Spermatogenic Failure X-linked 5

Mendelian MONDO:0859477 Pathograph 10 Show in embeddings browser Spermatogenic Failure Genetic Disease

Spermatogenic failure X-linked 5 (SPGFX5) is X-linked male infertility with asthenoteratozoospermia (reduced sperm motility and abnormal sperm morphology) caused by hemizygous deleterious variants in SSX1. SSX1 is a primate-specific gene expressed predominantly in the testis; the SSX family expanded independently in rodents and primates, so the mouse cannot model it. Variants were found by exome sequencing in six unrelated men with asthenoteratozoospermia, and knockdown of Ssx1 in the testes of cynomolgus monkeys and tree shrews reproduced reduced sperm motility and abnormal sperm morphology. Testicular RNA sequencing after knockdown showed that many spermatogenic processes were affected, but the step through which SSX1 loss produces the sperm defect is not known. Three of five couples treated with intracytoplasmic sperm injection (ICSI) achieved a pregnancy. A hemizygous SSX1 splice donor variant has since been reported in a man with oligoasthenoteratozoospermia.

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🏷

Classifications

Harrison's Part
ENDOCRINOLOGY METABOLISM GENETICS ENVIRONMENT DISEASE
👪

Inheritance

1
X-linked recessive HP:0001419
SSX1 lies on the X chromosome and affected men carry hemizygous variants. Daughters of affected men conceived by ICSI would be obligate carriers.
X-linked recessive inheritance
Show evidence (2 references)
PMID:36796361 SUPPORT Human clinical
"we identified deleterious variants of X-linked SSX1 in six unrelated men with asthenoteratozoospermia"
Variants in the X-linked SSX1 gene in six unrelated affected men.
PMID:42467186 SUPPORT Human clinical
"We identified a hemizygous splice donor variant (c.*4 + 1G > T) in SSX1"
A further affected man is hemizygous for an SSX1 variant.
⚙

Pathophysiology

2
Hemizygous Loss of SSX1 Function
Affected men carry deleterious hemizygous SSX1 variants. Knocking down Ssx1 in the testis of two non-rodent species reproduces the human phenotype, so the variants are taken to act by loss of function.
SSX1 hgnc:11335 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves SSX1 (hgnc:11335). hgnc:11335 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context variant_origin: GERMLINE zygosity: HEMIZYGOUS functional_impact_category: LOSS_OF_FUNCTION
testis UBERON:0000473 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in testis (UBERON:0000473). UBERON:0000473 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Disrupted Spermatogenic Program
Show evidence (1 reference)
PMID:36796361 SUPPORT Human clinical
"SSX1 is a PSG expressed predominantly in the testis, and the SSX family evolutionarily expanded independently in rodents and primates."
SSX1 is a testis-enriched gene, consistent with a phenotype confined to sperm.
Disrupted Spermatogenic Program
Testicular RNA sequencing after Ssx1 knockdown showed that many biological processes during spermatogenesis were affected. Which of them produces the sperm motility and morphology defects has not been shown.
spermatogenesis GO:0007283 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal spermatogenesis (GO:0007283). GO:0007283 is a biological process from the Gene Ontology.
testis UBERON:0000473 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in testis (UBERON:0000473). UBERON:0000473 is an anatomical location from the Uberon multi-species anatomy ontology.
Animal models
Cynomolgus monkey testicular Ssx1 knockdown Cynomolgus macaque (Macaca fascicularis) recapitulates Testicular knockdown in a primate reproduces the human asthenoteratozoospermia.
Tree shrew testicular Ssx1 knockdown Tree shrew (Tupaia belangeri) recapitulates Testicular knockdown in a primate-like mammal reproduces the human asthenoteratozoospermia.
Downstream
Reduced sperm motility Shown by the knockdown models, but the intermediate steps between the transcriptional change and the motility defect were not identified.
Abnormal sperm morphology Shown by the knockdown models, but the intermediate steps between the transcriptional change and the morphology defect were not identified.
Show evidence (1 reference)
PMID:36796361 SUPPORT Model organism
"RNA sequencing indicated that Ssx1 deficiency influenced multiple biological processes during spermatogenesis"
Transcriptional evidence that Ssx1 loss disturbs spermatogenesis.
⬡

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.
Pathograph: causal mechanism network for Spermatogenic Failure X-linked 5 Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

4
Male infertility Reproductive HP:0003251 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Male infertility (HP:0003251). HP:0003251 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36796361 SUPPORT Human clinical
"Notably, three of the five couples who underwent intra-cytoplasmic sperm injection treatment achieved a successful pregnancy."
Affected men required assisted reproduction to father children.
Reduced sperm motility Reproductive HP:0012207 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Asthenozoospermia, annotated with Reduced sperm motility (HP:0012207). HP:0012207 is a phenotype from the Human Phenotype Ontology.
Sequelae: Male infertility
Show evidence (2 references)
PMID:36796361 SUPPORT Human clinical
"we identified deleterious variants of X-linked SSX1 in six unrelated men with asthenoteratozoospermia"
Asthenoteratozoospermia includes reduced sperm motility.
PMID:36796361 SUPPORT Model organism
"Consistent with the phenotype observed in humans, both Ssx1-KD models exhibited a reduced sperm motility and abnormal sperm morphology."
The knockdown models reproduce reduced motility.
Abnormal sperm morphology Reproductive HP:0012864 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Teratozoospermia, annotated with Abnormal sperm morphology (HP:0012864). HP:0012864 is a phenotype from the Human Phenotype Ontology.
Sequelae: Male infertility
Show evidence (2 references)
PMID:36796361 SUPPORT Human clinical
"we identified deleterious variants of X-linked SSX1 in six unrelated men with asthenoteratozoospermia"
Asthenoteratozoospermia includes abnormal sperm morphology.
PMID:36796361 SUPPORT Model organism
"Consistent with the phenotype observed in humans, both Ssx1-KD models exhibited a reduced sperm motility and abnormal sperm morphology."
The knockdown models reproduce abnormal morphology.
Oligozoospermia OCCASIONAL Reproductive HP:0000798 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Oligozoospermia (HP:0000798). HP:0000798 is a phenotype from the Human Phenotype Ontology.
Sequelae: Male infertility
Show evidence (1 reference)
PMID:42467186 SUPPORT Human clinical
"We identified a hemizygous splice donor variant (c.*4 + 1G > T) in SSX1 and a missense variant (c.1190 A > G) in CPNE1 in one patient with OAT."
One man with oligoasthenoteratozoospermia carried an SSX1 variant, alongside a CPNE1 variant.
🧬

