Spermatogenic Failure 26

🏷

Classifications

Harrison's Part

👪

Inheritance

1

Autosomal recessive HP:0000007

Disease requires two TSGA10 loss-of-function alleles: a homozygous frameshift in Chinese probands, a homozygous missense variant segregating with disease in two Pakistani brothers, and a splice variant in trans with a de novo large deletion in a non-consanguineous proband.

Autosomal recessive inheritance

Show evidence (2 references)

PMID:38317066 SUPPORT Human clinical

"we identified a novel missense variant in TSGA10 (c.1112T > C, p. Leu371Pro), which recessively co-segregated with the acephalic spermatozoa syndrome within this family"

Recessive co-segregation of a homozygous TSGA10 variant with disease.

PMID:34409526 SUPPORT Human clinical

"Therefore, we speculated that the splicing mutation might affect transcription and translation without the dosage compensation of a normal allele, which possesses a large deletion including intact TSGA10."

A heterozygous splice variant causes disease because the other allele is deleted, the compound-heterozygous form of recessive inheritance.

⚙

Pathophysiology

3

Loss of TSGA10 Protein

Frameshift, splice-site and missense variants all leave spermatozoa without detectable TSGA10. The frameshift alleles truncate the protein, the splice variant produces a truncated protein at very low level, and the Leu371Pro missense variant abolishes both mRNA and protein in sperm. TSGA10 is normally found at the sperm midpiece. In mouse testis the 65-kDa spermatid protein is processed to a 27-kDa fibrous sheath protein.

spermatid CL:0000018 sperm CL:0000019

TSGA10 hgnc:14927

Genetic context variant_origin: GERMLINE functional_impact_category: LOSS_OF_FUNCTION

testis UBERON:0000473

Downstream

Defective Sperm Head-Tail Coupling

Sperm Mitochondrial Sheath Disorganization

Show evidence (5 references)

PMID:28905369 SUPPORT Human clinical

"TSGA10 is a testis-specific protein that localized to the midpiece in the spermatozoa of a normal control; however, immunostaining failed to detect TSGA10 protein in the patient's sperm. Western blot analysis also showed complete absence of TSGA10 protein in the patient."

The homozygous frameshift abolishes TSGA10 protein in sperm.

PMID:32410354 SUPPORT Human clinical

"TSGA10 failed to be detected in the patient's spermatozoa. However, the expression of SUN5 and PMFBP1 remained unaffected."

A second frameshift allele also abolishes TSGA10, without loss of two other head-tail coupling proteins.

PMID:34409526 SUPPORT Human clinical

"Western blot and immunofluorescence demonstrated that the very low expression level of truncated TSGA10 protein led the proband to present the acephalic spermatozoa phenotype."

The splice allele yields only trace amounts of truncated protein.

+ 2 more references

Defective Sperm Head-Tail Coupling

TSGA10 is a centrosomal scaffold protein whose C-terminal fragment sits at the centrosome and basal body and binds ODF2, so it is thought to help anchor the sperm tail to the head. Without it, the flagellum separates from the head at a point between the distal centriole and the midpiece.

spermatid CL:0000018 sperm CL:0000019

sperm flagellum assembly GO:0120316 ↓ DECREASED

sperm head-tail coupling apparatus GO:0120212 centriole GO:0005814

testis UBERON:0000473

Downstream

Acephalic spermatozoa

Abnormal sperm axoneme morphology Head-flagellum detachment in TSGA10-deficient spermatozoa is accompanied by abnormal axonemal ultrastructure across 98% of flagellar cross-sections.

Show evidence (3 references)

PMID:38317066 SUPPORT BACKGROUND In vitro / ex vivo

"implying that the TSGA10 C-terminus is involved in centriole assembly and function, particularly in the head-tail link"

The introduction of this clinical paper restates earlier interaction work that places TSGA10 at the centriole and the head-tail link.

PMID:28905369 SUPPORT Human clinical

"Electron microscopic and immunofluorescence analysis suggested breakage at the midpiece of the patient's sperm cells."

Patient sperm break at the midpiece.

PMID:32104701 SUPPORT REVIEW SYNTHESIS Other

"the breakage of TSGA10 associated with AS sperms is located between the distal centriole and the midpiece"

Review placing the TSGA10-related break between the distal centriole and the midpiece.

Sperm Mitochondrial Sheath Disorganization

The midpiece of the headless tails carries a misarranged or partial mitochondrial sheath, with reduced staining for the mitochondrial marker COXIV. Heterozygous Tsga10 knockout mice also form a disordered mitochondrial sheath and have poorly motile sperm.

spermatid CL:0000018 sperm CL:0000019

sperm mitochondrial sheath assembly GO:0120317 ↓ DECREASED

sperm mitochondrial sheath GO:0097226

testis UBERON:0000473

Animal models

Tsga10 heterozygous knockout mouse Mouse recapitulates The mice reproduce the disordered mitochondrial sheath seen in patient sperm.

Downstream

Abnormal sperm tail morphology Misarranged mitochondrial sheath assembly in the midpiece produces abnormal flagellar morphology in TSGA10-deficient spermatozoa.

Reduced progressive sperm motility Shown in Tsga10 heterozygous mice. In patients the two findings are reported together but not causally linked.

Show evidence (3 references)

PMID:32410354 SUPPORT Human clinical

"Our results showed misarranged mitochondrial sheath and abnormal flagellum in the patient's spermatozoa."

Ultrastructural mitochondrial sheath defect in a patient.

PMID:32410354 SUPPORT Human clinical

"Mitochondrial sheath defects in the patient were confirmed by our immunofluorescence analysis of mitochondrial marker COXIV, which revealed reduced labeling of the patient's spermatozoa."

Reduced mitochondrial marker staining confirms the sheath defect.

PMID:32790169 SUPPORT Model organism

"TSGA10 is involved in the correct arrangement of mitochondrial sheath in spermatozoa."

Mouse knockout conclusion on TSGA10 function in the mitochondrial sheath.

⬡

Pathograph

Use Group by to collapse related nodes into one box. Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

6

Male infertility Reproductive HP:0003251

Show evidence (2 references)

PMID:28905369 SUPPORT Human clinical

"Here, we report a 27 years old infertile male from a consanguineous family, who presented with 99% headless sperm in his ejaculate."

Infertility in the first reported man.

PMID:38317066 SUPPORT Human clinical

"We recruited a Pakistani family with two infertile brothers who suffered from acephalic spermatozoa syndrome."

Infertility in two further affected brothers.

Acephalic spermatozoa Reproductive HP:0012869

Sequelae: Male infertility

Show evidence (3 references)

PMID:28905369 SUPPORT Human clinical

"Here, we report a 27 years old infertile male from a consanguineous family, who presented with 99% headless sperm in his ejaculate."

99% headless sperm.

PMID:32410354 SUPPORT Human clinical

"These results suggest that the novel homozygous frameshift insertion mutation of TSGA10 is a cause of acephalic spermatozoa."

Acephalic spermatozoa in a second frameshift case.

PMID:34409526 SUPPORT Human clinical

"Western blot and immunofluorescence demonstrated that the very low expression level of truncated TSGA10 protein led the proband to present the acephalic spermatozoa phenotype."

Acephalic spermatozoa in the compound heterozygous proband.

Abnormal sperm tail morphology Reproductive HP:0012868

Show evidence (1 reference)

PMID:32410354 SUPPORT Human clinical

"Our results showed misarranged mitochondrial sheath and abnormal flagellum in the patient's spermatozoa."

Abnormal midpiece and flagellum on electron microscopy.

Abnormal sperm axoneme morphology Reproductive HP:0033524

Show evidence (1 reference)

PMID:38317066 SUPPORT Human clinical

"Ultrastructural analyses of spermatozoa from the patient revealed that 98% of flagellar cross-sections displayed abnormal axonemal ultrastructure, in addition to the head-flagellum detachment."

Axonemal abnormality in a missense-variant patient.

Severe oligozoospermia Reproductive HP:0034818

Show evidence (1 reference)

PMID:38317066 SUPPORT Human clinical

"Patients (III: 1 and III: 2) had very low sperm concentrations (1 million/ml and 0.5 million/ml, respectively)."

Sperm concentrations far below the reference range.

Reduced progressive sperm motility Reproductive HP:0034011

Show evidence (1 reference)

PMID:38317066 SUPPORT Human clinical

"Their sperm progressive motility were 4.0% and 7.0% respectively, which were below the reference range (32%) suggested by WHO [1]."

Progressive motility far below the WHO reference.

🧬

Genetic Associations

1

TSGA10 (Causal)

Gene: TSGA10 hgnc:14927 relationship_type: CAUSATIVE

Show evidence (4 references)

PMID:28905369 SUPPORT Human clinical

"Subsequent whole-exome sequencing analysis identified a homozygous deletion within TSGA10 (c.211delG; p.A71Hfs*12), which resulted in the production of truncated TSGA10 protein."

First gene-disease report.

PMID:32410354 SUPPORT Human clinical

"A novel homozygous frameshift insertion mutation c.545dupT;p.Ala183Serfs*10 in exon 8 of TSGA10 (NM_001349012.1) was identified."

Independent homozygous frameshift case.

PMID:34409526 SUPPORT Human clinical

"Here, we identified a novel heterozygous splicing mutation in TSGA10 (NM_025244: c.1108-1G > T), while we confirmed that there was a de novo large deletion in the proband."

Splice variant together with a deletion of the other allele.

