrates protein loss.

📚

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_46 · 2026-10-14T20:20:14Z · View source

New entry for MONDO:0033673 (DNAH8-related SPGF46), curated from the open stub, which was deleted. Evidence comes from the full texts of PMID:36308074 and PMID:33611675, the abstracts of PMID:32619401, PMID:32681648, PMID:33704367 and PMID:31178125, and the ClinGen records for DNAH8/SPGF46 (Strong, copied into gene_disease_validity) and DNAH8/PCD (Disputed, cited against a PCD reading), all fetched with just fetch-reference. The causal chain runs from DNAH8 loss, to loss of the sperm outer dynein arm (with co-depletion of DNAH17), to axonemal disorganization, to MMAF and the flagellar phenotypes. A CANONICAL hypothesis records the sperm-restricted gamma heavy chain (DNAH8 in sperm, its paralogue DNAH5 in respiratory cilia). The sperm-head phenotype is deliberately left unconnected because one family shows it and no mechanism is known. Deep research: just research-disorder falcon failed repeatedly with 503 'Failed to authenticate' from Edison over about 40 minutes, including with --fallback and --fallback-provider claude_code (the 503 is classed as temporary so no fallback fired). just research-disorder claude_code produced research/Spermatogenic_Failure_46-deep-research-claude_code.md; just preflight-dr returned PASS. The report added no claims beyond the cited primary papers. 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 ▸

Spermatogenic Failure 46 (SPGF46; DNAH8-related MMAF): research report

claude-haiku-5-5, claude-sonnet-5-5 11 citations 2026-10-14T20:32:43.602874

I'm pulling the abstracts of the other DNAH8 papers to get variant details and ICSI outcomes. Then I'll write the report.

Spermatogenic Failure 46 (SPGF46; DNAH8-related MMAF): research report

Evidence limits. The OMIM entry returned HTTP 403, so I could not read it. Its details (phenotype description, HPO annotations, allelic variants) come from search-result snippets and PubMed abstracts. PMIDs below were confirmed through PubMed E-utilities. Quotes marked "snippet" come from search-result text, not from a PubMed record I read in full. Anything I did not find is marked "not found".

1. Disease information

Overview. SPGF46 is an autosomal recessive form of primary male infertility. It is caused by bi-allelic loss-of-function or missense variants in DNAH8, which encodes an axonemal outer-arm dynein heavy chain. Affected men have asthenoteratozoospermia with multiple morphological abnormalities of the sperm flagella (MMAF). The MMAF phenotype combines absent, short, coiled, angulated and irregular-caliber flagella. The defect is restricted to the sperm tail, and ICSI can bypass it.

Identifiers

Item	Value	Source
OMIM phenotype	#619095	LOVD
MONDO	MONDO:0033673	DrugMap; only one source paired it with this disease, so check it in MONDO
MedGen	1726728	DrugMap
Gene	DNAH8 (OMIM gene 603337, 6p21.2)	OMIM-based gene table in search results
Orphanet, ICD-10/11, MeSH	Not found

Synonyms. SPGF46; spermatogenic failure, type 46; DNAH8-related MMAF; MMAF with DNAH8 variants.

Data source. The case reports are individual patients (exome sequencing plus semen and EM analysis). The OMIM, MONDO and LOVD entries are aggregated disease-level resources.

2. Etiology

Cause. Bi-allelic DNAH8 variants. The discovery paper reported that "Two cases (2.2%) were identified as carrying bi-allelic missense DNAH8 variants" among 90 Chinese MMAF men (snippet, PMID:32619401, Liu et al., Am J Hum Genet 2020). It also found a homozygous frameshift in a second cohort of 167 men from France, Iran and North Africa.
Gene-disease validity. DrugMap lists DNAH8 as "Strong" with autosomal recessive inheritance. The source of that tier is not stated; the label is consistent with a ClinGen-style classification. Check ClinGen directly before recording a gene_disease_validity entry. It must be copied from a source record and not assigned.
Risk and protective factors. None identified. No modifier genes, gene-environment interactions or protective variants were found for male infertility. A 2026 paper links DNAH8 dysfunction and DEHP exposure to hypospadias (PMID:42480140). I read only its title, so I make no claim about its content. It concerns a different phenotype and should not be merged into SPGF46.

3. Phenotypes

All phenotypes below are male-limited and restricted to the reproductive system. Frequencies are not quantified in the sources I read. Every patient described had the sperm phenotype.