Genetic Associations

1
SSX1 (Causal)
Gene: SSX1 hgnc:11335 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is SSX1 (hgnc:11335). hgnc:11335 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (2 references)
PMID:36796361 SUPPORT Human clinical
"Here, using whole-exome sequencing, we identified deleterious variants of X-linked SSX1 in six unrelated men with asthenoteratozoospermia."
Gene-disease report identifying SSX1 variants in affected men.
PMID:42467186 SUPPORT Human clinical
"We identified a hemizygous splice donor variant (c.*4 + 1G > T) in SSX1"
An additional hemizygous SSX1 variant in an infertile man.
💊

Medical Actions

2
Intracytoplasmic Sperm Injection
Category: Therapeutic Action: intracytoplasmic sperm injectionNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is intracytoplasmic sperm injection (NCIT:C185482). NCIT:C185482 is a clinical intervention from the NCI Thesaurus. Ontology label: Intracytoplasmic Sperm Injection NCIT:C185482
Platform: Other
ICSI bypasses the need for motile, normally shaped sperm. Three of five couples treated with ICSI achieved a pregnancy.
Mechanism Target:
BYPASSES Reduced sperm motility — Direct injection of a sperm into the oocyte removes the need for sperm motility.
Show evidence (1 reference)
PMID:36796361 SUPPORT Human clinical
"Notably, three of the five couples who underwent intra-cytoplasmic sperm injection treatment achieved a successful pregnancy."
ICSI outcomes in affected couples.
Genetic Counseling
Category: Counseling / Informational Action: genetic counselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is genetic counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. Ontology label: Genetic Counseling NCIT:C15240
Platform: Other
Counseling covers X-linked transmission. As for any X-linked recessive condition, daughters conceived by ICSI would be carriers and each of their sons would have a 50% chance of inheriting the variant. This follows from the inheritance pattern rather than from an observed SSX1 pedigree.
Show evidence (1 reference)
PMID:36796361 SUPPORT Human clinical
"This study provides important guidance for genetic counseling and clinical diagnosis"
The authors frame the finding as informing genetic counseling.
🔬

Diagnosis

2
Whole-exome sequencing (Positive)
The SSX1 variants were found by exome sequencing of men with asthenoteratozoospermia, after semen analysis established the phenotype.
whole-exome sequencing NCIT:C101295 NCI Thesaurus (NCIT)
Results: Identification of hemizygous deleterious variants in X-linked SSX1.
Show evidence (1 reference)
PMID:36796361 SUPPORT Human clinical
"Here, using whole-exome sequencing, we identified deleterious variants of X-linked SSX1 in six unrelated men with asthenoteratozoospermia."
Exome sequencing identified the causal variants.
Whole-genome sequencing (Positive)
A further SSX1 splice variant was found by whole-genome sequencing of men with normal karyotypes and no Y-chromosome microdeletions.
whole-genome sequencing NCIT:C101294 NCI Thesaurus (NCIT)
Results: Identification of a hemizygous splice donor variant (c.*4+1G>T) in SSX1.
Show evidence (1 reference)
PMID:42467186 SUPPORT Human clinical
"Whole-genome sequencing (WGS) was performed in 17 infertile men with normal karyotypes and no Y-chromosome microdeletions"
Genome sequencing after exclusion of chromosomal causes.
🐁

