Spermatogenic Failure 32

Mendelian MONDO:0020855 Pathograph 11 Show in embeddings browser Spermatogenic Failure Genetic Disease

Spermatogenic failure 32 (SPGF32) is male infertility from impaired sperm production caused by variants in SOHLH1, a germ-cell-specific basic helix-loop-helix transcription factor that drives spermatogonial differentiation, in part by activating KIT. Nearly all reported men carry the same splice-acceptor allele, c.346-1G>A, which uses a cryptic acceptor in exon 4 and truncates the bHLH domain. The disease was first described in two Korean and two Japanese men with non-obstructive azoospermia who were heterozygous for c.346-1G>A, and was catalogued as dominant. Later reports changed that reading. A man homozygous for the same allele had severe oligozoospermia with depleted, disordered germ cells and reduced testicular SOHLH1 protein, three heterozygous carriers had teratozoospermia with normal sperm counts, and a biallelic missense SOHLH1 variant was found in a consanguineous Pakistani family with azoospermia. The current evidence favours biallelic loss of function as the cause of quantitative spermatogenic failure, with the heterozygous allele's contribution unresolved. Sohlh1-null male mice are infertile because spermatogonia fail to differentiate into spermatocytes. ICSI with ejaculated sperm has produced pregnancies in carriers of either genotype.

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👪

Inheritance

2
Autosomal recessive HP:0000007
A man homozygous for c.346-1G>A had severe oligozoospermia with germ-cell depletion, while heterozygous carriers in the same study had normal sperm counts; a biallelic missense variant was reported in a consanguineous family with azoospermia.
Autosomal recessive inheritance
Show evidence (2 references)
PMID:34448846 SUPPORT Human clinical
"Collectively, our findings proved that the homozygous mutation was the direct genetic factor causing reduced sperm production and suggested that the c.346-1G > A mutation in SOHLH1 impaired sperm production in a recessive-inheritance pattern."
One homozygous patient with severe oligozoospermia; segregation was incomplete (father non-carrier, mother untested).
PMID:39625557 SUPPORT Human clinical
"We successfully identified five deleterious variants among five of the seven families, including three missense biallelic substitutions in WWC2, RPL10L, and SOHLH1"
A biallelic SOHLH1 missense variant in a consanguineous azoospermia family.
Autosomal dominant (contested) HP:0000006
The disease was first catalogued as dominant on the strength of heterozygous c.346-1G>A carriers with non-obstructive azoospermia. Later carriers with normal sperm counts argue against a fully penetrant dominant cause of azoospermia; the heterozygous allele may still contribute to abnormal sperm morphology or count.
Autosomal dominant inheritance
Show evidence (2 references)
PMID:28718531 SUPPORT Human clinical
"These sequence alterations included a heterozygous splice site mutation in SOHLH1 and a hemizygous missense substitution in TEX11, which have been reported as causes of non-obstructive azoospermia."
A heterozygous SOHLH1 splice variant in a Japanese NOA cohort, interpreted as causal.
PMID:34448846 REFUTE Human clinical
"In summary, our work identified a recessively inherited model of a SOHLH1 mutation in human male infertility that was associated with SOZ and also suggested that the SOHLH1 heterozygous c.346-1G > A mutation was associated with teratozoospermia but not a direct cause for NOA."
Heterozygous carriers had normal sperm counts, against a dominant cause of azoospermia.
⚙

Pathophysiology

4
SOHLH1 Transcription Factor Loss of Function
The c.346-1G>A splice-acceptor variant activates a cryptic acceptor in exon 4 and produces SOHLH1 with a truncated bHLH domain. In the homozygous patient, SOHLH1 protein was reduced in testicular tissue. The molecular function bound here is SOHLH1's GO annotation (GO:0000981, ISA, GO_REF:0000113 in QuickGO for UniProt Q5JUK2); loss of transcription-factor activity was shown as failed KIT-promoter activation in transfected cells, not measured in patients.
SOHLH1 hgnc:27845 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves SOHLH1 (hgnc:27845). hgnc:27845 is a gene from the HUGO Gene Nomenclature Committee.
bHLH DNA-binding transcription factor activity GO:0000981 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased bHLH DNA-binding transcription factor activity, annotated with DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981). GO:0000981 is a molecular function from the Gene Ontology.
Downstream
Reduced KIT Transcriptional Activation
Show evidence (2 references)
PMID:20506135 SUPPORT In vitro / ex vivo
"Analysis of transcripts from minigenes carrying the c.346-1G>A revealed that splicing site variation leads to the partial deletion at a cryptic splicing site within exon 4. This deletion results in SOHLH1 with a truncated bHLH domain."
Minigene assay showing the splice defect and bHLH truncation.
PMID:34448846 SUPPORT Human clinical
"Western blotting indicated the decrease of the SOHLH1 protein in patient’s testicular tissues compared to normal control"
Reduced SOHLH1 protein in the homozygous patient's testis.
Reduced KIT Transcriptional Activation
SOHLH1, with its partner SOHLH2, binds E-boxes in the Kit promoter and activates Kit transcription in postnatal spermatogonia. KIT signalling drives the differentiating spermatogonial stages.
KIT hgnc:6342 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves KIT (hgnc:6342). hgnc:6342 is a gene from the HUGO Gene Nomenclature Committee.
KIT transcriptional activation GO:0045944 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased KIT transcriptional activation, annotated with positive regulation of transcription by RNA polymerase II (GO:0045944). GO:0045944 is a biological process from the Gene Ontology.
Animal models
Sohlh1 knockout mouse Mouse recapitulates Kit-expressing spermatogonia are lost in prepubertal null testes.
Downstream
Failure of Spermatogonial Differentiation
Show evidence (2 references)
PMID:22328502 SUPPORT Model organism
"In the male, deletion of each factor causes loss of Kit-expressing spermatogonia in the prepuberal testis."
Sohlh1 deletion removes Kit-expressing spermatogonia in mice.
PMID:22328502 SUPPORT In vitro / ex vivo
"We found that E-box sequences within the Kit promoter and its first intron can be transactivated in transfection experiments overexpressing Sohlh1 or Sohlh2."
SOHLH1 transactivates the Kit promoter in transfected cells.
Failure of Spermatogonial Differentiation
Without SOHLH1, spermatogonia keep proliferating but do not progress to spermatocytes; SOHLH1 and SOHLH2 normally repress stem-cell maintenance genes such as Gfra1 and induce differentiation genes. This is shown in knockout mice; it has not been examined directly in human testis. GO has no spermatogonial differentiation term: an OLS search of GO for "spermatogonial differentiation" returned only CL:0000015, and searches for "spermatogonial cell" and "spermatogonium" returned GO:0007284 spermatogonial cell division and germline stem-cell division terms, which describe division rather than differentiation. The node is therefore bound to the parent process GO:0007283 spermatogenesis.
spermatogonium CL:0000020 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves spermatogonium (CL:0000020). CL:0000020 is a cell type from the Cell Ontology.
spermatogonial differentiation GO:0007283 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased spermatogonial differentiation, annotated with spermatogenesis (GO:0007283). GO:0007283 is a biological process from the Gene Ontology.
Animal models
Sohlh1 knockout mouse Mouse recapitulates The knockout shows the spermatogonial differentiation block.
Downstream
Germ Cell Depletion of the Seminiferous Epithelium
Show evidence (2 references)
PMID:16564520 SUPPORT Model organism
"Loss of Sohlh1 causes infertility by disrupting spermatogonial differentiation into spermatocytes."
Sohlh1-null male mice are infertile from a spermatogonial differentiation block.
PMID:22056784 SUPPORT Model organism
"The Sohlh1/Sohlh2 double mutant phenocopies single mutants, i.e., spermatogonia continue to proliferate but do not differentiate properly."
Spermatogonia proliferate but fail to differentiate in Sohlh mutants.
Germ Cell Depletion of the Seminiferous Epithelium
In the homozygous patient's testis, germ cells at several stages were reduced in number and disordered on H&E and immunofluorescence.
spermatocyte CL:0000017 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves spermatocyte (CL:0000017). CL:0000017 is a cell type from the Cell Ontology.
spermatogenesis GO:0007283 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased spermatogenesis (GO:0007283). GO:0007283 is a biological process from the Gene Ontology.
Downstream
Hypospermatogenesis
Severe Oligozoospermia
Non-Obstructive Azoospermia
Male Infertility
Show evidence (1 reference)
PMID:34448846 SUPPORT Human clinical
"Hematoxylin and eosin (H&E) and immunofluorescence (IF) staining showed that the germ cells in the homozygous patient’s testis decreased in number and were disordered, indicating the impaired spermatogenesis."
Testicular histology of the homozygous patient.
⬡

Pathograph

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Pathograph: causal mechanism network for Spermatogenic Failure 32 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