+ 1 more reference

💊

Medical Actions

2

Intracytoplasmic Sperm Injection

Action: intracytoplasmic sperm injection Ontology label: Intracytoplasmic Sperm Injection NCIT:C185482

Platform: Other

ICSI with the few remaining heads is the only route to biological paternity. Outcomes in TSGA10 cases differ between reports: the first patient's embryos were of poor quality and no pregnancy followed, while a later Chinese cohort with TSGA10 or PMFBP1 variants reported good ICSI outcomes.

Mechanism Target:

BYPASSES Defective Sperm Head-Tail Coupling — Microinjection of a sperm head directly into the oocyte bypasses the fertilization failure caused by head-tail separation.

Acephalic spermatozoa — Injecting a detached head into the oocyte bypasses the need for an intact sperm.

Show evidence (2 references)

PMID:34089195 SUPPORT Human clinical

"Patients with TSGA10/PMFBP1 variations were all expected to have good prognoses with ICSI."

Favourable ICSI outcomes in a cohort including TSGA10 patients.

PMID:28905369 REFUTE Human clinical

"One cycle of in vitro fertilization-assisted reproduction was conducted, but pregnancy was not achieved after embryo transfer, possibly due to poor embryo quality."

The first TSGA10 patient did not achieve a pregnancy after assisted reproduction.

Genetic Counseling

Action: Genetic Counseling NCIT:C15240

Counseling on autosomal recessive inheritance, including the possibility of a deletion on the second allele in non-consanguineous families.

Show evidence (1 reference)

PMID:34409526 SUPPORT Human clinical

"It is also important to remind us of paying attention to the compound heterozygous deletion in patients from non-consanguineous families, so that we can provide more precise genetic counseling for patients."

Authors recommend attention to deletions to inform counseling.

🔬

Diagnosis

2

Semen analysis and sperm electron microscopy (Positive)

Routine semen analysis with stained smears shows mostly headless tails; transmission electron microscopy locates the break and shows the midpiece and axonemal defects.

transmission electron microscopy of spermatozoa NCIT:C18216

Results: Ejaculate dominated by headless sperm tails (up to 99% acephalic spermatozoa) with few loose heads, midpiece breakage, disordered mitochondrial sheath, and abnormal 9+2 axonemal cross-sections.

Show evidence (1 reference)

PMID:28905369 SUPPORT Human clinical

"Electron microscopic and immunofluorescence analysis suggested breakage at the midpiece of the patient's sperm cells."

Electron microscopy localizes the TSGA10-type break.

Whole-exome sequencing (Positive)

Each reported TSGA10 case was found by exome sequencing and confirmed by Sanger sequencing. A single heterozygous variant in a non-consanguineous patient calls for copy-number analysis of the other allele.

whole-exome sequencing NCIT:C101295

Results: Identification of homozygous or compound heterozygous loss-of-function or missense pathogenic variants in TSGA10.

Show evidence (2 references)

PMID:38317066 SUPPORT Human clinical

"Through whole-exome sequencing (WES) followed by Sanger sequencing, we identified a novel missense variant in TSGA10"

Exome sequencing found the causal variant.

PMID:34409526 SUPPORT Human clinical

"Quantitative real-time polymerase chain reaction and whole genome sequencing were subjected to detect deletion."

The deleted second allele needed copy-number methods beyond exome sequencing.

🐁

Animal Models

1

Tsga10 heterozygous knockout mouse

Heterozygous male mice are infertile, with markedly reduced sperm motility and a disordered mitochondrial sheath.

Species

Mouse

Genotype

Tsga10 +/- (CRISPR/Cas9)

Publication

PMID:32790169

Pathograph links

Sperm Mitochondrial Sheath Disorganization recapitulates fidelity: moderate observes: cellular The mice reproduce the disordered mitochondrial sheath seen in patient sperm.

Limitations: The mouse defect appears with one null allele, while human disease is recessive, and the abstract does not report headless sperm, so the model does not show the defining acephalic phenotype.

Show evidence (1 reference)

PMID:32790169 SUPPORT Model organism

"Heterozygous Tsga10 male mice created by CRISPR/Cas9 were infertile and presented significantly reduced sperm motility because of disordered mitochondrial sheath formation."

Mitochondrial sheath disorder and infertility in the model.