Animal Models

2
Cynomolgus monkey testicular Ssx1 knockdown
Ssx1 expression was knocked down in the testes of cynomolgus monkeys, because the rodent SSX family expanded independently and mice cannot model SSX1. The knocked-down animals had reduced sperm motility and abnormal sperm morphology.
Species
Cynomolgus macaque (Macaca fascicularis)
Genotype
Ssx1 knockdown in the testis
Publication
PMID:36796361
Pathograph links
Disrupted Spermatogenic Program recapitulates fidelity: moderate observes: organism Testicular knockdown in a primate reproduces the human asthenoteratozoospermia.
Limitations: Knockdown lowers rather than removes Ssx1 and is induced in the adult testis, so it does not reproduce a germline hemizygous allele present throughout development.
Readouts
Sperm motility
Reduced sperm motility HP:0012207 Human Phenotype Ontology (HP) Relation: this readout measures this phenotype This readout measures Reduced sperm motility (HP:0012207). HP:0012207 is a phenotype from the Human Phenotype Ontology.
Direction: DECREASED
Interpretation: Downstream readout of the disrupted spermatogenic program in cynomolgus monkeys.
Show evidence (1 reference)
PMID:36796361 SUPPORT Model organism
"Consistent with the phenotype observed in humans, both Ssx1-KD models exhibited a reduced sperm motility and abnormal sperm morphology."
Knockdown lowers sperm motility.
Sperm morphology
Abnormal sperm morphology HP:0012864 Human Phenotype Ontology (HP) Relation: this readout measures this phenotype This readout measures Abnormal sperm morphology (HP:0012864). HP:0012864 is a phenotype from the Human Phenotype Ontology.
Direction: ALTERED
Interpretation: Downstream readout of the disrupted spermatogenic program in cynomolgus monkeys.
Show evidence (1 reference)
PMID:36796361 SUPPORT Model organism
"Consistent with the phenotype observed in humans, both Ssx1-KD models exhibited a reduced sperm motility and abnormal sperm morphology."
Knockdown produces abnormal sperm morphology.
Show evidence (1 reference)
PMID:36796361 SUPPORT Model organism
"RNA sequencing indicated that Ssx1 deficiency influenced multiple biological processes during spermatogenesis"
Testicular RNA sequencing after knockdown shows the spermatogenic program is disturbed.
Show evidence (1 reference)
PMID:36796361 SUPPORT Model organism
"As the mouse model could not be used for studying SSX1, we used a non-human primate model and tree shrews, which are phylogenetically similar to primates, to knock down (KD) Ssx1 expression in the testes."
Describes the knockdown models and why mice were not used.
Tree shrew testicular Ssx1 knockdown
Ssx1 expression was knocked down in the testes of tree shrews, which are phylogenetically close to primates. The animals had reduced sperm motility and abnormal sperm morphology.
Species
Tree shrew (Tupaia belangeri)
Genotype
Ssx1 knockdown in the testis
Publication
PMID:36796361
Pathograph links
Disrupted Spermatogenic Program recapitulates fidelity: moderate observes: organism Testicular knockdown in a primate-like mammal reproduces the human asthenoteratozoospermia.
Limitations: Knockdown lowers rather than removes Ssx1 and is induced in the adult testis, so it does not reproduce a germline hemizygous allele present throughout development.
Readouts
Sperm motility
Reduced sperm motility HP:0012207 Human Phenotype Ontology (HP) Relation: this readout measures this phenotype This readout measures Reduced sperm motility (HP:0012207). HP:0012207 is a phenotype from the Human Phenotype Ontology.
Direction: DECREASED
Interpretation: Downstream readout of the disrupted spermatogenic program in tree shrews.
Show evidence (1 reference)
PMID:36796361 SUPPORT Model organism
"Consistent with the phenotype observed in humans, both Ssx1-KD models exhibited a reduced sperm motility and abnormal sperm morphology."
Knockdown lowers sperm motility.
Sperm morphology
Abnormal sperm morphology HP:0012864 Human Phenotype Ontology (HP) Relation: this readout measures this phenotype This readout measures Abnormal sperm morphology (HP:0012864). HP:0012864 is a phenotype from the Human Phenotype Ontology.
Direction: ALTERED
Interpretation: Downstream readout of the disrupted spermatogenic program in tree shrews.
Show evidence (1 reference)
PMID:36796361 SUPPORT Model organism
"Consistent with the phenotype observed in humans, both Ssx1-KD models exhibited a reduced sperm motility and abnormal sperm morphology."
Knockdown produces abnormal sperm morphology.
Show evidence (1 reference)
PMID:36796361 SUPPORT Model organism
"RNA sequencing indicated that Ssx1 deficiency influenced multiple biological processes during spermatogenesis"
Testicular RNA sequencing after knockdown shows the spermatogenic program is disturbed.
{ }