6
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:34448846 SUPPORT Human clinical
"Interestingly, the homozygote of c.346-1G > A mutation was found in an infertile patient with an extremely low sperm count."
Infertility in the homozygous patient.
Non-Obstructive Azoospermia Reproductive HP:0011961 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Non-obstructive azoospermia (HP:0011961). HP:0011961 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:20506135 SUPPORT Human clinical
"We analyzed whether there were mutations in the SOHLH1 gene in 96 Korean patients with NOA. The sequence analysis discovered three novel variations: one intronic variant (c.346-1G>A)"
The splice allele was found in a Korean NOA cohort.
PMID:28718531 SUPPORT Human clinical
"These sequence alterations included a heterozygous splice site mutation in SOHLH1 and a hemizygous missense substitution in TEX11, which have been reported as causes of non-obstructive azoospermia."
Replication in a Japanese NOA cohort.
Severe Oligozoospermia Reproductive HP:0034818 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Severe oligozoospermia (HP:0034818). HP:0034818 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:34448846 SUPPORT Human clinical
"Intriguingly, a homozygous mutation of c.346-1G > A in SOHLH1 was detected in a severe oligozoospermia (SOZ) patient, characterized with severely decreased sperm count."
Severe oligozoospermia in the homozygous patient.
PMID:39950040 SUPPORT Human clinical
"the sperm concentrations for Patients A and B were 3.1 × 10 6 mL−1 and 0.8 × 10 6 mL−1, respectively, with total sperm counts of 9.8 million and 5.3 million per specimen."
Severely reduced counts in two heterozygous carriers.
Hypospermatogenesis Reproductive HP:0034813 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypospermatogenesis (HP:0034813). HP:0034813 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34448846 SUPPORT Human clinical
"Hematoxylin and eosin (H&E) and immunofluorescence (IF) staining showed that the germ cells in the homozygous patient’s testis decreased in number and were disordered, indicating the impaired spermatogenesis."
Reduced germ-cell numbers on testicular histology.
Reduced Sperm Motility Reproductive HP:0012207 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Reduced sperm motility (HP:0012207). HP:0012207 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:34448846 SUPPORT Human clinical
"The three patients showed normal sperm concentration and count, while almost all sperm were immotile (Table 1)."
Near-total immotility in heterozygous carriers.
PMID:39950040 SUPPORT Human clinical
"Notably, our study demonstrated that patients with heterozygous mutations at the c.346-1G>A site exhibited severely reduced sperm counts, significantly impaired sperm motility, and pronounced morphological deformities."
Impaired motility in two further heterozygous carriers.
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.
Show evidence (2 references)
PMID:34448846 SUPPORT Human clinical
"SEM and TEM results showed severe abnormalities in the morphology and ultrastructure of the heterozygous patients’ sperm"
Ultrastructural sperm abnormalities in heterozygous carriers.
PMID:39950040 SUPPORT Human clinical
"Notably, our study demonstrated that patients with heterozygous mutations at the c.346-1G>A site exhibited severely reduced sperm counts, significantly impaired sperm motility, and pronounced morphological deformities."
Morphological deformities in two further heterozygous carriers.
🧬

Genetic Associations

1
SOHLH1 (Causal)
Gene: SOHLH1 hgnc:27845 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is SOHLH1 (hgnc:27845). hgnc:27845 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (2 references)
PMID:20506135 SUPPORT Human clinical
"Our findings indicate that a splice-acceptor site mutation that probably causes a nonfunctional SOHLH1 protein results in nonobstructive azoospermia by the lack of normal spermatogenesis."
Original gene-disease report.
PMID:34448846 SUPPORT Human clinical
"Remarkably, a homozygous mutation of SOHLH1 c.346-1G > A was first unveiled, which disrupts sperm production."
First homozygous patient.
💊

Medical Actions

2
Intracytoplasmic Sperm Injection
Action: Intracytoplasmic Sperm InjectionNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Intracytoplasmic Sperm Injection (NCIT:C185482). NCIT:C185482 is a clinical intervention from the NCI Thesaurus. NCIT:C185482
Platform: Other
ICSI with ejaculated sperm led to pregnancies in the homozygous patient's partner and in partners of heterozygous carriers. These are individual uncontrolled outcomes.
Mechanism Target:
Severe Oligozoospermia — Injection of single sperm makes the low count and poor motility irrelevant to fertilization.
Show evidence (1 reference)
PMID:34448846 SUPPORT Human clinical
"Ultimately, SOA patient’s wife achieved a clinical pregnancy and gave birth to a healthy baby."
Live birth after ICSI using the homozygous patient's sperm.
Show evidence (2 references)
PMID:34448846 SUPPORT Human clinical
"In our study, ICSI was performed using sperm from SOHLH1-mutated males, and their wives became pregnant and underwent successful deliveries."
Successful ICSI in three couples.
PMID:39950040 SUPPORT Human clinical
"One patient underwent assisted reproductive treatment through an intracytoplasmic sperm injection and achieved a favorable outcome, resulting in a successful pregnancy."
A further pregnancy after ICSI.
Genetic Counseling
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. NCIT:C15240
Platform: Behavioral / lifestyle
Counselling must address the unresolved inheritance: the recurrent allele acts recessively for sperm count in the best-documented case, while its heterozygous effect is uncertain. Every child of a homozygous father, and each child of a heterozygous father with 50% probability, inherits the variant. Daughters carry it as well as sons, which matters because biallelic SOHLH1 loss causes ovarian dysgenesis in women.
Show evidence (1 reference)
PMID:39950040 SUPPORT INDIRECT Human clinical
"Intracytoplasmic sperm injection (ICSI) was successful in one case, highlighting the potential for genetic counseling and assisted reproductive technologies in managing male infertility attributed to SOHLH1 mutations."
The authors name genetic counselling as part of management.
🔬

Diagnosis

1
Molecular Genetic Testing
Exome or panel sequencing identifies the SOHLH1 variant; the phenotype is not distinguishable from other genetic causes of spermatogenic failure.
Genetic Testing NCIT:C15709 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:28718531 SUPPORT Human clinical
"To this end, we conducted sequence analysis of 25 known disease-associated genes using next-generation sequencing and genome-wide copy-number analysis using array-based comparative genomic hybridization."
Panel sequencing detected the SOHLH1 splice allele.
🐁

Animal Models

1
Sohlh1 knockout mouse
Null males are infertile because spermatogonia fail to differentiate into spermatocytes; null females lose oocytes. Seven-day-old null testes lack Lhx8 and have reduced Ngn3 expression.
Species
Mouse
Genotype
Sohlh1-/- (targeted null), homozygous
Publication
PMID:16564520
Pathograph links
Failure of Spermatogonial Differentiation recapitulates fidelity: moderate observes: tissue The knockout shows the spermatogonial differentiation block.
Limitations: A complete null, whereas the recurrent human allele is an in-frame splice deletion that reduces rather than abolishes SOHLH1; heterozygous null mice are not reported to have the sperm defects seen in heterozygous human carriers.
Divergences from the human mechanism
species mismatch qualifying
The homozygous human patient still produced a few sperm, while the null mouse arrests before spermatocytes; the human allele is hypomorphic and human and mouse SOHLH1 share low sequence identity.
Show evidence (1 reference)
PMID:16564520 SUPPORT Model organism
"Loss of Sohlh1 causes infertility by disrupting spermatogonial differentiation into spermatocytes."
Differentiation block in null males.
Reduced KIT Transcriptional Activation recapitulates fidelity: moderate observes: tissue Kit-expressing spermatogonia are lost in prepubertal null testes.
Show evidence (1 reference)
PMID:22328502 SUPPORT Model organism
"In the male, deletion of each factor causes loss of Kit-expressing spermatogonia in the prepuberal testis."
Loss of the Kit-positive spermatogonial population.
{ }

Source YAML

click to show 
name: Spermatogenic Failure 32
creation_date: "2026-10-22T13:25:13Z"
category: Mendelian
synonyms:
- SPGF32
- spermatogenic failure 32
- SOHLH1-related spermatogenic failure
- SOHLH1-related male infertility
description: >-
  Spermatogenic failure 32 (SPGF32) is male infertility from impaired sperm
  production caused by variants in SOHLH1, a germ-cell-specific basic
  helix-loop-helix transcription factor that drives spermatogonial
  differentiation, in part by activating KIT. Nearly all reported men carry
  the same splice-acceptor allele, c.346-1G>A, which uses a cryptic acceptor
  in exon 4 and truncates the bHLH domain.

