ZTTK syndrome

Mendelian MONDO:0014936 Pathograph 31 Show in embeddings browser hereditary disease neurodevelopmental disorder

ZTTK syndrome is a multisystem neurodevelopmental disorder caused by heterozygous loss-of-function variants in SON. The core disease mechanism is SON haploinsufficiency with downstream disturbance of RNA processing and neurodevelopmental programs, producing intellectual disability and broader congenital anomaly phenotypes.

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1
Inheritance
7
Pathophys.
23
Phenotypes
31
Pathograph
1
Genes
5
Medical Actions
1
References
1
Deep Research
👪

Inheritance

1
Autosomal dominant inheritance, usually de novo HP:0000006
ZTTK syndrome is autosomal dominant. Almost all probands reported to date whose parents have undergone molecular genetic testing have a de novo pathogenic SON variant. Each child of an affected individual has a 50% chance of inheriting the variant, and prenatal or preimplantation genetic testing is possible once the familial variant is known.
Autosomal dominant inheritance
Show evidence (2 references)
PMID:40991760 SUPPORT Human Clinical
"ZTTK syndrome is an autosomal dominant disorder. Almost all probands reported to date with ZTTK syndrome whose parents have undergone molecular genetic testing have the disorder as the result of a de novo SON pathogenic variant."
GeneReviews directly states the mode of inheritance and the predominantly de novo origin observed in affected families.
PMID:40991760 SUPPORT Human Clinical
"Each child of an individual with ZTTK syndrome has a 50% chance of inheriting the SON pathogenic variant (data on reproduction in affected individuals are currently lacking, as most reported individuals are not yet of reproductive age). Once the SON pathogenic variant has been identified in an..."
GeneReviews directly states recurrence risk and reproductive testing options while noting the limited reproductive experience in this cohort.
⚙

Pathophysiology

7
SON haploinsufficiency
ZTTK syndrome is caused by heterozygous loss-of-function variants in SON, establishing SON insufficiency as the proximal disease mechanism.
SON hgnc:11183 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves SON (hgnc:11183). hgnc:11183 is a gene from the HUGO Gene Nomenclature Committee.
Downstream
Erroneous SON-mediated RNA splicing Reduced SON dosage impairs correct processing of weak splice sites in developmentally important transcripts.
Impaired neuronal migration Reduced SON dosage disrupts developmental programs required for normal cortical neuron positioning.
Dendritic spine abnormalities SON insufficiency also perturbs maturation of synaptic structures in cortical neurons.
Neurodevelopmental delay SON haploinsufficiency causes neurodevelopmental delay through incompletely resolved developmental intermediates.
Facial dysmorphism SON haploinsufficiency produces a characteristic craniofacial phenotype through developmental intermediates that have not been resolved.
Musculoskeletal abnormalities SON haploinsufficiency causes musculoskeletal manifestations through developmental intermediates that have not been resolved.
Prominent forehead SON haploinsufficiency leads to prominent forehead through unresolved craniofacial developmental intermediates.
Ptosis SON haploinsufficiency leads to ptosis through unresolved developmental intermediates.
Downslanted palpebral fissures SON haploinsufficiency leads to downslanted palpebral fissures through unresolved craniofacial developmental intermediates.
High palate SON haploinsufficiency leads to high palate through unresolved craniofacial developmental intermediates.
Short stature SON haploinsufficiency leads to short stature through unresolved growth and developmental intermediates.
Eye abnormality SON haploinsufficiency causes ocular abnormalities through unresolved developmental intermediates.
Genitourinary abnormality SON haploinsufficiency causes genitourinary manifestations through unresolved developmental intermediates.
Hematologic abnormality SON haploinsufficiency causes hematologic abnormalities through unresolved intermediates.
Cardiovascular system abnormality SON haploinsufficiency causes cardiovascular abnormalities through unresolved developmental intermediates.
Immune system abnormality SON haploinsufficiency causes immune abnormalities through unresolved intermediates.
Gastrointestinal abnormality SON haploinsufficiency causes gastrointestinal abnormalities through unresolved intermediates.
Hearing impairment SON haploinsufficiency causes hearing abnormalities through unresolved developmental intermediates.
Show evidence (1 reference)
PMID:34521999 SUPPORT Human Clinical
"Zhu-Tokita-Takenouchi-Kim (ZTTK) syndrome, an intellectual disability syndrome first described in 2016, is caused by heterozygous loss-of-function variants in SON."
The 52-person cohort directly establishes heterozygous SON loss-of-function as the defining mechanism.
Erroneous SON-mediated RNA splicing
SON promotes pre-mRNA splicing, particularly for developmentally important transcripts with weak splice sites. Haploinsufficiency causes intron retention and other mis-splicing events that reduce productive transcripts.
RNA splicing GO:0008380 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal RNA splicing (GO:0008380). GO:0008380 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Reduced expression of neurodevelopmental and metabolic genes Mis-spliced transcripts accumulate and productive expression falls across SON-dependent developmental and metabolic targets.
Aberrant splicing of kidney-development genes The shared spliceopathy includes established CAKUT genes in kidney cells and cells from affected individuals.
Show evidence (2 references)
PMID:27545680 SUPPORT In Vitro
"Importantly, analyses of RNA from affected individuals revealed that genes critical for neuronal migration and cortex organization (TUBG1, FLNA, PNKP, WDR62, PSMD3, and HDAC6) and metabolism (PCK2, PFKL, IDH2, ACY1, and ADA) are significantly downregulated because of the accumulation of..."