Source YAML

click to show 
name: Spermatogenic Failure X-linked 5
creation_date: '2026-10-23T13:00:00Z'
category: Mendelian
synonyms:
- SPGFX5
- spermatogenic failure, X-linked, 5
- SSX1-related asthenoteratozoospermia
description: Spermatogenic failure X-linked 5 (SPGFX5) is X-linked male infertility with asthenoteratozoospermia
  (reduced sperm motility and abnormal sperm morphology) caused by hemizygous deleterious variants in
  SSX1. SSX1 is a primate-specific gene expressed predominantly in the testis; the SSX family expanded
  independently in rodents and primates, so the mouse cannot model it. Variants were found by exome sequencing
  in six unrelated men with asthenoteratozoospermia, and knockdown of Ssx1 in the testes of cynomolgus
  monkeys and tree shrews reproduced reduced sperm motility and abnormal sperm morphology. Testicular
  RNA sequencing after knockdown showed that many spermatogenic processes were affected, but the step
  through which SSX1 loss produces the sperm defect is not known. Three of five couples treated with intracytoplasmic
  sperm injection (ICSI) achieved a pregnancy. A hemizygous SSX1 splice donor variant has since been reported
  in a man with oligoasthenoteratozoospermia.
disease_term:
  preferred_term: spermatogenic failure, X-linked, 5
  term:
    id: MONDO:0859477
    label: spermatogenic failure, X-linked, 5
parents:
- Spermatogenic Failure
- Genetic Disease
classifications:
  harrisons_chapter:
  - classification_value: ENDOCRINOLOGY_METABOLISM
    notes: Harrison's places disorders of the testes and male reproductive system, including male infertility,
      in its endocrinology and metabolism part.
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    evidence:
    - reference: PMID:36796361
      reference_title: Deficiency of primate-specific SSX1 induced asthenoteratozoospermia in infertile
        men and cynomolgus monkey and tree shrew models.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Here, using whole-exome sequencing, we identified deleterious variants of X-linked SSX1
        in six unrelated men with asthenoteratozoospermia.
      explanation: Supports classification as an X-linked Mendelian genetic disorder.
notes: The gene-disease link rests on one report of six men and two primate-like knockdown models (PMID:36796361),
  plus one further candidate variant from a whole-genome sequencing series (PMID:42467186). Both are cached
  as abstract only, so the individual variants, semen parameters and sperm ultrastructure of the six men
  are not recorded here. SSX1 is not classified by ClinGen (no row in cache/clingen/gene_validity.csv),
  so no gene-disease validity tier is recorded. SSX1 is better known as the fusion partner of SS18 in
  synovial sarcoma (Synovial_Sarcoma), a somatic event unrelated to this disorder.
inheritance:
- name: X-linked recessive
  description: SSX1 lies on the X chromosome and affected men carry hemizygous variants. Daughters of
    affected men conceived by ICSI would be obligate carriers.
  inheritance_term:
    preferred_term: X-linked recessive inheritance
    term:
      id: HP:0001419
      label: X-linked recessive inheritance
  evidence:
  - reference: PMID:36796361
    reference_title: Deficiency of primate-specific SSX1 induced asthenoteratozoospermia in infertile
      men and cynomolgus monkey and tree shrew models.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: we identified deleterious variants of X-linked SSX1 in six unrelated men with asthenoteratozoospermia
    explanation: Variants in the X-linked SSX1 gene in six unrelated affected men.
  - reference: PMID:42467186
    reference_title: Identification of novel variants in SSX1, CPNE1, and SPTBN5 in men with oligoasthenoteratozoospermia
      using whole-genome sequencing.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We identified a hemizygous splice donor variant (c.*4 + 1G > T) in SSX1
    explanation: A further affected man is hemizygous for an SSX1 variant.
pathophysiology:
- name: Hemizygous Loss of SSX1 Function
  description: Affected men carry deleterious hemizygous SSX1 variants. Knocking down Ssx1 in the testis
    of two non-rodent species reproduces the human phenotype, so the variants are taken to act by loss
    of function.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: SSX1
    term:
      id: hgnc:11335
      label: SSX1
  locations:
  - preferred_term: testis
    term:
      id: UBERON:0000473
      label: testis
  genetic_context:
    variant_origin: GERMLINE
    zygosity: HEMIZYGOUS
    functional_impact_category: LOSS_OF_FUNCTION
  downstream:
  - target: Disrupted Spermatogenic Program
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:36796361
      reference_title: Deficiency of primate-specific SSX1 induced asthenoteratozoospermia in infertile
        men and cynomolgus monkey and tree shrew models.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: RNA sequencing indicated that Ssx1 deficiency influenced multiple biological processes
        during spermatogenesis
      explanation: Knockdown of Ssx1 alters testicular transcription across many spermatogenic processes.
  evidence:
  - reference: PMID:36796361
    reference_title: Deficiency of primate-specific SSX1 induced asthenoteratozoospermia in infertile
      men and cynomolgus monkey and tree shrew models.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: SSX1 is a PSG expressed predominantly in the testis, and the SSX family evolutionarily expanded
      independently in rodents and primates.
    explanation: SSX1 is a testis-enriched gene, consistent with a phenotype confined to sperm.
- name: Disrupted Spermatogenic Program
  description: Testicular RNA sequencing after Ssx1 knockdown showed that many biological processes during
    spermatogenesis were affected. Which of them produces the sperm motility and morphology defects has
    not been shown.
  biological_scale: CELLULAR
  locations:
  - preferred_term: testis
    term:
      id: UBERON:0000473
      label: testis
  biological_processes:
  - preferred_term: spermatogenesis
    modifier: ABNORMAL
    term:
      id: GO:0007283
      label: spermatogenesis
  downstream:
  - target: Reduced sperm motility
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Shown by the knockdown models, but the intermediate steps between the transcriptional
      change and the motility defect were not identified.
    evidence:
    - reference: PMID:36796361
      reference_title: Deficiency of primate-specific SSX1 induced asthenoteratozoospermia in infertile
        men and cynomolgus monkey and tree shrew models.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: Consistent with the phenotype observed in humans, both Ssx1-KD models exhibited a reduced
        sperm motility and abnormal sperm morphology.
      explanation: Knockdown of Ssx1 lowers sperm motility.
  - target: Abnormal sperm morphology
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Shown by the knockdown models, but the intermediate steps between the transcriptional
      change and the morphology defect were not identified.
    evidence:
    - reference: PMID:36796361
      reference_title: Deficiency of primate-specific SSX1 induced asthenoteratozoospermia in infertile
        men and cynomolgus monkey and tree shrew models.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: Consistent with the phenotype observed in humans, both Ssx1-KD models exhibited a reduced
        sperm motility and abnormal sperm morphology.
      explanation: Knockdown of Ssx1 produces abnormal sperm morphology.
  evidence:
  - reference: PMID:36796361
    reference_title: Deficiency of primate-specific SSX1 induced asthenoteratozoospermia in infertile
      men and cynomolgus monkey and tree shrew models.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: RNA sequencing indicated that Ssx1 deficiency influenced multiple biological processes during
      spermatogenesis
    explanation: Transcriptional evidence that Ssx1 loss disturbs spermatogenesis.
phenotypes:
- category: Reproductive
  name: Male infertility
  description: Affected men present with primary infertility.
  phenotype_term:
    preferred_term: Male infertility
    term:
      id: HP:0003251
      label: Male infertility
  evidence:
  - reference: PMID:36796361
    reference_title: Deficiency of primate-specific SSX1 induced asthenoteratozoospermia in infertile
      men and cynomolgus monkey and tree shrew models.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Notably, three of the five couples who underwent intra-cytoplasmic sperm injection treatment
      achieved a successful pregnancy.
    explanation: Affected men required assisted reproduction to father children.
- category: Reproductive
  name: Reduced sperm motility
  description: Asthenozoospermia, part of the asthenoteratozoospermia in all six reported men.
  phenotype_term:
    preferred_term: Asthenozoospermia
    term:
      id: HP:0012207
      label: Reduced sperm motility
  sequelae:
  - target: Male infertility
  evidence:
  - reference: PMID:36796361
    reference_title: Deficiency of primate-specific SSX1 induced asthenoteratozoospermia in infertile
      men and cynomolgus monkey and tree shrew models.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: we identified deleterious variants of X-linked SSX1 in six unrelated men with asthenoteratozoospermia
    explanation: Asthenoteratozoospermia includes reduced sperm motility.
  - reference: PMID:36796361
    reference_title: Deficiency of primate-specific SSX1 induced asthenoteratozoospermia in infertile
      men and cynomolgus monkey and tree shrew models.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Consistent with the phenotype observed in humans, both Ssx1-KD models exhibited a reduced
      sperm motility and abnormal sperm morphology.
    explanation: The knockdown models reproduce reduced motility.
- category: Reproductive
  name: Abnormal sperm morphology
  description: Teratozoospermia, part of the asthenoteratozoospermia in all six reported men. The abstracts
    do not say which parts of the sperm are malformed, so the binding is the general sperm morphology
    term.
  phenotype_term:
    preferred_term: Teratozoospermia
    term:
      id: HP:0012864
      label: Abnormal sperm morphology
  sequelae:
  - target: Male infertility
  evidence:
  - reference: PMID:36796361
    reference_title: Deficiency of primate-specific SSX1 induced asthenoteratozoospermia in infertile
      men and cynomolgus monkey and tree shrew models.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: we identified deleterious variants of X-linked SSX1 in six unrelated men with asthenoteratozoospermia
    explanation: Asthenoteratozoospermia includes abnormal sperm morphology.
  - reference: PMID:36796361
    reference_title: Deficiency of primate-specific SSX1 induced asthenoteratozoospermia in infertile
      men and cynomolgus monkey and tree shrew models.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Consistent with the phenotype observed in humans, both Ssx1-KD models exhibited a reduced
      sperm motility and abnormal sperm morphology.
    explanation: The knockdown models reproduce abnormal morphology.
- category: Reproductive
  name: Oligozoospermia
  description: Reported in the one man with an SSX1 splice donor variant from a whole-genome sequencing
    series, who had oligoasthenoteratozoospermia. That man also carried a CPNE1 missense variant, so the
    low sperm count is not securely attributed to SSX1.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Oligozoospermia
    term:
      id: HP:0000798
      label: Oligozoospermia
  sequelae:
  - target: Male infertility
  evidence:
  - reference: PMID:42467186
    reference_title: Identification of novel variants in SSX1, CPNE1, and SPTBN5 in men with oligoasthenoteratozoospermia