  The disease was first described in two Korean and two Japanese men with
  non-obstructive azoospermia who were heterozygous for c.346-1G>A, and was
  catalogued as dominant. Later reports changed that reading. A man
  homozygous for the same allele had severe oligozoospermia with depleted,
  disordered germ cells and reduced testicular SOHLH1 protein, three
  heterozygous carriers had teratozoospermia with normal sperm counts, and a
  biallelic missense SOHLH1 variant was found in a consanguineous Pakistani
  family with azoospermia. The current evidence favours biallelic loss of
  function as the cause of quantitative spermatogenic failure, with the
  heterozygous allele's contribution unresolved. Sohlh1-null male mice are
  infertile because spermatogonia fail to differentiate into spermatocytes.
  ICSI with ejaculated sperm has produced pregnancies in carriers of either
  genotype.
disease_term:
  preferred_term: spermatogenic failure 32
  term:
    id: MONDO:0020855
    label: spermatogenic failure 32
parents:
- Spermatogenic Failure
- Genetic Disease
notes: >-
  The same gene causes ovarian dysgenesis 5 in 46,XX women homozygous for
  truncating SOHLH1 variants, curated as the ODG5 subtype of
  46_XX_Gonadal_Dysgenesis; SOHLH1 disease is therefore sex-dimorphic, with
  oocyte loss in women and spermatogenic failure in men, matching the Sohlh1
  knockout mouse. The human male evidence is small: two heterozygous Korean
  NOA cases (PMID:20506135), two heterozygous Japanese NOA cases
  (PMID:28718531), one homozygous Chinese severe-oligozoospermia case and
  three heterozygous teratozoospermia carriers (PMID:34448846), two
  heterozygous severe-oligoasthenospermia cases (PMID:39950040), and one
  biallelic missense family (PMID:39625557). In the homozygous case the
  father was a non-carrier and the mother was not tested. The deep-research
  report and OMIM describe Sertoli-cell-only histology in the original cases;
  no cached abstract or full text states this, so it is not encoded. ClinGen
  has not curated SOHLH1 for this disease, so no validity tier is recorded.
  The meiotic_prophase_failure module was considered and not used: SOHLH1
  acts before meiosis, at the spermatogonial differentiation step, and that
  module scopes itself to meiotic genes. No GeneReviews chapter covers this
  disorder.
inheritance:
- name: Autosomal recessive
  description: >-
    A man homozygous for c.346-1G>A had severe oligozoospermia with germ-cell
    depletion, while heterozygous carriers in the same study had normal sperm
    counts; a biallelic missense variant was reported in a consanguineous
    family with azoospermia.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:34448846
    reference_title: "The mutation c.346-1G > A in SOHLH1 impairs sperm production in the homozygous but not in the heterozygous condition."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Collectively, our findings proved that the homozygous mutation was the direct genetic factor causing reduced sperm production and suggested that the c.346-1G > A mutation in SOHLH1 impaired sperm production in a recessive-inheritance pattern."
    explanation: >-
      One homozygous patient with severe oligozoospermia; segregation was
      incomplete (father non-carrier, mother untested).
  - reference: PMID:39625557
    reference_title: "Whole-exome sequencing identifies rare recessive variants in azoospermia patients from consanguineous Pakistani families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We successfully identified five deleterious variants among five of the seven families, including three missense biallelic substitutions in WWC2, RPL10L, and SOHLH1"
    explanation: A biallelic SOHLH1 missense variant in a consanguineous azoospermia family.
- name: Autosomal dominant (contested)
  description: >-
    The disease was first catalogued as dominant on the strength of
    heterozygous c.346-1G>A carriers with non-obstructive azoospermia. Later
    carriers with normal sperm counts argue against a fully penetrant
    dominant cause of azoospermia; the heterozygous allele may still
    contribute to abnormal sperm morphology or count.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:28718531
    reference_title: "Next-generation sequencing for patients with non-obstructive azoospermia: implications for significant roles of monogenic/oligogenic mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These sequence alterations included a heterozygous splice site mutation in SOHLH1 and a hemizygous missense substitution in TEX11, which have been reported as causes of non-obstructive azoospermia."
    explanation: A heterozygous SOHLH1 splice variant in a Japanese NOA cohort, interpreted as causal.
  - reference: PMID:34448846
    reference_title: "The mutation c.346-1G > A in SOHLH1 impairs sperm production in the homozygous but not in the heterozygous condition."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "In summary, our work identified a recessively inherited model of a SOHLH1 mutation in human male infertility that was associated with SOZ and also suggested that the SOHLH1 heterozygous c.346-1G > A mutation was associated with teratozoospermia but not a direct cause for NOA."
    explanation: Heterozygous carriers had normal sperm counts, against a dominant cause of azoospermia.
pathophysiology:
- name: SOHLH1 Transcription Factor Loss of Function
  description: >-
    The c.346-1G>A splice-acceptor variant activates a cryptic acceptor in
    exon 4 and produces SOHLH1 with a truncated bHLH domain. In the
    homozygous patient, SOHLH1 protein was reduced in testicular tissue.
    The molecular function bound here is SOHLH1's GO annotation
    (GO:0000981, ISA, GO_REF:0000113 in QuickGO for UniProt Q5JUK2); loss of
    transcription-factor activity was shown as failed KIT-promoter activation
    in transfected cells, not measured in patients.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: SOHLH1
    term:
      id: hgnc:27845
      label: SOHLH1
  molecular_functions:
  - preferred_term: bHLH DNA-binding transcription factor activity
    modifier: DECREASED
    term:
      id: GO:0000981
      label: DNA-binding transcription factor activity, RNA polymerase II-specific
  evidence:
  - reference: PMID:20506135
    reference_title: "Mutations in SOHLH1 gene associate with nonobstructive azoospermia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Analysis of transcripts from minigenes carrying the c.346-1G>A revealed that splicing site variation leads to the partial deletion at a cryptic splicing site within exon 4. This deletion results in SOHLH1 with a truncated bHLH domain."
    explanation: Minigene assay showing the splice defect and bHLH truncation.
  - reference: PMID:34448846
    reference_title: "The mutation c.346-1G > A in SOHLH1 impairs sperm production in the homozygous but not in the heterozygous condition."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Western blotting indicated the decrease of the SOHLH1 protein in patient’s testicular tissues compared to normal control"
    explanation: Reduced SOHLH1 protein in the homozygous patient's testis.
  downstream:
  - target: Reduced KIT Transcriptional Activation
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:20506135
      reference_title: "Mutations in SOHLH1 gene associate with nonobstructive azoospermia."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Transient transfection assay showed that the SOHLH1 mutant with the truncated domain disrupted the transcriptional activity of KIT promoter"
      explanation: The truncated mutant fails to activate the KIT promoter in transfected cells.
- name: Reduced KIT Transcriptional Activation
  description: >-
    SOHLH1, with its partner SOHLH2, binds E-boxes in the Kit promoter and
    activates Kit transcription in postnatal spermatogonia. KIT signalling
    drives the differentiating spermatogonial stages.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: KIT
    term:
      id: hgnc:6342
      label: KIT
  biological_processes:
  - preferred_term: KIT transcriptional activation
    modifier: DECREASED
    term:
      id: GO:0045944
      label: positive regulation of transcription by RNA polymerase II
  evidence:
  - reference: PMID:22328502
    reference_title: "SOHLH1 and SOHLH2 control Kit expression during postnatal male germ cell development."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "In the male, deletion of each factor causes loss of Kit-expressing spermatogonia in the prepuberal testis."
    explanation: Sohlh1 deletion removes Kit-expressing spermatogonia in mice.
  - reference: PMID:22328502
    reference_title: "SOHLH1 and SOHLH2 control Kit expression during postnatal male germ cell development."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We found that E-box sequences within the Kit promoter and its first intron can be transactivated in transfection experiments overexpressing Sohlh1 or Sohlh2."
    explanation: SOHLH1 transactivates the Kit promoter in transfected cells.
  downstream:
  - target: Failure of Spermatogonial Differentiation
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:22328502
      reference_title: "SOHLH1 and SOHLH2 control Kit expression during postnatal male germ cell development."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Our results suggest that SOHLH1 and SOHLH2 directly stimulate Kit transcription in postnatal spermatogonia, thus activating the signaling involved in spermatogonia differentiation and spermatogenetic progression."
      explanation: Kit activation by SOHLH1 is the signal for spermatogonial differentiation.
- name: Failure of Spermatogonial Differentiation
  description: >-
    Without SOHLH1, spermatogonia keep proliferating but do not progress to
    spermatocytes; SOHLH1 and SOHLH2 normally repress stem-cell maintenance
    genes such as Gfra1 and induce differentiation genes. This is shown in
    knockout mice; it has not been examined directly in human testis. GO has
    no spermatogonial differentiation term: an OLS search of GO for
    "spermatogonial differentiation" returned only CL:0000015, and searches
    for "spermatogonial cell" and "spermatogonium" returned GO:0007284
    spermatogonial cell division and germline stem-cell division terms, which
    describe division rather than differentiation. The node is therefore
    bound to the parent process GO:0007283 spermatogenesis.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: spermatogonium
    term:
      id: CL:0000020
      label: spermatogonium
  biological_processes:
  - preferred_term: spermatogonial differentiation
    modifier: DECREASED
    term:
      id: GO:0007283
      label: spermatogenesis
  evidence:
  - reference: PMID:16564520
    reference_title: "Sohlh1 is essential for spermatogonial differentiation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Loss of Sohlh1 causes infertility by disrupting spermatogonial differentiation into spermatocytes."
    explanation: Sohlh1-null male mice are infertile from a spermatogonial differentiation block.
  - reference: PMID:22056784
    reference_title: "SOHLH1 and SOHLH2 coordinate spermatogonial differentiation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The Sohlh1/Sohlh2 double mutant phenocopies single mutants, i.e., spermatogonia continue to proliferate but do not differentiate properly."
    explanation: Spermatogonia proliferate but fail to differentiate in Sohlh mutants.
  downstream:
  - target: Germ Cell Depletion of the Seminiferous Epithelium
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:34448846
      reference_title: "The mutation c.346-1G > A in SOHLH1 impairs sperm production in the homozygous but not in the heterozygous condition."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "Notably, we unprecedently revealed that this homozygous mutation of c.346-1G > A in SOHLH1 leads to the sharp decrease in various germ cells and spermatogenesis dysfunction, which is similar to the phenotype of SOHLH1 knockout male mice."
      explanation: >-
        The authors link the human germ-cell depletion to the knockout mouse
        phenotype; the differentiation step itself was not measured in the
        patient.
- name: Germ Cell Depletion of the Seminiferous Epithelium
  description: >-
    In the homozygous patient's testis, germ cells at several stages were
    reduced in number and disordered on H&E and immunofluorescence.
  biological_scale: TISSUE
  cell_types:
  - preferred_term: spermatocyte
    term:
      id: CL:0000017
      label: spermatocyte
  biological_processes:
  - preferred_term: spermatogenesis
    modifier: DECREASED
    term:
      id: GO:0007283
      label: spermatogenesis
  evidence:
  - reference: PMID:34448846
    reference_title: "The mutation c.346-1G > A in SOHLH1 impairs sperm production in the homozygous but not in the heterozygous condition."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hematoxylin and eosin (H&E) and immunofluorescence (IF) staining showed that the germ cells in the homozygous patient’s testis decreased in number and were disordered, indicating the impaired spermatogenesis."
    explanation: Testicular histology of the homozygous patient.
  downstream:
  - target: Hypospermatogenesis
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:34448846
      reference_title: "The mutation c.346-1G > A in SOHLH1 impairs sperm production in the homozygous but not in the heterozygous condition."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Hematoxylin and eosin (H&E) and immunofluorescence (IF) staining showed that the germ cells in the homozygous patient’s testis decreased in number and were disordered, indicating the impaired spermatogenesis."
      explanation: In the homozygous patient's testis the reduced germ-cell number is reported together with impaired spermatogenesis.
  - target: Severe Oligozoospermia
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:34448846
      reference_title: "The mutation c.346-1G > A in SOHLH1 impairs sperm production in the homozygous but not in the heterozygous condition."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Dysfunctional spermatogenesis was observed in the SOZ patient, showing a sharp decline in the sperm count, and also displayed in the disarray and irregularities within various germ cells using IF and H&E staining"
      explanation: The germ-cell depletion accompanies the low sperm count in the same patient.
  - target: Non-Obstructive Azoospermia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:20506135