Patient-derived RNA directly supports the central spliceopathy node.
PMID:31005274 SUPPORT In Vitro
"The results demonstrate that short introns with weak splice site(s) were retained in the PKD1, PAX8, and FRAS1 pre-mRNAs when SON expression is reduced (Figure 4a)."
The kidney-cell experiments demonstrate SON-dependent processing of weak splice sites in developmentally important transcripts.
Reduced expression of neurodevelopmental and metabolic genes
Mis-splicing lowers expression of genes required for neuronal migration, cortical organization, and metabolism, including TUBG1, FLNA, PNKP, WDR62, PSMD3, HDAC6, PCK2, PFKL, IDH2, ACY1, and ADA.
Downstream
Brain malformation Reduced expression of genes required for neuronal migration and cortical organization provides a mechanistic route to abnormal brain development.
Neurodevelopmental impairment Broad loss of neurodevelopmental target-gene expression contributes to the developmental and cognitive phenotype through incompletely resolved intermediates.
Show evidence (1 reference)
PMID:27545680 SUPPORT In Vitro
"Importantly, analyses of RNA from affected individuals revealed that genes critical for neuronal migration and cortex organization (TUBG1, FLNA, PNKP, WDR62, PSMD3, and HDAC6) and metabolism (PCK2, PFKL, IDH2, ACY1, and ADA) are significantly downregulated because of the accumulation of..."
This directly supports reduced expression of the named developmental and metabolic targets.
Impaired neuronal migration
SON insufficiency disrupts corticogenesis by impairing neuronal migration in the developing brain.
neuron migration GO:0001764 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal neuron migration (GO:0001764). GO:0001764 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Neurodevelopmental impairment Abnormal cortical development contributes to the syndrome's cognitive and developmental phenotype.
Show evidence (1 reference)
PMID:32448361 SUPPORT Model Organism
"These data indicate that SON insufficiency causes neuronal migration defects and dendritic spine abnormalities, which seem neuropathological bases of the neural symptoms of ZTTK syndrome."
This directly supports impaired neuronal migration as a mechanistic node.
Dendritic spine abnormalities
SON insufficiency reduces dendritic spine density, indicating impaired synaptic maturation.
pyramidal neuron CL:0000598 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves pyramidal neuron (CL:0000598). CL:0000598 is a cell type from the Cell Ontology.
dendritic spine morphogenesis GO:0060997 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal dendritic spine morphogenesis (GO:0060997). GO:0060997 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Intellectual disability Reduced dendritic spine density provides a model-supported route from SON insufficiency to intellectual disability.
Neurodevelopmental impairment Synaptic structural abnormalities are likely to contribute to cognitive dysfunction in affected individuals.
Show evidence (1 reference)
PMID:32448361 SUPPORT Model Organism
"Son knockdown in neural progenitors resulted in defective migration during corticogenesis and reduced spine density on mature cortical neurons."
This directly supports reduced dendritic spine density as a parallel downstream consequence of SON insufficiency.
Aberrant splicing of kidney-development genes
SON insufficiency causes abnormal splicing and reduced expression of several genes required for kidney development, creating a mechanistic branch for the heterogeneous renal phenotype.
kidney proximal tubule epithelial cell CL:0002306 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves kidney proximal tubule epithelial cell, annotated with epithelial cell of proximal tubule (CL:0002306). CL:0002306 is a cell type from the Cell Ontology.
RNA splicing GO:0008380 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal RNA splicing (GO:0008380). GO:0008380 is a biological process from the Gene Ontology. ⚠ ABNORMAL
kidney UBERON:0002113 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in kidney (UBERON:0002113). UBERON:0002113 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Kidney abnormalities Impaired processing of multiple kidney-development transcripts provides a mechanistic explanation for the heterogeneous structural renal anomalies.
Horseshoe kidney The renal spliceopathy contributes to horseshoe kidney through unresolved developmental intermediates.
Renal hypoplasia The renal spliceopathy contributes to renal hypoplasia through unresolved developmental intermediates.
Renal cyst The renal spliceopathy contributes to renal cyst formation through unresolved developmental intermediates.
Show evidence (1 reference)
PMID:31005274 SUPPORT In Vitro
"SON knockdown in kidney cell lines leads to abnormal pre-mRNA splicing, resulting in decreased expression of several established CAKUT genes. Furthermore, these molecular events were observed in patient-derived cells with SON haploinsufficiency."
The experiments directly demonstrate the renal-cell splicing defect and reproduce it in patient-derived cells.
Neurodevelopmental impairment
The convergent consequence of SON haploinsufficiency in the nervous system is a broad neurodevelopmental disorder centered on intellectual disability.
Downstream
Seizure Seizures are reported in more than half of affected individuals.
Atypical behavior Behavioral issues are reported in more than half of affected individuals.
Show evidence (1 reference)
PMID:40991760 SUPPORT Human Clinical
"Zhu-Tokita-Takenouchi-Kim (ZTTK) syndrome is characterized by developmental delay and intellectual disability."
GeneReviews identifies developmental delay and intellectual disability as the defining neurodevelopmental manifestations.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for ZTTK syndrome Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