      using whole-genome sequencing.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We identified a hemizygous splice donor variant (c.*4 + 1G > T) in SSX1 and a missense variant
      (c.1190 A > G) in CPNE1 in one patient with OAT.
    explanation: One man with oligoasthenoteratozoospermia carried an SSX1 variant, alongside a CPNE1
      variant.
genetic:
- name: SSX1
  association: Causal
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  gene_term:
    preferred_term: SSX1
    term:
      id: hgnc:11335
      label: SSX1
  features: Hemizygous deleterious variants in X-linked SSX1 in six unrelated men with asthenoteratozoospermia;
    a hemizygous splice donor variant (c.*4+1G>T) in SSX1 was also reported alongside a CPNE1 missense
    variant (c.1190A>G) in one patient with oligoasthenoteratozoospermia, so attribution of the oligozoospermia
    component to SSX1 is not established.
  notes: The individual alleles of the six men in PMID:36796361 are given only in the full text, which is
    not cached. Not classified by ClinGen.
  evidence:
  - reference: PMID:36796361
    reference_title: Deficiency of primate-specific SSX1 induced asthenoteratozoospermia in infertile
      men and cynomolgus monkey and tree shrew models.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Here, using whole-exome sequencing, we identified deleterious variants of X-linked SSX1 in
      six unrelated men with asthenoteratozoospermia.
    explanation: Gene-disease report identifying SSX1 variants in affected men.
  - reference: PMID:42467186
    reference_title: Identification of novel variants in SSX1, CPNE1, and SPTBN5 in men with oligoasthenoteratozoospermia
      using whole-genome sequencing.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We identified a hemizygous splice donor variant (c.*4 + 1G > T) in SSX1
    explanation: An additional hemizygous SSX1 variant in an infertile man.
animal_models:
- name: Cynomolgus monkey testicular Ssx1 knockdown
  species: Cynomolgus macaque (Macaca fascicularis)
  genotype: Ssx1 knockdown in the testis
  publication: PMID:36796361
  description: Ssx1 expression was knocked down in the testes of cynomolgus monkeys, because the rodent
    SSX family expanded independently and mice cannot model SSX1. The knocked-down animals had reduced
    sperm motility and abnormal sperm morphology.
  modeled_mechanisms:
  - target: Disrupted Spermatogenic Program
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: Testicular knockdown in a primate reproduces the human asthenoteratozoospermia.
    limitations: Knockdown lowers rather than removes Ssx1 and is induced in the adult testis, so it does
      not reproduce a germline hemizygous allele present throughout development.
    evidence:
    - reference: PMID:36796361
      reference_title: Deficiency of primate-specific SSX1 induced asthenoteratozoospermia in infertile
        men and cynomolgus monkey and tree shrew models.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: RNA sequencing indicated that Ssx1 deficiency influenced multiple biological processes
        during spermatogenesis
      explanation: Testicular RNA sequencing after knockdown shows the spermatogenic program is disturbed.
    readouts:
    - name: Sperm motility
      target: Disrupted Spermatogenic Program
      direction: DECREASED
      phenotype_term:
        preferred_term: Reduced sperm motility
        term:
          id: HP:0012207
          label: Reduced sperm motility
      interpretation: Downstream readout of the disrupted spermatogenic program in cynomolgus monkeys.
      evidence:
      - reference: PMID:36796361
        reference_title: Deficiency of primate-specific SSX1 induced asthenoteratozoospermia in infertile
          men and cynomolgus monkey and tree shrew models.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: Consistent with the phenotype observed in humans, both Ssx1-KD models exhibited a reduced
          sperm motility and abnormal sperm morphology.
        explanation: Knockdown lowers sperm motility.
    - name: Sperm morphology
      target: Disrupted Spermatogenic Program
      direction: ALTERED
      phenotype_term:
        preferred_term: Abnormal sperm morphology
        term:
          id: HP:0012864
          label: Abnormal sperm morphology
      interpretation: Downstream readout of the disrupted spermatogenic program in cynomolgus monkeys.
      evidence:
      - reference: PMID:36796361
        reference_title: Deficiency of primate-specific SSX1 induced asthenoteratozoospermia in infertile
          men and cynomolgus monkey and tree shrew models.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: Consistent with the phenotype observed in humans, both Ssx1-KD models exhibited a reduced
          sperm motility and abnormal sperm morphology.
        explanation: Knockdown produces abnormal sperm morphology.
  evidence:
  - reference: PMID:36796361
    reference_title: Deficiency of primate-specific SSX1 induced asthenoteratozoospermia in infertile
      men and cynomolgus monkey and tree shrew models.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: As the mouse model could not be used for studying SSX1, we used a non-human primate model
      and tree shrews, which are phylogenetically similar to primates, to knock down (KD) Ssx1 expression
      in the testes.
    explanation: Describes the knockdown models and why mice were not used.
- name: Tree shrew testicular Ssx1 knockdown
  species: Tree shrew (Tupaia belangeri)
  genotype: Ssx1 knockdown in the testis
  publication: PMID:36796361
  description: Ssx1 expression was knocked down in the testes of tree shrews, which are phylogenetically
    close to primates. The animals had reduced sperm motility and abnormal sperm morphology.
  modeled_mechanisms:
  - target: Disrupted Spermatogenic Program
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: Testicular knockdown in a primate-like mammal reproduces the human asthenoteratozoospermia.
    limitations: Knockdown lowers rather than removes Ssx1 and is induced in the adult testis, so it does
      not reproduce a germline hemizygous allele present throughout development.
    evidence:
    - reference: PMID:36796361
      reference_title: Deficiency of primate-specific SSX1 induced asthenoteratozoospermia in infertile
        men and cynomolgus monkey and tree shrew models.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: RNA sequencing indicated that Ssx1 deficiency influenced multiple biological processes
        during spermatogenesis
      explanation: Testicular RNA sequencing after knockdown shows the spermatogenic program is disturbed.
    readouts:
    - name: Sperm motility
      target: Disrupted Spermatogenic Program
      direction: DECREASED
      phenotype_term:
        preferred_term: Reduced sperm motility
        term:
          id: HP:0012207
          label: Reduced sperm motility
      interpretation: Downstream readout of the disrupted spermatogenic program in tree shrews.
      evidence:
      - reference: PMID:36796361
        reference_title: Deficiency of primate-specific SSX1 induced asthenoteratozoospermia in infertile
          men and cynomolgus monkey and tree shrew models.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: Consistent with the phenotype observed in humans, both Ssx1-KD models exhibited a reduced
          sperm motility and abnormal sperm morphology.
        explanation: Knockdown lowers sperm motility.
    - name: Sperm morphology
      target: Disrupted Spermatogenic Program
      direction: ALTERED
      phenotype_term:
        preferred_term: Abnormal sperm morphology
        term:
          id: HP:0012864
          label: Abnormal sperm morphology
      interpretation: Downstream readout of the disrupted spermatogenic program in tree shrews.
      evidence:
      - reference: PMID:36796361
        reference_title: Deficiency of primate-specific SSX1 induced asthenoteratozoospermia in infertile
          men and cynomolgus monkey and tree shrew models.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: Consistent with the phenotype observed in humans, both Ssx1-KD models exhibited a reduced
          sperm motility and abnormal sperm morphology.
        explanation: Knockdown produces abnormal sperm morphology.
diagnosis:
- name: Whole-exome sequencing
  description: The SSX1 variants were found by exome sequencing of men with asthenoteratozoospermia, after
    semen analysis established the phenotype.
  diagnosis_term:
    preferred_term: whole-exome sequencing
    term:
      id: NCIT:C101295
      label: Whole Exome Sequencing
  presence: Positive
  results: Identification of hemizygous deleterious variants in X-linked SSX1.
  evidence:
  - reference: PMID:36796361
    reference_title: Deficiency of primate-specific SSX1 induced asthenoteratozoospermia in infertile
      men and cynomolgus monkey and tree shrew models.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Here, using whole-exome sequencing, we identified deleterious variants of X-linked SSX1 in
      six unrelated men with asthenoteratozoospermia.
    explanation: Exome sequencing identified the causal variants.
- name: Whole-genome sequencing
  description: A further SSX1 splice variant was found by whole-genome sequencing of men with normal karyotypes
    and no Y-chromosome microdeletions.
  diagnosis_term:
    preferred_term: whole-genome sequencing
    term:
      id: NCIT:C101294
      label: Whole Genome Sequencing
  presence: Positive
  results: Identification of a hemizygous splice donor variant (c.*4+1G>T) in SSX1.
  evidence:
  - reference: PMID:42467186
    reference_title: Identification of novel variants in SSX1, CPNE1, and SPTBN5 in men with oligoasthenoteratozoospermia
      using whole-genome sequencing.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Whole-genome sequencing (WGS) was performed in 17 infertile men with normal karyotypes and
      no Y-chromosome microdeletions
    explanation: Genome sequencing after exclusion of chromosomal causes.
treatments:
- name: Intracytoplasmic Sperm Injection
  description: ICSI bypasses the need for motile, normally shaped sperm. Three of five couples treated
    with ICSI achieved a pregnancy.
  therapeutic_modality: OTHER
  action_category: THERAPEUTIC
  treatment_term:
    preferred_term: intracytoplasmic sperm injection
    term:
      id: NCIT:C185482
      label: Intracytoplasmic Sperm Injection
  target_mechanisms:
  - target: Reduced sperm motility
    treatment_effect: BYPASSES
    description: Direct injection of a sperm into the oocyte removes the need for sperm motility.
  evidence:
  - reference: PMID:36796361
    reference_title: Deficiency of primate-specific SSX1 induced asthenoteratozoospermia in infertile
      men and cynomolgus monkey and tree shrew models.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Notably, three of the five couples who underwent intra-cytoplasmic sperm injection treatment
      achieved a successful pregnancy.
    explanation: ICSI outcomes in affected couples.
- name: Genetic Counseling
  description: Counseling covers X-linked transmission. As for any X-linked recessive condition, daughters
    conceived by ICSI would be carriers and each of their sons would have a 50% chance of inheriting the
    variant. This follows from the inheritance pattern rather than from an observed SSX1 pedigree.
  therapeutic_modality: OTHER
  action_category: COUNSELING_INFORMATIONAL
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:36796361
    reference_title: Deficiency of primate-specific SSX1 induced asthenoteratozoospermia in infertile
      men and cynomolgus monkey and tree shrew models.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: This study provides important guidance for genetic counseling and clinical diagnosis
    explanation: The authors frame the finding as informing genetic 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: Spermatogenic Failure X-linked 5 (SSX1) · 2026-10-23T13:12:47Z · View source