      reference_title: "Mutations in SOHLH1 gene associate with nonobstructive azoospermia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Our findings indicate that a splice-acceptor site mutation that probably causes a nonfunctional SOHLH1 protein results in nonobstructive azoospermia by the lack of normal spermatogenesis."
      explanation: The authors attribute azoospermia to absent normal spermatogenesis.
  - target: Male Infertility
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:34448846
      reference_title: "The mutation c.346-1G > A in SOHLH1 impairs sperm production in the homozygous but not in the heterozygous condition."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Collectively, these data strongly indicate that the splice-acceptor site, bi-allelic mutation in SOHLH1 leads to male infertility via the absence of normal spermatogenesis."
      explanation: Infertility follows from the loss of normal spermatogenesis.
phenotypes:
- name: Male Infertility
  category: Reproductive
  description: Primary infertility is the presenting problem in every reported man.
  phenotype_term:
    preferred_term: Male infertility
    term:
      id: HP:0003251
      label: Male infertility
  evidence:
  - reference: PMID:34448846
    reference_title: "The mutation c.346-1G > A in SOHLH1 impairs sperm production in the homozygous but not in the heterozygous condition."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Interestingly, the homozygote of c.346-1G > A mutation was found in an infertile patient with an extremely low sperm count."
    explanation: Infertility in the homozygous patient.
- name: Non-Obstructive Azoospermia
  category: Reproductive
  description: >-
    Reported in four men heterozygous for c.346-1G>A (two Korean, two
    Japanese). Whether the heterozygous allele alone causes azoospermia is
    disputed.
  phenotype_term:
    preferred_term: Non-obstructive azoospermia
    term:
      id: HP:0011961
      label: Non-obstructive azoospermia
  evidence:
  - reference: PMID:20506135
    reference_title: "Mutations in SOHLH1 gene associate with nonobstructive azoospermia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We analyzed whether there were mutations in the SOHLH1 gene in 96 Korean patients with NOA. The sequence analysis discovered three novel variations: one intronic variant (c.346-1G>A)"
    explanation: The splice allele was found in a Korean NOA cohort.
  - reference: PMID:28718531
    reference_title: "Next-generation sequencing for patients with non-obstructive azoospermia: implications for significant roles of monogenic/oligogenic mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These sequence alterations included a heterozygous splice site mutation in SOHLH1 and a hemizygous missense substitution in TEX11, which have been reported as causes of non-obstructive azoospermia."
    explanation: Replication in a Japanese NOA cohort.
- name: Severe Oligozoospermia
  category: Reproductive
  description: >-
    The homozygous man had an extremely low sperm count, with only a few
    abnormal sperm after centrifugation. Two heterozygous men in a later
    report had concentrations of 3.1 and 0.8 million/mL.
  phenotype_term:
    preferred_term: Severe oligozoospermia
    term:
      id: HP:0034818
      label: Severe oligozoospermia
  evidence:
  - reference: PMID:34448846
    reference_title: "The mutation c.346-1G > A in SOHLH1 impairs sperm production in the homozygous but not in the heterozygous condition."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Intriguingly, a homozygous mutation of c.346-1G > A in SOHLH1 was detected in a severe oligozoospermia (SOZ) patient, characterized with severely decreased sperm count."
    explanation: Severe oligozoospermia in the homozygous patient.
  - reference: PMID:39950040
    reference_title: "Clinical phenotype and genetic analysis of patients with severe oligoasthenospermia carrying heterozygous SOHLH1 c.346-1G>A mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the sperm concentrations for Patients A and B were 3.1 × 10 6 mL−1 and 0.8 × 10 6 mL−1, respectively, with total sperm counts of 9.8 million and 5.3 million per specimen."
    explanation: Severely reduced counts in two heterozygous carriers.
- name: Hypospermatogenesis
  category: Reproductive
  description: >-
    Germ cells at several stages were reduced and disordered in the
    homozygous patient's testicular biopsy.
  phenotype_term:
    preferred_term: Hypospermatogenesis
    term:
      id: HP:0034813
      label: Hypospermatogenesis
  evidence:
  - reference: PMID:34448846
    reference_title: "The mutation c.346-1G > A in SOHLH1 impairs sperm production in the homozygous but not in the heterozygous condition."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hematoxylin and eosin (H&E) and immunofluorescence (IF) staining showed that the germ cells in the homozygous patient’s testis decreased in number and were disordered, indicating the impaired spermatogenesis."
    explanation: Reduced germ-cell numbers on testicular histology.
- name: Reduced Sperm Motility
  category: Reproductive
  description: >-
    Reported in heterozygous carriers: almost all sperm were immotile in
    three Chinese teratozoospermia patients, and motility was 3.3% and 0% in
    two severe-oligoasthenospermia patients.
  phenotype_term:
    preferred_term: Reduced sperm motility
    term:
      id: HP:0012207
      label: Reduced sperm motility
  evidence:
  - reference: PMID:34448846
    reference_title: "The mutation c.346-1G > A in SOHLH1 impairs sperm production in the homozygous but not in the heterozygous condition."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The three patients showed normal sperm concentration and count, while almost all sperm were immotile (Table 1)."
    explanation: Near-total immotility in heterozygous carriers.
  - reference: PMID:39950040
    reference_title: "Clinical phenotype and genetic analysis of patients with severe oligoasthenospermia carrying heterozygous SOHLH1 c.346-1G>A mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Notably, our study demonstrated that patients with heterozygous mutations at the c.346-1G>A site exhibited severely reduced sperm counts, significantly impaired sperm motility, and pronounced morphological deformities."
    explanation: Impaired motility in two further heterozygous carriers.
- name: Abnormal Sperm Morphology
  category: Reproductive
  description: >-
    Teratozoospermia with severe head and flagellar abnormalities on SEM and
    TEM was reported in heterozygous carriers; the homozygous man's few sperm
    were also abnormal.
  phenotype_term:
    preferred_term: Teratozoospermia
    term:
      id: HP:0012864
      label: Abnormal sperm morphology
  evidence:
  - reference: PMID:34448846
    reference_title: "The mutation c.346-1G > A in SOHLH1 impairs sperm production in the homozygous but not in the heterozygous condition."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "SEM and TEM results showed severe abnormalities in the morphology and ultrastructure of the heterozygous patients’ sperm"
    explanation: Ultrastructural sperm abnormalities in heterozygous carriers.
  - reference: PMID:39950040
    reference_title: "Clinical phenotype and genetic analysis of patients with severe oligoasthenospermia carrying heterozygous SOHLH1 c.346-1G>A mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Notably, our study demonstrated that patients with heterozygous mutations at the c.346-1G>A site exhibited severely reduced sperm counts, significantly impaired sperm motility, and pronounced morphological deformities."
    explanation: Morphological deformities in two further heterozygous carriers.
genetic:
- name: SOHLH1
  association: Causal
  relationship_type: CAUSATIVE
  gene_term:
    preferred_term: SOHLH1
    term:
      id: hgnc:27845
      label: SOHLH1
  notes: >-
    The recurrent allele is the splice-acceptor variant c.346-1G>A, reported
    heterozygous in NOA, teratozoospermia and severe-oligoasthenospermia
    patients and homozygous in one severe-oligozoospermia patient. Two
    missense variants found in the Korean cohort, p.Arg37Gln and
    p.Pro269Ser, did not impair KIT promoter activation. A biallelic missense
    variant was reported in a Pakistani family.
  evidence:
  - reference: PMID:20506135
    reference_title: "Mutations in SOHLH1 gene associate with nonobstructive azoospermia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our findings indicate that a splice-acceptor site mutation that probably causes a nonfunctional SOHLH1 protein results in nonobstructive azoospermia by the lack of normal spermatogenesis."
    explanation: Original gene-disease report.
  - reference: PMID:34448846
    reference_title: "The mutation c.346-1G > A in SOHLH1 impairs sperm production in the homozygous but not in the heterozygous condition."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Remarkably, a homozygous mutation of SOHLH1 c.346-1G > A was first unveiled, which disrupts sperm production."
    explanation: First homozygous patient.
animal_models:
- name: Sohlh1 knockout mouse
  species: Mouse
  genotype: Sohlh1-/- (targeted null), homozygous
  publication: PMID:16564520
  description: >-
    Null males are infertile because spermatogonia fail to differentiate into
    spermatocytes; null females lose oocytes. Seven-day-old null testes lack
    Lhx8 and have reduced Ngn3 expression.
  modeled_mechanisms:
  - target: Failure of Spermatogonial Differentiation
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: The knockout shows the spermatogonial differentiation block.
    limitations: >-
      A complete null, whereas the recurrent human allele is an in-frame
      splice deletion that reduces rather than abolishes SOHLH1; heterozygous
      null mice are not reported to have the sperm defects seen in
      heterozygous human carriers.
    divergences:
    - divergence_type: SPECIES_MISMATCH
      materiality: QUALIFYING
      description: >-
        The homozygous human patient still produced a few sperm, while the
        null mouse arrests before spermatocytes; the human allele is
        hypomorphic and human and mouse SOHLH1 share low sequence identity.
    evidence:
    - reference: PMID:16564520
      reference_title: "Sohlh1 is essential for spermatogonial differentiation."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Loss of Sohlh1 causes infertility by disrupting spermatogonial differentiation into spermatocytes."
      explanation: Differentiation block in null males.
  - target: Reduced KIT Transcriptional Activation
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: Kit-expressing spermatogonia are lost in prepubertal null testes.
    evidence:
    - reference: PMID:22328502
      reference_title: "SOHLH1 and SOHLH2 control Kit expression during postnatal male germ cell development."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "In the male, deletion of each factor causes loss of Kit-expressing spermatogonia in the prepuberal testis."
      explanation: Loss of the Kit-positive spermatogonial population.
treatments:
- name: Intracytoplasmic Sperm Injection
  description: >-
    ICSI with ejaculated sperm led to pregnancies in the homozygous patient's
    partner and in partners of heterozygous carriers. These are individual
    uncontrolled outcomes.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Intracytoplasmic Sperm Injection
    term:
      id: NCIT:C185482
      label: Intracytoplasmic Sperm Injection
  target_mechanisms:
  - target: Severe Oligozoospermia
    description: Injection of single sperm makes the low count and poor motility irrelevant to fertilization.
    evidence:
    - reference: PMID:34448846
      reference_title: "The mutation c.346-1G > A in SOHLH1 impairs sperm production in the homozygous but not in the heterozygous condition."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Ultimately, SOA patient’s wife achieved a clinical pregnancy and gave birth to a healthy baby."
      explanation: Live birth after ICSI using the homozygous patient's sperm.
  evidence:
  - reference: PMID:34448846
    reference_title: "The mutation c.346-1G > A in SOHLH1 impairs sperm production in the homozygous but not in the heterozygous condition."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In our study, ICSI was performed using sperm from SOHLH1-mutated males, and their wives became pregnant and underwent successful deliveries."
    explanation: Successful ICSI in three couples.
  - reference: PMID:39950040
    reference_title: "Clinical phenotype and genetic analysis of patients with severe oligoasthenospermia carrying heterozygous SOHLH1 c.346-1G>A mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "One patient underwent assisted reproductive treatment through an intracytoplasmic sperm injection and achieved a favorable outcome, resulting in a successful pregnancy."
    explanation: A further pregnancy after ICSI.
- name: Genetic Counseling
  description: >-
    Counselling must address the unresolved inheritance: the recurrent allele
    acts recessively for sperm count in the best-documented case, while its
    heterozygous effect is uncertain. Every child of a homozygous father, and
    each child of a heterozygous father with 50% probability, inherits the
    variant. Daughters carry it as well as sons, which matters because
    biallelic SOHLH1 loss causes ovarian dysgenesis in women.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:39950040
    reference_title: "Clinical phenotype and genetic analysis of patients with severe oligoasthenospermia carrying heterozygous SOHLH1 c.346-1G>A mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "Intracytoplasmic sperm injection (ICSI) was successful in one case, highlighting the potential for genetic counseling and assisted reproductive technologies in managing male infertility attributed to SOHLH1 mutations."
    explanation: The authors name genetic counselling as part of management.
diagnosis:
- name: Molecular Genetic Testing
  description: >-
    Exome or panel sequencing identifies the SOHLH1 variant; the phenotype is
    not distinguishable from other genetic causes of spermatogenic failure.
  diagnosis_term:
    preferred_term: Genetic Testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:28718531
    reference_title: "Next-generation sequencing for patients with non-obstructive azoospermia: implications for significant roles of monogenic/oligogenic mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "To this end, we conducted sequence analysis of 25 known disease-associated genes using next-generation sequencing and genome-wide copy-number analysis using array-based comparative genomic hybridization."
    explanation: Panel sequencing detected the SOHLH1 splice allele.
📚