23
Cardiovascular 1
Cardiovascular system abnormality Abnormality of the cardiovascular system HP:0001626 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormality of the cardiovascular system (HP:0001626). HP:0001626 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40991760 SUPPORT Human Clinical
"Hematologic, cardiac, immune, gastrointestinal, and hearing abnormalities have also been reported."
GeneReviews directly reports generic cardiac abnormalities without specifying a structural subtype.
Digestive 1
Gastrointestinal abnormality Abnormality of the digestive system HP:0025031 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormality of the digestive system (HP:0025031). HP:0025031 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40991760 SUPPORT Human Clinical
"Hematologic, cardiac, immune, gastrointestinal, and hearing abnormalities have also been reported."
GeneReviews directly includes gastrointestinal abnormalities.
Ear 1
Hearing impairment HP:0000365 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hearing impairment (HP:0000365). HP:0000365 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40991760 SUPPORT Human Clinical
"Hematologic, cardiac, immune, gastrointestinal, and hearing abnormalities have also been reported."
GeneReviews directly includes hearing abnormalities in the phenotype.
Eye 1
Ptosis HP:0000508 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ptosis (HP:0000508). HP:0000508 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40991760 SUPPORT Human Clinical
"Characteristic facial features include facial asymmetry, prominent forehead, horizontal eyebrows, ptosis, downslanted palpebral fissures, epicanthal folds, deep-set eyes, midface retrusion, depressed or other abnormality of the nasal bridge, low-set ears that may be posteriorly rotated, short..."
GeneReviews directly lists ptosis.
Genitourinary 4
Kidney abnormalities FREQUENT Abnormality of the kidney HP:0000077 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormality of the kidney (HP:0000077). HP:0000077 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31005274 SUPPORT Human Clinical
"Detailed phenotyping of 14 patients with SON haploinsufficiency identified kidney anomalies in 8 patients, including horseshoe kidney, unilateral renal hypoplasia, and renal cysts."
The study directly documents kidney anomalies in 8 of 14 examined patients, supporting both the association and FREQUENT band.
Horseshoe kidney HP:0000085 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Horseshoe kidney (HP:0000085). HP:0000085 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31005274 SUPPORT Human Clinical
"Detailed phenotyping of 14 patients with SON haploinsufficiency identified kidney anomalies in 8 patients, including horseshoe kidney, unilateral renal hypoplasia, and renal cysts."
The renal cohort directly reports horseshoe kidney.
Renal cyst HP:0000107 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Renal cyst (HP:0000107). HP:0000107 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31005274 SUPPORT Human Clinical
"Detailed phenotyping of 14 patients with SON haploinsufficiency identified kidney anomalies in 8 patients, including horseshoe kidney, unilateral renal hypoplasia, and renal cysts."
The renal cohort directly reports renal cysts.
Genitourinary abnormality Abnormality of the genitourinary system HP:0000119 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormality of the genitourinary system (HP:0000119). HP:0000119 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40991760 SUPPORT Human Clinical
"Skeletal and ocular abnormalities, short stature, and genitourinary and kidney manifestations are common."
GeneReviews directly identifies genitourinary manifestations as common.
Head and Neck 3
Prominent forehead HP:0011220 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Prominent forehead (HP:0011220). HP:0011220 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40991760 SUPPORT Human Clinical
"Characteristic facial features include facial asymmetry, prominent forehead, horizontal eyebrows, ptosis, downslanted palpebral fissures, epicanthal folds, deep-set eyes, midface retrusion, depressed or other abnormality of the nasal bridge, low-set ears that may be posteriorly rotated, short..."
GeneReviews directly lists prominent forehead.
Downslanted palpebral fissures HP:0000494 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Downslanted palpebral fissures (HP:0000494). HP:0000494 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40991760 SUPPORT Human Clinical
"Characteristic facial features include facial asymmetry, prominent forehead, horizontal eyebrows, ptosis, downslanted palpebral fissures, epicanthal folds, deep-set eyes, midface retrusion, depressed or other abnormality of the nasal bridge, low-set ears that may be posteriorly rotated, short..."
GeneReviews directly lists downslanted palpebral fissures.
High palate HP:0000218 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is High palate (HP:0000218). HP:0000218 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40991760 SUPPORT Human Clinical
"Characteristic facial features include facial asymmetry, prominent forehead, horizontal eyebrows, ptosis, downslanted palpebral fissures, epicanthal folds, deep-set eyes, midface retrusion, depressed or other abnormality of the nasal bridge, low-set ears that may be posteriorly rotated, short..."
GeneReviews directly lists high palate.
Nervous System 4
Intellectual disability HP:0001249 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intellectual disability (HP:0001249). HP:0001249 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40991760 SUPPORT Human Clinical
"Zhu-Tokita-Takenouchi-Kim (ZTTK) syndrome is characterized by developmental delay and intellectual disability."
This directly supports intellectual disability as a defining phenotype.
Neurodevelopmental delay HP:0012758 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Neurodevelopmental delay (HP:0012758). HP:0012758 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40991760 SUPPORT Human Clinical
"Zhu-Tokita-Takenouchi-Kim (ZTTK) syndrome is characterized by developmental delay and intellectual disability."
GeneReviews directly identifies developmental delay as a defining manifestation without asserting global developmental delay.
Seizure HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40991760 SUPPORT Human Clinical
"Behavioral issues and seizures are reported in more than half of affected individuals."
GeneReviews supports the association and reports that it occurs in more than half of affected individuals without fixing an upper frequency bound.
Atypical behavior HP:0000708 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Atypical behavior (HP:0000708). HP:0000708 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40991760 SUPPORT Human Clinical
"Behavioral issues and seizures are reported in more than half of affected individuals."
GeneReviews supports the association and reports that it occurs in more than half of affected individuals without fixing an upper frequency bound.
Growth 1
Short stature HP:0004322 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short stature (HP:0004322). HP:0004322 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40991760 SUPPORT Human Clinical
"Skeletal and ocular abnormalities, short stature, and genitourinary and kidney manifestations are common."
GeneReviews directly identifies short stature as common.
Other 7
Facial dysmorphism Abnormality of the face HP:0000271 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormality of the face (HP:0000271). HP:0000271 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40991760 SUPPORT Human Clinical
"Characteristic facial features include facial asymmetry, prominent forehead, horizontal eyebrows, ptosis, downslanted palpebral fissures, epicanthal folds, deep-set eyes, midface retrusion, depressed or other abnormality of the nasal bridge, low-set ears that may be posteriorly rotated, short..."
The current clinical review directly enumerates the characteristic facial phenotype.
Brain malformation Abnormal brain morphology HP:0012443 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Brain malformation, annotated with Abnormal brain morphology (HP:0012443). HP:0012443 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:27545680 SUPPORT Human Clinical
"Here, we report on an ID syndrome caused by de novo heterozygous loss-of-function (LoF) mutations in SON. The syndrome is characterized by ID and/or DD, malformations of the cerebral cortex, epilepsy, vision problems, musculoskeletal abnormalities, and congenital malformations."
The original human cohort directly reports malformations of the cerebral cortex.
Musculoskeletal abnormalities Abnormality of the musculoskeletal system HP:0033127 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Musculoskeletal abnormality, annotated with Abnormality of the musculoskeletal system (HP:0033127). HP:0033127 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:27545680 SUPPORT Human Clinical
"Here, we report on an ID syndrome caused by de novo heterozygous loss-of-function (LoF) mutations in SON. The syndrome is characterized by ID and/or DD, malformations of the cerebral cortex, epilepsy, vision problems, musculoskeletal abnormalities, and congenital malformations."
The original human cohort directly reports musculoskeletal abnormalities.
Renal hypoplasia HP:0000089 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Renal hypoplasia (HP:0000089). HP:0000089 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31005274 SUPPORT Human Clinical
"Detailed phenotyping of 14 patients with SON haploinsufficiency identified kidney anomalies in 8 patients, including horseshoe kidney, unilateral renal hypoplasia, and renal cysts."
The renal cohort directly reports unilateral renal hypoplasia.
Eye abnormality Abnormality of the eye HP:0000478 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormality of the eye (HP:0000478). HP:0000478 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40991760 SUPPORT Human Clinical
"Skeletal and ocular abnormalities, short stature, and genitourinary and kidney manifestations are common."
GeneReviews directly identifies ocular abnormalities as common.
Hematologic abnormality Abnormality of blood and blood-forming tissues HP:0001871 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormality of blood and blood-forming tissues (HP:0001871). HP:0001871 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40991760 SUPPORT Human Clinical
"Hematologic, cardiac, immune, gastrointestinal, and hearing abnormalities have also been reported."
GeneReviews directly includes hematologic abnormalities.
Immune system abnormality Abnormality of the immune system HP:0002715 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormality of the immune system (HP:0002715). HP:0002715 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40991760 SUPPORT Human Clinical
"Hematologic, cardiac, immune, gastrointestinal, and hearing abnormalities have also been reported."
GeneReviews directly includes immune abnormalities.
🧬

