👪

Inheritance

1

Autosomal recessive HP:0000007

Disease requires biallelic TEX14 variants. Reported genotypes include homozygous stop-gain and frameshift variants, a compound heterozygous multi-exon deletion with a truncating allele, and a compound heterozygous missense and nonsense pair.

Autosomal recessive inheritance

Show evidence (2 references)

PMID:32741963 SUPPORT Human clinical

"11-063 is compound-heterozygous for a ~38Kb deletion comprising exons 6 to 21"

One of two unrelated men is compound heterozygous for a multi-exon deletion and a frameshift; the other carries a homozygous stop-gain. Both genotypes are biallelic, consistent with recessive inheritance.

PMID:40492599 SUPPORT Human clinical

"Our findings provide robust evidence that pathogenic biallelic TEX14 mutations are recurrent genetic etiologies of NOA in humans."

Biallelic (compound heterozygous) variants in a further patient.

◈

Mechanistic Hypotheses

1

TEX14 loss causes male-restricted infertility because female germ cells do not need the bridges for fertility

tex14_male_restricted_phenotype EMERGING

Evidence balance 2 support

TEX14 forms intercellular bridges in both male and female embryonic germ cells, but Tex14-null female mice are fertile, with fewer oocytes and altered germline cysts. Only men have been reported with SPGF23, and fertility in women with biallelic TEX14 variants has not been studied.

Show evidence (2 references)

PMID:19020301 SUPPORT Model organism

"Despite the absence of embryonic intercellular bridges in the Tex14-null mice, male mice initiate spermatogenesis, and female mice are fertile."

Female Tex14-null mice are fertile despite lacking bridges.

PMID:34156079 SUPPORT INDIRECT Model organism

"In Tex14 homozygous mutant fetal ovaries, germ cells divide to form a reduced number of cysts in which germ cells remained connected via syncytia or fragmented cell membranes, rather than normal intercellular bridges."

Female germ cells are still affected, so the sparing is of fertility and not of the ovary itself.

?

Discussions and Knowledge Gaps

1

Why do TEX14 carriers range from Sertoli-cell-only and spermatogonial arrest to zygotene or pachytene meiotic arrest?

KNOWLEDGE GAP tex14_arrest_stage_heterogeneity

Attached to

phenotypes#Spermatogonial maturation arrest

Tex14-null mice arrest in meiosis but also show reduced, asynchronous spermatogonial output, so the earlier arrest seen in some men may reflect progressive germ cell loss, allele severity, or age at biopsy. The reports are too few to tell these apart.

Show evidence (1 reference)

PMID:32741963 SUPPORT REVIEW SYNTHESIS Human clinical

"For two of them, TEX14 and DMRT1, the previously described testis phenotypes are heterogeneous"

The heterogeneity is noted by the authors.

⚙

Pathophysiology

5

Loss of TEX14 Function

Most reported alleles are truncating. Loss of TEX14 protein has been shown for a compound heterozygous missense and nonsense pair and for a knock-in of a patient frameshift in mice; the splice and missense alleles from the other reports have not been tested. TEX14 is a catalytically inactive kinase-like protein. Its conserved AxGPPx3Y motif binds the EABR domain of CEP55 and competes with ALIX and TSG101, the ESCRT-associated factors that CEP55 recruits to complete abscission in somatic cells.

TEX14 hgnc:11737

Negative regulation of cytokinesis GO:0032466 ↓ DECREASED

Protein sequestering activity GO:0140311 ↓ DECREASED

Downstream

Failed Germ Cell Intercellular Bridge Formation Without TEX14 the midbody of a dividing germ cell is not converted into a stable intercellular bridge.

Show evidence (5 references)

PMID:20176808 SUPPORT In vitro / ex vivo

"an evolutionarily conserved GPPX3Y motif of TEX14 binds strongly to CEP55 to block similar GPPX3Y motifs of ALIX and TSG101 from interacting and localizing to the midbody"

Molecular basis of the TEX14 block on abscission.

PMID:26392564 SUPPORT In vitro / ex vivo

"TEX14 competitively binds to CEP55-EABR to prevent the recruitment of ALIX, which is a component of the ESCRT machinery with the AxGPPx3Y motif."

Crystal structure and binding data for the TEX14-CEP55 interaction.

PMID:21669984 SUPPORT REVIEW SYNTHESIS Other

"TEX14 is an inactive kinase essential for the maintenance of stable intercellular bridges in gametes of both sexes but whose loss specifically impairs male meiosis."

Review summarizing TEX14 as an inactive kinase required for germ cell bridges.

+ 2 more references

Failed Germ Cell Intercellular Bridge Formation

Dividing spermatogonia and spermatocytes do not form the stable intercellular bridges that normally connect a clone of germ cells into a syncytium. Bridges are absent by electron microscopy and bridge markers in Tex14-null mice and in patient testes, and the cytoplasmic sharing of transcripts between connected germ cells is reduced.

Spermatogonium CL:0000020 Primary spermatocyte CL:0000656

Intercellular bridge organization GO:0043063 ↓ DECREASED

Intercellular bridge GO:0045171

Animal models

Tex14 knockout mouse Mouse recapitulates The knockout removes the bridges, as in patient testes.

Downstream

Asynchronous Spermatogonial Differentiation

Meiotic Prophase I Failure in Spermatocytes

Retrotransposon Derepression in Meiotic Germ Cells

Show evidence (4 references)

PMID:16549803 SUPPORT Model organism

"In the absence of TEX14, intercellular bridges are not observed by using electron microscopy and other markers."

Bridges are absent in Tex14-null mouse testes.

PMID:40492599 SUPPORT Human clinical

"This led to spermatogenic failure characterized by meiotic arrest at the pachytene stage and impaired ICB assembly in the testes harboring the mutations."

Impaired bridge assembly in a patient's testis.

PMID:41603674 SUPPORT Human clinical

"Consistent with this, testicular histology from the patient carrying the c.2908dupC variant also showed meiotic arrest at zygotene and absent ICBs."

Absent bridges in a further patient's testis.

+ 1 more reference

Asynchronous Spermatogonial Differentiation

Without bridges, spermatogonia still proliferate and differentiate, but in lower numbers and out of step with one another. Whether this explains the spermatogonial arrest seen in some patients is open (see the discussion on arrest-stage heterogeneity), so no edge is drawn to that phenotype.

Spermatogonium CL:0000020

Show evidence (1 reference)

PMID:32438343 SUPPORT Model organism

"Thus although spermatogonial development is able to proceed, in the absence of ICBs in Tex14-/- mutants, the yield of cells, specific steps of differentiation, the synchrony of the cell kinetics, and the subsequent progression in meiosis are quantitatively lower than normal."

Quantitative spermatogonial defects in Tex14-null mice.

Retrotransposon Derepression in Meiotic Germ Cells

Bridge-deficient spermatocytes derepress retrotransposons and accumulate retrotransposon-encoded proteins. The authors propose that bridges protect germline genome integrity; whether this causes the arrest or accompanies it is not established, so no edge is drawn from this node.

Primary spermatocyte CL:0000656

Animal models

Tex14 hypomorph mouse Mouse recapitulates Bridge-deficient mice show retrotransposon derepression during meiosis; this has not been examined in patients.

Show evidence (1 reference)

PMID:39929837 SUPPORT Model organism

"They also derepress retrotransposons and accumulate retrotransposon-encoded proteins during meiosis."

Retrotransposon derepression in Tex14-deficient mouse spermatocytes.

Meiotic Prophase I Failure in Spermatocytes

Spermatocytes enter meiosis and express early meiotic markers but fail to complete meiotic DNA replication, homolog synapsis and double-strand break repair, and arrest before the first meiotic division. The reported arrest point is zygotene in a knock-in mouse and one patient, and pachytene in another patient.

Primary spermatocyte CL:0000656

Male meiosis I GO:0007141 ↓ DECREASED

Animal models

Tex14 MT1 knock-in mouse Mouse recapitulates Zygotene arrest in the mouse matches the arrest stage in the patient carrying the same allele.

Finnish Yorkshire boar with Tex14 exon 27 insertion Pig recapitulates Early meiotic arrest in a large-animal model with a truncating allele.

Downstream

Spermatocyte maturation arrest

Non-obstructive azoospermia No germ cells complete meiosis, so no sperm are produced.

Male infertility Infertility follows from the absence of sperm.

Show evidence (4 references)

PMID:16549803 SUPPORT Model organism

"Spermatogenesis in Tex14(-/-) mice progresses through the transit amplification of diploid spermatogonia and the expression of early meiotic markers but halts before the completion of the first meiotic division."

Meiotic arrest before the first division in Tex14-null mice.

PMID:39929837 SUPPORT Model organism

"We report that in males deficient for TEX14 and intercellular bridges, germ cells fail to complete meiotic DNA replication, synapsis and meiotic double-strand break repair."

Names the meiotic prophase events that fail.

PMID:40492599 SUPPORT Human clinical

"This led to spermatogenic failure characterized by meiotic arrest at the pachytene stage and impaired ICB assembly in the testes harboring the mutations."

Pachytene arrest in a patient.

+ 1 more reference

⬡

Pathograph

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

●

Phenotypes

5

Male infertility Reproductive HP:0003251

Show evidence (1 reference)

PMID:41603674 SUPPORT Human clinical

"We identified six novel TEX14 variants in four unrelated infertile Chinese men"

Infertile men carrying TEX14 variants.

Non-obstructive azoospermia VERY_FREQUENT Reproductive HP:0011961

Show evidence (2 references)

PMID:40492599 SUPPORT Human clinical

"we identified a novel compound heterozygous mutation in TEX14 (c.802A>T, p.S268C and c.1021C>T, p.R341*) in a patient with NOA"

Non-obstructive azoospermia in a biallelic carrier.

PMID:28206990 SUPPORT Human clinical

"We identified three novel likely causative mutations of azoospermia in three genes: MEIOB, TEX14, and DNAH6."

The founding report of TEX14 as a human azoospermia gene.

Spermatocyte maturation arrest Reproductive HP:0031039

Show evidence (3 references)

PMID:41603674 SUPPORT Human clinical

"Consistent with this, testicular histology from the patient carrying the c.2908dupC variant also showed meiotic arrest at zygotene and absent ICBs."

Zygotene arrest in a patient.

PMID:40492599 SUPPORT Human clinical

"This led to spermatogenic failure characterized by meiotic arrest at the pachytene stage and impaired ICB assembly in the testes harboring the mutations."

Pachytene arrest in a patient.

PMID:28206990 SUPPORT INDIRECT Human clinical

"Our objective was to uncover novel human mutations and genes causing azoospermia due to testicular meiotic maturation arrest."

The founding families were ascertained for meiotic maturation arrest.

Spermatogonial maturation arrest Reproductive HP:4000187

Show evidence (1 reference)

PMID:32741963 SUPPORT Human clinical

"We identified two homozygous LoF variants in TEX14 in two unrelated patients affected by incomplete spermatogonial arrest."

Spermatogonial arrest in two unrelated patients.

Sertoli cell-only phenotype Reproductive HP:0034299

Show evidence (1 reference)

PMID:32741963 SUPPORT REVIEW SYNTHESIS Human clinical

"Previously reported TEX14 variants were associated with testis histology ranging from SCO to complete SCA"

Summarizes earlier reports as ranging from Sertoli-cell-only to complete spermatocyte arrest.

🧬

Genetic Associations

1

TEX14 (Causal)

Gene: TEX14 hgnc:11737

Show evidence (7 references)

PMID:28206990 SUPPORT Human clinical

"We identified three novel likely causative mutations of azoospermia in three genes: MEIOB, TEX14, and DNAH6."

Primary gene-disease report.