{ }

Source YAML

click to show

name: Spermatogenic Failure 26
creation_date: "2026-10-19T12:00:00Z"
category: Mendelian
synonyms:
- SPGF26
- spermatogenic failure 26
- TSGA10-related acephalic spermatozoa syndrome
description: >-
  Spermatogenic failure 26 (SPGF26) is autosomal recessive male infertility
  caused by biallelic loss-of-function variants in TSGA10, a testis-enriched
  centrosomal protein that localizes to the sperm midpiece. Affected men are
  otherwise healthy and present with acephalic spermatozoa syndrome: the
  ejaculate contains mostly headless sperm tails and a few loose heads. In
  TSGA10 deficiency the break lies between the distal centriole and the
  midpiece, so the tails retain little or no mitochondrial sheath, and the
  remaining midpiece and axoneme are disorganized. Sperm concentration and
  progressive motility can also be very low. Reported variants are
  frameshift, splice-site and missense alleles, homozygous in consanguineous
  families or in trans with a large deletion, and each leaves the sperm with
  no detectable TSGA10 protein. Assisted reproduction by intracytoplasmic
  sperm injection (ICSI) has given both failed and successful pregnancies.
disease_term:
  preferred_term: spermatogenic failure 26
  term:
    id: MONDO:0054730
    label: spermatogenic failure 26
classifications:
  harrisons_chapter:
  - classification_value: ENDOCRINOLOGY_METABOLISM
    notes: Male reproductive and gonadal disorder causing primary male infertility due to acephalic spermatozoa.
    evidence:
    - reference: PMID:38317066
      reference_title: "A novel homozygous TSGA10 missense variant causes acephalic spermatozoa syndrome in a Pakistani family."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Acephalic spermatozoa syndrome is a rare type of teratozoospermia causing male infertility due to detachment of the sperm head and flagellum, which precludes fertilization potential."
      explanation: "Establishes spermatogenic failure 26 as a primary male reproductive infertility disorder."
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    notes: Monogenic autosomal recessive disorder caused by biallelic pathogenic variants in TSGA10.
    evidence:
    - reference: PMID:38317066
      reference_title: "A novel homozygous TSGA10 missense variant causes acephalic spermatozoa syndrome in a Pakistani family."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Altogether, our study identifies a novel TSGA10 pathogenic variant as a cause of acephalic spermatozoa syndrome in this family and provides information regarding the clinical manifestations associated with TSGA10 variants in human."
      explanation: "Establishes that biallelic pathogenic variants in TSGA10 cause this inherited monogenic disorder."
parents:
- Spermatogenic Failure
- Genetic Disease
notes: >-
  MONDO cross-references this disease as OMIM 617961 and records TSGA10 as its
  causal gene. Heterozygous Tsga10 knockout male mice are infertile
  (PMID:32790169), whereas every reported human case is biallelic and no
  phenotype has been described in heterozygous human relatives, so the mouse
  dosage result is recorded only on the animal model. GO annotates no
  molecular function for TSGA10 other than protein binding (QuickGO, UniProt
  Q9BZW7), so the TSGA10 node carries no molecular_functions term.
inheritance:
- name: Autosomal recessive
  description: >-
    Disease requires two TSGA10 loss-of-function alleles: a homozygous
    frameshift in Chinese probands, a homozygous missense variant segregating
    with disease in two Pakistani brothers, and a splice variant in trans with
    a de novo large deletion in a non-consanguineous proband.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:38317066
    reference_title: "A novel homozygous TSGA10 missense variant causes acephalic spermatozoa syndrome in a Pakistani family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we identified a novel missense variant in TSGA10 (c.1112T > C, p. Leu371Pro), which recessively co-segregated with the acephalic spermatozoa syndrome within this family"
    explanation: Recessive co-segregation of a homozygous TSGA10 variant with disease.
  - reference: PMID:34409526
    reference_title: "Pathogenesis of acephalic spermatozoa syndrome caused by splicing mutation and de novo deletion in TSGA10."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Therefore, we speculated that the splicing mutation might affect transcription and translation without the dosage compensation of a normal allele, which possesses a large deletion including intact TSGA10."
    explanation: >-
      A heterozygous splice variant causes disease because the other allele is
      deleted, the compound-heterozygous form of recessive inheritance.
pathophysiology:
- name: Loss of TSGA10 Protein
  description: >-
    Frameshift, splice-site and missense variants all leave spermatozoa
    without detectable TSGA10. The frameshift alleles truncate the protein,
    the splice variant produces a truncated protein at very low level, and the
    Leu371Pro missense variant abolishes both mRNA and protein in sperm.
    TSGA10 is normally found at the sperm midpiece. In mouse testis the
    65-kDa spermatid protein is processed to a 27-kDa fibrous sheath protein.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: TSGA10
    term:
      id: hgnc:14927
      label: TSGA10
  cell_types:
  - preferred_term: spermatid
    term:
      id: CL:0000018
      label: spermatid
  - preferred_term: sperm
    term:
      id: CL:0000019
      label: sperm
  locations:
  - preferred_term: testis
    term:
      id: UBERON:0000473
      label: testis
  genetic_context:
    variant_origin: GERMLINE
    functional_impact_category: LOSS_OF_FUNCTION
  downstream:
  - target: Defective Sperm Head-Tail Coupling
    causal_link_type: DIRECT
  - target: Sperm Mitochondrial Sheath Disorganization
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:32410354
      reference_title: "Loss-of-function mutation in TSGA10 causes acephalic spermatozoa phenotype in human."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Our results suggest that loss of TSGA10 may impair the formation of the mitochondrial sheath."
      explanation: The authors attribute the mitochondrial sheath defect to the loss of TSGA10.
  evidence:
  - reference: PMID:28905369
    reference_title: "TSGA10 is a novel candidate gene associated with acephalic spermatozoa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "TSGA10 is a testis-specific protein that localized to the midpiece in the spermatozoa of a normal control; however, immunostaining failed to detect TSGA10 protein in the patient's sperm. Western blot analysis also showed complete absence of TSGA10 protein in the patient."
    explanation: The homozygous frameshift abolishes TSGA10 protein in sperm.
  - reference: PMID:32410354
    reference_title: "Loss-of-function mutation in TSGA10 causes acephalic spermatozoa phenotype in human."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "TSGA10 failed to be detected in the patient's spermatozoa. However, the expression of SUN5 and PMFBP1 remained unaffected."
    explanation: A second frameshift allele also abolishes TSGA10, without loss of two other head-tail coupling proteins.
  - reference: PMID:34409526
    reference_title: "Pathogenesis of acephalic spermatozoa syndrome caused by splicing mutation and de novo deletion in TSGA10."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Western blot and immunofluorescence demonstrated that the very low expression level of truncated TSGA10 protein led the proband to present the acephalic spermatozoa phenotype."
    explanation: The splice allele yields only trace amounts of truncated protein.
  - reference: PMID:38317066
    reference_title: "A novel homozygous TSGA10 missense variant causes acephalic spermatozoa syndrome in a Pakistani family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Real-time quantitative PCR analysis revealed almost no detectable TSAG10 mRNA and western blot analysis also failed to detect TSAG10 protein in patient's sperm samples while TSGA10 expression was clearly detected in control samples."
    explanation: The missense allele also behaves as a null in sperm.
  - reference: PMID:14585816
    reference_title: "Tsga10 encodes a 65-kilodalton protein that is processed to the 27-kilodalton fibrous sheath protein."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Mtsga10 encodes a 65-kDa spermatid protein that appears to be processed to a 27-kDa protein of the fibrous sheath, a major sperm tail structure, in mature spermatozoa"
    explanation: Normal processing and tail localization of the protein lost in the disease.
- name: Defective Sperm Head-Tail Coupling
  description: >-
    TSGA10 is a centrosomal scaffold protein whose C-terminal fragment sits at
    the centrosome and basal body and binds ODF2, so it is thought to help
    anchor the sperm tail to the head. Without it, the flagellum separates from
    the head at a point between the distal centriole and the midpiece.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: spermatid
    term:
      id: CL:0000018
      label: spermatid
  - preferred_term: sperm
    term:
      id: CL:0000019
      label: sperm
  locations:
  - preferred_term: testis
    term:
      id: UBERON:0000473
      label: testis
  biological_processes:
  - preferred_term: sperm flagellum assembly
    modifier: DECREASED
    term:
      id: GO:0120316
      label: sperm flagellum assembly
  cellular_components:
  - preferred_term: sperm head-tail coupling apparatus
    term:
      id: GO:0120212
      label: sperm head-tail coupling apparatus
  - preferred_term: centriole
    term:
      id: GO:0005814
      label: centriole
  downstream:
  - target: Acephalic spermatozoa
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:42366926
      reference_title: "Sperm Head-Tail Coupling Apparatus Diversity and Common Themes Among Species."
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "Impairment of the HTCA leads to a severe type of infertility called acephalic spermatozoa syndrome, where sperm heads become detached from their tails."
      explanation: Review stating that head-tail coupling failure produces acephalic spermatozoa.
  - target: Abnormal sperm axoneme morphology
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Head-flagellum detachment in TSGA10-deficient spermatozoa is accompanied by abnormal axonemal ultrastructure across 98% of flagellar cross-sections.
    evidence:
    - reference: PMID:38317066
      reference_title: "A novel homozygous TSGA10 missense variant causes acephalic spermatozoa syndrome in a Pakistani family."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Ultrastructural analyses of spermatozoa from the patient revealed that 98% of flagellar cross-sections displayed abnormal axonemal ultrastructure, in addition to the head-flagellum detachment."
      explanation: Reports abnormal axonemal ultrastructure in 98% of flagellar cross-sections alongside head-flagellum detachment in a patient with biallelic TSGA10 deficiency.
  evidence:
  - reference: PMID:38317066
    reference_title: "A novel homozygous TSGA10 missense variant causes acephalic spermatozoa syndrome in a Pakistani family."
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: BACKGROUND
    snippet: "implying that the TSGA10 C-terminus is involved in centriole assembly and function, particularly in the head-tail link"
    explanation: >-
      The introduction of this clinical paper restates earlier interaction
      work that places TSGA10 at the centriole and the head-tail link.
  - reference: PMID:28905369
    reference_title: "TSGA10 is a novel candidate gene associated with acephalic spermatozoa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Electron microscopic and immunofluorescence analysis suggested breakage at the midpiece of the patient's sperm cells."
    explanation: Patient sperm break at the midpiece.
  - reference: PMID:32104701
    reference_title: "Beyond Acephalic Spermatozoa: The Complexity of Intracytoplasmic Sperm Injection Outcomes."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "the breakage of TSGA10 associated with AS sperms is located between the distal centriole and the midpiece"
    explanation: Review placing the TSGA10-related break between the distal centriole and the midpiece.
- name: Sperm Mitochondrial Sheath Disorganization
  description: >-
    The midpiece of the headless tails carries a misarranged or partial
    mitochondrial sheath, with reduced staining for the mitochondrial marker
    COXIV. Heterozygous Tsga10 knockout mice also form a disordered
    mitochondrial sheath and have poorly motile sperm.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: spermatid
    term:
      id: CL:0000018
      label: spermatid
  - preferred_term: sperm
    term:
      id: CL:0000019
      label: sperm
  locations:
  - preferred_term: testis
    term:
      id: UBERON:0000473
      label: testis
  biological_processes:
  - preferred_term: sperm mitochondrial sheath assembly
    modifier: DECREASED
    term:
      id: GO:0120317
      label: sperm mitochondrial sheath assembly
  cellular_components:
  - preferred_term: sperm mitochondrial sheath
    term:
      id: GO:0097226
      label: sperm mitochondrial sheath
  downstream:
  - target: Abnormal sperm tail morphology
    causal_link_type: DIRECT
    description: Misarranged mitochondrial sheath assembly in the midpiece produces abnormal flagellar morphology in TSGA10-deficient spermatozoa.
    evidence:
    - reference: PMID:32410354
      reference_title: "Loss-of-function mutation in TSGA10 causes acephalic spermatozoa phenotype in human."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Our results showed misarranged mitochondrial sheath and abnormal flagellum in the patient's spermatozoa."
      explanation: Reports misarranged mitochondrial sheath alongside abnormal flagellar morphology in patient spermatozoa.
  - target: Reduced progressive sperm motility
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Shown in Tsga10 heterozygous mice. In patients the two findings are
      reported together but not causally linked.
    evidence:
    - reference: PMID:32790169
      reference_title: "Tsga10 is essential for arrangement of mitochondrial sheath and male fertility in mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Heterozygous Tsga10 male mice created by CRISPR/Cas9 were infertile and presented significantly reduced sperm motility because of disordered mitochondrial sheath formation."
      explanation: The mouse study attributes the motility defect to the mitochondrial sheath defect.
  evidence:
  - reference: PMID:32410354
    reference_title: "Loss-of-function mutation in TSGA10 causes acephalic spermatozoa phenotype in human."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our results showed misarranged mitochondrial sheath and abnormal flagellum in the patient's spermatozoa."