Genetic Associations

1
SON (Heterozygous loss-of-function causal gene)
Gene: SON hgnc:11183 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is SON (hgnc:11183). hgnc:11183 is a gene from the HUGO Gene Nomenclature Committee. variant_origin: GERMLINE
Show evidence (2 references)
PMID:34521999 SUPPORT Human Clinical
"In total, loss-of-function variants were detected in 49 individuals (de novo in 47, inheritance unknown in 2), and in 3, a missense variant was observed (2 de novo, 1 inheritance unknown)."
The cohort establishes the predominant loss-of-function variant class and de novo origin in molecularly characterized individuals.
CGGV:assertion_b7e86b1d-154a-40b5-b454-fad392f87782-2025-11-10T170000.000Z SUPPORT Other
"SON | HGNC:11183 | ZTTK syndrome | MONDO:0014936 | AD | Definitive"
ClinGen classifies the SON-ZTTK syndrome gene-disease relationship as definitive with autosomal dominant inheritance.
💊

Medical Actions

5
Supportive multidisciplinary care
Action: Supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
No therapy directly corrects SON deficiency. Management is supportive and individualized across developmental, neurologic, nutritional, renal, cardiac, musculoskeletal, ophthalmologic, hearing, immune, and other manifestations.
Show evidence (1 reference)
PMID:40991760 SUPPORT Other
"None of the treatments available directly address SON deficiency. Supportive measures include developmental and educational support; standard treatment for seizures and movement disorder; treatment of craniosynostosis per craniofacial team; treatment of musculoskeletal manifestations per..."
GeneReviews states that care is supportive rather than disease-modifying and enumerates the affected systems requiring individualized management.
Kidney ultrasound surveillance
Action: Supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Kidney ultrasound is recommended annually or as clinically needed.
Show evidence (1 reference)
PMID:40991760 SUPPORT Human Clinical
"Surveillance: Assess developmental progress, educational needs, behavioral issues, neurologic manifestations, musculoskeletal evaluation, growth, nutrition, gastrointestinal and hematologic issues, and for recurrent infections at each visit; ophthalmologic evaluation per ophthalmologist;..."
GeneReviews directly recommends the renal surveillance schedule.
Annual audiology surveillance
Action: Supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Audiology evaluation is recommended annually.
Show evidence (1 reference)
PMID:40991760 SUPPORT Human Clinical
"Surveillance: Assess developmental progress, educational needs, behavioral issues, neurologic manifestations, musculoskeletal evaluation, growth, nutrition, gastrointestinal and hematologic issues, and for recurrent infections at each visit; ophthalmologic evaluation per ophthalmologist;..."
GeneReviews directly recommends annual audiology evaluation.
Ophthalmologic surveillance
Action: Supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Ophthalmologic evaluation is scheduled by the treating ophthalmologist.
Show evidence (1 reference)
PMID:40991760 SUPPORT Human Clinical
"Surveillance: Assess developmental progress, educational needs, behavioral issues, neurologic manifestations, musculoskeletal evaluation, growth, nutrition, gastrointestinal and hematologic issues, and for recurrent infections at each visit; ophthalmologic evaluation per ophthalmologist;..."
GeneReviews directly recommends specialist-directed eye surveillance.
Endocrine surveillance for growth hormone deficiency
Action: Supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Endocrine evaluation is recommended when growth hormone deficiency is present.
Show evidence (1 reference)
PMID:40991760 SUPPORT Human Clinical
"Surveillance: Assess developmental progress, educational needs, behavioral issues, neurologic manifestations, musculoskeletal evaluation, growth, nutrition, gastrointestinal and hematologic issues, and for recurrent infections at each visit; ophthalmologic evaluation per ophthalmologist;..."
GeneReviews directly recommends endocrine follow-up when growth hormone deficiency is present.
🔬

Diagnosis

1
Characteristic features and molecular genetic testing
The diagnosis is established in a proband with characteristic features and a heterozygous pathogenic variant in SON identified by molecular genetic testing.
molecular genetic testing NCIT:C19770 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:40991760 SUPPORT Human Clinical
"The diagnosis of ZTTK syndrome is established in a proband with characteristic features and a heterozygous pathogenic variant in SON identified by molecular genetic testing."
GeneReviews directly states the molecular diagnostic criterion.
{ }