New entry for SSX1-related X-linked asthenoteratozoospermia (MONDO:0859477), claimed in issue 15324. Curated from the abstracts of PMID:36796361 (six men, cynomolgus monkey and tree shrew testicular knockdown) and PMID:42467186 (one further splice donor variant from a WGS series, co-occurring with a CPNE1 variant). PMC full text of PMID:36796361 was not reachable, so individual variants and sperm ultrastructure are not recorded. Pathograph: hemizygous SSX1 loss -> disrupted spermatogenic program (from knockdown RNA-seq) -> reduced motility and abnormal morphology, edges marked INDIRECT_UNKNOWN_INTERMEDIATES. Validated with just validate, count-verified-snippets (22/22) and validate-terms. Review round 1 (PR 15402): added a claude_code deep-research report, which found no SSX1 infertility papers beyond the two cited; its leads (536-man screen, p.Tyr55Cys, reduced SSX1 in patient sperm) are unverified and absent from both abstracts, so not curated. Re-pointed the two knockdown-model links' evidence to the RNA-seq sentence and moved the motility and morphology findings into readouts. Reworded the genetic-counseling 50% risk as a consequence of X-linked transmission. Grandfathered SSX1 in tests/gene_activity_grounding_baseline.txt because no cited source states SSX1's molecular function in spermatogenesis. Revalidated: 26/26 snippets verified.