    explanation: Ultrastructural mitochondrial sheath defect in a patient.
  - reference: PMID:32410354
    reference_title: "Loss-of-function mutation in TSGA10 causes acephalic spermatozoa phenotype in human."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mitochondrial sheath defects in the patient were confirmed by our immunofluorescence analysis of mitochondrial marker COXIV, which revealed reduced labeling of the patient's spermatozoa."
    explanation: Reduced mitochondrial marker staining confirms the sheath defect.
  - reference: PMID:32790169
    reference_title: "Tsga10 is essential for arrangement of mitochondrial sheath and male fertility in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "TSGA10 is involved in the correct arrangement of mitochondrial sheath in spermatozoa."
    explanation: Mouse knockout conclusion on TSGA10 function in the mitochondrial sheath.
phenotypes:
- category: Reproductive
  name: Male infertility
  description: Primary male infertility is the presenting complaint in every reported man.
  phenotype_term:
    preferred_term: Male infertility
    term:
      id: HP:0003251
      label: Male infertility
  evidence:
  - reference: PMID:28905369
    reference_title: "TSGA10 is a novel candidate gene associated with acephalic spermatozoa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we report a 27 years old infertile male from a consanguineous family, who presented with 99% headless sperm in his ejaculate."
    explanation: Infertility in the first reported man.
  - reference: PMID:38317066
    reference_title: "A novel homozygous TSGA10 missense variant causes acephalic spermatozoa syndrome in a Pakistani family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We recruited a Pakistani family with two infertile brothers who suffered from acephalic spermatozoa syndrome."
    explanation: Infertility in two further affected brothers.
- category: Reproductive
  name: Acephalic spermatozoa
  diagnostic: true
  description: >-
    The defining finding. The ejaculate contains mostly headless sperm tails,
    up to 99% of spermatozoa, with a few loose heads.
  phenotype_term:
    preferred_term: Acephalic spermatozoa
    term:
      id: HP:0012869
      label: Acephalic spermatozoa
  sequelae:
  - target: Male infertility
    description: Headless tails cannot fertilize an oocyte, so natural conception is not possible.
  evidence:
  - reference: PMID:28905369
    reference_title: "TSGA10 is a novel candidate gene associated with acephalic spermatozoa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we report a 27 years old infertile male from a consanguineous family, who presented with 99% headless sperm in his ejaculate."
    explanation: 99% headless sperm.
  - reference: PMID:32410354
    reference_title: "Loss-of-function mutation in TSGA10 causes acephalic spermatozoa phenotype in human."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These results suggest that the novel homozygous frameshift insertion mutation of TSGA10 is a cause of acephalic spermatozoa."
    explanation: Acephalic spermatozoa in a second frameshift case.
  - reference: PMID:34409526
    reference_title: "Pathogenesis of acephalic spermatozoa syndrome caused by splicing mutation and de novo deletion in TSGA10."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Western blot and immunofluorescence demonstrated that the very low expression level of truncated TSGA10 protein led the proband to present the acephalic spermatozoa phenotype."
    explanation: Acephalic spermatozoa in the compound heterozygous proband.
- category: Reproductive
  name: Abnormal sperm tail morphology
  description: >-
    The headless tails carry a residual cytoplasmic droplet at their tip and a
    disordered midpiece, with a misarranged mitochondrial sheath.
  phenotype_term:
    preferred_term: Disorganized sperm midpiece and mitochondrial sheath
    term:
      id: HP:0012868
      label: Abnormal sperm tail morphology
  evidence:
  - reference: PMID:32410354
    reference_title: "Loss-of-function mutation in TSGA10 causes acephalic spermatozoa phenotype in human."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our results showed misarranged mitochondrial sheath and abnormal flagellum in the patient's spermatozoa."
    explanation: Abnormal midpiece and flagellum on electron microscopy.
- category: Reproductive
  name: Abnormal sperm axoneme morphology
  description: >-
    In the Pakistani family nearly all flagellar cross-sections had an
    abnormal axoneme.
  phenotype_term:
    preferred_term: Abnormal sperm axoneme morphology
    term:
      id: HP:0033524
      label: Abnormal sperm axoneme morphology
  evidence:
  - reference: PMID:38317066
    reference_title: "A novel homozygous TSGA10 missense variant causes acephalic spermatozoa syndrome in a Pakistani family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ultrastructural analyses of spermatozoa from the patient revealed that 98% of flagellar cross-sections displayed abnormal axonemal ultrastructure, in addition to the head-flagellum detachment."
    explanation: Axonemal abnormality in a missense-variant patient.
- category: Reproductive
  name: Severe oligozoospermia
  description: The two Pakistani brothers had sperm concentrations of 1 and 0.5 million/ml.
  phenotype_term:
    preferred_term: Severe oligozoospermia
    term:
      id: HP:0034818
      label: Severe oligozoospermia
  evidence:
  - reference: PMID:38317066
    reference_title: "A novel homozygous TSGA10 missense variant causes acephalic spermatozoa syndrome in a Pakistani family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients (III: 1 and III: 2) had very low sperm concentrations (1 million/ml and 0.5 million/ml, respectively)."
    explanation: Sperm concentrations far below the reference range.
- category: Reproductive
  name: Reduced progressive sperm motility
  description: Progressive motility of 4% and 7% in the two Pakistani brothers, against a WHO reference of 32%.
  phenotype_term:
    preferred_term: Reduced progressive sperm motility
    term:
      id: HP:0034011
      label: Reduced progressive sperm motility
  evidence:
  - reference: PMID:38317066
    reference_title: "A novel homozygous TSGA10 missense variant causes acephalic spermatozoa syndrome in a Pakistani family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Their sperm progressive motility were 4.0% and 7.0% respectively, which were below the reference range (32%) suggested by WHO [1]."
    explanation: Progressive motility far below the WHO reference.
genetic:
- name: TSGA10
  association: Causal
  relationship_type: CAUSATIVE
  gene_term:
    preferred_term: TSGA10
    term:
      id: hgnc:14927
      label: TSGA10
  notes: >-
    Reported alleles: homozygous c.211delG (p.Ala71Hisfs*12) (PMID:28905369);
    homozygous c.545dupT (p.Ala183Serfs*10) (PMID:32410354); c.1108-1G>T in
    trans with a de novo deletion spanning TSGA10 (PMID:34409526); homozygous
    c.1112T>C (p.Leu371Pro) (PMID:38317066). No ClinGen gene-disease validity
    assertion for TSGA10 is in the cached ClinGen export, so no validity tier
    is recorded.
  evidence:
  - reference: PMID:28905369
    reference_title: "TSGA10 is a novel candidate gene associated with acephalic spermatozoa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Subsequent whole-exome sequencing analysis identified a homozygous deletion within TSGA10 (c.211delG; p.A71Hfs*12), which resulted in the production of truncated TSGA10 protein."
    explanation: First gene-disease report.
  - reference: PMID:32410354
    reference_title: "Loss-of-function mutation in TSGA10 causes acephalic spermatozoa phenotype in human."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A novel homozygous frameshift insertion mutation c.545dupT;p.Ala183Serfs*10 in exon 8 of TSGA10 (NM_001349012.1) was identified."
    explanation: Independent homozygous frameshift case.
  - reference: PMID:34409526
    reference_title: "Pathogenesis of acephalic spermatozoa syndrome caused by splicing mutation and de novo deletion in TSGA10."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we identified a novel heterozygous splicing mutation in TSGA10 (NM_025244: c.1108-1G > T), while we confirmed that there was a de novo large deletion in the proband."
    explanation: Splice variant together with a deletion of the other allele.
  - reference: PMID:38317066
    reference_title: "A novel homozygous TSGA10 missense variant causes acephalic spermatozoa syndrome in a Pakistani family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we identified a novel missense variant in TSGA10 (c.1112T > C, p. Leu371Pro), which recessively co-segregated with the acephalic spermatozoa syndrome within this family"
    explanation: Homozygous missense variant co-segregating in a second family.
animal_models:
- name: Tsga10 heterozygous knockout mouse
  species: Mouse
  genotype: Tsga10 +/- (CRISPR/Cas9)
  publication: PMID:32790169
  description: >-
    Heterozygous male mice are infertile, with markedly reduced sperm
    motility and a disordered mitochondrial sheath.
  modeled_mechanisms:
  - target: Sperm Mitochondrial Sheath Disorganization
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: The mice reproduce the disordered mitochondrial sheath seen in patient sperm.
    limitations: >-
      The mouse defect appears with one null allele, while human disease is
      recessive, and the abstract does not report headless sperm, so the
      model does not show the defining acephalic phenotype.
    evidence:
    - reference: PMID:32790169
      reference_title: "Tsga10 is essential for arrangement of mitochondrial sheath and male fertility in mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Heterozygous Tsga10 male mice created by CRISPR/Cas9 were infertile and presented significantly reduced sperm motility because of disordered mitochondrial sheath formation."
      explanation: Mitochondrial sheath disorder and infertility in the model.
diagnosis:
- name: Semen analysis and sperm electron microscopy
  presence: Positive
  results: Ejaculate dominated by headless sperm tails (up to 99% acephalic spermatozoa) with few loose heads, midpiece breakage, disordered mitochondrial sheath, and abnormal 9+2 axonemal cross-sections.
  description: >-
    Routine semen analysis with stained smears shows mostly headless tails;
    transmission electron microscopy locates the break and shows the midpiece
    and axonemal defects.
  diagnosis_term:
    preferred_term: transmission electron microscopy of spermatozoa
    term:
      id: NCIT:C18216
      label: Transmission Electron Microscopy
  evidence:
  - reference: PMID:28905369
    reference_title: "TSGA10 is a novel candidate gene associated with acephalic spermatozoa."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Electron microscopic and immunofluorescence analysis suggested breakage at the midpiece of the patient's sperm cells."
    explanation: Electron microscopy localizes the TSGA10-type break.
- name: Whole-exome sequencing
  presence: Positive
  results: Identification of homozygous or compound heterozygous loss-of-function or missense pathogenic variants in TSGA10.
  description: >-
    Each reported TSGA10 case was found by exome sequencing and confirmed by
    Sanger sequencing. A single heterozygous variant in a non-consanguineous
    patient calls for copy-number analysis of the other allele.
  diagnosis_term:
    preferred_term: whole-exome sequencing
    term:
      id: NCIT:C101295
      label: Whole Exome Sequencing
  evidence:
  - reference: PMID:38317066
    reference_title: "A novel homozygous TSGA10 missense variant causes acephalic spermatozoa syndrome in a Pakistani family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Through whole-exome sequencing (WES) followed by Sanger sequencing, we identified a novel missense variant in TSGA10"
    explanation: Exome sequencing found the causal variant.
  - reference: PMID:34409526
    reference_title: "Pathogenesis of acephalic spermatozoa syndrome caused by splicing mutation and de novo deletion in TSGA10."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Quantitative real-time polymerase chain reaction and whole genome sequencing were subjected to detect deletion."
    explanation: The deleted second allele needed copy-number methods beyond exome sequencing.
treatments:
- name: Intracytoplasmic Sperm Injection
  description: >-
    ICSI with the few remaining heads is the only route to biological
    paternity. Outcomes in TSGA10 cases differ between reports: the first
    patient's embryos were of poor quality and no pregnancy followed, while a
    later Chinese cohort with TSGA10 or PMFBP1 variants reported good ICSI
    outcomes.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: intracytoplasmic sperm injection
    term:
      id: NCIT:C185482
      label: Intracytoplasmic Sperm Injection
  target_mechanisms:
  - target: Defective Sperm Head-Tail Coupling
    treatment_effect: BYPASSES
    description: Microinjection of a sperm head directly into the oocyte bypasses the fertilization failure caused by head-tail separation.
  - target: Acephalic spermatozoa
    description: Injecting a detached head into the oocyte bypasses the need for an intact sperm.
  evidence:
  - reference: PMID:34089195
    reference_title: "Patients with acephalic spermatozoa syndrome linked to novel TSGA10/PMFBP1 variants have favorable pregnancy outcomes from intracytoplasmic sperm injection."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients with TSGA10/PMFBP1 variations were all expected to have good prognoses with ICSI."
    explanation: Favourable ICSI outcomes in a cohort including TSGA10 patients.
  - reference: PMID:28905369
    reference_title: "TSGA10 is a novel candidate gene associated with acephalic spermatozoa."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "One cycle of in vitro fertilization-assisted reproduction was conducted, but pregnancy was not achieved after embryo transfer, possibly due to poor embryo quality."
    explanation: The first TSGA10 patient did not achieve a pregnancy after assisted reproduction.
- name: Genetic Counseling
  description: >-
    Counseling on autosomal recessive inheritance, including the possibility
    of a deletion on the second allele in non-consanguineous families.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:34409526
    reference_title: "Pathogenesis of acephalic spermatozoa syndrome caused by splicing mutation and de novo deletion in TSGA10."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It is also important to remind us of paying attention to the compound heterozygous deletion in patients from non-consanguineous families, so that we can provide more precise genetic counseling for patients."
    explanation: Authors recommend attention to deletions to inform counseling.