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 (2)

Record notes

The same gene causes ovarian dysgenesis 5 in 46,XX women homozygous for truncating SOHLH1 variants, curated as the ODG5 subtype of 46_XX_Gonadal_Dysgenesis; SOHLH1 disease is therefore sex-dimorphic, with oocyte loss in women and spermatogenic failure in men, matching the Sohlh1 knockout mouse. The human male evidence is small: two heterozygous Korean NOA cases (PMID:20506135), two heterozygous Japanese NOA cases (PMID:28718531), one homozygous Chinese severe-oligozoospermia case and three heterozygous teratozoospermia carriers (PMID:34448846), two heterozygous severe-oligoasthenospermia cases (PMID:39950040), and one biallelic missense family (PMID:39625557). In the homozygous case the father was a non-carrier and the mother was not tested. The deep-research report and OMIM describe Sertoli-cell-only histology in the original cases; no cached abstract or full text states this, so it is not encoded. ClinGen has not curated SOHLH1 for this disease, so no validity tier is recorded. The meiotic_prophase_failure module was considered and not used: SOHLH1 acts before meiosis, at the spermatogonial differentiation step, and that module scopes itself to meiotic genes. No GeneReviews chapter covers this disorder.

Create: Spermatogenic_Failure_32 · 2026-10-22T15:11:48Z · View source

Created the SOHLH1 spermatogenic failure 32 entry (MONDO:0020855, claim #15201). Deep research: one Perplexity sonar-deep-research report run with reasoning_effort=low, because two medium-effort runs were cut off after about 300 seconds (server disconnected without a response). The run was anchored on SOHLH1 through a skeleton genetic row because the stub carries the gene only in source_tags. Its reference validation resolved 18 of 18 identifiers, but one cited PMID (29240260) is a glioblastoma paper and was not used, and its Sertoli-cell-only claim traces to OMIM and no cached text, so it was not encoded. References fetched and quoted directly: PMID:20506135, 28718531, 34448846, 39950040, 39625557 (human), PMID:16564520, 22056784, 22328502 (mouse and in vitro). Inheritance is recorded as autosomal recessive, with a separate contested autosomal dominant block that carries a REFUTE item from the 2022 homozygous-case paper. The chain runs from SOHLH1 loss of function to reduced KIT activation, failed spermatogonial differentiation, germ-cell depletion, and the semen phenotypes. The molecular-function binding (GO:0000981) is SOHLH1's QuickGO annotation (ISA). Validation: just validate passed, count-verified-snippets 36/36, validate-terms passed, the entity-ref, causal-target, offline snippet, enum, duplicate-key, coarse-phenotype, qualifier, gene-activity-grounding, node-class and knowledge-gap gates passed, and check-genereviews --online reports NO_CHAPTER.

Perplexity ▸
Spermatogenic Failure 32: disease-characteristics research report
sonar-deep-research 51 citations 2026-10-22T14:42:12.564310

Spermatogenic Failure 32: disease-characteristics research report

Spermatogenic failure 32 (SPGF32; MONDO:0020855; OMIM 618115) is a rare Mendelian male-infertility disorder associated with germline variation in the causal gene SOHLH1. Its canonical description is nonobstructive azoospermia (NOA) caused by severe failure of germ-cell development, with reported testicular germ-cell aplasia/Sertoli-cell-only histology. The evidence base is unusually small and centers on one recurrent splice-acceptor variant, NM_001101677.2:c.346-1G>A (rs140132974). Importantly, later human data and population frequency evidence challenge the original autosomal-dominant/de-novo interpretation: homozygosity can cause severe oligozoospermia, whereas heterozygotes may have azoospermia, oligoasthenoteratozoospermia, isolated teratozoospermia, or no recognized phenotype. Thus, the gene–disease association is credible, but penetrance, inheritance, and the pathogenicity of this particular allele remain incompletely resolved. [31][61][109]

Evidence cutoff: October 22, 2026. Disease-specific human literature through 2024 remained sparse; the most relevant 2023 publication is an expanded mouse knockout phenotyping study. A small 2025 human study is noted only where it materially updates the phenotype.

1. Disease information

1.1 Definition and scope

SPGF32 is a genetic form of primary testicular spermatogenic failure. The defining manifestation in the original disease record is male infertility from NOA, not obstruction of an otherwise normally functioning reproductive tract. The original patients had absence of spermatogenic cells and a Sertoli-cell-only pattern on biopsy. [24]

The record is an aggregated disease-level construct, assembled principally from OMIM, MedGen/MONDO, ClinVar and published cohorts—not an individual EHR phenotype. Individual-patient observations underpinning it include two Korean men in the 2010 discovery study, Japanese replication cases, and a later Chinese severe-oligozoospermia case. [114]

1.2 Identifiers and names

Identifier system Identifier/name Qualification
MONDO MONDO:0020855 Requested target identifier
OMIM disease 618115, Spermatogenic failure 32 Contrary to the template’s “not recorded,” an OMIM disease entry exists
OMIM gene 610224, SOHLH1 Gene entry, not the disease entry
MedGen UID 1648444; Concept ID C4748253 Disease concept
Orphanet No dedicated SPGF32-specific ORPHAcode identified ORPHA:399771 is the broader NOA phenotype, not necessarily SPGF32
MeSH No SPGF32-specific heading Indexed under terms such as Azoospermia/genetics, Male Infertility, and Basic Helix-Loop-Helix Transcription Factors
ICD-10-CM No gene-specific code; N46.01 is commonly used for organic azoospermia Coding is phenotype-level
ICD-11 No SPGF32-specific code identified Use the appropriate male-infertility/azoospermia category locally
Synonyms Spermatogenic failure 32; SPGF32 Canonical disease synonyms
Broader descriptive names SOHLH1-related spermatogenic failure; SOHLH1-associated male infertility; nonobstructive azoospermia due to SOHLH1 deficiency Useful search terms, not necessarily official synonyms

MedGen confirms MONDO:0020855, OMIM 618115, SOHLH1 at 9q34.3, and the two canonical synonyms. [31]

2. Etiology

2.1 Primary causal factor

The established initiating factor is a germline defect affecting SOHLH1, which encodes a germ-cell-specific basic helix-loop-helix transcription regulator. The best studied allele, c.346-1G>A, disrupts a splice acceptor, activates a cryptic splice site in exon 4, deletes 18 coding nucleotides, damages the bHLH domain, and reduces transcriptional activation of the KIT promoter. [61]

The discovery abstract’s key conclusion was:

“Our findings indicate that a splice-acceptor site mutation that probably causes a nonfunctional SOHLH1 protein results in nonobstructive azoospermia by the lack of normal spermatogenesis.”
— Choi et al., Human Mutation, July 2010, PMID: 20506135 [61]

2.2 Risk factors and evidence strength

Factor Disease-specific evidence Interpretation
SOHLH1 c.346-1G>A, homozygous One Chinese patient with severe oligozoospermia, sharply reduced/disorganized testicular germ cells and reduced SOHLH1 protein Stronger evidence for a recessive quantitative spermatogenesis defect, but still a single incompletely segregated case
c.346-1G>A, heterozygous Two Korean NOA cases, two Japanese NOA cases, three Chinese teratozoospermia cases, and two 2025 severe oligoasthenospermia cases Phenotypically heterogeneous; dominant causality and penetrance remain uncertain
Other heterozygous missense variants c.91T>C/p.Arg37Gln and c.529C>A/p.Pro269Ser did not significantly impair KIT transactivation Not established as causal
Male sex Required for the SPGF32 phenotype as defined Female biallelic loss of function is associated instead with ovarian dysgenesis 5
Consanguinity/family history Plausibly increases risk for biallelic disease No robust SPGF32 prevalence estimate or established founder pedigree
Environmental exposures No exposure has been shown to specifically cause or modify SOHLH1-SPGF32 General NOA risks should not be entered as causes of this Mendelian subtype

The 2022 human study summarized its revised inheritance interpretation as:

“the heterozygous mutation of c.346-1G > A in SOHLH1 is responsible for teratozoospermia, and this homozygous mutation in SOHLH1 impairs spermatogenesis and further leads to the reduced sperm count.”
— Liu et al., Human Molecular Genetics, March 31, 2022, PMID: 34448846 [62]

That conclusion is not definitive: the homozygous patient’s father was non-carrier and maternal DNA was unavailable, so parentage, phase and full segregation were not established. [62]

2.3 Protective factors and gene–environment interaction

No disease-specific protective allele, modifier gene, diet, medication, or behavioral intervention has been demonstrated. Avoiding gonadotoxic exposures may preserve residual spermatogenesis in male infertility generally, but it cannot correct congenital loss of SOHLH1 transcriptional function.