Phenotype	HPO (verify by lookup before binding)	Notes
Male infertility	HP:0003251	Primary; present at reproductive age
Asthenozoospermia	HP:0012206	Reduced motility (PMID:32681648, PMID:33611675)
Teratozoospermia / MMAF	HP:0012864 (teratozoospermia)	Flagella absent, short, coiled, angulated or irregular caliber
Abnormal sperm flagellum ultrastructure	Likely a child of HP:0012206 or HP:0012864; look up	Disorganized axoneme and periaxonemal structures on EM

There is no consistent respiratory, laterality or other ciliary phenotype in the reports I read. DNAH8 was initially proposed as a candidate primary ciliary dyskinesia gene, but later studies showed MMAF in infertile men (snippet from the follow-up abstract).
Quality-of-life data were not found.
HPO term IDs above are from memory. Per the project rules, confirm each one with a lookup before binding it.

4. Genetic and molecular information

Gene. DNAH8, 6p21.2, encoding dynein axonemal heavy chain 8. Confirm the HGNC ID by lookup, in the lowercase hgnc: form. I did not retrieve it.
Inheritance. Autosomal recessive.
Reported variants (from the abstracts I read):

Variant	Type	Zygosity	Source
c.6311-2A>G (predicted p.G2104Efs*19, exon 45 skipping)	Splice acceptor	Homozygous, two brothers, consanguineous family	PMID:33611675
c.6158_6159insT	Frameshift	Homozygous, two brothers, consanguineous Pakistani family	PMID:36308074
Two missense variants (HGVS not in the abstract)	Missense	Bi-allelic, 2 of 90 Chinese men	PMID:32619401
Homozygous frameshift (HGVS not in the abstract)	Frameshift	Homozygous, 1 of 167 men	PMID:32619401
Compound heterozygous (HGVS not in the abstract)	Not specified	Two patients	PMID:33704367
Loss-of-function (HGVS not in the abstract)	Not specified	One patient	PMID:32681648

Consequence. Loss of function. mRNA decay was shown for the frameshift in PMID:36308074, and DNAH8 protein is absent or reduced in patient sperm.
Not found. ClinVar classifications, gnomAD allele frequencies, epigenetic data, chromosomal abnormalities. This is a germline monogenic disorder.

5. Environmental information

No environmental, lifestyle or infectious causes are established for SPGF46. The DEHP/hypospadias paper above is outside this phenotype.

6. Mechanism and pathophysiology

Causal chain

Bi-allelic loss-of-function or missense variants in DNAH8 are the initiating lesion (demonstrated, PMID:32619401).
These lead to reduced or absent DNAH8 protein in the sperm flagellum. The evidence is immunofluorescence plus mRNA decay (demonstrated, PMID:36308074, PMID:33704367).
Loss of DNAH8 also reduces DNAH17, an associated dynein heavy chain, in sperm. This points to destabilization of outer dynein arm components (demonstrated for the association, per the discovery abstract; the exact mechanism is inferred).
Axonemal and periaxonemal organization is disrupted during spermiogenesis, producing MMAF flagella (demonstrated by EM).
Sperm motility is lost, which causes asthenoteratozoospermia and male infertility.

Branching. There is no demonstrated branch. Whether DNAH8 loss also affects motile cilia is unresolved. The reports show no strong ciliary phenotype.

Ontology suggestions (look up before binding). GO: axonemal dynein complex / outer dynein arm; sperm flagellum assembly; sperm axoneme assembly. CL: spermatid, spermatozoon. Uberon: testis, sperm flagellum.

Omics, single-cell and functional screens. Not found.

7. Anatomical structures affected

Organ. Testis and male reproductive tract. Spermatogenesis proceeds, but the sperm are defective.
Cells. Late spermatids and spermatozoa.
Subcellular. Sperm flagellum axoneme, outer dynein arms, periaxonemal structures.
Lateralization. Not applicable (bilateral germ-cell phenotype).

8. Temporal development

Onset. Presents in adulthood as infertility. Congenital cause, with no childhood manifestations reported.
Progression. Not described as progressive. Longitudinal data were not found.
Remission. None reported.