PMID:29790874 SUPPORT Human clinical

"In five of eight families, we identified rare deleterious recessive variants in CCDC155, NANOS2, SPO11, TEX14, and WNK3 segregating with disease"

A recessive TEX14 variant segregating with infertility in a second family.

PMID:32741963 SUPPORT Human clinical

"With the discovery of the two new TEX14 variant carriers, this gene can now be upgraded to strong clinical evidence."

Independent replication raising the clinical evidence level.

+ 4 more references

💊

Medical Actions

2

Avoidance of Futile Testicular Sperm Extraction

Action: testicular sperm retrieval Ontology label: Sperm Retrieval NCIT:C94427

Platform: Surgery

In the carriers whose outcome is reported, no sperm were retrieved by testicular sperm extraction, and panel studies class TEX14 among the meiotic genes with a poor retrieval prognosis. One of the two studies recruited only men with negative retrieval, so its carriers show the association but not its rate. A molecular diagnosis therefore supports counselling about the low chance of retrieval before surgery, and about donor sperm or adoption; it is not a certainty.

Show evidence (2 references)

PMID:33728612 SUPPORT Human clinical

"Only the patient with NR5A1 mutations produced viable spermatozoa through micro-TESE, but other patients with TEX11 and TEX14 had poor micro-TESE prognoses."

TEX14 carriers in this cohort had a poor micro-TESE prognosis, unlike the NR5A1 carrier.

PMID:32741963 SUPPORT INDIRECT Human clinical

"We conclude that TEX14 defects are a relatively frequent cause of NOA due to SCO or early MA with TESE negative outcome."

TESE was negative in the TEX14 carriers, but the discovery cohort was recruited from TESE-negative men, so this shows the association rather than a retrieval rate.

Genetic Counseling

Action: Genetic Counseling NCIT:C15240

Platform: Behavioral / lifestyle

Counselling on autosomal recessive recurrence, carrier testing of relatives once the familial TEX14 alleles are known, and the poor prognosis for sperm retrieval.

Show evidence (1 reference)

PMID:33728612 SUPPORT INDIRECT Human clinical

"Considering previous reports, we suggest that only a few genes that are directly linked to meiosis can indicate poor micro-TESE prognosis, such as TEX11, TEX14, and SYCE1."

A TEX14 result carries prognostic information that belongs in counselling.

🔬

Diagnosis

2

Molecular Genetic Testing

Establishes the diagnosis, usually by exome, genome or a non-obstructive azoospermia gene panel. Copy-number analysis matters as well as sequencing, since one reported allele is a multi-exon deletion.

Genetic Testing NCIT:C15709

Show evidence (3 references)

PMID:41603674 SUPPORT Human clinical

"Exome sequencing was performed on genomic DNA from a cohort of 673 patients with NOA, 143 individuals with oligozoospermia, and 100 fertile controls."

Exome sequencing identified the carriers.

PMID:32741963 SUPPORT Human clinical

"11-063 is compound-heterozygous for a ~38Kb deletion comprising exons 6 to 21"

A multi-exon deletion allele, which sequencing alone could miss, so copy-number analysis is needed.

PMID:33728612 SUPPORT Human clinical

"Mutations in TEX11, TEX14, and NR5A1 genes are recurrent causes of NOA, but each gene explains only a very small percentage"

Panel sequencing detects TEX14 among other recurrent genes.

Testicular biopsy

Shows meiotic arrest, spermatogonial arrest or Sertoli-cell-only tubules. Where examined, bridges are absent.

testicular biopsy NCIT:C15189

Show evidence (1 reference)

PMID:41603674 SUPPORT Human clinical

"Consistent with this, testicular histology from the patient carrying the c.2908dupC variant also showed meiotic arrest at zygotene and absent ICBs."

Biopsy findings in a patient.

🐁

Animal Models

4

Tex14 knockout mouse

Male Tex14 knockout mice lack germ cell intercellular bridges and are sterile, with arrest before the first meiotic division. Females are fertile.

Species

Mouse

Genotype

Tex14-/- (knockout), homozygous

Publication

PMID:16549803

Pathograph links

Failed Germ Cell Intercellular Bridge Formation recapitulates fidelity: high observes: cellular The knockout removes the bridges, as in patient testes.

Show evidence (1 reference)

PMID:16549803 SUPPORT Model organism

"Thus, TEX14 is required for intercellular bridges in vertebrate germ cells, and these studies provide evidence that the intercellular bridge is essential for spermatogenesis and fertility."

Bridge loss and male sterility in the knockout.

Tex14 MT1 knock-in mouse

A knock-in of an allele analogous to a patient frameshift abolishes TEX14 in the testis, prevents bridge formation and arrests spermatogenesis at zygotene, matching the patient's testicular histology.

Species

Mouse

Genotype

Tex14 MT1/MT1, modelling the patient c.2908dupC frameshift

Publication

PMID:41603674

Pathograph links

Meiotic Prophase I Failure in Spermatocytes recapitulates fidelity: high observes: cellular Zygotene arrest in the mouse matches the arrest stage in the patient carrying the same allele.

Show evidence (1 reference)

PMID:41603674 SUPPORT Model organism

"Immunofluorescence and histological analyses revealed that spermatogenesis in Tex14MT1/MT1 mice was arrested at the zygotene stage due to a complete failure of the ICB formation."

Zygotene arrest in the knock-in.

Tex14 hypomorph mouse

A hypomorphic allele reduces rather than abolishes bridges. Together with Tex14-null mice it showed failed meiotic DNA replication, synapsis and double-strand break repair, retrotransposon derepression, and reduced transcript sharing between connected germ cells.

Species

Mouse

Genotype

Tex14 hypomorphic allele, homozygous, with reduced intercellular bridges

Publication

PMID:39929837

Pathograph links

Retrotransposon Derepression in Meiotic Germ Cells recapitulates fidelity: moderate observes: cellular Bridge-deficient mice show retrotransposon derepression during meiosis; this has not been examined in patients.

Show evidence (1 reference)

PMID:39929837 SUPPORT Model organism

"Here we utilized a Tex14 hypomorph with reduced intercellular bridges along with Tex14-null mice that completely lack bridges to examine the roles of germ cell connectivity during spermatogenesis."

Describes the hypomorph and its use alongside the null.

Finnish Yorkshire boar with Tex14 exon 27 insertion

A naturally occurring insertion causes aberrant splicing, a premature stop codon and loss of TEX14 protein, with spermatogenic arrest at an early meiotic phase and no spermatozoa.

Species

Pig

Genotype

51 bp insertion in Tex14 exon 27

Publication

PMID:22136159

Pathograph links

Meiotic Prophase I Failure in Spermatocytes recapitulates fidelity: moderate observes: cellular Early meiotic arrest in a large-animal model with a truncating allele.

Show evidence (1 reference)

PMID:22136159 SUPPORT Model organism

"Sequencing of a candidate gene Tex14 revealed a 51 bp insertion within exon 27, which caused differential splicing of the exon and created a premature translation stop codon."

A truncating Tex14 allele in pigs with spermatogenic arrest.

{ }

Source YAML

click to show

name: Spermatogenic Failure 23
creation_date: "2026-10-17T00:00:00Z"
category: Mendelian
synonyms:
- SPGF23
- spermatogenic failure 23
- TEX14-related non-obstructive azoospermia
- TEX14-related spermatogenic failure
description: >-
  Spermatogenic failure 23 (SPGF23) is autosomal recessive male infertility
  with non-obstructive azoospermia caused by biallelic loss-of-function
  variants in TEX14. TEX14 is a testis-expressed, catalytically inactive
  kinase-like protein that is recruited to the midbody of dividing germ cells,
  binds CEP55 and blocks abscission, converting the midbody into a stable
  intercellular bridge. In the absence of TEX14 the bridges that link clones
  of male germ cells do not form, and spermatogenesis fails; in the mouse
  models and in some patients the arrest is in meiotic prophase I.