Source YAML

click to show 
name: ZTTK syndrome
creation_date: '2026-04-14T12:05:00Z'
category: Mendelian
description: >-
  ZTTK syndrome is a multisystem neurodevelopmental disorder caused by
  heterozygous loss-of-function variants in SON. The core disease mechanism is
  SON haploinsufficiency with downstream disturbance of RNA processing and
  neurodevelopmental programs, producing intellectual disability and broader
  congenital anomaly phenotypes.
disease_term:
  preferred_term: ZTTK syndrome
  term:
    id: MONDO:0014936
    label: ZTTK syndrome
synonyms:
- Zhu-Tokita-Takenouchi-Kim syndrome
- SON deficiency syndrome
- SON-related neurodevelopmental disorder
- SON-related ZTTK syndrome
parents:
- hereditary disease
- neurodevelopmental disorder
references:
- reference: PMID:40991760
  title: Zhu-Tokita-Takenouchi-Kim Syndrome.
  tags:
  - GeneReviews
inheritance:
- name: Autosomal dominant inheritance, usually de novo
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    ZTTK syndrome is autosomal dominant. Almost all probands reported to date
    whose parents have undergone molecular genetic testing have a de novo
    pathogenic SON variant. Each child of an affected individual has a 50%
    chance of inheriting the variant, and prenatal or preimplantation genetic
    testing is possible once the familial variant is known.
  evidence:
  - reference: PMID:40991760
    reference_title: Zhu-Tokita-Takenouchi-Kim Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      ZTTK syndrome is an autosomal dominant disorder. Almost all probands
      reported to date with ZTTK syndrome whose parents have undergone molecular
      genetic testing have the disorder as the result of a de novo SON pathogenic
      variant.
    explanation: >-
      GeneReviews directly states the mode of inheritance and the predominantly
      de novo origin observed in affected families.
  - reference: PMID:40991760
    reference_title: Zhu-Tokita-Takenouchi-Kim Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Each child of an individual with ZTTK syndrome has a 50% chance of
      inheriting the SON pathogenic variant (data on reproduction in affected
      individuals are currently lacking, as most reported individuals are not
      yet of reproductive age). Once the SON pathogenic variant has been
      identified in an affected family member, prenatal and preimplantation
      genetic testing are possible.
    explanation: >-
      GeneReviews directly states recurrence risk and reproductive testing
      options while noting the limited reproductive experience in this cohort.
pathophysiology:
- name: SON haploinsufficiency
  biological_scale: MOLECULAR
  description: >-
    ZTTK syndrome is caused by heterozygous loss-of-function variants in SON,
    establishing SON insufficiency as the proximal disease mechanism.
  genes:
  - preferred_term: SON
    term:
      id: hgnc:11183
      label: SON
  evidence:
  - reference: PMID:34521999
    reference_title: >-
      Establishing the phenotypic spectrum of ZTTK syndrome by analysis of 52
      individuals with variants in SON.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Zhu-Tokita-Takenouchi-Kim (ZTTK) syndrome, an intellectual disability
      syndrome first described in 2016, is caused by heterozygous loss-of-function
      variants in SON.
    explanation: >-
      The 52-person cohort directly establishes heterozygous SON
      loss-of-function as the defining mechanism.
  downstream:
  - target: Erroneous SON-mediated RNA splicing
    description: >-
      Reduced SON dosage impairs correct processing of weak splice sites in
      developmentally important transcripts.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:27545680
      reference_title: >-
        De Novo Mutations in SON Disrupt RNA Splicing of Genes Essential for
        Brain Development and Metabolism, Causing an Intellectual-Disability
        Syndrome.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Importantly, analyses of RNA from affected individuals revealed that
        genes critical for neuronal migration and cortex organization (TUBG1,
        FLNA, PNKP, WDR62, PSMD3, and HDAC6) and metabolism (PCK2, PFKL, IDH2,
        ACY1, and ADA) are significantly downregulated because of the accumulation
        of mis-spliced transcripts resulting from erroneous SON-mediated RNA
        splicing.
      explanation: >-
        RNA from affected individuals directly demonstrates mis-splicing after
        SON loss-of-function.
    - reference: PMID:31005274
      reference_title: >-
        SON haploinsufficiency causes impaired pre-mRNA splicing of CAKUT genes
        and heterogeneous renal phenotypes.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        The results demonstrate that short introns with weak splice site(s) were
        retained in the PKD1, PAX8, and FRAS1 pre-mRNAs when SON expression is
        reduced (Figure 4a).
      explanation: >-
        SON knockdown experimentally demonstrates intron retention at weak
        splice sites in developmentally important kidney transcripts.
  - target: Impaired neuronal migration
    description: >-
      Reduced SON dosage disrupts developmental programs required for normal
      cortical neuron positioning.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:32448361
      reference_title: >-
        Knockdown of Son, a mouse homologue of the ZTTK syndrome gene, causes
        neuronal migration defects and dendritic spine abnormalities.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        These data indicate that SON insufficiency causes neuronal migration
        defects and dendritic spine abnormalities, which seem neuropathological
        bases of the neural symptoms of ZTTK syndrome.
      explanation: >-
        This model-organism study links SON insufficiency directly to abnormal
        neuronal migration.
  - target: Dendritic spine abnormalities
    description: >-
      SON insufficiency also perturbs maturation of synaptic structures in
      cortical neurons.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:32448361
      reference_title: >-
        Knockdown of Son, a mouse homologue of the ZTTK syndrome gene, causes
        neuronal migration defects and dendritic spine abnormalities.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Son knockdown in neural progenitors resulted in defective migration
        during corticogenesis and reduced spine density on mature cortical
        neurons.
      explanation: >-
        The mouse study directly reports reduced dendritic spine density after
        Son knockdown.
  - target: Neurodevelopmental delay
    description: >-
      SON haploinsufficiency causes neurodevelopmental delay through incompletely
      resolved developmental intermediates.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:40991760
      reference_title: Zhu-Tokita-Takenouchi-Kim Syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Zhu-Tokita-Takenouchi-Kim (ZTTK) syndrome is characterized by developmental
        delay and intellectual disability.
      explanation: >-
        GeneReviews establishes developmental delay as a defining manifestation,
        while the specific causal route remains unresolved.
  - target: Facial dysmorphism
    description: >-
      SON haploinsufficiency produces a characteristic craniofacial phenotype
      through developmental intermediates that have not been resolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:40991760
      reference_title: Zhu-Tokita-Takenouchi-Kim Syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Characteristic facial features include facial asymmetry, prominent
        forehead, horizontal eyebrows, ptosis, downslanted palpebral fissures,
        epicanthal folds, deep-set eyes, midface retrusion, depressed or other
        abnormality of the nasal bridge, low-set ears that may be posteriorly
        rotated, short and/or smooth philtrum, thin vermilion of the upper lip,
        bifid uvula, and high palate.
      explanation: >-
        GeneReviews establishes the craniofacial phenotype of the SON-related
        syndrome, while the intervening developmental mechanism remains unknown.
  - target: Musculoskeletal abnormalities
    description: >-
      SON haploinsufficiency causes musculoskeletal manifestations through
      developmental intermediates that have not been resolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:27545680
      reference_title: >-
        De Novo Mutations in SON Disrupt RNA Splicing of Genes Essential for
        Brain Development and Metabolism, Causing an Intellectual-Disability
        Syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Here, we report on an ID syndrome caused by de novo heterozygous
        loss-of-function (LoF) mutations in SON. The syndrome is characterized by