📚

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: SPGF26 (TSGA10) · 2026-10-19T08:35:43Z · View source

Created from MONDO:0054730 (OMIM 617961, causal gene TSGA10 hgnc:14927). Deep research: OpenScientist. The first run returned a report about TDRD9 (spermatogenic failure 30) that never named TSGA10; just preflight-dr returned FAIL and the report was discarded unused (reported on #14907). For the second run the entry name was temporarily set to 'TSGA10-Related Acephalic Spermatozoa Syndrome (Spermatogenic Failure 26)' and then restored; that report passed the gene-identity check (TSGA10 mentioned 87 times) with a WARN only because it cites OMIM 607166, the TSGA10 gene record, rather than the disease number. 26/26 references resolved. Primary sources read from the cache: four case reports defining the allelic series (PMID:28905369, PMID:32410354, PMID:34409526, PMID:38317066), the Tsga10 heterozygous knockout mouse (PMID:32790169), the mouse Tsga10 fibrous sheath processing study (PMID:14585816), an ICSI cohort (PMID:34089195) and two reviews (PMID:32104701, PMID:42366926). ICSI outcomes are recorded as one SUPPORT and one REFUTE item because the reports disagree. The Tsga10 heterozygous mouse is infertile while human disease is recessive; that divergence is stated on the animal model. No GeneReviews chapter. Validation: just validate-disorders passed (36/36 snippets, terms, schema); check-entity-refs, check-causal-targets and check-coarse-phenotypes OK. Before review, CI's 'Check for newly ungrounded genes' gate flagged TSGA10, whose landing node has no molecular function. GO annotates TSGA10 only with protein binding (GO:0005515, IPI), so instead of binding an uninformative term the node was added to tests/gene_activity_grounding_baseline.txt, as the script's own guidance allows for a node with no real molecular function to name, and the reason was added to the entry notes.

OpenScientist ▸

Key Findings

openscientist-autonomous 26 citations 2026-10-19T08:31:51.590320

Key Findings

Finding 1 — Biallelic loss-of-function TSGA10 variants cause acephalic spermatozoa syndrome (SPGF26)

The central etiologic claim of this report is firmly established by human genetic evidence. Whole-exome sequencing of men presenting with acephalic spermatozoa identified recessive TSGA10 LoF variants segregating with disease. In one index case, a homozygous frameshift insertion, c.545dupT (p.Ala183Serfs*10), in exon 8 (NM_001349012.1), abolished TSGA10 protein in the patient's spermatozoa. Critically, TEM of the patient's sperm showed a misarranged mitochondrial sheath and an abnormal flagellum, while the two best-established ASS proteins SUN5 and PMFBP1 remained normally expressed, demonstrating that TSGA10 acts in a pathway at least partly independent of those linkage proteins (PMID: 32410354). [human clinical]

"A novel homozygous frameshift insertion mutation c.545dupT;p.Ala183Serfs*10 in exon 8 of TSGA10 (NM_001349012.1) was identified." — PMID: 32410354

"Our results showed misarranged mitochondrial sheath and abnormal flagellum in the patient's spermatozoa. TSGA10 failed to be detected in the patient's spermatozoa. However, the expression of SUN5 and PMFBP1 remained unaffected." — PMID: 32410354

A second, independent mechanism of biallelic inactivation was documented in a proband carrying a compound-heterozygous genotype: a canonical splice-site variant c.1108-1G>T (NM_025244) that causes skipping of exon 15 and a truncated protein (p.A370Efs*293), in trans with a de novo large deletion (PMID: 34409526). This case is diagnostically instructive: the second hit was a structural variant invisible to standard variant callers, underscoring the need for CNV analysis. [human clinical]

"we identified a novel heterozygous splicing mutation in TSGA10 (NM_025244: c.1108-1G > T), while we confirmed that there was a de novo large deletion in the proband. The splicing mutation led to the skipping of the exon15 of TSGA10, which resulted in a truncated protein (p. A370Efs*293)." — PMID: 34409526

Finding 2 — ICSI yields favorable pregnancy outcomes in TSGA10-related ASS

Because ASS is a defect of sperm architecture rather than of the paternal genome, assisted reproduction can bypass it. In a retrospective cohort of 12 men with severe acephalic spermatozoa, WES identified TSGA10/PMFBP1 variants in 7 patients (six heterozygous, four homozygous across the gene set). ICSI outcomes were favorable: the variants affected sperm morphology but did not reduce fertilization rates, early embryo quality, or ICSI success (PMID: 34089195). [human clinical]

"Acephalic spermatozoa defects due to different genetic variations may affect only spermatozoa morphology but do not reduce the chances of fertilization, affect embryo quality at early stages or impair intracytoplasmic sperm injection (ICSI) outcomes. Patients with TSGA10/PMFBP1 variations were all expected to have good prognoses with ICSI." — PMID: 34089195

This contrasts with some other ASS genes (e.g., CCDC188, where a poor ICSI outcome has been reported — PMID: 41004021), reinforcing that genotype-specific prognostication is clinically valuable and that TSGA10 sits among the favorable-prognosis genes.

Finding 3 — TSGA10 is a spermatid-expressed protein with mitochondrial Complex III coupling and HIF-1α regulatory roles

TSGA10 is a cancer/testis antigen that is highly expressed in round spermatids during the meiotic-to-post-meiotic transition (PMID: 41864117) — precisely the developmental window when the flagellum, midpiece, and mitochondrial sheath are assembled. Mechanistically, TSGA10 directly binds cytochrome c1 (CytC1) of mitochondrial Complex III, optimizing electron transport to minimize reactive oxygen species (ROS) and heat while enhancing ATP synthesis (PMID: 40507237). This mitochondrial-coupling role is highly relevant to the sperm midpiece, where the mitochondrial sheath powers motility and where TSGA10 is concentrated. [in vitro / computational]

"TSGA10 interacts with mitochondrial Complex III: it directly binds cytochrome c1 (CytC1). In our model, TSGA10 optimizes electron transport to minimize reactive oxygen species (ROS) and heat production while enhancing Adenosine Triphosphate (ATP) synthesis." — PMID: 40507237

Beyond spermatogenesis, TSGA10 inhibits angiogenesis by preventing nuclear localization of HIF-1α; overexpression decreases HIF-1α transcriptional activity (PMID: 28739310; PMID: 26573430). These pleiotropic roles explain the gene's prominence in cancer biology but are not implicated in the infertility phenotype.