  Affected men present with primary infertility and azoospermia. Testicular
  histology is heterogeneous between reports, ranging from Sertoli-cell-only
  tubules and incomplete spermatogonial arrest to meiotic arrest at the
  zygotene or pachytene stage. No sperm were retrieved in the carriers whose
  testicular sperm extraction outcome is reported, though one of those cohorts
  was selected for negative retrieval. Tex14 knockout mice and a pig line with a truncating
  Tex14 insertion reproduce meiotic arrest and male sterility, while Tex14-null
  female mice are fertile.
disease_term:
  preferred_term: spermatogenic failure 23
  term:
    id: MONDO:0054727
    label: spermatogenic failure 23
parents:
- Spermatogenic Failure
- Genetic Disease
notes: >-
  No GeneReviews chapter covers this disease. TEX14 was first named as a human
  azoospermia gene in a familial exome study of meiotic maturation arrest
  (PMID:28206990) and in a second family exome study (PMID:29790874), and has
  since been found in exome, genome and panel cohorts
  of non-obstructive azoospermia (PMID:32741963, PMID:33728612, PMID:36017582,
  PMID:39843174, PMID:40896145) and in single-family and cohort reports with
  functional work (PMID:40492599, PMID:41603674). The reported arrest stage
  differs between studies, which Krausz et al. (PMID:32741963) note
  explicitly, so the histological phenotypes below are recorded as variable
  rather than as a single arrest point. This entry is not added to the Meiotic
  Gametogenic Failure grouping: that grouping is defined by a defect of the
  meiotic prophase I pairing and recombination machinery, whereas TEX14 acts
  upstream on germ cell connectivity, and whether its meiotic failure conforms
  to the grouping's module is a separate decision.
inheritance:
- name: Autosomal recessive
  description: >-
    Disease requires biallelic TEX14 variants. Reported genotypes include
    homozygous stop-gain and frameshift variants, a compound heterozygous
    multi-exon deletion with a truncating allele, and a compound heterozygous
    missense and nonsense pair.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:32741963
    reference_title: "Genetic dissection of spermatogenic arrest through exome analysis: clinical implications for the management of azoospermic men."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "11-063 is compound-heterozygous for a ~38Kb deletion comprising exons 6 to 21"
    explanation: >-
      One of two unrelated men is compound heterozygous for a multi-exon
      deletion and a frameshift; the other carries a homozygous stop-gain.
      Both genotypes are biallelic, consistent with recessive inheritance.
  - reference: PMID:40492599
    reference_title: "A Novel Compound Heterozygous Mutation in TEX14 Causes Human Non-Obstructive Azoospermia by Disrupting the Assembly of Intercellular Bridges."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our findings provide robust evidence that pathogenic biallelic TEX14 mutations are recurrent genetic etiologies of NOA in humans."
    explanation: Biallelic (compound heterozygous) variants in a further patient.
pathophysiology:
- name: Loss of TEX14 Function
  description: >-
    Most reported alleles are truncating. Loss of TEX14 protein has been shown
    for a compound heterozygous missense and nonsense pair and for a
    knock-in of a patient frameshift in mice; the splice and missense alleles
    from the other reports have not been tested. TEX14 is a catalytically inactive
    kinase-like protein. Its conserved AxGPPx3Y motif binds the EABR domain of
    CEP55 and competes with ALIX and TSG101, the ESCRT-associated factors that
    CEP55 recruits to complete abscission in somatic cells.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: TEX14
    term:
      id: hgnc:11737
      label: TEX14
  molecular_functions:
  - preferred_term: Protein sequestering activity
    modifier: DECREASED
    term:
      id: GO:0140311
      label: protein sequestering activity
  biological_processes:
  - preferred_term: Negative regulation of cytokinesis
    modifier: DECREASED
    term:
      id: GO:0032466
      label: negative regulation of cytokinesis
  downstream:
  - target: Failed Germ Cell Intercellular Bridge Formation
    causal_link_type: DIRECT
    description: >-
      Without TEX14 the midbody of a dividing germ cell is not converted into a
      stable intercellular bridge.
    evidence:
    - reference: PMID:20176808
      reference_title: "TEX14 interacts with CEP55 to block cell abscission."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Thus, TEX14 prevents the completion of cytokinesis by altering the destiny of CEP55 from a nidus for abscission to an integral component of the intercellular bridge."
      explanation: Places TEX14 at the step that turns the midbody into a bridge instead of letting abscission complete.
    - reference: PMID:17383626
      reference_title: "Conversion of midbodies into germ cell intercellular bridges."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "TEX14 co-localizes with the centralspindlin complex, mitotic kinesin-like protein 1 (MKLP1) and male germ cell Rac GTPase-activating protein (MgcRacGAP) and converts these midbody matrix proteins into stable intercellular bridge components."
      explanation: TEX14 converts midbody proteins into stable bridge components in mouse germ cells.
  evidence:
  - reference: PMID:20176808
    reference_title: "TEX14 interacts with CEP55 to block cell abscission."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "an evolutionarily conserved GPPX3Y motif of TEX14 binds strongly to CEP55 to block similar GPPX3Y motifs of ALIX and TSG101 from interacting and localizing to the midbody"
    explanation: Molecular basis of the TEX14 block on abscission.
  - reference: PMID:26392564
    reference_title: "Structural and biochemical insights into the role of testis-expressed gene 14 (TEX14) in forming the stable intercellular bridges of germ cells."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "TEX14 competitively binds to CEP55-EABR to prevent the recruitment of ALIX, which is a component of the ESCRT machinery with the AxGPPx3Y motif."
    explanation: Crystal structure and binding data for the TEX14-CEP55 interaction.
  - reference: PMID:21669984
    reference_title: "Germ cell intercellular bridges."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "TEX14 is an inactive kinase essential for the maintenance of stable intercellular bridges in gametes of both sexes but whose loss specifically impairs male meiosis."
    explanation: Review summarizing TEX14 as an inactive kinase required for germ cell bridges.
  - reference: PMID:40492599
    reference_title: "A Novel Compound Heterozygous Mutation in TEX14 Causes Human Non-Obstructive Azoospermia by Disrupting the Assembly of Intercellular Bridges."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Functional analyses demonstrated that these mutations disrupted TEX14 synthesis."
    explanation: Patient variants abolish TEX14 protein production.
  - reference: PMID:41603674
    reference_title: "Pathogenic TEX14 Variants Disrupt Intercellular Bridge Formation, Causing Meiotic Arrest and Non-Obstructive Azoospermia in Humans and Mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "These mice recapitulated the human NOA phenotype, showing a complete loss of TEX14 expression in the testis."
    explanation: A mouse knock-in of a patient frameshift allele abolishes testicular TEX14.
- name: Failed Germ Cell Intercellular Bridge Formation
  description: >-
    Dividing spermatogonia and spermatocytes do not form the stable
    intercellular bridges that normally connect a clone of germ cells into a
    syncytium. Bridges are absent by electron microscopy and bridge markers in
    Tex14-null mice and in patient testes, and the cytoplasmic sharing of
    transcripts between connected germ cells is reduced.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: Spermatogonium
    term:
      id: CL:0000020
      label: spermatogonium
  - preferred_term: Primary spermatocyte
    term:
      id: CL:0000656
      label: primary spermatocyte
  biological_processes:
  - preferred_term: Intercellular bridge organization
    modifier: DECREASED
    term:
      id: GO:0043063
      label: intercellular bridge organization
  cellular_components:
  - preferred_term: Intercellular bridge
    term:
      id: GO:0045171
      label: intercellular bridge
  downstream:
  - target: Asynchronous Spermatogonial Differentiation
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:32438343
      reference_title: "Spermatogonial asynchrony in Tex14 mutant mice lacking intercellular bridges."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Thus although spermatogonial development is able to proceed, in the absence of ICBs in Tex14-/- mutants, the yield of cells, specific steps of differentiation, the synchrony of the cell kinetics, and the subsequent progression in meiosis are quantitatively lower than normal."
      explanation: Bridge loss reduces spermatogonial yield and synchrony in Tex14-null mice.
  - target: Meiotic Prophase I Failure in Spermatocytes
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:39929837
      reference_title: "Intercellular bridges are essential for transposon repression and meiosis in the male germline."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "We report that in males deficient for TEX14 and intercellular bridges, germ cells fail to complete meiotic DNA replication, synapsis and meiotic double-strand break repair."
      explanation: Links bridge loss to failure of the core meiotic prophase events.
    - reference: PMID:41603674
      reference_title: "Pathogenic TEX14 Variants Disrupt Intercellular Bridge Formation, Causing Meiotic Arrest and Non-Obstructive Azoospermia in Humans and Mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Immunofluorescence and histological analyses revealed that spermatogenesis in Tex14MT1/MT1 mice was arrested at the zygotene stage due to a complete failure of the ICB formation."
      explanation: The authors attribute zygotene arrest to the failure of bridge formation.
  - target: Retrotransposon Derepression in Meiotic Germ Cells
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:39929837
      reference_title: "Intercellular bridges are essential for transposon repression and meiosis in the male germline."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "They also derepress retrotransposons and accumulate retrotransposon-encoded proteins during meiosis."
      explanation: Bridge-deficient germ cells derepress retrotransposons during meiosis.
  evidence:
  - reference: PMID:16549803
    reference_title: "TEX14 is essential for intercellular bridges and fertility in male mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "In the absence of TEX14, intercellular bridges are not observed by using electron microscopy and other markers."
    explanation: Bridges are absent in Tex14-null mouse testes.
  - reference: PMID:40492599
    reference_title: "A Novel Compound Heterozygous Mutation in TEX14 Causes Human Non-Obstructive Azoospermia by Disrupting the Assembly of Intercellular Bridges."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This led to spermatogenic failure characterized by meiotic arrest at the pachytene stage and impaired ICB assembly in the testes harboring the mutations."
    explanation: Impaired bridge assembly in a patient's testis.
  - reference: PMID:41603674
    reference_title: "Pathogenic TEX14 Variants Disrupt Intercellular Bridge Formation, Causing Meiotic Arrest and Non-Obstructive Azoospermia in Humans and Mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Consistent with this, testicular histology from the patient carrying the c.2908dupC variant also showed meiotic arrest at zygotene and absent ICBs."
    explanation: Absent bridges in a further patient's testis.
  - reference: PMID:39929837
    reference_title: "Intercellular bridges are essential for transposon repression and meiosis in the male germline."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Single-cell RNA-sequencing confirms sharing of transcripts between wild-type spermatids and demonstrates its partial attenuation in Tex14 hypomorphs, indicating that intercellular bridges enable cytoplasmic exchange between connected germ cells in testes."
    explanation: Shows what the bridges carry, and that reduced TEX14 reduces that exchange.
- name: Asynchronous Spermatogonial Differentiation
  description: >-
    Without bridges, spermatogonia still proliferate and differentiate, but in
    lower numbers and out of step with one another. Whether this explains the
    spermatogonial arrest seen in some patients is open (see the discussion on
    arrest-stage heterogeneity), so no edge is drawn to that phenotype.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: Spermatogonium
    term:
      id: CL:0000020
      label: spermatogonium
  evidence:
  - reference: PMID:32438343
    reference_title: "Spermatogonial asynchrony in Tex14 mutant mice lacking intercellular bridges."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Thus although spermatogonial development is able to proceed, in the absence of ICBs in Tex14-/- mutants, the yield of cells, specific steps of differentiation, the synchrony of the cell kinetics, and the subsequent progression in meiosis are quantitatively lower than normal."
    explanation: Quantitative spermatogonial defects in Tex14-null mice.
- name: Retrotransposon Derepression in Meiotic Germ Cells
  description: >-
    Bridge-deficient spermatocytes derepress retrotransposons and accumulate
    retrotransposon-encoded proteins. The authors propose that bridges protect
    germline genome integrity; whether this causes the arrest or accompanies it
    is not established, so no edge is drawn from this node.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: Primary spermatocyte
    term:
      id: CL:0000656
      label: primary spermatocyte
  evidence:
  - reference: PMID:39929837
    reference_title: "Intercellular bridges are essential for transposon repression and meiosis in the male germline."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "They also derepress retrotransposons and accumulate retrotransposon-encoded proteins during meiosis."
    explanation: Retrotransposon derepression in Tex14-deficient mouse spermatocytes.
- name: Meiotic Prophase I Failure in Spermatocytes
  description: >-
    Spermatocytes enter meiosis and express early meiotic markers but fail to
    complete meiotic DNA replication, homolog synapsis and double-strand break
    repair, and arrest before the first meiotic division. The reported arrest
    point is zygotene in a knock-in mouse and one patient, and pachytene in
    another patient.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: Primary spermatocyte
    term:
      id: CL:0000656
      label: primary spermatocyte
  biological_processes:
  - preferred_term: Male meiosis I
    modifier: DECREASED
    term:
      id: GO:0007141
      label: male meiosis I
  downstream:
  - target: Spermatocyte maturation arrest
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:41603674
      reference_title: "Pathogenic TEX14 Variants Disrupt Intercellular Bridge Formation, Causing Meiotic Arrest and Non-Obstructive Azoospermia in Humans and Mice."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Consistent with this, testicular histology from the patient carrying the c.2908dupC variant also showed meiotic arrest at zygotene and absent ICBs."
      explanation: The meiotic failure seen in the mouse appears as zygotene arrest on the patient's biopsy.
  - target: Non-obstructive azoospermia
    causal_link_type: DIRECT
    description: No germ cells complete meiosis, so no sperm are produced.
    evidence:
    - reference: PMID:41603674
      reference_title: "Pathogenic TEX14 Variants Disrupt Intercellular Bridge Formation, Causing Meiotic Arrest and Non-Obstructive Azoospermia in Humans and Mice."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Our results demonstrate that loss-of-function mutations in TEX14 disrupt meiotic ICB formation, leading to zygotene arrest and NOA in both mice and humans"
      explanation: States the chain from bridge loss through zygotene arrest to azoospermia.
  - target: Male infertility
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Infertility follows from the absence of sperm.
  evidence:
  - reference: PMID:16549803
    reference_title: "TEX14 is essential for intercellular bridges and fertility in male mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Spermatogenesis in Tex14(-/-) mice progresses through the transit amplification of diploid spermatogonia and the expression of early meiotic markers but halts before the completion of the first meiotic division."
    explanation: Meiotic arrest before the first division in Tex14-null mice.
  - reference: PMID:39929837
    reference_title: "Intercellular bridges are essential for transposon repression and meiosis in the male germline."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We report that in males deficient for TEX14 and intercellular bridges, germ cells fail to complete meiotic DNA replication, synapsis and meiotic double-strand break repair."
    explanation: Names the meiotic prophase events that fail.
  - reference: PMID:40492599
    reference_title: "A Novel Compound Heterozygous Mutation in TEX14 Causes Human Non-Obstructive Azoospermia by Disrupting the Assembly of Intercellular Bridges."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This led to spermatogenic failure characterized by meiotic arrest at the pachytene stage and impaired ICB assembly in the testes harboring the mutations."
    explanation: Pachytene arrest in a patient.
  - reference: PMID:22136159
    reference_title: "An exonic insertion within Tex14 gene causes spermatogenic arrest in pigs."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "In this study we report the identification of a causal mutation for infertility caused by spermatogenic arrest at an early meiotic phase."
    explanation: Early meiotic arrest in a second species with a natural Tex14 truncation.
phenotypes:
- category: Reproductive
  name: Male infertility
  description: Primary male infertility is the presenting complaint.
  phenotype_term:
    preferred_term: Male infertility
    term:
      id: HP:0003251
      label: Male infertility
  evidence:
  - reference: PMID:41603674
    reference_title: "Pathogenic TEX14 Variants Disrupt Intercellular Bridge Formation, Causing Meiotic Arrest and Non-Obstructive Azoospermia in Humans and Mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified six novel TEX14 variants in four unrelated infertile Chinese men"
    explanation: Infertile men carrying TEX14 variants.
- category: Reproductive
  name: Non-obstructive azoospermia
  description: >-
    No sperm in the ejaculate, due to failed spermatogenesis rather than
    obstruction. All carriers in the cited reports were ascertained with
    non-obstructive azoospermia, which defines the condition, so the
    frequency reflects how patients were found.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Non-obstructive azoospermia
    term:
      id: HP:0011961
      label: Non-obstructive azoospermia
  evidence:
  - reference: PMID:40492599