        ID and/or DD, malformations of the cerebral cortex, epilepsy, vision
        problems, musculoskeletal abnormalities, and congenital malformations.
      explanation: >-
        The original human cohort links SON loss-of-function with
        musculoskeletal abnormalities but does not resolve the causal route.
  - target: Prominent forehead
    description: >-
      SON haploinsufficiency leads to prominent forehead through unresolved
      craniofacial developmental intermediates.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:40991760
      reference_title: Zhu-Tokita-Takenouchi-Kim Syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Characteristic facial features include facial asymmetry, prominent
        forehead, horizontal eyebrows, ptosis, downslanted palpebral fissures,
        epicanthal folds, deep-set eyes, midface retrusion, depressed or other
        abnormality of the nasal bridge, low-set ears that may be posteriorly
        rotated, short and/or smooth philtrum, thin vermilion of the upper lip,
        bifid uvula, and high palate.
      explanation: The phenotype is established, but its causal route is unresolved.
  - target: Ptosis
    description: >-
      SON haploinsufficiency leads to ptosis through unresolved developmental
      intermediates.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:40991760
      reference_title: Zhu-Tokita-Takenouchi-Kim Syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Characteristic facial features include facial asymmetry, prominent
        forehead, horizontal eyebrows, ptosis, downslanted palpebral fissures,
        epicanthal folds, deep-set eyes, midface retrusion, depressed or other
        abnormality of the nasal bridge, low-set ears that may be posteriorly
        rotated, short and/or smooth philtrum, thin vermilion of the upper lip,
        bifid uvula, and high palate.
      explanation: The phenotype is established, but its causal route is unresolved.
  - target: Downslanted palpebral fissures
    description: >-
      SON haploinsufficiency leads to downslanted palpebral fissures through
      unresolved craniofacial developmental intermediates.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:40991760
      reference_title: Zhu-Tokita-Takenouchi-Kim Syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Characteristic facial features include facial asymmetry, prominent
        forehead, horizontal eyebrows, ptosis, downslanted palpebral fissures,
        epicanthal folds, deep-set eyes, midface retrusion, depressed or other
        abnormality of the nasal bridge, low-set ears that may be posteriorly
        rotated, short and/or smooth philtrum, thin vermilion of the upper lip,
        bifid uvula, and high palate.
      explanation: The phenotype is established, but its causal route is unresolved.
  - target: High palate
    description: >-
      SON haploinsufficiency leads to high palate through unresolved craniofacial
      developmental intermediates.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:40991760
      reference_title: Zhu-Tokita-Takenouchi-Kim Syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Characteristic facial features include facial asymmetry, prominent
        forehead, horizontal eyebrows, ptosis, downslanted palpebral fissures,
        epicanthal folds, deep-set eyes, midface retrusion, depressed or other
        abnormality of the nasal bridge, low-set ears that may be posteriorly
        rotated, short and/or smooth philtrum, thin vermilion of the upper lip,
        bifid uvula, and high palate.
      explanation: The phenotype is established, but its causal route is unresolved.
  - target: Short stature
    description: >-
      SON haploinsufficiency leads to short stature through unresolved growth and
      developmental intermediates.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:40991760
      reference_title: Zhu-Tokita-Takenouchi-Kim Syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Skeletal and ocular abnormalities, short stature, and genitourinary and
        kidney manifestations are common.
      explanation: The phenotype is established, but its causal route is unresolved.
  - target: Eye abnormality
    description: >-
      SON haploinsufficiency causes ocular abnormalities through unresolved
      developmental intermediates.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:40991760
      reference_title: Zhu-Tokita-Takenouchi-Kim Syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Skeletal and ocular abnormalities, short stature, and genitourinary and
        kidney manifestations are common.
      explanation: The phenotype is established, but its causal route is unresolved.
  - target: Genitourinary abnormality
    description: >-
      SON haploinsufficiency causes genitourinary manifestations through
      unresolved developmental intermediates.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:40991760
      reference_title: Zhu-Tokita-Takenouchi-Kim Syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Skeletal and ocular abnormalities, short stature, and genitourinary and
        kidney manifestations are common.
      explanation: The phenotype is established, but its causal route is unresolved.
  - target: Hematologic abnormality
    description: >-
      SON haploinsufficiency causes hematologic abnormalities through unresolved
      intermediates.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:40991760
      reference_title: Zhu-Tokita-Takenouchi-Kim Syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Hematologic, cardiac, immune, gastrointestinal, and hearing abnormalities
        have also been reported.
      explanation: The phenotype is established, but its causal route is unresolved.
  - target: Cardiovascular system abnormality
    description: >-
      SON haploinsufficiency causes cardiovascular abnormalities through
      unresolved developmental intermediates.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:40991760
      reference_title: Zhu-Tokita-Takenouchi-Kim Syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Hematologic, cardiac, immune, gastrointestinal, and hearing abnormalities
        have also been reported.
      explanation: >-
        GeneReviews establishes generic cardiac involvement, while the specific
        phenotype and causal route remain unresolved.
  - target: Immune system abnormality
    description: >-
      SON haploinsufficiency causes immune abnormalities through unresolved
      intermediates.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:40991760
      reference_title: Zhu-Tokita-Takenouchi-Kim Syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Hematologic, cardiac, immune, gastrointestinal, and hearing abnormalities
        have also been reported.
      explanation: The phenotype is established, but its causal route is unresolved.
  - target: Gastrointestinal abnormality
    description: >-
      SON haploinsufficiency causes gastrointestinal abnormalities through
      unresolved intermediates.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:40991760
      reference_title: Zhu-Tokita-Takenouchi-Kim Syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Hematologic, cardiac, immune, gastrointestinal, and hearing abnormalities
        have also been reported.
      explanation: The phenotype is established, but its causal route is unresolved.
  - target: Hearing impairment
    description: >-
      SON haploinsufficiency causes hearing abnormalities through unresolved
      developmental intermediates.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:40991760
      reference_title: Zhu-Tokita-Takenouchi-Kim Syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Hematologic, cardiac, immune, gastrointestinal, and hearing abnormalities
        have also been reported.
      explanation: The phenotype is established, but its causal route is unresolved.
- name: Erroneous SON-mediated RNA splicing
  biological_scale: MOLECULAR
  description: >-
    SON promotes pre-mRNA splicing, particularly for developmentally important
    transcripts with weak splice sites. Haploinsufficiency causes intron
    retention and other mis-splicing events that reduce productive transcripts.
  biological_processes:
  - preferred_term: RNA splicing
    term:
      id: GO:0008380
      label: RNA splicing
    modifier: ABNORMAL
  evidence:
  - reference: PMID:27545680
    reference_title: >-
      De Novo Mutations in SON Disrupt RNA Splicing of Genes Essential for Brain
      Development and Metabolism, Causing an Intellectual-Disability Syndrome.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Importantly, analyses of RNA from affected individuals revealed that genes
      critical for neuronal migration and cortex organization (TUBG1, FLNA, PNKP,