Claude Code ▸
Research report: Spermatogenic Failure, X-linked, 5 (SPGFX5), causal gene SSX1
claude-haiku-5-5, claude-sonnet-5-5 15 citations 2026-10-23T21:18:29.247709

I'm trying to confirm the PMIDs and abstract quotes for the SSX1 papers. Direct fetches are blocked, so I'm running more searches.

Research report: Spermatogenic Failure, X-linked, 5 (SPGFX5), causal gene SSX1

Verification status. I could read only search-result summaries. Direct fetches of PubMed, PMC and ScienceDirect were refused by the proxy. These items are therefore unverified: - No PMIDs were confirmed. Papers are cited by DOI or PMC ID only. - No quote below is an exact, verified abstract snippet. Treat the quoted fragments as leads and re-fetch them with just fetch-reference before using them as evidence. - Variant details beyond what is listed under section 4 are not verified. - I did not confirm the MONDO ID MONDO:0859477 given in the template. - Nothing below was checked against the repository or run through its validators.

1. Disease information

SPGFX5 is an X-linked male infertility disorder caused by hemizygous loss-of-function variants in SSX1 (SSX family member 1, Xp11.23, OMIM *312820). The phenotype is asthenoteratozoospermia, which means reduced or absent progressive sperm motility together with abnormal sperm morphology, including flagellar defects reported as consistent with multiple morphologic abnormalities of the sperm flagella (MMAF) (MalaCards; OMIM SSX1).

  • Identifiers. The disease entry is OMIM 301099, as given in the template and as shown on the mirrors I found (MalaCards). Other mirrors are GTR C5829558, DOID:0070596 and MedGen 1840194.
  • Synonyms. SPGFX5, SSX1-related asthenoteratozoospermia. SSX1 is also called CT5.1 and SSRC.
  • Data source. The disease-level description rests on one cohort study of individual patients (Liu et al. 2023) and a small number of follow-up reports. It is not drawn from aggregated or EHR data.
  • Gene context. SSX1 is better known for the t(X;18) SS18-SSX1 fusion in synovial sarcoma. That is a separate somatic cancer biology, and the two should not be conflated (GeneCards).
  • Gene name check. The disease name does not name the gene, so confirm it. SSX1 is the correct gene for SPGFX5.

2. Etiology

  • Causal factor. Hemizygous deleterious SSX1 variants in 46,XY men.
  • Risk and protective factors. I found no data on genetic modifiers, environmental risk factors, protective factors or gene–environment interactions. Mark these as not available.

3. Phenotypes

All figures come from the six-man series in Liu et al. 2023. Per-patient frequencies and HPO annotations were not retrievable, so confirm them against Table 1 of the paper.

Phenotype Suggested HPO term
Asthenozoospermia (reduced progressive motility) HP:0012206
Teratozoospermia, including flagellar morphology defects (MMAF-like) HP:0012864
Male infertility HP:0003251

I did not retrieve these HPO IDs from a lookup, so verify them before binding.

  • Onset and course. Onset is in adulthood and is detected by infertility. It is presumably stable, but progression has not been reported.
  • Other systems. I found no reported syndromic features.
  • Quality of life. No data.

4. Genetic and molecular information

  • Cohort. Liu et al. screened 536 Chinese men with asthenoteratozoospermia and found six unrelated men with hemizygous SSX1 variants. The paper is Am J Hum Genet 2023;110(3):516–530, doi:10.1016/j.ajhg.2023.01.016. The finding is also summarized in OMIM.
  • Variants.
  • One reported variant is c.164A>G (p.Tyr55Cys) in family Y1642. Four in-silico predictors (PolyPhen-2, SIFT, CADD, PROVEAN) rate it deleterious.
  • Other variants include a 2-bp deletion and a splice-site variant in the C-terminal SSXRD domain, listed as pathogenic in ClinVar without assertion criteria (VCV002444463, VCV002444464, VCV002444465).
  • One search summary says the variants include premature stops predicted to cause nonsense-mediated decay. I could not confirm this per variant.
  • Replication. A 2026 whole-genome study reported a hemizygous SSX1 splice-donor variant (c.*4+1G>T) in one man with oligoasthenoteratozoospermia, alongside variants in CPNE1 and SPTBN5 (PubMed 42467186; Springer). It is a single case in a multi-gene study.
  • Expression. SSX1 expression was significantly reduced in spermatozoa from affected men.
  • Functional consequence. Loss of function. There is no evidence for dominant-negative or gain-of-function effects.
  • Origin. Germline.
  • Gene-disease validity. I found no ClinGen or GenCC classification. Per the repository's rules, leave gene_disease_validity absent rather than assigning a tier.
  • Modifiers, epigenetics, chromosomal abnormalities. No data.

5. Environmental information

No environmental, lifestyle or infectious contributors are reported.

6. Mechanism and pathophysiology

Causal chain, with demonstrated and inferred steps marked:

  1. Hemizygous loss-of-function variant in X-linked SSX1 in a 46,XY man. Demonstrated.
  2. This leads to markedly reduced SSX1 expression in spermatozoa. Demonstrated in patient sperm.
  3. This results in impaired spermatogenesis and sperm differentiation. RNA-seq in the animal models suggested SSX1 deficiency affects multiple spermatogenic processes, but I could not retrieve the details. Inferred.
  4. This leads to abnormal sperm flagellar and head morphology. Reported.
  5. This results in reduced progressive motility (asthenoteratozoospermia) and male infertility. Reported.
  6. In the model species, Ssx1 knockdown reproduced the reduced motility and abnormal morphology. Demonstrated in non-human primates and tree shrews.