    reference_title: "A Novel Compound Heterozygous Mutation in TEX14 Causes Human Non-Obstructive Azoospermia by Disrupting the Assembly of Intercellular Bridges."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we identified a novel compound heterozygous mutation in TEX14 (c.802A>T, p.S268C and c.1021C>T, p.R341*) in a patient with NOA"
    explanation: Non-obstructive azoospermia in a biallelic carrier.
  - reference: PMID:28206990
    reference_title: "A familial study of azoospermic men identifies three novel causative mutations in three new human azoospermia genes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified three novel likely causative mutations of azoospermia in three genes: MEIOB, TEX14, and DNAH6."
    explanation: The founding report of TEX14 as a human azoospermia gene.
- category: Reproductive
  name: Spermatocyte maturation arrest
  description: >-
    Meiotic arrest of spermatocytes, at zygotene or pachytene where the stage
    was reported. Seen in the founding families and in two later patients;
    no study has counted arrest stages across reports.
  phenotype_term:
    preferred_term: Spermatocyte maturation arrest
    term:
      id: HP:0031039
      label: Spermatocyte maturation arrest
  evidence:
  - reference: PMID:41603674
    reference_title: "Pathogenic TEX14 Variants Disrupt Intercellular Bridge Formation, Causing Meiotic Arrest and Non-Obstructive Azoospermia in Humans and Mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Consistent with this, testicular histology from the patient carrying the c.2908dupC variant also showed meiotic arrest at zygotene and absent ICBs."
    explanation: Zygotene arrest in a patient.
  - reference: PMID:40492599
    reference_title: "A Novel Compound Heterozygous Mutation in TEX14 Causes Human Non-Obstructive Azoospermia by Disrupting the Assembly of Intercellular Bridges."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This led to spermatogenic failure characterized by meiotic arrest at the pachytene stage and impaired ICB assembly in the testes harboring the mutations."
    explanation: Pachytene arrest in a patient.
  - reference: PMID:28206990
    reference_title: "A familial study of azoospermic men identifies three novel causative mutations in three new human azoospermia genes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "Our objective was to uncover novel human mutations and genes causing azoospermia due to testicular meiotic maturation arrest."
    explanation: The founding families were ascertained for meiotic maturation arrest.
- category: Reproductive
  name: Spermatogonial maturation arrest
  description: >-
    Incomplete spermatogonial arrest was the histology in two men with
    biallelic loss-of-function variants, showing that the arrest point
    varies between patients.
  phenotype_term:
    preferred_term: Spermatogonial maturation arrest
    term:
      id: HP:4000187
      label: Spermatogonial maturation arrest
  evidence:
  - reference: PMID:32741963
    reference_title: "Genetic dissection of spermatogenic arrest through exome analysis: clinical implications for the management of azoospermic men."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified two homozygous LoF variants in TEX14 in two unrelated patients affected by incomplete spermatogonial arrest."
    explanation: Spermatogonial arrest in two unrelated patients.
- category: Reproductive
  name: Sertoli cell-only phenotype
  description: >-
    Sertoli-cell-only histology has been reported in some TEX14 carriers. The
    statement comes from a synthesis across earlier reports rather than a
    primary patient description, so it is recorded without a frequency.
  phenotype_term:
    preferred_term: Sertoli cell-only phenotype
    term:
      id: HP:0034299
      label: Sertoli cell-only phenotype
  evidence:
  - reference: PMID:32741963
    reference_title: "Genetic dissection of spermatogenic arrest through exome analysis: clinical implications for the management of azoospermic men."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Previously reported TEX14 variants were associated with testis histology ranging from SCO to complete SCA"
    explanation: Summarizes earlier reports as ranging from Sertoli-cell-only to complete spermatocyte arrest.
genetic:
- name: TEX14
  association: Causal
  gene_term:
    preferred_term: TEX14
    term:
      id: hgnc:11737
      label: TEX14
  notes: >-
    Reported alleles are mostly truncating: homozygous stop-gain and frameshift
    variants, a compound heterozygous deletion of exons 6 to 21 with a second
    loss-of-function allele (PMID:32741963), and frameshift, splice and missense
    variants in a Chinese cohort (PMID:41603674). The nonsense variant
    c.1021C>T (p.Arg341*) has been reported both in compound heterozygous form
    with a missense allele (PMID:40492599) and homozygous (PMID:39843174). Each
    study finds TEX14 in a small fraction of men with non-obstructive
    azoospermia, and Krausz et al. upgraded the gene to strong clinical
    evidence.
  evidence:
  - reference: PMID:28206990
    reference_title: "A familial study of azoospermic men identifies three novel causative mutations in three new human azoospermia genes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified three novel likely causative mutations of azoospermia in three genes: MEIOB, TEX14, and DNAH6."
    explanation: Primary gene-disease report.
  - reference: PMID:29790874
    reference_title: "Point-of-care whole-exome sequencing of idiopathic male infertility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In five of eight families, we identified rare deleterious recessive variants in CCDC155, NANOS2, SPO11, TEX14, and WNK3 segregating with disease"
    explanation: A recessive TEX14 variant segregating with infertility in a second family.
  - reference: PMID:32741963
    reference_title: "Genetic dissection of spermatogenic arrest through exome analysis: clinical implications for the management of azoospermic men."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "With the discovery of the two new TEX14 variant carriers, this gene can now be upgraded to strong clinical evidence."
    explanation: Independent replication raising the clinical evidence level.
  - reference: PMID:33728612
    reference_title: "Targeted next-generation sequencing panel screening of 668 Chinese patients with non-obstructive azoospermia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutations in TEX11, TEX14, and NR5A1 genes are recurrent causes of NOA, but each gene explains only a very small percentage"
    explanation: TEX14 is a recurrent but rare cause in a large panel cohort.
  - reference: PMID:39843174
    reference_title: "Genetic Testing for Monogenic Forms of Male Infertility Contributes to the Clinical Diagnosis of Men with Severe Idiopathic Male Infertility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "With WES of 191 infertile men, potential monogenic disease-causing variants in four of them (STAG3, MSH4, TEX14, TEX15) were identified."
    explanation: A further TEX14 carrier in an exome cohort.
  - reference: PMID:40896145
    reference_title: "Genetic determinants of testicular sperm extraction outcomes: insights from a large multicentre study of men with non-obstructive azoospermia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Three infertile men carried LP/P mutations in TEX14."
    explanation: Three further carriers in a multicentre cohort.
  - reference: PMID:41603674
    reference_title: "Pathogenic TEX14 Variants Disrupt Intercellular Bridge Formation, Causing Meiotic Arrest and Non-Obstructive Azoospermia in Humans and Mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified six novel TEX14 variants in four unrelated infertile Chinese men"
    explanation: Four further unrelated carriers.
mechanistic_hypotheses:
- hypothesis_group_id: tex14_male_restricted_phenotype
  hypothesis_label: TEX14 loss causes male-restricted infertility because female germ cells do not need the bridges for fertility
  status: EMERGING
  description: >-
    TEX14 forms intercellular bridges in both male and female embryonic germ
    cells, but Tex14-null female mice are fertile, with fewer oocytes and
    altered germline cysts. Only men have been reported with SPGF23, and
    fertility in women with biallelic TEX14 variants has not been studied.
  evidence:
  - reference: PMID:19020301
    reference_title: "Mouse TEX14 is required for embryonic germ cell intercellular bridges but not female fertility."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Despite the absence of embryonic intercellular bridges in the Tex14-null mice, male mice initiate spermatogenesis, and female mice are fertile."
    explanation: Female Tex14-null mice are fertile despite lacking bridges.
  - reference: PMID:34156079
    reference_title: "Altered germline cyst formation and oogenesis in Tex14 mutant mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: "In Tex14 homozygous mutant fetal ovaries, germ cells divide to form a reduced number of cysts in which germ cells remained connected via syncytia or fragmented cell membranes, rather than normal intercellular bridges."
    explanation: >-
      Female germ cells are still affected, so the sparing is of fertility and
      not of the ovary itself.
animal_models:
- name: Tex14 knockout mouse
  species: Mouse
  genotype: Tex14-/- (knockout), homozygous
  publication: PMID:16549803
  description: >-
    Male Tex14 knockout mice lack germ cell intercellular bridges and are
    sterile, with arrest before the first meiotic division. Females are
    fertile.
  modeled_mechanisms:
  - target: Failed Germ Cell Intercellular Bridge Formation
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: CELLULAR
    description: The knockout removes the bridges, as in patient testes.
    evidence:
    - reference: PMID:16549803
      reference_title: "TEX14 is essential for intercellular bridges and fertility in male mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Thus, TEX14 is required for intercellular bridges in vertebrate germ cells, and these studies provide evidence that the intercellular bridge is essential for spermatogenesis and fertility."
      explanation: Bridge loss and male sterility in the knockout.
- name: Tex14 MT1 knock-in mouse
  species: Mouse
  genotype: Tex14 MT1/MT1, modelling the patient c.2908dupC frameshift
  publication: PMID:41603674
  description: >-
    A knock-in of an allele analogous to a patient frameshift abolishes TEX14
    in the testis, prevents bridge formation and arrests spermatogenesis at
    zygotene, matching the patient's testicular histology.
  modeled_mechanisms:
  - target: Meiotic Prophase I Failure in Spermatocytes
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: CELLULAR
    description: Zygotene arrest in the mouse matches the arrest stage in the patient carrying the same allele.
    evidence:
    - reference: PMID:41603674
      reference_title: "Pathogenic TEX14 Variants Disrupt Intercellular Bridge Formation, Causing Meiotic Arrest and Non-Obstructive Azoospermia in Humans and Mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Immunofluorescence and histological analyses revealed that spermatogenesis in Tex14MT1/MT1 mice was arrested at the zygotene stage due to a complete failure of the ICB formation."
      explanation: Zygotene arrest in the knock-in.
- name: Tex14 hypomorph mouse
  species: Mouse
  genotype: Tex14 hypomorphic allele, homozygous, with reduced intercellular bridges
  publication: PMID:39929837
  description: >-
    A hypomorphic allele reduces rather than abolishes bridges. Together with
    Tex14-null mice it showed failed meiotic DNA replication, synapsis and
    double-strand break repair, retrotransposon derepression, and reduced
    transcript sharing between connected germ cells.
  modeled_mechanisms:
  - target: Retrotransposon Derepression in Meiotic Germ Cells
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: Bridge-deficient mice show retrotransposon derepression during meiosis; this has not been examined in patients.
    evidence:
    - reference: PMID:39929837
      reference_title: "Intercellular bridges are essential for transposon repression and meiosis in the male germline."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Here we utilized a Tex14 hypomorph with reduced intercellular bridges along with Tex14-null mice that completely lack bridges to examine the roles of germ cell connectivity during spermatogenesis."
      explanation: Describes the hypomorph and its use alongside the null.
- name: Finnish Yorkshire boar with Tex14 exon 27 insertion
  species: Pig
  genotype: 51 bp insertion in Tex14 exon 27
  publication: PMID:22136159
  description: >-
    A naturally occurring insertion causes aberrant splicing, a premature stop
    codon and loss of TEX14 protein, with spermatogenic arrest at an early
    meiotic phase and no spermatozoa.
  modeled_mechanisms:
  - target: Meiotic Prophase I Failure in Spermatocytes
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: Early meiotic arrest in a large-animal model with a truncating allele.
    evidence:
    - reference: PMID:22136159
      reference_title: "An exonic insertion within Tex14 gene causes spermatogenic arrest in pigs."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Sequencing of a candidate gene Tex14 revealed a 51 bp insertion within exon 27, which caused differential splicing of the exon and created a premature translation stop codon."
      explanation: A truncating Tex14 allele in pigs with spermatogenic arrest.
treatments:
- name: Avoidance of Futile Testicular Sperm Extraction
  description: >-
    In the carriers whose outcome is reported, no sperm were retrieved by
    testicular sperm extraction, and panel studies class TEX14 among the
    meiotic genes with a poor retrieval prognosis. One of the two studies
    recruited only men with negative retrieval, so its carriers show the
    association but not its rate. A molecular diagnosis therefore supports
    counselling about the low chance of retrieval before surgery, and about
    donor sperm or adoption; it is not a certainty.
  therapeutic_modality: SURGERY
  notes: >-
    The therapeutic_modality here tags the intervention being withheld, not one
    being administered.
  treatment_term:
    preferred_term: testicular sperm retrieval
    term:
      id: NCIT:C94427
      label: Sperm Retrieval
  evidence:
  - reference: PMID:33728612
    reference_title: "Targeted next-generation sequencing panel screening of 668 Chinese patients with non-obstructive azoospermia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Only the patient with NR5A1 mutations produced viable spermatozoa through micro-TESE, but other patients with TEX11 and TEX14 had poor micro-TESE prognoses."
    explanation: TEX14 carriers in this cohort had a poor micro-TESE prognosis, unlike the NR5A1 carrier.
  - reference: PMID:32741963
    reference_title: "Genetic dissection of spermatogenic arrest through exome analysis: clinical implications for the management of azoospermic men."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We conclude that TEX14 defects are a relatively frequent cause of NOA due to SCO or early MA with TESE negative outcome."
    directness: INDIRECT
    explanation: >-
      TESE was negative in the TEX14 carriers, but the discovery cohort was
      recruited from TESE-negative men, so this shows the association rather
      than a retrieval rate.
- name: Genetic Counseling
  description: >-
    Counselling on autosomal recessive recurrence, carrier testing of
    relatives once the familial TEX14 alleles are known, and the poor
    prognosis for sperm retrieval.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:33728612
    reference_title: "Targeted next-generation sequencing panel screening of 668 Chinese patients with non-obstructive azoospermia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "Considering previous reports, we suggest that only a few genes that are directly linked to meiosis can indicate poor micro-TESE prognosis, such as TEX11, TEX14, and SYCE1."
    explanation: A TEX14 result carries prognostic information that belongs in counselling.
diagnosis:
- name: Molecular Genetic Testing
  description: >-
    Establishes the diagnosis, usually by exome, genome or a non-obstructive
    azoospermia gene panel. Copy-number analysis matters as well as
    sequencing, since one reported allele is a multi-exon deletion.
  diagnosis_term:
    preferred_term: Genetic Testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:41603674
    reference_title: "Pathogenic TEX14 Variants Disrupt Intercellular Bridge Formation, Causing Meiotic Arrest and Non-Obstructive Azoospermia in Humans and Mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Exome sequencing was performed on genomic DNA from a cohort of 673 patients with NOA, 143 individuals with oligozoospermia, and 100 fertile controls."
    explanation: Exome sequencing identified the carriers.
  - reference: PMID:32741963
    reference_title: "Genetic dissection of spermatogenic arrest through exome analysis: clinical implications for the management of azoospermic men."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "11-063 is compound-heterozygous for a ~38Kb deletion comprising exons 6 to 21"
    explanation: A multi-exon deletion allele, which sequencing alone could miss, so copy-number analysis is needed.
  - reference: PMID:33728612
    reference_title: "Targeted next-generation sequencing panel screening of 668 Chinese patients with non-obstructive azoospermia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutations in TEX11, TEX14, and NR5A1 genes are recurrent causes of NOA, but each gene explains only a very small percentage"
    explanation: Panel sequencing detects TEX14 among other recurrent genes.
- name: Testicular biopsy
  description: >-
    Shows meiotic arrest, spermatogonial arrest or Sertoli-cell-only tubules.
    Where examined, bridges are absent.
  diagnosis_term:
    preferred_term: testicular biopsy
    term:
      id: NCIT:C15189
      label: Biopsy Procedure
  evidence:
  - reference: PMID:41603674
    reference_title: "Pathogenic TEX14 Variants Disrupt Intercellular Bridge Formation, Causing Meiotic Arrest and Non-Obstructive Azoospermia in Humans and Mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Consistent with this, testicular histology from the patient carrying the c.2908dupC variant also showed meiotic arrest at zygotene and absent ICBs."
    explanation: Biopsy findings in a patient.
discussions:
- discussion_id: tex14_arrest_stage_heterogeneity
  kind: KNOWLEDGE_GAP
  attaches_to:
  - phenotypes#Spermatogonial maturation arrest
  prompt: >-
    Why do TEX14 carriers range from Sertoli-cell-only and spermatogonial
    arrest to zygotene or pachytene meiotic arrest?
  rationale: >-
    Tex14-null mice arrest in meiosis but also show reduced, asynchronous
    spermatogonial output, so the earlier arrest seen in some men may reflect
    progressive germ cell loss, allele severity, or age at biopsy. The reports
    are too few to tell these apart.
  evidence:
  - reference: PMID:32741963
    reference_title: "Genetic dissection of spermatogenic arrest through exome analysis: clinical implications for the management of azoospermic men."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "For two of them, TEX14 and DMRT1, the previously described testis phenotypes are heterogeneous"
    explanation: The heterogeneity is noted by the authors.