"TSGA10 could also play an important role in the inhibition of angiogenesis by preventing nuclear localization of HIF-1α." — PMID: 28739310

Finding 4 — ASS arises from failure of the head-tail coupling apparatus (HTCA); TSGA10 is one of several HTCA/linkage genes

ASS is a rare, severe teratozoospermia defined by predominantly headless spermatozoa with an abnormal head-tail junction, causing severe male infertility (PMID: 32233213). It is genetically heterogeneous: causative or associated genes include SUN5, PMFBP1, TSGA10, BRDT, SPATC1L, HOOK1, CEP112, DNAH6, CCDC188, NME5, ZMYND15, with SUN5 and PMFBP1 the most established (PMID: 33452591). SUN5, a LINC-complex protein, forms a hexagonal lattice at the nuclear envelope base of the sperm head that maintains the head-tail junction (PMID: 41855266); impairment of the HTCA leads to head-tail detachment (PMID: 42366926). [human clinical / review]

"Impairment of the HTCA leads to a severe type of infertility called acephalic spermatozoa syndrome, where sperm heads become detached from their tails." — PMID: 42366926

"Whole-exome and Sanger sequencing have helped in the identification of variants in SUN5, PMFBP1, BRDT, TSGA10, DNAH6, HOOK1, and CEP112 genes as possible causes of this phenotype in humans." — PMID: 33452591

Finding 5 — TSGA10 is a 65-kDa spermatid protein processed to a 27-kDa fibrous-sheath/midpiece protein containing an ERM domain

Molecular and cell-biological work defines the protein precisely. TSGA10 (human 2q11.2; mouse Tsga10 on chr1 band B) is testis-specifically transcribed and encodes a 65-kDa spermatid protein that is processed to a 27-kDa protein of the fibrous sheath, a major sperm-tail structure (PMID: 14585816). The protein contains a myosin/Ezrin-radixin-moesin (ERM) domain; GFP-tagged TSGA10 forms short thick filaments in fibroblasts, and deletion of the ERM domain abolishes filament formation, establishing it as a cytoskeletal, filament-building protein. [in vitro]

"Mtsga10 encodes a 65-kDa spermatid protein that appears to be processed to a 27-kDa protein of the fibrous sheath, a major sperm tail structure, in mature spermatozoa. Mtsga10 protein contains a putative myosin/Ezrin/radixin/moesin (ERM) domain. Transfection of fibroblasts with GFP-Mtsga10 fusion protein results in formation of short, thick filaments and deletion of the myosin/ERM domain abolished filament formation." — PMID: 14585816

The C-terminal portion accumulates in the midpiece of spermatozoa, where it co-localizes with HIF-1α (PMID: 16777103). Diagnostically, immunofluorescence shows TSGA10 in the midpiece of control sperm and its complete absence in patients (PMID: 38317066).

"the C-terminal part of TSGA10 accumulates in the midpiece of spermatozoa, where it co-localizes with HIF-1alpha." — PMID: 16777103

Finding 6 — The pathogenic variant spectrum is diverse and can combine head detachment with axonemal defects

Reported recessive TSGA10 alleles span multiple variant classes:

Variant (nomenclature)	Type	Zygosity	Protein effect	Notable phenotype	PMID
c.545dupT (p.Ala183Serfs*10), exon 8, NM_001349012.1	Frameshift	Homozygous	Protein abolished	Misarranged mitochondrial sheath; SUN5/PMFBP1 normal	32410354
c.1108-1G>T (p.A370Efs*293), NM_025244 + large deletion	Splice (exon 15 skip) + CNV	Compound het	Truncated protein	Classic ASS	34409526
c.1112T>C (p.Leu371Pro)	Missense	Homozygous	Absent mRNA/protein	Head-flagellum detachment + 98% abnormal axonemes	38317066

The homozygous missense c.1112T>C (p.Leu371Pro) was found in a consanguineous Pakistani family, recessively co-segregating; strikingly, 98% of flagellar cross-sections displayed abnormal axonemal ultrastructure in addition to head-flagellum detachment, with absent TSGA10 mRNA/protein (PMID: 38317066). This expands the phenotype from a pure head-detachment defect to a combined head-detachment-plus-axonemal disorder, consistent with TSGA10's broad role in tail/fibrous-sheath assembly. [human clinical]

"we identified a novel missense variant in TSGA10 (c.1112T > C, p. Leu371Pro), which recessively co-segregated with the acephalic spermatozoa syndrome within this family. Ultrastructural analyses of spermatozoa from the patient revealed that 98% of flagellar cross-sections displayed abnormal axonemal ultrastructure, in addition to the head-flagellum detachment." — PMID: 38317066

Finding 7 — Tsga10 expression is modulated by oxidative/chemical stress and linked to autophagy

In teratospermic patients, TSGA10 mRNA and protein are significantly decreased versus controls (P<0.05), accompanied by reduced expression of sperm-maturation and autophagy genes and significantly higher ROS production (PMID: 34232471). This connects the protein's mitochondrial-coupling/ROS-limiting role (Finding 3) to a broader quality-control axis in spermiogenesis. [human clinical / in vitro]

"the expression levels of TSGA10 mRNA and protein decreased significantly in the teratospermic patients compared to controls (P < 0.05)." — PMID: 34232471

Environmental modulation is seen in rodents: formaldehyde exposure altered sperm profiles and Tsga10 expression, with antioxidant (manganese) partially protective, and Tsga10 is explicitly described as a cytoskeletal protein in the sperm tail that impacts motility (PMID: 26791599). Tsga10 is also expressed during mouse embryogenesis (from 4.5–7.5 dpc) and in adult brain/neural-crest derivatives, consistent with a conserved ciliary role (PMID: 16643851). [model organism]

"Testis-specific gene antigen10 (Tsga10), as a cytoskeletal protein in the sperm tail, impacts the sperm motility." — PMID: 26791599

Finding 8 — TSGA10 is a cancer/testis antigen on 2q11.2 (19 exons) with pleiotropic roles

TSGA10 was originally isolated from normal testis by differential mRNA display; it maps to 2q11.2, comprises 19 exons over ~3 kb, and is predominantly expressed in adult testis but over-expressed in several cancers (hepatocellular, ovarian, prostate, bladder) (PMID: 15107545). It is an anti-angiogenic factor that reduces endothelial tube formation, migration, and proliferation and down-regulates VEGF-A/VEGFR-2 via decreased ERK and AKT phosphorylation (PMID: 32512160). It is also an autoantigen targeted by autoantibodies in ~5% of autoimmune polyendocrine syndrome type 1 (APS1) and some SLE patients (PMID: 21198756). The original testis-specific Tsga10 clone was noted as "not expressed in testes from two infertile patients" (PMID: 14585816) — the first hint of its infertility link. [in vitro / human clinical]

"TSGA10 is located on chromosome 2q11.2 and consists of 19 exons extending over 3 kb… It was predominantly expressed in the testis in adult normal tissues." — PMID: 15107545

Finding 9 — Tsga10-knockout mice are infertile with a disordered mitochondrial sheath, validating causality

The definitive in-vivo proof: CRISPR/Cas9-generated Tsga10-knockout male mice are infertile with significantly reduced sperm motility caused by disordered mitochondrial sheath formation; TSGA10 is testis-specific and highly conserved across species (PMID: 32790169). The knockout also revealed interactions with GRP78 and NSUN2 (linked to peri-implantation lethality and the GnRH network), hinting at additional developmental roles. [model organism]

"TSGA10 is involved in the correct arrangement of mitochondrial sheath in spermatozoa." — PMID: 32790169

"TSGA10 can interact with GRP78 and NSUN2, which are associated with peri-implantation lethality and the gonadotropin-releasing hormone (GnRH) network." — PMID: 32790169

Section-by-Section Disease Characterization

1. Disease Information

Overview: A Mendelian, autosomal-recessive male infertility disorder in which TSGA10 loss produces an ejaculate of predominantly headless spermatozoa with defective head-tail junctions and disorganized mitochondrial sheaths, causing severe teratozoospermia and primary infertility (PMID: 32410354, PMID: 32233213).
Key identifiers: MONDO:0054730; OMIM phenotype #617961 (SPGF26); gene TSGA10 (OMIM 607166, HGNC:30748); concept "Acephalic spermatozoa / Teratozoospermia"; ICD-11 GB04 (male infertility). (MONDO per template; OMIM/HGNC per standard catalogs — verify exact phenotype number in production.)
Synonyms: Spermatogenic failure 26; SPGF26; TSGA10-related acephalic spermatozoa syndrome; decapitated/headless sperm syndrome (TSGA10 subtype); acephalic spermatozoa syndrome associated with TSGA10.
Source type: Knowledge is aggregated from individual patient case reports and small cohorts (WES + TEM) plus mechanistic model-organism and in-vitro studies — not from large EHR-derived datasets.

2. Etiology

Causal factor: Genetic — biallelic (homozygous or compound-heterozygous) loss-of-function variants in TSGA10 (Findings 1, 6). Inheritance is autosomal recessive.
Genetic risk factors: Consanguinity (e.g., the Pakistani family with homozygous p.Leu371Pro, PMID: 38317066); carriership of a TSGA10 LoF allele. No susceptibility/modifier loci are established for the TSGA10 subtype specifically.
Environmental risk factors: None established as causal for this Mendelian disease. Experimentally, formaldehyde and pesticide (diazinon) exposures down-regulate Tsga10 in rodents (PMID: 26791599, PMID: 40567906), and 5-alpha-reductase inhibitors (finasteride/dutasteride) reduce Tsga10 expression among spermatogenesis genes (PMID: 42069234) — relevant to acquired teratozoospermia, not to the inherited syndrome.
Protective factors: Antioxidants (manganese in the formaldehyde model; chrysin against diazinon) partially preserve expression in rodents (PMID: 26791599, PMID: 40567906); not applicable to the germline disease.
Gene-environment interaction: The oxidative-stress/ROS axis (Findings 3, 7) is biologically plausible but not demonstrated to modify penetrance of germline TSGA10 LoF.

3. Phenotypes

Phenotype	Type	HPO suggestion	Onset	Severity	Frequency
Male infertility	Clinical/functional	HP:0003251 Male infertility	Post-pubertal (detected at fertility workup)	Severe	~100%
Acephalic (headless) spermatozoa	Lab/morphology	HP:0012869 Abnormal sperm morphology	Congenital, detected in adulthood	Severe	Predominant in ejaculate
Abnormal sperm head-tail junction	Ultrastructural	HP:0012207 Abnormal spermatogenesis	Congenital	Severe	~100%
Reduced/absent sperm motility (asthenozoospermia)	Lab	HP:0012207	Congenital	Severe	High
Teratozoospermia	Lab	HP:0030086	Congenital	Severe	~100%
Disorganized mitochondrial sheath	Ultrastructural	(midpiece defect)	Congenital	Severe	~100%
Abnormal axonemal ultrastructure (some alleles)	Ultrastructural	HP:0012207	Congenital	Severe (98% cross-sections, p.Leu371Pro)	Allele-dependent

Quality-of-life impact: Confined to reproductive function and the psychosocial burden of infertility; no systemic morbidity, pain, or reduced life expectancy. Daily physical functioning is unaffected.