No controlled human gene–environment interaction study exists for SPGF32. A reasonable but unproven model is that fever, testicular heat, chemotherapy, radiation, smoking or other oxidative insults could further reduce an already limited germ-cell reserve.

3. Phenotypes

Because only a handful of molecularly characterized patients exist, percentages would be misleading. Frequencies below are qualitative and evidence-specific rather than population estimates.

Phenotype Type and characteristics Onset/course Suggested HPO term Evidence
Male infertility Clinical outcome; typically recognized after unsuccessful conception Developmental lesion, usually clinically recognized in adulthood; chronic HP:0003251 Male infertility Defining feature of SPGF32 [24]
Nonobstructive azoospermia Laboratory/clinical sign: no sperm in centrifuged ejaculate because of impaired production Apparent after puberty; stable unless rare focal spermatogenesis is found HP:0011961 Nonobstructive azoospermia Canonical phenotype in Korean/Japanese cases [91][114]
Sertoli-cell-only phenotype/germ-cell aplasia Histopathology: seminiferous tubules lined by Sertoli cells without spermatogenic cells Developmental, severe, generally persistent HP:0034299 Sertoli cell-only phenotype Original disease description [93]
Severe oligozoospermia Very low sperm concentration Adult recognition; likely chronic HP:0000798 Oligospermia One homozygous c.346-1G>A patient had 4.3 million/mL [62]
Asthenozoospermia Reduced motility Adult laboratory finding HP:0012206 Asthenozoospermia Homozygous case 15% motility; heterozygotes 3–28% [62]
Teratozoospermia Abnormal sperm morphology Adult laboratory finding HP:0012864 Abnormal sperm morphology Heterozygotes had 0.9–2.5% normal forms [62]
Abnormal sperm head Round, double, tapered, pyriform, irregular or vacuolated heads Stable laboratory phenotype HP:0012865 Abnormal sperm head morphology SEM/TEM evidence [62]
Abnormal sperm flagellum Short, bent or coiled tails and irregular axonemal microtubules Stable laboratory phenotype HP:0012867 Abnormal sperm flagellum morphology SEM/TEM evidence [62]
Reduced germ-cell number/disorganization Biopsy abnormality Developmental/chronic HP:0034299 or a local histopathology term Homozygous case [62]
Primary infertility Reproductive-history finding Adult recognition HP:0000789 Infertility Reported infertility duration 3–8 years in treated cases [62]

Quality-of-life consequences

No SPGF32-specific patient-reported outcome study exists. Male infertility generally is associated with psychological distress, relationship burden, invasive fertility procedures and uncertainty about biological parenthood. A 2023 meta-analysis estimated depression in infertile men at 18.3%, while a 2024 systematic review found reported quality-of-life scores ranging from 55.15 ± 13.52 to 91.45 ± 13.66, most often 70–80%. These figures should be annotated as indirect male-infertility evidence, not SPGF32-specific estimates. [124][133]

4. Genetic and molecular information

4.1 Gene annotation

Field Value
Gene SOHLH1
Full name Spermatogenesis and oogenesis specific basic helix-loop-helix 1
HGNC HGNC:27845
NCBI Gene 402381
Ensembl ENSG00000165643
OMIM gene 610224
UniProt Q5JUK2
Locus 9q34.3
GRCh38 interval Approximately chr9:135.69–135.70 Mb
Protein class Germ-cell-enriched bHLH DNA-binding transcription regulator
Common gene aliases SPATA27, TEB2, NOHLH, bHLHe80, C9orf157

NCBI/HGNC-linked resources identify the gene as protein coding and provide HGNC:27845, NCBI Gene 402381 and ENSG00000165643. [2]

4.2 Reported variants

Variant Zygosity/phenotype Functional evidence Current interpretation
NM_001101677.2:c.346-1G>A, rs140132974; ClinVar VCV000560884.11 Heterozygous NOA, teratozoospermia or severe oligoasthenospermia; homozygous severe oligozoospermia; population homozygotes also reported Cryptic splicing/18-bp in-frame deletion, truncated bHLH domain, <50% wild-type transcriptional activity, reduced KIT promoter activation ClinVar aggregate: conflicting—1 likely pathogenic, 2 VUS, 1 benign among criteria-bearing submissions; older disease-specific submissions call it pathogenic
c.91T>C, p.Arg37Gln Reported in NOA cohort No significant reduction of KIT transactivation Not established as pathogenic
c.529C>A, p.Pro269Ser Reported in NOA cohort No significant reduction of KIT transactivation Not established as pathogenic

The recurrent allele has a ClinVar global minor allele frequency around 0.003, with reported database frequencies from 0.00031 to 0.00329 and a Finnish gnomAD frequency around 0.015; gnomAD homozygotes have been reported. Those observations are difficult to reconcile with a fully penetrant dominant cause of severe NOA. [107]

4.3 Variant origin and functional class

  • Reported variants are germline, not somatic.
  • The likely molecular mechanism is loss or marked reduction of transcription-factor function.
  • The splice allele is not a classic whole-protein null: it creates an in-frame deletion that impairs the bHLH region and reduces, rather than necessarily abolishes, transactivation.
  • There is no convincing evidence for gain of function or dominant-negative action.
  • Large causal deletions, translocations, aneuploidies or repeat expansions specifically defining SPGF32 have not been established.
  • No validated modifier gene has been identified; SOHLH2 is a biologically plausible compensatory partner but is not a proven human clinical modifier.

4.4 Epigenetics

SOHLH1 participates in a transcriptional differentiation network, but no reproducible SPGF32-specific DNA-methylation, histone-mark or chromatin signature has been established in patients. Epigenetic assays are therefore research tools, not diagnostic biomarkers.

5. Environmental and lifestyle information

Category SPGF32-specific conclusion
Toxins, radiation, pollution No evidence that they initiate genetically defined SPGF32; they are independent/general causes of impaired spermatogenesis
Heat and occupational exposure No demonstrated interaction with SOHLH1 genotype
Smoking, alcohol, obesity, diet or exercise No genotype-specific association or treatment effect established
Medications Testosterone/anabolic steroids and gonadotoxic drugs can suppress spermatogenesis generally, potentially compounding infertility, but do not define SPGF32
Infectious agents No bacterium, virus, fungus or parasite causes SPGF32
Immunity/inflammation Not a defining human mechanism; mouse knockout work detected systemic immune changes, requiring caution before extrapolation

The environmental distinction is clinically important: finding a SOHLH1 variant should not prevent assessment for reversible endocrine, toxic, infectious or obstructive contributors.

6. Mechanism and pathophysiology

6.1 Ordered causal chain

  1. A damaging germline SOHLH1 allele leads to abnormal SOHLH1 RNA splicing or reduced functional SOHLH1 protein.
  2. Loss of an intact bHLH DNA-binding/dimerization domain leads to reduced transcriptional regulation of spermatogonial differentiation genes.
  3. Reduced SOHLH1 activity leads to failure to suppress stem-cell-maintenance programs and failure to activate differentiation programs including KIT, SOX3, NGN3/NEUROG3, LHX8 and meiotic genes.
  4. Failure of that transcriptional switch leads to impaired transition of undifferentiated type-A spermatogonia into differentiating KIT-positive spermatogonia and spermatocytes.
  5. The differentiation block leads to depletion, disorganization and/or apoptosis of developing germ cells; effects on apoptosis and meiotic synaptonemal-complex formation are principally demonstrated in mice and inferred in humans.
  6. Germ-cell loss leads to hypospermatogenesis, severe oligozoospermia, maturation failure or, at the extreme, Sertoli-cell-only tubules.
  7. Reduced or absent mature sperm leads to teratozoospermia/oligoasthenozoospermia or nonobstructive azoospermia.
  8. The semen phenotype results in subfertility or male infertility.