📚

References & Deep Research

Deep Research

1

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

Evaluations and curation notes (1)

Create: Spermatogenic_Failure_23 · 2026-10-17T05:36:58Z · View source

Created the SPGF23 (TEX14, MONDO:0054727) entry from the stub, claimed in #14667. Pathophysiology is a chain: TEX14 loss -> failed germ cell intercellular bridge formation (CEP55/ALIX block on abscission) -> asynchronous spermatogonial differentiation, retrotransposon derepression and meiotic prophase I failure -> non-obstructive azoospermia. Phenotypes record the variable testis histology (spermatocyte arrest, spermatogonial arrest, Sertoli-cell-only) rather than one arrest stage. Evidence is from primary papers fetched by PubMed search (Gershoni 2017, Fakhro 2018, Krausz 2020, Li 2025, Xu 2026, the Tex14 mouse and pig models). Deep research: falcon was requested but the Edison key returned 403; the run used --fallback and OpenScientist produced research/Spermatogenic_Failure_23-deep-research-openscientist.md (first OpenScientist attempt failed with a ReadError and was retried). That report's references were retro-validated (18/18 resolved, 9/9 quotes found, 0 off topic); term validation 20/20 resolved; preflight-dr named TEX14 (70 mentions) with CEP55 as its binding partner. From the report, Fakhro 2018 (PMID:29790874) was added; its diagnostic-yield and karyotype papers were not used because they do not report TEX14 carriers. No GeneReviews chapter (check-genereviews NO_CHAPTER). A pre-PR red-team subagent review led to scoping the sperm-retrieval claim (Krausz recruited TESE-negative men), correcting one Krausz patient to compound heterozygous, crediting Krausz rather than Riera-Escamilla, dropping an inferred spermatogonial edge, and adding the Tex14 hypomorph model. Validated with just validate (54/54 snippets) and count-verified-snippets.

OpenScientist ▸

Spermatogenic Failure 23 (SPGF23 / TEX14): Comprehensive Disease Characteristics Report

openscientist-autonomous 18 citations 2026-10-17T01:33:29.502018

Spermatogenic Failure 23 (SPGF23 / TEX14): Comprehensive Disease Characteristics Report

Disease: Spermatogenic Failure 23 (SPGF23) MONDO ID: MONDO:0054727 · OMIM: #617707 · Causal gene: TEX14 (MIM 605792) Category: Mendelian, autosomal recessive Report date: 2026-10-17

Summary

Spermatogenic Failure 23 (SPGF23) is a rare, autosomal-recessive Mendelian form of non-obstructive azoospermia (NOA) caused by biallelic loss-of-function mutations in TEX14 (testis-expressed gene 14), located on chromosome 17q22. TEX14 encodes a 1,497-amino-acid, testis-restricted inactive serine/threonine (pseudo)kinase that serves as the essential structural scaffold of germ-cell intercellular bridges (ICBs) — stable cytoplasmic channels that connect developing male germ cells into a functional syncytium. When TEX14 is lost, these bridges fail to form, spermatogenesis arrests at the pachytene/meiotic stage (a "maturation arrest" histology), no mature spermatozoa are produced, and the affected man is azoospermic and infertile.

The molecular mechanism is well defined. TEX14 carries a conserved GPPX₃Y motif that binds the midbody protein CEP55 with high affinity, competitively excluding the ESCRT-recruiting proteins ALIX (PDCD6IP) and TSG101. This converts what would be a transient cytokinetic midbody into a permanent intercellular bridge, arresting abscission so that daughter germ cells remain connected. These bridges enable cytoplasmic sharing of mRNAs and proteins required to complete meiotic DNA replication, chromosome synapsis, meiotic double-strand-break repair, and transposon repression. Loss of the bridges therefore produces downstream meiotic failure and genome-integrity defects, culminating in germ-cell arrest and azoospermia. The phenotype is strikingly male-specific: female Tex14-null mice lack embryonic ICBs yet remain fertile.

SPGF23 is a non-lethal, non-progressive, isolated reproductive disorder with no systemic features. Diagnosis relies on semen analysis (azoospermia), hormonal/karyotype workup to exclude other causes, and gene-panel or exome sequencing identifying biallelic TEX14 variants; testicular histology shows meiotic/maturation arrest. There is no disease-modifying therapy. Management centers on assisted reproduction via microdissection testicular sperm extraction (micro-TESE) with intracytoplasmic sperm injection (ICSI); however, because SPGF23 causes complete (pre-spermatid) meiotic arrest, the probability of recovering usable spermatozoa is low. Genetic counseling is the principal preventive intervention.

1. Disease Information

Overview. SPGF23 is an inherited male infertility disorder defined by non-obstructive azoospermia (absence of sperm in the ejaculate due to failed sperm production, not blockage) resulting from an intrinsic germ-cell defect. The spermatogenic program initiates normally through spermatogonial amplification and entry into meiosis but halts before the completion of the first meiotic division, so post-meiotic spermatids and spermatozoa are absent or severely depleted.

Key identifiers.

Resource	Identifier
OMIM (phenotype)	#617707 (Spermatogenic failure 23)
OMIM (gene)	605792 (TEX14)
MONDO	MONDO:0054727
Gene (NCBI)	56155 (TEX14)
UniProt	Q8IWB6
HGNC	TEX14
Cytoband	17q22
Mouse ortholog	Tex14 (MGI)

Synonyms / alternative names: Spermatogenic failure 23; SPGF23; non-obstructive azoospermia due to TEX14 deficiency; TEX14-related maturation (meiotic) arrest. In the broader literature the condition falls under "non-obstructive azoospermia (NOA)" and "maturation arrest / meiotic arrest."