      WDR62, PSMD3, and HDAC6) and metabolism (PCK2, PFKL, IDH2, ACY1, and ADA)
      are significantly downregulated because of the accumulation of mis-spliced
      transcripts resulting from erroneous SON-mediated RNA splicing.
    explanation: >-
      Patient-derived RNA directly supports the central spliceopathy node.
  - reference: PMID:31005274
    reference_title: >-
      SON haploinsufficiency causes impaired pre-mRNA splicing of CAKUT genes and
      heterogeneous renal phenotypes.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The results demonstrate that short introns with weak splice site(s) were
      retained in the PKD1, PAX8, and FRAS1 pre-mRNAs when SON expression is
      reduced (Figure 4a).
    explanation: >-
      The kidney-cell experiments demonstrate SON-dependent processing of weak
      splice sites in developmentally important transcripts.
  downstream:
  - target: Reduced expression of neurodevelopmental and metabolic genes
    description: >-
      Mis-spliced transcripts accumulate and productive expression falls across
      SON-dependent developmental and metabolic targets.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:27545680
      reference_title: >-
        De Novo Mutations in SON Disrupt RNA Splicing of Genes Essential for
        Brain Development and Metabolism, Causing an Intellectual-Disability
        Syndrome.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Importantly, analyses of RNA from affected individuals revealed that
        genes critical for neuronal migration and cortex organization (TUBG1,
        FLNA, PNKP, WDR62, PSMD3, and HDAC6) and metabolism (PCK2, PFKL, IDH2,
        ACY1, and ADA) are significantly downregulated because of the accumulation
        of mis-spliced transcripts resulting from erroneous SON-mediated RNA
        splicing.
      explanation: >-
        The study directly connects transcript mis-splicing with reduced target
        gene expression.
  - target: Aberrant splicing of kidney-development genes
    description: >-
      The shared spliceopathy includes established CAKUT genes in kidney cells
      and cells from affected individuals.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:31005274
      reference_title: >-
        SON haploinsufficiency causes impaired pre-mRNA splicing of CAKUT genes
        and heterogeneous renal phenotypes.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        SON knockdown in kidney cell lines leads to abnormal pre-mRNA splicing,
        resulting in decreased expression of several established CAKUT genes.
        Furthermore, these molecular events were observed in patient-derived
        cells with SON haploinsufficiency.
      explanation: >-
        Kidney-cell knockdown and patient-derived cells establish a renal branch
        of the SON-dependent spliceopathy.
- name: Reduced expression of neurodevelopmental and metabolic genes
  biological_scale: MOLECULAR
  description: >-
    Mis-splicing lowers expression of genes required for neuronal migration,
    cortical organization, and metabolism, including TUBG1, FLNA, PNKP, WDR62,
    PSMD3, HDAC6, PCK2, PFKL, IDH2, ACY1, and ADA.
  evidence:
  - reference: PMID:27545680
    reference_title: >-
      De Novo Mutations in SON Disrupt RNA Splicing of Genes Essential for Brain
      Development and Metabolism, Causing an Intellectual-Disability Syndrome.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Importantly, analyses of RNA from affected individuals revealed that genes
      critical for neuronal migration and cortex organization (TUBG1, FLNA, PNKP,
      WDR62, PSMD3, and HDAC6) and metabolism (PCK2, PFKL, IDH2, ACY1, and ADA)
      are significantly downregulated because of the accumulation of mis-spliced
      transcripts resulting from erroneous SON-mediated RNA splicing.
    explanation: >-
      This directly supports reduced expression of the named developmental and
      metabolic targets.
  downstream:
  - target: Brain malformation
    description: >-
      Reduced expression of genes required for neuronal migration and cortical
      organization provides a mechanistic route to abnormal brain development.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:27545680
      reference_title: >-
        De Novo Mutations in SON Disrupt RNA Splicing of Genes Essential for
        Brain Development and Metabolism, Causing an Intellectual-Disability
        Syndrome.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Importantly, analyses of RNA from affected individuals revealed that
        genes critical for neuronal migration and cortex organization (TUBG1,
        FLNA, PNKP, WDR62, PSMD3, and HDAC6) and metabolism (PCK2, PFKL, IDH2,
        ACY1, and ADA) are significantly downregulated because of the accumulation
        of mis-spliced transcripts resulting from erroneous SON-mediated RNA
        splicing.
      explanation: >-
        The molecular data support the route to cortical malformation, while the
        intervening developmental steps remain unresolved.
  - target: Neurodevelopmental impairment
    description: >-
      Broad loss of neurodevelopmental target-gene expression contributes to the
      developmental and cognitive phenotype through incompletely resolved
      intermediates.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:27545680
      reference_title: >-
        De Novo Mutations in SON Disrupt RNA Splicing of Genes Essential for
        Brain Development and Metabolism, Causing an Intellectual-Disability
        Syndrome.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Our data highlight SON as a master regulator governing neurodevelopment
        and demonstrate the importance of SON-mediated RNA splicing in human
        development.
      explanation: >-
        The study supports a neurodevelopmental consequence but does not resolve
        every intermediate causal step.
- name: Impaired neuronal migration
  biological_scale: CELLULAR
  description: >-
    SON insufficiency disrupts corticogenesis by impairing neuronal migration in
    the developing brain.
  biological_processes:
  - preferred_term: neuron migration
    term:
      id: GO:0001764
      label: neuron migration
    modifier: ABNORMAL
  evidence:
  - reference: PMID:32448361
    reference_title: >-
      Knockdown of Son, a mouse homologue of the ZTTK syndrome gene, causes
      neuronal migration defects and dendritic spine abnormalities.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      These data indicate that SON insufficiency causes neuronal migration
      defects and dendritic spine abnormalities, which seem neuropathological
      bases of the neural symptoms of ZTTK syndrome.
    explanation: >-
      This directly supports impaired neuronal migration as a mechanistic node.
  downstream:
  - target: Neurodevelopmental impairment
    description: >-
      Abnormal cortical development contributes to the syndrome's cognitive and
      developmental phenotype.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:32448361
      reference_title: >-
        Knockdown of Son, a mouse homologue of the ZTTK syndrome gene, causes
        neuronal migration defects and dendritic spine abnormalities.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        These data indicate that SON insufficiency causes neuronal migration
        defects and dendritic spine abnormalities, which seem neuropathological
        bases of the neural symptoms of ZTTK syndrome.
      explanation: >-
        The mouse study identifies impaired migration as a plausible basis of
        neural symptoms, with model-to-human uncertainty retained.
- name: Dendritic spine abnormalities
  biological_scale: CELLULAR
  description: >-
    SON insufficiency reduces dendritic spine density, indicating impaired
    synaptic maturation.
  cell_types:
  - preferred_term: pyramidal neuron
    term:
      id: CL:0000598
      label: pyramidal neuron
  biological_processes:
  - preferred_term: dendritic spine morphogenesis
    term:
      id: GO:0060997
      label: dendritic spine morphogenesis
    modifier: ABNORMAL
  evidence:
  - reference: PMID:32448361
    reference_title: >-
      Knockdown of Son, a mouse homologue of the ZTTK syndrome gene, causes
      neuronal migration defects and dendritic spine abnormalities.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Son knockdown in neural progenitors resulted in defective migration during
      corticogenesis and reduced spine density on mature cortical neurons.
    explanation: >-
      This directly supports reduced dendritic spine density as a parallel
      downstream consequence of SON insufficiency.
  downstream:
  - target: Intellectual disability
    description: >-
      Reduced dendritic spine density provides a model-supported route from SON