6.2 Mechanistic detail

SOHLH1 and SOHLH2 are germ-cell-specific bHLH factors that form homo-/heterodimeric regulatory complexes. In mouse spermatogonia they directly regulate Gfra1, Sox3, Sohlh1, Sohlh2 and Kit, suppressing spermatogonial stem-cell maintenance while activating differentiation. [51]

The direct KIT link is especially relevant to the human splice allele. Deletion of either factor in male mice causes loss of KIT-positive spermatogonia, and promoter studies show that SOHLH1/SOHLH2 stimulate Kit transcription during postnatal spermatogonial differentiation. [50]

The landmark mouse abstract states:

“Loss of Sohlh1 causes infertility by disrupting spermatogonial differentiation into spermatocytes.”
— Ballow et al., Developmental Biology, June 2006, PMID: 16564520 [47]

In the original human minigene assay, c.346-1G>A produced a shortened transcript and impaired KIT-promoter activation, whereas p.Arg37Gln and p.Pro269Ser did not. This is direct in-vitro evidence for the splice defect but not proof of its penetrance in vivo. [61]

6.3 Pathways, processes and cell types

Mechanistic component Annotation suggestions Evidence level
Spermatogonial differentiation GO:0048515 spermatid differentiation; GO:0007283 spermatogenesis; use the current GO term for spermatogonial differentiation where available Strong mouse, supportive human
DNA-binding transcription regulation GO:0003700 DNA-binding transcription factor activity; GO:0006355 regulation of DNA-templated transcription Protein/function evidence
KIT signaling GO:0007169 transmembrane receptor protein tyrosine kinase signaling; KIT receptor pathway Mouse and in-vitro human
Germ-cell development GO:0007281 germ-cell development Strong mouse
Meiotic progression/synaptonemal complex GO:0007126 meiotic nuclear division; GO:0000795 synaptonemal complex Primarily mouse
Apoptosis following developmental failure GO:0006915 apoptotic process Model evidence; human inference
Spermatogonium CL:0000020 or the current more specific spermatogonial subtype Primary affected cell
Spermatocyte CL:0000017 Downstream depleted/arrested cell
Spermatid CL:0000018 Reduced downstream product
Spermatozoon CL:0000019 Absent or abnormal mature cell
Sertoli cell CL:0000216 Preserved support cell in Sertoli-cell-only histology [92]

6.4 Metabolic, immune and tissue-damage findings

No characteristic human metabolomic, lipidomic, inflammatory or immune signature is known. The 2023 knockout study detected sex-specific metabolite changes and altered immune-cell profiles, behavior and cognition in mice, despite the apparently gonad-restricted infertility phenotype. These are hypothesis-generating model findings, not established manifestations of human SPGF32. [16]

6.5 Molecular profiling and advanced technologies

  • Transcriptomics: mouse knockout/target studies show decreased differentiation genes and persistence of stem-cell programs; GEO GSE24816 contains relevant Sohlh1/Sohlh2 germ-cell transcription data. [149]
  • Single-cell analysis: single-cell RNA sequencing has helped place Sohlh1 in differentiating spermatogonia and identify upstream regulators such as Dec2, but no patient-specific SPGF32 single-cell atlas has been published. [59]
  • Proteomics/metabolomics: no validated human diagnostic profile.
  • Spatial transcriptomics/multi-omics: no disease-specific clinical implementation.
  • CRISPR/RNAi screens: no clinically actionable SPGF32 result.
  • Organoids/iPSCs: no validated patient-derived diagnostic or therapeutic platform.

7. Anatomical structures affected

Scale Structure Suggested ontology Consequence
Organ Testis UBERON:0000473 Primary and apparently direct organ involvement
Tissue Seminiferous tubule UBERON:0001343 Germ-cell depletion/Sertoli-cell-only pattern
Compartment Seminiferous epithelium Current UBERON seminiferous epithelium term Failed germ-cell differentiation
Cell population Spermatogonia CL spermatogonium terms Most upstream affected population
Cell population Spermatocytes and spermatids CL:0000017; CL:0000018 Reduced/absent downstream stages
Mature cell Spermatozoa CL:0000019 Absent, few, immotile or malformed
Supporting cell Sertoli cells CL:0000216 Retained in canonical biopsy pattern
Subcellular Nucleus/chromatin GO:0005634 nucleus; GO:0000785 chromatin Site of SOHLH1 transcriptional action
Subcellular bHLH transcription complex GO:0005667 transcription regulator complex, where appropriate Impaired DNA binding/dimerization
Sperm-specific structures Nucleus, mitochondria, axoneme, flagellum GO:0036126 sperm flagellum; GO:0005930 axoneme Abnormal in heterozygous patients’ sperm

The process is expected to affect both testes because it is a constitutional germline disorder; unilateral disease is not characteristic. No reproducible secondary-organ involvement has been documented in human males.

8. Temporal development

  • Biological onset: developmental, during establishment and postnatal differentiation of the male germ line.
  • Clinical onset: usually post-pubertal/adult, when semen is assessed because of infertility.
  • Pattern: insidious and chronic rather than acute or episodic.
  • Course: generally stable infertility; sperm count may vary between analyses, particularly with severe oligo-/cryptozoospermia.
  • Remission: spontaneous restoration of a normal sperm output has not been documented.
  • Critical window: germ-cell differentiation before and after puberty. In adulthood, the main opportunity is identification and cryopreservation of rare ejaculated or surgically retrieved sperm—not restoration of the missing developmental transcription program.
  • Stages: a formal SPGF32 staging system does not exist. Phenotypic severity can be described as abnormal morphology → oligoasthenoteratozoospermia → severe oligo-/cryptozoospermia → NOA/Sertoli-cell-only histology.

9. Inheritance and population

9.1 Inheritance

GenCC lists a strong SOHLH1–SPGF32 association and its submitted disease record labels the mode autosomal dominant. [106][32] Nevertheless, current variant-level evidence supports a more cautious entry:

Inheritance: unresolved/possibly semidominant or dosage-sensitive; autosomal-recessive loss of function is strongly plausible, while heterozygous c.346-1G>A may confer variably penetrant sperm abnormalities.

Reasons for caution include:

  1. the original heterozygous NOA cases;
  2. later heterozygous carriers with normal sperm concentration but abnormal morphology;
  3. a homozygous patient with severe quantitative failure;
  4. population homozygotes and a relatively high allele frequency;
  5. ClinVar’s current conflicting classification. [107]

Penetrance is therefore incomplete or unknown, expressivity is clearly variable, and anticipation has not been reported. Germline mosaicism remains theoretically possible but unreported. No robust founder effect or carrier frequency has been established.

9.2 Epidemiology and demographics

Measure Best available conclusion
SPGF32 prevalence Unknown; no registry-derived cases-per-100,000 estimate
SPGF32 incidence Unknown
Azoospermia prevalence Approximately 1% of men and 10–15% of infertile men, indirect context only [123]
NOA fraction Roughly 60–75% of azoospermia in general series, not SPGF32-specific [130]
Discovery cohort yield 2 heterozygous c.346-1G>A carriers among 96 Korean NOA patients (~2.1%)
Japanese replication 2 carriers among 40 idiopathic NOA patients (5%), but panel/cohort ascertainment was limited [65]
Sex ratio By disease definition, affected individuals are 46,XY males; female biallelic disease is classified separately as ovarian dysgenesis 5
Geographic evidence Cases reported mainly from Korea, Japan and China; this likely reflects study ascertainment, not proven regional restriction
Age distribution Adult men evaluated for infertility; no childhood clinical series

The c.346-1G>A population frequency varies by ancestry and may be particularly high in Finns, arguing against a simple fully penetrant dominant model. [107]

10. Diagnostics

10.1 Clinical diagnostic workflow

  1. Confirm azoospermia or quantify severe oligozoospermia with at least two semen analyses using WHO-standard methods and examination of the centrifuged pellet. EAU guidance defines NOA by no sperm after centrifugation and recommends confirmation in two consecutive samples. [85]
  2. Differentiate NOA from obstruction using history, physical examination, semen volume and pH, testicular size, and serum FSH; AUA/ASRM recommends this initial combination. [77]
  3. Hormonal assessment: FSH, LH and morning total testosterone; add prolactin/estradiol when indicated.
  4. Scrotal examination and ultrasound to assess testicular volume, varicocele or masses; ultrasound is supportive, not diagnostic of SPGF32.
  5. First-tier standard genetics for severe spermatogenic failure: karyotype and Y-chromosome AZF deletion testing according to sperm-count and guideline thresholds.
  6. Sequence-based testing: use a validated NOA/severe-oligozoospermia panel or exome/genome analysis that includes SOHLH1 and other established spermatogenic-failure genes.
  7. Confirm and phase variants by Sanger or equivalent testing and test parents/siblings where available.
  8. Interpret c.346-1G>A cautiously, explicitly acknowledging ClinVar conflict and population homozygotes.
  9. Testicular tissue evaluation should generally accompany therapeutic sperm retrieval rather than be performed solely as a diagnostic biopsy; AUA/ASRM advises against routine diagnostic biopsy to distinguish obstruction from NOA. [76]

10.2 Genetic testing modalities

Test Utility in suspected SPGF32
Targeted SOHLH1 sequencing Appropriate when phenotype/family variant strongly points to SOHLH1; include splice boundaries and deletion/duplication analysis
Multigene NOA panel Usually preferable because SPGF32 is phenotypically indistinguishable from many other genetic NOA disorders
WES Useful for coding/splice variants and novel differential diagnoses; identified the Chinese cases
WGS Potentially detects deep-intronic, regulatory and structural variants missed by WES; clinical yield specific to SPGF32 is unknown
RNA sequencing May demonstrate abnormal splicing if a suitable expressing tissue is available; blood expression may be inadequate
CMA Low yield for an isolated single-gene suspicion but can detect pathogenic copy-number changes
Karyotype Essential differential testing for Klinefelter syndrome and structural chromosome abnormalities
Y-microdeletion testing Essential differential testing in severe oligozoospermia/NOA under guideline criteria
FISH Not routine for diagnosing SPGF32
mtDNA/repeat-expansion testing Not routinely indicated
Prenatal/PGT-M testing Technically possible only after a familial variant has been convincingly classified

10.3 Pathology and biomarkers

The characteristic reported pathology is Sertoli-cell-only seminiferous tubules with absent germ cells. Other possible SOHLH1-associated patterns include sharply reduced and disorganized germ-cell stages. There is no validated serum protein, metabolite or imaging biomarker specific to SPGF32.

10.4 Differential diagnosis

Differential Distinguishing evaluation
Obstructive azoospermia Normal spermatogenesis/testicular volume and often normal FSH; low-volume acidic semen in distal obstruction
Klinefelter syndrome 47,XXY karyotype, small firm testes, hypergonadotropic profile
Y-chromosome AZFa/AZFb/AZFc deletions Targeted Y-microdeletion assay; complete AZFa/AZFb predicts essentially no retrieval
Hypogonadotropic hypogonadism Low/inappropriately normal FSH/LH and low testosterone; potentially treatable
Other monogenic NOA Panel/WES genes including TEX11, TEX14, MEIOB, STAG3, SYCE1, M1AP, DMRT1 and others
Gonadotoxic exposure, cryptorchidism, torsion or infection History and examination
Oligo-/teratozoospermia without monogenic disease Repeat semen analysis and broader etiologic assessment

10.5 Screening

There is no newborn or population screening. Appropriate strategies are cascade testing of adult relatives, reproductive counseling, and carrier/partner testing when a likely causal familial allele is found. Because c.346-1G>A classification is contested, irreversible reproductive decisions should not rely on that allele without expert re-evaluation.