Source of information. The entry is derived from aggregated disease-level resources (OMIM, ClinVar, UniProt) combined with individual-patient reports (consanguineous/affected families described by Gershoni et al. 2017, Fakhro et al. 2018, and a compound-heterozygous NOA patient in PMID: 40492599) and model-organism data (Tex14-null mouse, PMID: 16549803). It is not EHR-derived population data.

2. Etiology

Primary cause — genetic. SPGF23 is monogenic: it is caused by biallelic (homozygous or compound-heterozygous) loss-of-function mutations in TEX14. There is no environmental or infectious cause for this specific Mendelian entity; it is a germline genetic disorder of meiosis.

Genetic risk factors. The causal variants are LoF TEX14 alleles. In the original human families the mutations were homozygous (consanguineous Iraqi-Jewish brothers, Gershoni et al. 2017; Jordanian brothers with maturation arrest, Fakhro et al. 2018). A recurrent compound-heterozygous genotype — c.802A>T (p.Ser268Cys) together with c.1021C>T (p.Arg341) — was identified in an NOA patient with pachytene meiotic arrest and impaired intercellular-bridge assembly (PMID: 40492599). ClinVar (RefSeq NM_031272.5) catalogs 352 TEX14 records, 42 classified pathogenic/likely-pathogenic, predominantly nonsense, frameshift, and canonical splice variants. Being autosomal recessive, carriers of a single allele are unaffected; consanguinity* increases homozygosity risk and is a documented contributor.

Environmental / lifestyle risk factors. Not applicable as a cause of SPGF23 — the disorder is fully genetic. General male-fertility risk modifiers (heat, gonadotoxins, smoking) are not established disease modifiers for this entity.

Protective factors. None established. No protective TEX14 alleles or environmental modifiers are known. Given complete recessive inheritance with apparently complete penetrance in males, biallelic LoF essentially determines the phenotype.

Gene–environment interactions. No specific GxE interactions are documented for SPGF23. This is a classical high-penetrance Mendelian disorder in which genotype is the dominant determinant.

3. Phenotypes

The phenotype is reproductive and essentially monosystemic. There are no neurological, cardiac, skeletal, or other somatic manifestations.

Phenotype	Type	Onset	Severity	Frequency	Suggested HPO term
Non-obstructive azoospermia	Laboratory/clinical	Post-pubertal (detected in adulthood)	Severe	Obligate (defining)	HP:0011961 (Azoospermia)
Male infertility	Clinical	Adult	Severe	~100% of affected males	HP:0003251 (Male infertility)
Meiotic / maturation arrest (spermatogenic arrest)	Histological	Adult	Severe	Characteristic	HP:0008669 (Abnormal spermatogenesis)
Decreased testicular size (variable)	Physical sign	Adult	Mild–moderate/variable	Variable	HP:0008734 (Decreased testicular size)
Normal secondary sexual characteristics / normal androgens	(Context)	—	—	Typical	—

Phenotype characteristics. - Age of onset: Clinically manifest in adulthood, usually at infertility workup; biologically the defect begins at the onset of meiosis after puberty. - Severity: Severe with respect to fertility (complete azoospermia). - Progression: Stable/non-progressive. The germ-cell arrest is fixed; it is not a degenerative disorder. - Frequency: Azoospermia and infertility are obligate features in affected (biallelic) males.

Quality-of-life impact. The impact is confined to reproduction and its psychosocial sequelae (involuntary childlessness, distress associated with infertility). There is no effect on lifespan, physical functioning, or general health. No disease-specific QoL instrument has been applied to SPGF23 specifically.

4. Genetic / Molecular Information

Causal gene. TEX14 (testis-expressed 14), OMIM 605792, NCBI Gene 56155, UniProt Q8IWB6, chromosome 17q22. Transcript reference NM_031272.5; protein 1,497 aa.

Protein architecture (UniProt Q8IWB6): - Protein-kinase-like domain, residues ~227–518 — catalytically inactive (pseudokinase) - Conserved CEP55-binding GPPX₃Y motif, residues ~795–801 - Destruction box (D-box), residues ~852–860 - Ankyrin (ANK) repeats and multiple intrinsically disordered regions - Testis-restricted expression; subcellular localization to cytoplasm, midbody, and chromosome/centromere/kinetochore

Pathogenic variant spectrum (ClinVar, NM_031272.5). The spectrum is dominated by loss-of-function alleles, consistent with a LoF disease mechanism:

Variant type	Representative alleles
Nonsense	c.2943G>A (p.Trp981Ter); c.2944C>T (p.Gln982Ter); c.3549C>A (p.Cys1183Ter); c.3168C>A (p.Tyr1056Ter); c.3652A>T (p.Arg1218Ter); c.1021C>T (p.Arg341*)
Frameshift	c.1380dup (p.Ala461fs); c.899dup (p.Tyr300Ter); c.3482_3486del (p.Pro1161fs); c.3625_3628del (p.Ser1209fs); c.2650_2660del (p.Ser884fs)
Canonical splice-site	c.137-1G>A; c.4267+1G>A; c.2576+2T>G
Missense (likely pathogenic)	c.1490T>C (p.Leu497Pro), in the kinase-like domain
Missense (VUS)	p.Pro893Arg; p.Ala64Val; p.Asn83His; p.Glu1351Gly; p.Ser268Cys
Conflicting	c.1003C>T (p.Arg335Ter)

Classification follows ACMG/AMP criteria; the predominance of nonsense, frameshift, and splice variants supports loss of function as the mechanism. Variant counts: 352 total records, 42 pathogenic/likely-pathogenic.

Allele frequency. Pathogenic TEX14 LoF alleles are individually rare in gnomAD, consistent with a recessive, reproduction-limiting disorder. Variants are germline in origin (somatic/COSMIC not applicable).

Functional consequence. Loss of function. Haploinsufficiency is not the issue — heterozygotes are fertile; biallelic LoF is required. The compound-heterozygous human variants disrupt intercellular-bridge assembly (PMID: 40492599).

Modifier genes. No validated clinical modifiers. Partner/pathway proteins include CEP55, ALIX (PDCD6IP), TSG101, KIF23/MKLP1, and RBM44; of these, RBM44 is dispensable (its knockout does not impair fertility; PMID: 21364893).

Epigenetics. No disease-specific methylation/chromatin signature is defined for SPGF23. Notably, loss of ICBs causes retrotransposon derepression during meiosis — an epigenetic/genome-defense consequence rather than a primary cause (PMID: 39929837).

Chromosomal abnormalities. Large 17q22 copy-number losses/gains encompassing TEX14 exist in ClinVar/DECIPHER but are non-specific contiguous-gene CNVs, not the typical cause of isolated SPGF23. (Chromosomal causes of NOA generally — Klinefelter syndrome, Y-microdeletions — are distinct entities to exclude.)

5. Environmental Information

Environmental factors: None causal. SPGF23 is a Mendelian disorder. Lifestyle factors: None established as modifiers of this specific genotype–phenotype. Infectious agents: Not applicable — SPGF23 is not infectious or acquired.

(General NOA can have environmental/toxic contributors, but these do not apply to the TEX14-defined Mendelian entity.)

6. Mechanism / Pathophysiology

Causal chain (initiating lesion → clinical manifestation)

Biallelic LoF mutation in TEX14 → leads to absence or non-functional TEX14 protein in germ cells. (Demonstrated — human families and mouse knockout.)
Loss of TEX14 → the conserved GPPX₃Y motif is no longer available to bind CEP55, so TEX14 cannot outcompete ALIX/TSG101 at the midbody. (Demonstrated biochemically — PMID: 20176808; simulation PMID: 37409705.)
ESCRT abscission machinery (ALIX/TSG101) is recruited to the midbody unopposed → cytokinetic abscission proceeds to completion instead of being arrested. (Inferred from the competitive-binding model.)
Daughter germ cells separate rather than remaining connected → intercellular bridges fail to form (undetectable by EM in TEX14-null testis). (Demonstrated — PMID: 16549803.)
Loss of ICBs abolishes cytoplasmic sharing of mRNAs and proteins between connected germ cells. (Demonstrated by scRNA-seq — PMID: 39929837.)

Branch A → Spermatogonial compartment: reduced expansion of undifferentiated type-A spermatogonia and fewer differentiating A1 spermatogonia, with loss of synchrony from the type-B stage onward. (PMID: 32438343.)

Branch B → Meiotic compartment: germ cells fail to complete meiotic DNA replication, chromosome synapsis, and meiotic double-strand-break repair; retrotransposons are derepressed and retrotransposon-encoded proteins accumulate. (PMID: 39929837.)

Meiotic progression halts before completion of the first meiotic division (pachytene/meiotic maturation arrest) → post-meiotic spermatids and spermatozoa are not produced. (Demonstrated — PMID: 16549803.)
No mature sperm in testis/ejaculate → non-obstructive azoospermia → male infertility (clinical manifestation). (Demonstrated — human NOA patients.)

 TEX14 biallelic LoF
  │
  ▼
 No GPPX3Y–CEP55 binding ──► ALIX/TSG101 occupy midbody ──► abscission completes
  │                                                        │
  ▼                                                        ▼
 Intercellular bridges NOT formed ◄──────────────── daughter cells separate
  │
  ├──► Branch A: spermatogonial asynchrony, fewer A1 spermatogonia
  │
  └──► Branch B: failed meiotic DNA replication / synapsis / DSB repair
                 + retrotransposon derepression
  │
  ▼
 Meiotic (pachytene) arrest ──► no spermatids/spermatozoa ──► NON-OBSTRUCTIVE AZOOSPERMIA

Supporting detail

Molecular pathway — abscission control via CEP55/ESCRT. The central event is competition at the midbody. In somatic cells CEP55 recruits ALIX and TSG101 to activate ESCRT-III-mediated abscission. In germ cells, TEX14's GPPX₃Y motif binds CEP55 strongly, blocking the homologous GPPX₃Y motifs of ALIX and TSG101, thereby preventing ESCRT recruitment and arresting abscission to create a stable bridge (PMID: 20176808). Metadynamics simulations confirm TEX14's high affinity and low dissociation rate for CEP55 outcompete ALIX (PMID: 37409705). Reinforcing CEP55's central role, Cep55 overexpression also causes male-specific sterility, acting through sustained PI3K/AKT signaling and loss of FOXO1 nuclear retention (PMID: 29683733).

Cellular processes. Arrested cytokinetic abscission (bridge formation); cytoplasmic/organelle sharing across the germ-cell syncytium; meiotic cell-cycle progression; DNA double-strand-break repair during meiotic recombination; transposon silencing. Downstream, disrupted bridges can produce multinucleated giant cells and apoptosis, as seen when ICBs are destabilized by FAR1 loss (PMID: 37039784) or YKT6 loss (PMID: 40528727).

Protein dysfunction. LoF alleles (nonsense/frameshift/splice) eliminate or truncate TEX14, removing the GPPX₃Y–CEP55 scaffolding function. TEX14 is a pseudokinase — its kinase-like domain is catalytically inactive — so it acts structurally, not enzymatically. Beyond bridges, TEX14 also contributes to kinetochore–microtubule attachment during mitosis, a second function (UniProt).

Transcriptomic / single-cell evidence. scRNA-seq shows ICBs enable transcript sharing between connected germ cells, and integrative RNA-seq of bridge-deficient testis reveals downregulation of late germ-cell developmental genes and upregulation of ECM/cell–cell-interaction genes (PMID: 39929837; PMID: 37039784).

Suggested ontology terms. - GO biological process: GO:0007283 (spermatogenesis); GO:0045172 (intercellular bridge / germline ring canal); GO:0007140 (male meiotic nuclear division); GO:0000281/GO:0007093 (cytokinesis/abscission regulation); GO:0010526 (retrotransposon silencing). - GO cellular component: GO:0045172 (intercellular bridge); GO:0030496 (midbody); GO:0000776 (kinetochore). - CL cell types: CL:0000020 (spermatogonium); CL:0000017 (spermatocyte); CL:0000019 (sperm); CL:0000216 (Sertoli cell, context).