4. Genetic / Molecular Information

Causal gene: TSGA10, 2q11.2, 19 exons (~3 kb coding footprint), HGNC:30748, OMIM 607166 (PMID: 15107545).
Variant classes (ACMG-relevant): frameshift (c.545dupT, pathogenic), canonical splice (c.1108-1G>T, pathogenic) often with a trans large deletion (structural, pathogenic), and missense with demonstrated LoF (c.1112T>C/p.Leu371Pro, pathogenic given absent transcript and co-segregation) (Finding 6).
Functional consequence: Loss of function — abolished/truncated protein and loss of midpiece TSGA10 immunostaining (Findings 1, 5, 6).
Allele frequency: Reported alleles are rare/private (consistent with recessive disease); population frequencies in gnomAD are expected to be very low, consistent with a highly penetrant recessive trait (no common risk allele described).
Origin: Germline. One documented second hit was a de novo large deletion (PMID: 34409526).
Modifier genes / epigenetics / chromosomal abnormalities: None established specifically for the TSGA10 subtype beyond the large-deletion mechanism noted above.

5. Environmental Information

Not etiologic for the Mendelian disease. Experimental exposures (formaldehyde, diazinon pesticide, 5-alpha-reductase inhibitors) reduce Tsga10 expression and sperm quality in models (PMID: 26791599, PMID: 40567906, PMID: 42069234). No infectious agents implicated.

6. Mechanism / Pathophysiology

Ordered causal chain (initiating lesion → clinical manifestation):

Biallelic LoF variant in TSGA10 (frameshift, splice+deletion, or LoF missense) → leads to loss or truncation of TSGA10 protein (demonstrated: absent sperm staining / absent mRNA) (PMID: 32410354, PMID: 34409526, PMID: 38317066).
Loss of the 27-kDa fibrous-sheath/ERM-domain cytoskeletal protein in round/elongating spermatids (its peak expression window) → results in failure to build normal sperm-tail fibrous-sheath/midpiece cytoskeletal filaments (demonstrated in vitro: ERM-domain deletion abolishes filament formation) (PMID: 14585816, PMID: 41864117).
Branch A — Head-tail coupling: Defective neck/midpiece architecture → leads to an unstable head-tail coupling apparatus (HTCA) → results in detachment of the sperm head from the flagellum → acephalic (headless) spermatozoa (demonstrated by TEM/semen morphology) (PMID: 42366926, PMID: 32410354).
Branch B — Mitochondrial sheath: Loss of TSGA10's midpiece/mitochondrial-coupling function (direct CytC1/Complex-III binding, inferred to operate in sperm) → leads to a misarranged mitochondrial sheath → results in impaired ATP supply/elevated ROS and reduced/absent motility (demonstrated in patients and in the knockout mouse) (PMID: 40507237, PMID: 32790169).
Branch C — Axoneme (allele-dependent): For some alleles (e.g., p.Leu371Pro), additional abnormal axonemal ultrastructure (98% of cross-sections) → compounds motility failure (PMID: 38317066).
Convergence → severe teratozoospermia (headless, immotile sperm) → male infertility (clinical manifestation).

 TSGA10 biallelic LoF
  │
   loss/truncation of 27-kDa fibrous-sheath ERM protein (spermatids)
  │
   ┌──────┴───────────┬────────────────────┬────────────────┐
   ▼                  ▼                     ▼                ▼
 HTCA unstable   mitochondrial         axonemal defect   ROS↑ / ATP↓
   │              sheath disorganized    (some alleles)   (CytC1/CxIII
   ▼                  │                     │              uncoupling)
 head-tail           ▼                     ▼                  │
 detachment      motility loss ◄──────── motility loss ◄──────┘
   └──────────────────┴─────────────────────┘
              ▼
   Acephalic, immotile spermatozoa → severe teratozoospermia → male infertility

Upstream = the mutation and protein loss; downstream = HTCA failure, mitochondrial-sheath disorder, axonemal defect, and clinical infertility.
Molecular pathways / biochemistry: mitochondrial electron transport (Complex III/CytC1), ATP synthesis, ROS homeostasis (PMID: 40507237); cytoskeletal filament assembly via the myosin/ERM domain (PMID: 14585816); autophagy/maturation program linkage (PMID: 34232471).
Cell types & GO/CL suggestions: CL:0000019 spermatozoon, CL:0000018 spermatid (round/elongating). GO:0007283 spermatogenesis, GO:0030317 flagellated sperm motility, GO:0035082 axoneme assembly, GO:0007005 mitochondrion organization. Subcellular (GO CC): GO:0005929 cilium/flagellum, GO:1990385 sperm fibrous sheath (midpiece), GO:0005739 mitochondrion.

7. Anatomical Structures Affected

Organ: Testis (UBERON:0000473); reproductive system (UBERON:0000990). No secondary organ involvement.
Tissue/cell: Seminiferous epithelium (UBERON:0000400); spermatids/spermatozoa (CL:0000018 / CL:0000019).
Subcellular: Sperm midpiece / fibrous sheath, mitochondrial sheath (GO:0005739), head-tail coupling apparatus/neck, flagellar axoneme (GO:0005930).
Localization & lateralization: Bilateral (both testes); the defect manifests at the single-cell (spermatozoon) level.

8. Temporal Development

Onset: Congenital molecular defect, clinically recognized post-pubertally/in adulthood at infertility evaluation. Insidious (asymptomatic until fertility is attempted).
Progression: Stable and non-progressive — a fixed developmental defect of spermatogenesis, not a degenerative process. Lifelong.
Critical period: The vulnerable window is spermiogenesis (round→elongating spermatid stage), when TSGA10 peaks and the midpiece/HTCA/sheath are assembled (PMID: 41864117).

9. Inheritance and Population

Inheritance: Autosomal recessive; biallelic LoF required (Findings 1, 6).
Penetrance/expressivity: Apparently complete penetrance for the infertility phenotype in reported biallelic cases; expressivity varies at the ultrastructural level (pure head-detachment vs. combined axonemal defect, allele-dependent) (PMID: 38317066).
Consanguinity/founder: Consanguinity contributes (homozygous cases in related parents) (PMID: 38317066); no founder allele established.
Epidemiology: ASS overall is rare; the TSGA10 subtype is ultra-rare, with only a handful of families reported worldwide (China, Pakistan, and others). Precise prevalence/incidence are not available. SUN5 and PMFBP1 account for the largest share of ASS; TSGA10 is a minority cause.
Sex: Affects males (phenotype is in spermatozoa); carrier females are asymptomatic.

10. Diagnostics

Semen analysis + morphology: Predominance of headless spermatozoa (acephalic), low motility (PMID: 32233213).
TEM: Misarranged mitochondrial sheath, abnormal head-tail junction/neck, ± axonemal abnormalities (PMID: 32410354, PMID: 38317066).
Immunofluorescence: Absence of TSGA10 in the sperm midpiece (preserved SUN5/PMFBP1 distinguishes it from those subtypes) (PMID: 32410354, PMID: 38317066).
Genetic testing: WES is the primary modality; because a trans large deletion has been reported, pipelines must include CNV/structural-variant detection (read-depth CNV calling, CMA, or MLPA) (PMID: 34409526). Sanger confirmation and segregation analysis support classification. ASS gene panels should include TSGA10 alongside SUN5, PMFBP1, BRDT, HOOK1, CEP112, DNAH6, CCDC188, NME5, ZMYND15 (PMID: 33452591).
Differential diagnosis: Other ASS genotypes (SUN5/PMFBP1 most common); globozoospermia, MMAF (multiple morphological abnormalities of the flagella), and other teratozoospermias — distinguished by morphology, TEM, and gene panel (PMID: 39417902).

11. Outcome / Prognosis

Survival/mortality: Not applicable — no effect on life expectancy or systemic health.
Reproductive prognosis: Favorable with ICSI for TSGA10 carriers — fertilization, early embryo quality, and ICSI outcomes are preserved (PMID: 34089195). Natural conception is essentially impossible.
Prognostic factor: The specific ASS gene matters — TSGA10/PMFBP1 carry good ICSI prognoses, whereas some genes (CCDC188) have been associated with poor ICSI outcomes (PMID: 41004021).

12. Treatment

Definitive fertility treatment: Intracytoplasmic sperm injection (ICSI) — NCIT:C116283 (Intracytoplasmic Sperm Injection); generally successful (Finding 2). No pharmacotherapy corrects the structural defect.
Supportive: Genetic counseling; assisted reproductive technology (IVF-ICSI). Antioxidant strategies are experimental and unproven for the germline disease.
Advanced/experimental: No gene, cell, or RNA therapy exists or is in trials for this indication.

13. Prevention

Primary prevention: Not possible for a congenital recessive disorder; relevant interventions are genetic counseling and carrier/cascade testing in consanguineous families.
Secondary: Early fertility evaluation; preimplantation genetic testing (PGT) can select unaffected embryos during ICSI cycles.
Counseling: Autosomal-recessive recurrence risk (25% affected offspring if both parents carry; all sons of an affected man are obligate carriers).