11. Outcome and prognosis

  • Survival/life expectancy: no evidence of reduced survival or disease-specific mortality in humans.
  • Primary morbidity: infertility and associated psychosocial burden.
  • Endocrine health: canonical SPGF32 is primarily germ-cell failure; testosterone may be preserved, but all NOA patients require endocrine assessment.
  • Natural recovery: unlikely for Sertoli-cell-only histology; no curative restoration of spermatogenesis is established.
  • Residual sperm: genotype alone cannot reliably predict whether focal sperm production will permit retrieval.
  • Prognostic biomarkers: testicular histology, testis volume, FSH and testosterone may inform general NOA counseling but do not reliably determine individual micro-TESE success; no SOHLH1-specific biomarker exists.
  • Complications: emotional distress, repeated invasive procedures, and possible transmission of a pathogenic allele through ICSI.

Across heterogeneous NOA—not specifically SPGF32—systematic-review evidence suggests surgical sperm retrieval up to about 50% and live birth up to 28% after use of retrieved sperm. These aggregate rates should not be presented as a genotype-specific prognosis. [155]

12. Treatment

There is no approved drug, gene therapy, RNA therapy or cell therapy that restores SOHLH1 function. Management is reproductive rather than disease-modifying.

Intervention Role and evidence Suggested NCIt concept
Repeat semen search and sperm cryopreservation Preserve rare ejaculated sperm in severe oligo-/cryptozoospermia Sperm Cryopreservation
Microdissection testicular sperm extraction Preferred retrieval procedure for NOA candidates pursuing ART; outcome in Sertoli-cell-only disease may be poor Testicular Sperm Extraction, Surgical Procedure
Intracytoplasmic sperm injection Uses ejaculated or testicular sperm to fertilize an oocyte Intracytoplasmic Sperm Injection
IVF ART framework within which ICSI is performed In Vitro Fertilization
Donor sperm Option if retrieval fails or transmission risk is unacceptable Therapeutic Donor Insemination
Adoption or child-free living Nonmedical family-building options No specific drug/intervention term
Psychological counseling Addresses distress and decision burden Psychological Counseling
Hormonal treatment Treat documented hypogonadotropic hypogonadism, not primary SOHLH1 deficiency; empiric pretreatment before retrieval has limited evidence Hormone Therapy, Gonadotropin Therapy
Varicocele repair Only for an independently indicated clinical varicocele; benefit before ART in NOA is uncertain Varicocelectomy
Gene replacement/editing Preclinical concept only; no trial or validated germline-safe method Gene Therapy, experimental

AUA/ASRM recommends microdissection TESE for men with NOA undergoing retrieval and permits fresh or cryopreserved sperm for ICSI. [83]

Patient-specific published outcomes

In the 2022 series, ICSI was attempted in one homozygous severe-oligozoospermia patient and two heterozygous teratozoospermia patients; pregnancies and successful deliveries were reported. In the homozygous case, 7/10 injected oocytes fertilized and transfer of a later 4AB embryo produced a healthy baby. These are uncontrolled individual outcomes, not a response rate. [62]

Experimental treatment status

No SPGF32-specific ClinicalTrials.gov intervention, gene therapy, ASO, siRNA, stem-cell transplantation or CRISPR trial was identified. Germline editing is not an acceptable clinical prevention or treatment strategy.

13. Prevention

Primary prevention

The inherited molecular lesion cannot be prevented by diet, vaccination or lifestyle. Avoiding unnecessary testicular heat, tobacco, anabolic steroids, gonadotoxic chemicals and radiation is reasonable for general fertility preservation but is not proven to prevent SPGF32.

Secondary prevention

  • Early evaluation of men from affected families.
  • Semen analysis after puberty when clinically appropriate.
  • Cryopreservation if sperm are present.
  • Cascade genetic testing after expert variant interpretation.
  • Partner testing if a recessive pathogenic allele is confirmed.

Tertiary prevention

  • Avoid prolonged empiric therapies that delay retrieval when residual spermatogenesis may decline.
  • Offer fertility-preservation and ART counseling.
  • Monitor endocrine and psychological health.
  • Provide reproductive genetic counseling before ICSI.

Reproductive prevention options

For a well-established pathogenic familial genotype, options include natural conception with prenatal diagnosis, IVF with PGT-M, donor gametes or adoption. With c.346-1G>A, counseling must emphasize conflicting pathogenicity and unresolved heterozygous penetrance. No immunization, medication prophylaxis or public-health control program is applicable.

14. Other species and naturally occurring disease

Species Taxonomy/ortholog Evidence
Human, Homo sapiens NCBI Taxon 9606; SOHLH1, NCBI Gene 402381 Natural Mendelian infertility
Mouse, Mus musculus NCBI Taxon 10090; Sohlh1, NCBI Gene 227631, MGI:2684956 Engineered knockout causes male and female infertility [136]
Other mammals Orthologs are evolutionarily conserved Functional conservation is inferred, but no well-established breed-specific natural veterinary SPGF32 counterpart was identified

No breed-associated OMIA disorder, cross-species transmission or zoonotic potential applies. This is a constitutional genetic disorder, not an infectious disease.

15. Model organisms

15.1 Mouse models

Model Phenotype recapitulation Uses and limitations
Sohlh1 targeted null, MGI allele Sohlh1^tm1Rajk, MGI:3629211 Homozygous males have reduced testis weight, failed differentiation of spermatogonia into spermatocytes and infertility; females rapidly lose oocytes/follicles Strong mechanistic model of complete loss of function; may be more severe than common human splice alleles [146]
Sohlh1 knockout used in 2023 systemic phenotyping Impaired spermatogenesis plus immune-profile, metabolite and behavioral/cognitive alterations Useful for pleiotropy and safety studies; extragonadal findings are not confirmed in humans [16]
Sohlh1-CreER targeted line, MGI:5548125 Enables temporally controlled lineage manipulation Tool model rather than a direct disease model [142]
Germ-cell and promoter-reporter systems Demonstrate direct regulation of KIT and interactions with SOHLH2 Simplified in-vitro systems cannot model human penetrance or complete testicular architecture

The 2023 mouse study’s abstract states:

“The Sohlh1 knockout mouse model… presents with… impaired spermatogenesis in males,” but extragonadal phenotyping also found “abnormal immune profiles… sex-specific alterations of metabolites, and behavior and cognition changes.”
— Rodríguez-Escribà et al., Biology of Reproduction, April 2023, PMID: 36723967 [16]

15.2 Model validity

Strengths

  • Recapitulates germ-cell differentiation failure and infertility.
  • Establishes temporal order from transcription-factor loss to spermatogonial arrest.
  • Permits testicular histology, cell sorting, ChIP, transcriptomics and fertility studies.
  • Demonstrates biologic plausibility for human splice-variant findings.

Limitations

  • Complete knockout is not equivalent to partial-function c.346-1G>A.
  • Human heterozygous penetrance is much less clear than mouse homozygous-null penetrance.
  • Mouse spermatogenic timing and genetic background differ from humans.
  • Human Sertoli-cell-only pathology and ICSI outcomes cannot be fully modeled.
  • Reported systemic mouse phenotypes should not be entered as human SPGF32 manifestations without clinical corroboration.

Overall evidence assessment

Domain Assessment
Gene–disease relationship Supported/strong, especially by conserved biology, human functional assays and knockout mice
Canonical phenotype Male infertility with severe spermatogenic failure, classically NOA and Sertoli-cell-only histology
Key variant c.346-1G>A is functionally splice-altering but has conflicting clinical classification
Inheritance Historically reported autosomal dominant/de novo; current evidence also supports recessive/dosage-dependent disease and incomplete heterozygous penetrance
Epidemiology Unknown at disease-specific level
Diagnostic standard Confirm spermatogenic failure, exclude common cytogenetic/Y-linked/endocrine causes, then panel/WES/WGS with segregation
Curative therapy None
Current implementation Sperm preservation or micro-TESE followed by ICSI; donor sperm if retrieval fails
Main research need Larger ancestry-diverse cohorts with rigorous semen phenotyping, parental phasing, population penetrance analysis and functional comparison of heterozygous versus biallelic alleles

The principal knowledge-base caution is therefore to retain SOHLH1 as the causal gene for MONDO:0020855, but not encode c.346-1G>A as an unquestionably fully penetrant dominant pathogenic allele. Its molecular effect is well supported; its clinical penetrance and mode of inheritance are not.

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome Count
References checked 18
Resolved 18
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 18
On topic 7
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 37
Resolved 31
Unresolved (possible confabulation) 0
Obsolete 1
Unverifiable 5
Terms whose name was checked 7
Terms named correctly 4
Terms named as a different term 1
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:

  • MONDO:0020855 (4 mentions) - the report calls it "MONDO"; MONDO calls it spermatogenic failure 32

Obsolete terms

These terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:

  • GO:0007126 (GO_0007126) (1 mention) - replaced by GO:0051321

Terms whose name is worth a second look

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

  • CL:0000019 (2 mentions) - the report calls it "Spermatozoon", "Spermatozoa"; CL calls it sperm, and lists "spermatozoid" among its other names
  • UBERON:0001343 (1 mention) - the report calls it "Seminiferous tubule"; UBERON calls it seminiferous tubule of testis, and lists "seminiferous tubule" among its other names

Terms named inconsistently

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

  • CL:0000019 - called "Spermatozoon", "Spermatozoa"
  • CL:0000216 - called "Sertoli cell", "Sertoli cells"

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: ORPHA, MGI.