7. Anatomical Structures Affected

Organ level. - Primary organ: Testis (UBERON:0000473), specifically the seminiferous tubules (UBERON:0001343) / seminiferous epithelium. - Body system: Male reproductive system (UBERON:0000079). No secondary organ involvement; this is an isolated gonadal/germ-cell disorder.

Tissue and cell level. - Tissue: germinal (seminiferous) epithelium. - Target cell populations: male germ cells — spermatogonia (CL:0000020), spermatocytes (CL:0000017) — which fail to progress; spermatids/spermatozoa (CL:0000019) are absent. Sertoli cells (CL:0000216) remain and support the arrested epithelium.

Subcellular level. - Intercellular bridge (GO:0045172) — the structure that fails. - Midbody (GO:0030496) — site of the CEP55/TEX14/ESCRT decision. - Kinetochore/centromere (GO:0000776) — TEX14's secondary mitotic site. - Cytoplasm — the shared compartment lost when bridges fail.

Localization / lateralization. Bilateral (both testes affected); diffuse within the seminiferous epithelium.

8. Temporal Development

Onset. Biologically, the defect manifests at the first wave of meiosis after pubertal activation of spermatogenesis; clinically it is detected in adulthood during infertility evaluation. Onset pattern is chronic/insidious — there is no acute event.

Progression. The disorder is stable and non-progressive. Spermatogenesis is arrested at a fixed developmental checkpoint (pachytene/meiotic division) rather than degenerating over time. Disease duration is lifelong, but it does not worsen systemically and does not shorten life.

Patterns. No spontaneous remission; no treatment-induced remission of the germ-cell defect (assisted reproduction bypasses, but does not cure, the block). The relevant "critical period" is developmental — the meiotic-entry window where the bridge-dependent syncytium is required.

9. Inheritance and Population

Inheritance. Autosomal recessive (OMIM #617707). Affected individuals are homozygous or compound heterozygous for TEX14 LoF alleles; heterozygous carriers are unaffected and fertile.

Penetrance / expressivity. In males, biallelic LoF appears highly/completely penetrant for azoospermia. Expressivity of secondary features (e.g., testicular volume) may be variable. No genetic anticipation (not a repeat-expansion disorder).

Sex-specificity. The requirement for TEX14 is male-specific. TEX14 is an essential component of both male and female embryonic ICBs, yet female Tex14-null mice are fertile while males are sterile (PMID: 19020301). Thus SPGF23 is a disorder of male fertility; female biallelic carriers would be expected to be unaffected for fertility.

Consanguinity / founder effects. Consanguinity is a documented contributor (homozygous cases in consanguineous families). No broad founder effect is established; individual rare alleles predominate.

Carrier frequency. Individual pathogenic TEX14 alleles are rare in gnomAD; aggregate carrier frequency for SPGF23-causing biallelic genotypes is low but not precisely quantified.

Epidemiology. Precise prevalence/incidence of SPGF23 specifically are not established. Context: NOA affects ~1% of all men and is the most severe form of male infertility (PMID: 40658795); TEX14 is one of many monogenic causes within this heterogeneous group and accounts for a small fraction of cases. The sex ratio is effectively male-only for the fertility phenotype.

10. Diagnostics

Clinical tests. - Semen analysis: azoospermia on ≥2 centrifuged specimens (HP:0011961). Normal ejaculate volume with azoospermia points to a non-obstructive etiology when combined with hormones/volume. - Hormonal profile: FSH, LH, testosterone, inhibin B — to classify as non-obstructive (often elevated FSH) and exclude hypogonadotropic causes. - Imaging: scrotal ultrasound to assess testicular volume and exclude obstruction/varicocele. - Biopsy/histopathology: testicular histology shows meiotic/maturation arrest — germ cells present up to the spermatocyte stage, with absent or markedly reduced post-meiotic spermatids. This histological pattern is the hallmark.

Genetic testing (the definitive diagnostic route). - Karyotype and Y-chromosome microdeletion (AZF) screening first, to exclude Klinefelter syndrome and AZF deletions (the commonest chromosomal causes of NOA; see PMID: 42223426, PMID: 38511217). - Whole-exome sequencing (WES) or NOA gene panels including TEX14 to detect biallelic variants. WES is an effective tool for genetic diagnosis of primary male infertility (PMID: 39267058), and targeted NGS panels increase diagnostic yield in idiopathic SPGF (PMID: 32655042). - Confirm biallelic status by segregation/Sanger and apply ACMG/AMP classification (biallelic LoF = pathogenic).

Biomarkers / omics-based prognostic diagnostics. Testicular transcript markers of post-meiotic germ cells correlate with sperm-retrieval success: post-meiotic markers are significantly reduced in maturation-arrest testes and in negative vs positive sperm-retrieval groups (PMID: 30054974). No validated circulating biomarker is SPGF23-specific.

Clinical criteria / differential diagnosis. No disease-specific criteria beyond azoospermia + meiotic arrest + biallelic TEX14. The differential diagnosis of NOA/maturation arrest includes Klinefelter syndrome, Y-microdeletions, Sertoli-cell-only syndrome (PMID: 41485595), and other single-gene meiotic-arrest genes (TEX11, TEX15, MEIOB, SYCP3, SOHLH1, NR5A1, SOX30, etc.) — distinguished by genetic testing.

Screening. Carrier/cascade screening within affected families; no population newborn screening (reproductive, non-lethal phenotype).

11. Outcome / Prognosis

Survival / mortality. SPGF23 does not affect survival, life expectancy, or mortality. It is confined to reproductive function.

Morbidity / quality of life. Morbidity is reproductive (infertility) and psychosocial. No physical disability.

Disease course. Stable, lifelong, non-progressive.

Fertility prognosis (the key outcome). Because SPGF23 produces a complete meiotic (pachytene) maturation arrest with absent spermatids, the prognosis for recovering mature spermatozoa at micro-TESE is poor. Post-meiotic transcript markers are significantly lower in failed sperm-retrieval cases (PMID: 30054974), and a pre-spermatid arrest implies few or no retrievable sperm. Focal residual spermatogenesis cannot be excluded a priori, so micro-TESE may still be attempted, but with counseling about low yield.

Prognostic factors. Degree/completeness of the arrest; presence of any post-meiotic cells on histology; FSH and testicular volume (general NOA predictors).

12. Treatment

No disease-modifying or curative therapy exists. There is no pharmacologic, gene, cell, or RNA therapy for the underlying germ-cell defect. Management is reproductive.

Intervention	Role in SPGF23	Suggested NCIT concept
Microdissection TESE (micro-TESE)	Surgical attempt to recover focal spermatozoa from testicular tissue; low expected yield given complete meiotic arrest	NCIT: Testicular Sperm Extraction
ICSI (intracytoplasmic sperm injection)	If any viable sperm are retrieved, used for assisted fertilization	NCIT: Intracytoplasmic Sperm Injection
Donor sperm / adoption	Family-building alternatives when retrieval fails	—
Genetic counseling	Risk assessment, family planning, cascade testing	NCIT: Genetic Counseling

Pharmacotherapy / hormonal therapy: No evidence of benefit for a structural meiotic-arrest genotype (empirical gonadotropin/antiestrogen therapy used in some NOA is not expected to overcome a TEX14-null block).
Advanced therapeutics (gene/cell/RNA/targeted/immuno): None available or in trials for SPGF23.
Experimental: No SPGF23-specific registered trials identified.
Personalized medicine: Genotype confirms etiology and informs realistic counseling about micro-TESE yield.

13. Prevention

Because SPGF23 is a non-lethal recessive reproductive disorder, "prevention" is reproductive-genetic rather than public-health.

Primary prevention: Not applicable in the conventional sense; avoidance of the affected genotype is only possible via reproductive planning.
Genetic / reproductive prevention: Carrier screening in relatives, genetic counseling, and, for couples at risk, preimplantation genetic testing (PGT) or prenatal diagnosis to inform reproductive choices. (Note: because affected males are infertile, transmission to offspring occurs only through assisted reproduction using retrieved sperm, in which case sons could inherit a pathogenic allele.)
Immunization / behavioral / environmental / prophylaxis: Not applicable.
Counseling: The principal preventive intervention — informs recurrence risk and reproductive options.

14. Other Species / Natural Disease

Taxonomy / model species: Mus musculus (NCBI Taxon 10090) is the principal model.
Orthologous gene: mouse Tex14 (MGI; NCBI Gene ortholog). The GPPX₃Y–CEP55 interaction and bridge function are evolutionarily conserved (PMID: 20176808); RBM44, another bridge protein, is conserved between mouse and human (PMID: 21364893).
Natural disease in other species / veterinary relevance: No naturally occurring companion-animal or wildlife SPGF23 equivalent is documented (OMIA); intercellular bridges are, however, a conserved feature of metazoan germlines.
Comparative biology: The male-specific essentiality of TEX14 (sterile males, fertile females) is conserved in mouse, mirroring the expected human sex-specific phenotype.
Zoonotic potential: Not applicable (non-infectious genetic disorder).

15. Model Organisms

Primary model — Tex14-knockout mouse. The Tex14⁻/⁻ mouse is the foundational and highly faithful model of SPGF23.

Feature	Mouse Tex14⁻/⁻	Human SPGF23	Concordance
Male fertility	Sterile	Infertile (azoospermic)	✔
Spermatogenic block	Halts before completion of the first meiotic division	Pachytene/meiotic maturation arrest	✔
Intercellular bridges	Absent (undetectable by EM)	Impaired bridge assembly	✔
Female fertility	Normal (fertile)	Expected unaffected (male-specific)	✔
Early meiotic markers	Expressed	—	✔

Model types: Mammalian (mouse) germline knockout; also conditional/cell-type-specific models of related bridge genes (e.g., Ykt6 cKO, PMID: 40528727; Far1 KO, PMID: 37039784) that destabilize TEX14/ICBs secondarily.
Phenotype recapitulation: Excellent — the mouse reproduces the azoospermia, meiotic arrest, and bridge loss, and provided the mechanistic framework (PMID: 16549803; PMID: 19020301).
Model limitations: Human allelic heterogeneity (missense VUS, hypomorphs, potential focal residual spermatogenesis) is not fully captured by a null mouse; the complete-null mouse may be more severe than some human hypomorphic genotypes.
Applications: Dissecting bridge biology, cytoplasmic sharing (scRNA-seq), meiotic DSB repair and transposon control, and testing whether residual spermatogenesis is ever achievable.
Resources: MGI / IMSR for Tex14 alleles.

Key Findings (with evidence)

Finding 1 — Biallelic TEX14 LoF causes SPGF23 (NOA with meiotic arrest)

OMIM #617707 attributes SPGF23 to homozygous/biallelic TEX14 mutation (17q22), autosomal recessive. Human families (Gershoni 2017; Fakhro 2018) and a recurrent compound-heterozygous genotype (c.802A>T p.Ser268Cys; c.1021C>T p.Arg341) in an NOA patient with pachytene arrest and impaired bridge assembly establish causality in humans. Tex14⁻/⁻* mice are sterile with arrest before the first meiotic division.