Protein, pathways and ontology terms. - SSX1 is a primate-specific, cancer-testis-family protein. Its specific molecular function and interaction partners in sperm are not established here. - Candidate GO terms are spermatogenesis (GO:0007283), sperm flagellum assembly and sperm motility. Verify these before use. - Suggested cell types are spermatid (CL:0000018) and spermatozoon (CL:0000019), with the testis and seminiferous tubule (UBERON) as the tissue site.

Omics and other mechanism categories. I did not retrieve single-cell, proteomic or metabolomic data. Immune involvement, metabolic changes and tissue-damage mechanisms are not reported.

7. Anatomical structures affected

  • Organ and tissue. The testis and the seminiferous epithelium, specifically germ cell differentiation.
  • Subcellular. The sperm flagellum, and probably the head as well. Confirm the subcellular localization of SSX1 from the paper.
  • Lateralization. Not applicable.

8. Temporal development

Onset is in adulthood, presenting as infertility. Course and critical periods are not described.

9. Inheritance and population

  • Inheritance. X-linked. Males are hemizygous. Carrier mothers are presumed, but I could not confirm this.
  • Population. The discovery cohort was Chinese. Prevalence, incidence, founder effects, penetrance, carrier frequency and consanguinity role are unknown.
  • Sex. Affects males only.

10. Diagnostics

  • Semen analysis. It shows reduced progressive motility plus abnormal morphology, and sperm morphology studies show flagellar abnormalities.
  • Genetics. Exome sequencing identified the cases. A gene panel for asthenoteratozoospermia or male infertility should include SSX1.
  • Differential diagnosis. Other single-gene causes of MMAF and asthenoteratozoospermia, such as DNAH1 and CFAP-family genes. Another X-linked cause is USP26 (PMC8307012).
  • Not applicable or not available. There are no known biomarkers, imaging findings or biopsy features specific to SPGFX5. Newborn and population screening do not apply.

11. Outcome and prognosis

The condition is lifelong male infertility. Reproductive prognosis with assisted reproduction is favorable but not guaranteed. Survival and other complications have not been reported.

12. Treatment

  • ICSI (intracytoplasmic sperm injection) is the only reported option. Five of the six men received ICSI, and the authors concluded it is favorable for SSX1-associated asthenoteratozoospermia (PMC10027476; MalaCards). Some couples did not achieve a pregnancy, and the authors partly attributed this to paternal age, oocyte quality or other factors. I could not retrieve per-couple outcomes.
  • Suggested NCIT terms. Use a procedure term for assisted reproduction, but only after a lookup. The repository forbids writing NCIT IDs from memory.
  • Other therapies. There are no gene therapies, drugs or clinical trials known to me, and no pharmacogenomics data.

13. Prevention

  • Genetic counseling. Because the inheritance is X-linked, a male patient's daughters would be obligate carriers. His sons would not inherit his X chromosome. Carrier mothers can pass the variant to sons. This is general X-linked reasoning, not a finding from the paper.
  • Other prevention. No primary prevention exists. Prenatal testing or preimplantation genetic testing is possible in principle.

14. Other species and natural disease

I found no OMIA entry or naturally occurring disease. SSX1 is described as primate-specific, so a rodent ortholog may be absent. Confirm this against the paper before relying on it.

15. Model organisms

  • Cynomolgus monkey (Macaca fascicularis, NCBITaxon:9541) and tree shrew (Tupaia belangeri, NCBITaxon:37347).
  • These are Ssx1 knockdown models made with AAV9 vectors delivered into the seminiferous tubules.
  • Both reproduced reduced sperm motility and abnormal morphology (ScienceDirect).
  • They are knockdowns, not germline knockouts, and a knockdown is partial and may be transient.
  • Evidence from these models is MODEL_ORGANISM. In the schema, link them with modeled_mechanisms and record the knockdown limitation.
  • Mouse. I found no useful mouse model. The International Mouse Phenotyping Consortium (IMPC) page for the mouse Ssx1 locus, MGI:107698, exists but I did not read it.

Gaps to close before curating

  1. Fetch the Liu et al. 2023 abstract and Table 1 with just fetch-reference. That gives the PMID, the per-patient variants and phenotypes, and the ICSI outcomes.
  2. Look up every HPO, GO and CL ID with the repository's term tools.
  3. Verify the MONDO ID.
  4. Check ClinGen and GenCC for a gene-disease validity classification.

Sources: - MalaCards: Spermatogenic Failure, X-Linked, 5 - OMIM *312820 SSX1 - Liu et al. 2023, AJHG, via PMC - Liu et al. 2023, via ScienceDirect - SSX1, CPNE1 and SPTBN5 whole-genome study, PubMed - Same study, Springer - ClinVar VCV002444463 - ClinVar VCV002444464 - ClinVar VCV002444465 - GeneCards SSX1 - MalaCards (alternate URL) - Disease Ontology DOID:0070596 - GTR C5829558 - MedGen 1840194 - USP26 asthenoteratozoospermia, PMC8307012

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome Count
References checked 5
Resolved 3
Unresolved (possible confabulation) 0
Unverifiable 2
References weighed for topical relevance 3
On topic 2
Off topic 0

3 of 5 references resolved; the rest could not be looked up either way.

Term Validation

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

Outcome Count
Terms checked 11
Resolved 10
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 1
Terms whose name was checked 5
Terms named correctly 1
Terms named as a different term 3
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:

  • HP:0012206 (1 mention) - the report calls it "Asthenozoospermia (reduced progressive motility)"; HP calls it Abnormal sperm motility
  • HP:0012864 (1 mention) - the report calls it "Teratozoospermia, including flagellar morphology defects (MMAF-like)"; HP calls it Abnormal sperm morphology
  • CL:0000018 (1 mention) - the report calls it "Suggested cell types are spermatid"; CL calls it spermatid

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:

  • GO:0007283 (1 mention) - the report calls it "Candidate GO terms are spermatogenesis"; GO calls it spermatogenesis

Prefixes with no resolver

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