9. Inheritance and population

Inheritance. Autosomal recessive. Both homozygous variants (in consanguineous families) and compound heterozygous variants are reported.
Consanguinity. Two of the reported families were consanguineous (PMID:33611675, PMID:36308074).
Population. Chinese, Pakistani and North African/Iranian/French cohorts. About 2.2% of the Chinese MMAF cohort carried bi-allelic missense variants. Prevalence, carrier frequency, founder effects and the share of MMAF explained by DNAH8 were not established in what I read.
Sex. Males only.

10. Diagnostics

Semen analysis. Asthenoteratozoospermia with an MMAF pattern.
Electron microscopy. Disorganized axoneme and periaxonemal structures.
Immunofluorescence. Absent or reduced DNAH8 and DNAH17 in sperm.
Genetic testing. Exome sequencing found the variants in the cohort studies. A male-infertility or MMAF gene panel that includes DNAH8, or targeted sequencing, would be the practical approach. Specific panels and GTR listings were not retrieved.
Differential diagnosis. Other MMAF genes (the search results name DNAH2, DNAH6, DNAH11 and CFAP61) and primary ciliary dyskinesia.
Screening. None.

11. Prognosis

Fertility is not spontaneously restored. The disorder appears to cause no systemic disease in the reports I read, but long-term follow-up data were not found.

12. Treatment

ICSI works. PMID:33611675 reports that ICSI produced a healthy child for the proband. PMID:33704367 reports a clinical pregnancy with ICSI. Per the discovery abstract, ICSI with sperm from Dnah8-knockout mice "resulted in good pregnancy outcomes".
Suggested NCIT terms (verify by lookup): assisted reproductive technology / intracytoplasmic sperm injection. Choose the most specific NCIT term under the clinical-intervention root, and if none fits, keep a free-text preferred_term.
Not found. Drug therapy, gene therapy, clinical trials, pharmacogenomics. No evidence-based medical therapy exists in what I read.
Counseling. Genetic counseling is appropriate. This is my inference from recessive inheritance and not a cited guideline.

13. Prevention

There is no primary prevention. Genetic counseling and carrier testing in relatives of known families are the relevant measures, again as inference. I found no guideline source.

14. Other species

Not found: OMIA entries, breeds, NCBI Taxon or Gene IDs for natural disease in other species.

15. Model organisms

Mouse. The Dnah8 knockout shows MMAF and male sterility, and ICSI with its sperm gives good pregnancy outcomes (PMID:32619401, MODEL_ORGANISM evidence). It closely recapitulates the human sperm phenotype.
Limitations. I did not retrieve the knockout design, MGI or IMPC records, or any data on non-reproductive phenotypes.
A caution for evidence grading. The mouse ICSI result is model-organism evidence. It should not be used as the only support for the human ICSI claim, which has its own human reports above.

Open items before curation

Look up HGNC, HPO, GO, CL and NCIT identifiers. I recalled the HPO IDs above from memory.
Fetch the references with just fetch-reference and quote snippets from the cache. The snippets in this report come from search-result text, and I did not read the abstracts verbatim.
Check MONDO:0033673 directly in MONDO.
Check the ClinGen validity record for DNAH8.

Sources: - LOVD disease entry SPGF46 - DrugMap disease record - Liu et al. 2020, AJHG (PMID 32619401) - Weng et al. 2021 (PMID 33704367) - Dil et al. 2023 (PMID 36308074) - Yang et al. 2020 (PMID 32681648) - Zhou et al. 2021 (PMID 33611675) - Li et al. 2026 (PMID 42480140)

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome	Count
References checked	7
Resolved	7
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	7
On topic	6
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	4
Resolved	4
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	0
Terms whose name was checked	4
Terms named correctly	1
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:0033673 (2 mentions) - the report calls it "MONDO"; MONDO calls it spermatogenic failure 46
HP:0012206 (2 mentions) - 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:

HP:0012864 (2 mentions) - the report calls it "teratozoospermia"; HP calls it Abnormal sperm morphology, and lists "Teratozoospermia" among its other names

Spermatogenic Failure 46

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Spermatogenic Failure 46 (SPGF46; DNAH8-related MMAF): research report

1. Disease information

2. Etiology

3. Phenotypes

4. Genetic and molecular information

5. Environmental information

6. Mechanism and pathophysiology

7. Anatomical structures affected

8. Temporal development

9. Inheritance and population

10. Diagnostics

11. Prognosis

12. Treatment

13. Prevention

14. Other species

15. Model organisms

Open items before curation

Reference Validation

Term Validation

Terms the report names something else

Terms whose name is worth a second look