"we identified a novel compound heterozygous mutation in TEX14 (c.802A>T, p.S268C and c.1021C>T, p.R341*) in a patient with NOA" — PMID: 40492599 "Spermatogenesis in Tex14(-/-) mice progresses through the transit amplification of diploid spermatogonia and the expression of early meiotic markers but halts before the completion of the first meiotic division" — PMID: 16549803

Finding 2 — TEX14 builds intercellular bridges by converting CEP55 from abscission factor to bridge component

TEX14's conserved GPPX₃Y motif binds CEP55, competitively excluding ALIX/TSG101 and the ESCRT machinery from the midbody, arresting abscission to form a stable bridge. Without TEX14, bridges are undetectable by EM. Simulations confirm TEX14's high affinity/low dissociation outcompetes ALIX; Cep55 overexpression independently causes male sterility.

"an evolutionarily conserved GPPX3Y motif of TEX14 binds strongly to CEP55 to block similar GPPX3Y motifs of ALIX and TSG101 from interacting and localizing to the midbody" — PMID: 20176808 "In the absence of TEX14, intercellular bridges are not observed by using electron microscopy and other markers" — PMID: 16549803

Finding 3 — Intercellular bridges enable cytoplasmic sharing required for meiosis, DSB repair, synapsis, and transposon repression

In bridge-deficient male germ cells, meiotic DNA replication, synapsis, and DSB repair fail, and retrotransposons are derepressed with accumulation of retrotransposon-encoded proteins; scRNA-seq shows bridges enable transcript sharing. Bridge loss also causes spermatogonial asynchrony and, downstream (e.g., FAR1 loss), multinucleated giant cells.

"germ cells fail to complete meiotic DNA replication, synapsis and meiotic double-strand break repair. They also derepress retrotransposons and accumulate retrotransposon-encoded proteins during meiosis" — PMID: 39929837 "intercellular bridges enable cytoplasmic exchange between connected germ cells in testes" — PMID: 39929837

Finding 4 — TEX14 requirement is male-specific

TEX14 is essential for both male and female embryonic bridges (with MKLP1/KIF23), but female Tex14-null mice are fertile while males are sterile — making SPGF23 a male-specific fertility disorder. RBM44, another bridge protein, is dispensable.

"TEX14 is an essential component of male and female embryonic intercellular bridges" — PMID: 19020301

Finding 5 — Meiotic/maturation arrest predicts low surgical sperm-retrieval yield

Post-meiotic transcript markers are significantly reduced in maturation-arrest testes and lower in negative vs positive micro-TESE groups; SPGF23's complete pachytene arrest therefore implies a low-yield retrieval prognosis.

"Post-meiotic markers were significantly reduced in negative vs. positive sperm retrieval groups" — PMID: 30054974

Finding 6 — TEX14 is a 1,497-aa testis-restricted inactive (pseudo)kinase with dual bridge/kinetochore roles

UniProt Q8IWB6: pseudokinase domain (227–518), GPPX₃Y CEP55-binding motif (795–801), D-box, ANK repeats; testis-restricted; localizes to cytoplasm, midbody, and kinetochore; required for intercellular bridges and for mitotic kinetochore–microtubule attachment; disease annotation SPGF23.

Finding 7 — ClinVar variant spectrum is LoF-dominated, confirming the LoF mechanism

352 TEX14 records (42 P/LP); pathogenic alleles for SPGF23/NOA are overwhelmingly nonsense, frameshift, and canonical splice variants, with one likely-pathogenic kinase-domain missense (p.Leu497Pro) and several VUS missense — consistent with loss of function.

"pathogenic biallelic TEX14 mutations are recurrent genetic etiologies of NOA in humans" — PMID: 40492599

Mechanistic Model / Interpretation

SPGF23 is best understood as a structural disorder of the germ-cell syncytium. The male germline is normally a connected network: after each mitotic/meiotic division, cells deliberately fail abscission and remain joined by intercellular bridges. This is not a byproduct but a programmed requirement — the bridges allow haploid and diploid cells to share transcripts and proteins so that the entire clone matures synchronously and so that genome-defense (transposon silencing) and meiotic recombination machinery are adequately supplied.

TEX14 is the molecular switch that creates these bridges. By binding CEP55 at the midbody, it blocks the ESCRT abscission pathway that would otherwise sever the cells. Remove TEX14 and the switch defaults to "abscission on": cells separate, the syncytium never forms, cytoplasmic sharing is lost, and the meiotic program stalls at pachytene. The ClinVar spectrum (nonsense/frameshift/splice) and the fertile-female/sterile-male dichotomy both point to simple loss of function as the disease mechanism, with no dominant-negative or gain-of-function contribution required. The clinical endpoint — complete azoospermia with meiotic arrest — follows deterministically, which is why management is limited to assisted reproduction (with a sobering, low expected yield) and genetic counseling.

Evidence Base

PMID	Role	Contribution
16549803	Landmark (mouse)	TEX14 essential for bridges and male fertility; meiotic arrest phenotype
20176808	Mechanism	GPPX₃Y–CEP55 binding blocks ALIX/TSG101 abscission
19020301	Mechanism/sex-specificity	Embryonic bridges in both sexes; female fertile, male sterile
39929837	Downstream function	Bridges required for meiosis, DSB repair, transposon repression
32438343	Downstream function	Spermatogonial asynchrony without bridges
37039784	Corroborating	FAR1 loss disrupts TEX14/ICBs → giant cells, arrest
40528727	Corroborating	YKT6 loss destabilizes TEX14 bridges → meiotic arrest
29683733	Partner biology	CEP55 overexpression → male-specific sterility
37409705	Computational	Simulations confirm TEX14 outcompetes ALIX for CEP55
21364893	Contrast	RBM44 bridge protein dispensable — highlights TEX14's unique essentiality
40492599	Human causality	Recurrent compound-het TEX14 in NOA; disrupted bridge assembly
30054974	Prognosis	Post-meiotic markers predict sperm-retrieval success
32655042, 39267058, 38511217	Diagnostics	NGS/WES panels for SPGF/NOA diagnostic yield
41485595, 40658795, 42223426	Context/DDx	SCOS, NOA epidemiology, chromosomal causes to exclude

Limitations and Knowledge Gaps

Epidemiology is unquantified. Precise prevalence, incidence, and carrier frequency for SPGF23 specifically are not established; it is a minor fraction within the broad ~1% NOA population.
Allelic heterogeneity and genotype–phenotype correlation. Most functional evidence comes from null alleles/mouse knockout. Whether human missense/hypomorphic variants (several current VUS) produce partial phenotypes or permit focal residual spermatogenesis is not resolved.
Micro-TESE yield in human SPGF23 is inferred, largely from the maturation-arrest biology and marker studies rather than direct TEX14-cohort retrieval data; actual success rates are unreported.
Human histopathology detail is limited — bridge ultrastructure in human TEX14 patients is less characterized than in mouse.
No disease modifiers or therapeutics are known; no SPGF23-specific trials exist.
Female carriers/homozygotes — the male-specific prediction rests on mouse data; human female biallelic carriers are essentially unstudied.

Proposed Follow-up Experiments / Actions

Assemble a TEX14 patient registry to quantify prevalence, allelic spectrum, testicular histology, and micro-TESE success rates, directly validating the low-yield prognosis.
Functional validation of VUS (p.Pro893Arg, p.Ala64Val, p.Asn83His, p.Glu1351Gly, p.Ser268Cys, p.Leu497Pro) via CEP55-binding assays and bridge-reconstitution in cell models to reclassify per ACMG.
Single-cell/spatial transcriptomics of human TEX14 testis to confirm the bridge-dependent cytoplasmic-sharing and transposon-derepression mechanisms seen in mouse.
Correlate residual post-meiotic markers (PMID: 30054974) with retrieval outcomes in genotype-confirmed SPGF23 to build a predictive tool.
Humanized/knock-in mouse models of specific patient missense alleles to test for hypomorphic phenotypes and any rescue windows.
Genetic-counseling protocol for families, including cascade carrier testing and reproductive options (PGT, donor sperm), given confirmed autosomal-recessive inheritance.

Evidence source types represented: human clinical (families, NOA cohorts, ClinVar, OMIM, UniProt), model organism (mouse Tex14/Cep55/Far1/Ykt6), in vitro (binding/IP), and computational (metadynamics).

Artifacts

Term Validation

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

Outcome	Count
Terms checked	20
Resolved	20
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	0
Terms whose name was checked	18
Terms named correctly	8
Terms named as a different term	6
Terms whose name is worth a second look	4

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:0054727 (3 mentions) - the report calls it "if available", "MONDO"; MONDO calls it spermatogenic failure 23
HP:0011961 (2 mentions) - the report calls it "Azoospermia", "Semen analysis: azoospermia on ≥2 centrifuged specimens"; HP calls it Non-obstructive azoospermia**
GO:0045172 (3 mentions) - the report calls it "intercellular bridge / germline ring canal", "intercellular bridge", "Intercellular bridge"; GO calls it germline ring canal
GO:0007093 (1 mention) - the report calls it "cytokinesis/abscission regulation"; GO calls it mitotic cell cycle checkpoint signaling
CL:0000020 (2 mentions) - the report calls it "spermatogonium", "Target cell populations: male germ cells — spermatogonia"; CL calls it spermatogonium**
UBERON:0000473 (1 mention) - the report calls it "Primary organ: Testis"; UBERON calls it testis**

Terms whose name is worth a second look

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

GO:0010526 (1 mention) - the report calls it "retrotransposon silencing"; GO calls it transposable element silencing, and lists "retrotransposon silencing" among its other names
GO:0000776 (2 mentions) - the report calls it "kinetochore", "Kinetochore/centromere"; GO calls it kinetochore
CL:0000216 (2 mentions) - the report calls it "Sertoli cell, context"; CL calls it Sertoli cell
UBERON:0000079 (1 mention) - the report calls it "Body system: Male reproductive system"; UBERON calls it male reproductive system**

Terms named inconsistently

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

MONDO:0054727 - called "if available", "MONDO"
HP:0011961 - called "Azoospermia", "Semen analysis:** azoospermia on ≥2 centrifuged specimens"
GO:0045172 - called "intercellular bridge / germline ring canal", "intercellular bridge", "Intercellular bridge"
GO:0030496 - called "midbody", "Midbody"
GO:0000776 - called "kinetochore", "Kinetochore/centromere"
CL:0000020 - called "spermatogonium", "Target cell populations:** male germ cells — spermatogonia"

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome	Count
References checked	18
Resolved	18
Unresolved (possible confabulation)	0
Unverifiable	0
Quoted claims checked	9
Quoted claims found in source	9
Quoted claims not found in source	0
References weighed for topical relevance	18
On topic	12
Off topic	0

All extracted references resolved successfully.

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Inheritance

Mechanistic Hypotheses

Discussions and Knowledge Gaps

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Diagnosis

Animal Models

Source YAML

References & Deep Research

Deep Research

Spermatogenic Failure 23 (SPGF23 / TEX14): Comprehensive Disease Characteristics Report

Summary

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic / Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

Causal chain (initiating lesion → clinical manifestation)

Supporting detail

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome / Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Key Findings (with evidence)

Finding 1 — Biallelic TEX14 LoF causes SPGF23 (NOA with meiotic arrest)

Finding 2 — TEX14 builds intercellular bridges by converting CEP55 from abscission factor to bridge component

Finding 3 — Intercellular bridges enable cytoplasmic sharing required for meiosis, DSB repair, synapsis, and transposon repression

Finding 4 — TEX14 requirement is male-specific

Finding 5 — Meiotic/maturation arrest predicts low surgical sperm-retrieval yield

Finding 6 — TEX14 is a 1,497-aa testis-restricted inactive (pseudo)kinase with dual bridge/kinetochore roles

Finding 7 — ClinVar variant spectrum is LoF-dominated, confirming the LoF mechanism

Mechanistic Model / Interpretation

Evidence Base

Limitations and Knowledge Gaps

Proposed Follow-up Experiments / Actions

Artifacts

Term Validation

Terms the report names something else

Terms whose name is worth a second look

Terms named inconsistently

Reference Validation