14. Other Species / Natural Disease

Orthologue: Mouse Tsga10 (chr1 band B); highly conserved and testis-specific (PMID: 14585816, PMID: 32790169).
Natural disease in animals: No naturally occurring veterinary ASS specifically attributed to TSGA10 is documented; the rodent evidence is from engineered/exposure models. A sterility-associated tsga10 signal was noted in hybrid yellow catfish transcriptomics (PMID: 38891632).
Conservation: The protein is conserved wherever a ciliary structure exists (PMID: 16643851).

15. Model Organisms

Definitive model: CRISPR/Cas9 Tsga10-knockout mouse — infertile males, reduced motility, disordered mitochondrial sheath; recapitulates the core human mechanism (PMID: 32790169).
Induced/exposure models: Formaldehyde- and diazinon-exposed rodents (expression down-regulation) (PMID: 26791599, PMID: 40567906).
In vitro: Fibroblast GFP-TSGA10 filament-formation assay (ERM-domain dependence) (PMID: 14585816); HUVEC overexpression (angiogenesis) (PMID: 32512160).
Recapitulation/limitations: The knockout captures mitochondrial-sheath/motility pathology well; the human head-detachment phenotype and allele-specific axonemal defects are less completely modeled, and the knockout's GRP78/NSUN2 interactions suggest developmental roles beyond infertility (PMID: 32790169).

Mechanistic Model / Interpretation

The coherent narrative is that TSGA10 is a stage-specific spermatid cytoskeletal and mitochondrial-coupling protein whose loss destabilizes two tightly linked midpiece structures — the head-tail coupling apparatus and the mitochondrial sheath. Its 27-kDa processed form is a fibrous-sheath component built via a myosin/ERM domain required for filament assembly; its C-terminus concentrates in the midpiece where it physically couples to Complex III (cytochrome c1). When both alleles are inactivated, spermatids cannot assemble a competent neck/midpiece: the head-tail junction fails (yielding headless sperm) and the mitochondrial sheath is disorganized (yielding immotility and a ROS/ATP imbalance). Some missense alleles additionally disrupt the axoneme. Because the defect is structural rather than genomic, the sperm nucleus remains competent — which is precisely why ICSI works. The Tsga10-knockout mouse closes the causal loop by reproducing the mitochondrial-sheath disorder and infertility in vivo.

The key distinction from the most common ASS genes (SUN5, PMFBP1) is mechanistic: SUN5/PMFBP1 are LINC/linkage proteins at the implantation-fossa/nuclear-envelope interface, whereas TSGA10 acts more on the fibrous sheath/mitochondrial-sheath/midpiece axis — demonstrated by preserved SUN5/PMFBP1 expression in a TSGA10-null patient. This positions TSGA10 as a distinct molecular subtype within the HTCA-failure disease family.

Evidence Base

PMID	Role	Contribution
32410354	Supports	Homozygous frameshift; abolished protein; mitochondrial-sheath defect; SUN5/PMFBP1 intact
34409526	Supports	Compound-het splice + de novo large deletion (CNV mechanism)
38317066	Supports/extends	Homozygous missense p.Leu371Pro; head-detachment + 98% axonemal defects; absent protein
34089195	Supports	Favorable ICSI prognosis for TSGA10/PMFBP1
40507237	Mechanism	TSGA10–CytC1/Complex III coupling; ROS/ATP regulation
14585816	Mechanism	65→27 kDa processing; ERM domain; filament formation; infertility link
16777103	Localization	Midpiece accumulation; HIF-1α co-localization
32790169	Causality	Knockout mouse: infertility + disordered mitochondrial sheath
42366926	Framework	HTCA failure → head-tail detachment
33452591 / 32233213	Framework	ASS definition and gene heterogeneity
15107545	Gene facts	2q11.2, 19 exons, testis-predominant expression
34232471	Supports	Reduced TSGA10 in teratospermia; autophagy/ROS link
26791599	Context	Environmental modulation; sperm-tail cytoskeletal/motility role
41864117	Expression	Round-spermatid, meiotic→post-meiotic expression
41004021	Contrast	CCDC188 poor ICSI outcome (prognostic genotype distinction)

Limitations and Knowledge Gaps

Small evidence base: Only a handful of TSGA10-specific families are reported; prevalence/incidence and allele-frequency data are unavailable, and penetrance estimates rest on few cases.
Mechanistic inference: The mitochondrial Complex-III/CytC1 coupling and HIF-1α roles are demonstrated biochemically/in model systems, but their quantitative contribution to the human head-detachment phenotype (vs. a purely structural fibrous-sheath role) is inferred, not directly dissected in patient sperm.
Genotype-phenotype correlation: Why some alleles (p.Leu371Pro) add prominent axonemal defects while others present as "pure" head detachment is unexplained.
CNV under-ascertainment: Standard WES pipelines may miss large deletions (as in the de novo deletion case), so the true variant spectrum may be broader than reported.
ICSI long-term data: Favorable early outcomes are documented, but long-term offspring health and live-birth rates across larger TSGA10 cohorts are limited.
Model gaps: The knockout mouse emphasizes mitochondrial-sheath/motility pathology; it less completely models the human head-detachment and allele-specific axonemal phenotypes.

Proposed Follow-up Experiments / Actions

Systematically add CNV/SV calling (read-depth, CMA, or MLPA for TSGA10) to every ASS diagnostic workflow to capture deletion alleles in trans.
Genotype-stratified ICSI registry for ASS genes to confirm the favorable TSGA10 prognosis at scale and compare with poor-prognosis genes (CCDC188).
Structure-function dissection of patient missense alleles (e.g., p.Leu371Pro) via knock-in mice or spermatid organoids to separate the fibrous-sheath (ERM) role from Complex-III coupling.
Quantitative mitochondrial phenotyping (ROS, membrane potential, ATP) in patient and knockout sperm to test whether the CytC1-coupling defect is a primary driver of immotility or a secondary consequence of sheath disorganization.
Proteomic interactome mapping of TSGA10 in spermatids (confirm CytC1, GRP78, NSUN2; search for HTCA partners) to place it precisely within the SUN5/PMFBP1 linkage network.
Carrier-screening and counseling guidance for consanguineous populations with TSGA10 founder-like alleles, incorporating PGT options.

Evidence source types: human clinical case/cohort (PMIDs 32410354, 34409526, 38317066, 34089195, 33452591, 32233213); model organism (32790169, 26791599, 16643851); in vitro/biochemical (14585816, 40507237, 16777103, 32512160); gene/genomic characterization (15107545, 28739310).

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome	Count
References checked	26
Resolved	26
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	26
On topic	18
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	20
Resolved	19
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	1
Terms whose name was checked	7
Terms named correctly	0
Terms named as a different term	5
Terms whose name is worth a second look	2

Terms the report names something else

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

HP:0012207 (3 mentions) - the report calls it "Lab", "Ultrastructural"; HP calls it Reduced sperm motility
HP:0030086 (1 mention) - the report calls it "Lab"; HP calls it Reduced CSF lactate
GO:0005739 (2 mentions) - the report calls it "mitochondrial sheath", "Subcellular: Sperm midpiece / fibrous sheath, mitochondrial sheath"; GO calls it mitochondrion
UBERON:0000400 (1 mention) - the report calls it "Tissue/cell: Seminiferous epithelium"; UBERON calls it jejunal epithelium**
NCIT:C116283 (1 mention) - the report calls it "Intracytoplasmic Sperm Injection"; NCIT calls it Worst Severity Past Seven Days Aching Joints Question

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:

UBERON:0000473 (1 mention) - the report calls it "Organ: Testis"; UBERON calls it testis**
GO:0005930 (1 mention) - the report calls it "flagellar axoneme"; GO calls it axoneme, and lists "flagellar axoneme" among its other names

Terms named inconsistently

The report gives these identifiers more than one name of its own:

HP:0012207 - called "Lab", "Ultrastructural"
GO:0005739 - called "mitochondrial sheath", "Subcellular: Sperm midpiece / fibrous sheath, mitochondrial sheath"

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Inheritance

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Diagnosis

Animal Models

Source YAML

References & Deep Research

Deep Research

Key Findings

Finding 1 — Biallelic loss-of-function TSGA10 variants cause acephalic spermatozoa syndrome (SPGF26)

Finding 2 — ICSI yields favorable pregnancy outcomes in TSGA10-related ASS

Finding 3 — TSGA10 is a spermatid-expressed protein with mitochondrial Complex III coupling and HIF-1α regulatory roles

Finding 4 — ASS arises from failure of the head-tail coupling apparatus (HTCA); TSGA10 is one of several HTCA/linkage genes

Finding 5 — TSGA10 is a 65-kDa spermatid protein processed to a 27-kDa fibrous-sheath/midpiece protein containing an ERM domain

Finding 6 — The pathogenic variant spectrum is diverse and can combine head detachment with axonemal defects

Finding 7 — Tsga10 expression is modulated by oxidative/chemical stress and linked to autophagy

Finding 8 — TSGA10 is a cancer/testis antigen on 2q11.2 (19 exons) with pleiotropic roles

Finding 9 — Tsga10-knockout mice are infertile with a disordered mitochondrial sheath, validating causality

Section-by-Section Disease Characterization

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic / Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome / Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Mechanistic Model / Interpretation

Evidence Base

Limitations and Knowledge Gaps

Proposed Follow-up Experiments / Actions

Artifacts

Reference Validation

Term Validation

Terms the report names something else

Terms whose name is worth a second look

Terms named inconsistently