      insufficiency to intellectual disability.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:32448361
      reference_title: >-
        Knockdown of Son, a mouse homologue of the ZTTK syndrome gene, causes
        neuronal migration defects and dendritic spine abnormalities.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Therefore, reduced spine density on Son knockdown neurons is an important
        finding and suggests that spine defects are the pathological basis of ID
        in ZTTK syndrome.
      explanation: >-
        The mouse study proposes a specific dendritic-spine route to intellectual
        disability while retaining model-to-human uncertainty.
  - target: Neurodevelopmental impairment
    description: >-
      Synaptic structural abnormalities are likely to contribute to cognitive
      dysfunction in affected individuals.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:32448361
      reference_title: >-
        Knockdown of Son, a mouse homologue of the ZTTK syndrome gene, causes
        neuronal migration defects and dendritic spine abnormalities.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        These data indicate that SON insufficiency causes neuronal migration
        defects and dendritic spine abnormalities, which seem neuropathological
        bases of the neural symptoms of ZTTK syndrome.
      explanation: >-
        The mouse study supports dendritic pathology as a candidate basis of
        neural symptoms but not as a fully resolved human causal chain.
- name: Aberrant splicing of kidney-development genes
  biological_scale: MOLECULAR
  description: >-
    SON insufficiency causes abnormal splicing and reduced expression of several
    genes required for kidney development, creating a mechanistic branch for the
    heterogeneous renal phenotype.
  cell_types:
  - preferred_term: kidney proximal tubule epithelial cell
    term:
      id: CL:0002306
      label: epithelial cell of proximal tubule
  biological_processes:
  - preferred_term: RNA splicing
    term:
      id: GO:0008380
      label: RNA splicing
    modifier: ABNORMAL
  locations:
  - preferred_term: kidney
    term:
      id: UBERON:0002113
      label: kidney
  evidence:
  - reference: PMID:31005274
    reference_title: >-
      SON haploinsufficiency causes impaired pre-mRNA splicing of CAKUT genes and
      heterogeneous renal phenotypes.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      SON knockdown in kidney cell lines leads to abnormal pre-mRNA splicing,
      resulting in decreased expression of several established CAKUT genes.
      Furthermore, these molecular events were observed in patient-derived cells
      with SON haploinsufficiency.
    explanation: >-
      The experiments directly demonstrate the renal-cell splicing defect and
      reproduce it in patient-derived cells.
  downstream:
  - target: Kidney abnormalities
    description: >-
      Impaired processing of multiple kidney-development transcripts provides a
      mechanistic explanation for the heterogeneous structural renal anomalies.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:31005274
      reference_title: >-
        SON haploinsufficiency causes impaired pre-mRNA splicing of CAKUT genes
        and heterogeneous renal phenotypes.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Taken together, our data suggest that the wide spectrum of phenotypes in
        patients with a pathogenic SON mutation is a consequence of impaired
        pre-mRNA splicing of several CAKUT genes.
      explanation: >-
        The authors infer the organ-level phenotype from patient and functional
        cell evidence; the edge is therefore marked indirect and partial.
  - target: Horseshoe kidney
    description: >-
      The renal spliceopathy contributes to horseshoe kidney through unresolved
      developmental intermediates.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:31005274
      reference_title: >-
        SON haploinsufficiency causes impaired pre-mRNA splicing of CAKUT genes
        and heterogeneous renal phenotypes.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Detailed phenotyping of 14 patients with SON haploinsufficiency identified
        kidney anomalies in 8 patients, including horseshoe kidney, unilateral
        renal hypoplasia, and renal cysts.
      explanation: The renal phenotype is established, but its causal route is unresolved.
  - target: Renal hypoplasia
    description: >-
      The renal spliceopathy contributes to renal hypoplasia through unresolved
      developmental intermediates.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:31005274
      reference_title: >-
        SON haploinsufficiency causes impaired pre-mRNA splicing of CAKUT genes
        and heterogeneous renal phenotypes.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Detailed phenotyping of 14 patients with SON haploinsufficiency identified
        kidney anomalies in 8 patients, including horseshoe kidney, unilateral
        renal hypoplasia, and renal cysts.
      explanation: The renal phenotype is established, but its causal route is unresolved.
  - target: Renal cyst
    description: >-
      The renal spliceopathy contributes to renal cyst formation through
      unresolved developmental intermediates.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:31005274
      reference_title: >-
        SON haploinsufficiency causes impaired pre-mRNA splicing of CAKUT genes
        and heterogeneous renal phenotypes.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Detailed phenotyping of 14 patients with SON haploinsufficiency identified
        kidney anomalies in 8 patients, including horseshoe kidney, unilateral
        renal hypoplasia, and renal cysts.
      explanation: The renal phenotype is established, but its causal route is unresolved.
- name: Neurodevelopmental impairment
  biological_scale: ORGANISM
  description: >-
    The convergent consequence of SON haploinsufficiency in the nervous system
    is a broad neurodevelopmental disorder centered on intellectual disability.
  evidence:
  - reference: PMID:40991760
    reference_title: Zhu-Tokita-Takenouchi-Kim Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Zhu-Tokita-Takenouchi-Kim (ZTTK) syndrome is characterized by developmental
      delay and intellectual disability.
    explanation: >-
      GeneReviews identifies developmental delay and intellectual disability as
      the defining neurodevelopmental manifestations.
  downstream:
  - target: Seizure
    description: Seizures are reported in more than half of affected individuals.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:40991760
      reference_title: Zhu-Tokita-Takenouchi-Kim Syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Behavioral issues and seizures are reported in more than half of affected
        individuals.
      explanation: The outcome is established, but its causal route is unresolved.
  - target: Atypical behavior
    description: Behavioral issues are reported in more than half of affected individuals.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:40991760
      reference_title: Zhu-Tokita-Takenouchi-Kim Syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Behavioral issues and seizures are reported in more than half of affected
        individuals.
      explanation: The outcome is established, but its causal route is unresolved.
phenotypes:
- name: Intellectual disability
  category: Neurologic
  description: >-
    Intellectual disability is a core and defining manifestation of ZTTK
    syndrome.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:40991760
    reference_title: Zhu-Tokita-Takenouchi-Kim Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Zhu-Tokita-Takenouchi-Kim (ZTTK) syndrome is characterized by developmental
      delay and intellectual disability.
    explanation: >-
      This directly supports intellectual disability as a defining phenotype.
- name: Neurodevelopmental delay
  category: Neurologic
  description: >-
    Developmental delay is a defining neurodevelopmental manifestation of ZTTK
    syndrome.
  phenotype_term:
    preferred_term: Neurodevelopmental delay
    term:
      id: HP:0012758
      label: Neurodevelopmental delay
  evidence:
  - reference: PMID:40991760
    reference_title: Zhu-Tokita-Takenouchi-Kim Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Zhu-Tokita-Takenouchi-Kim (ZTTK) syndrome is characterized by developmental
      delay and intellectual disability.
    explanation: >-
      GeneReviews directly identifies developmental delay as a defining
      manifestation without asserting global developmental delay.
- name: Seizure
  category: Neurologic
  description: >-
    Seizures occur in more than half of reported affected individuals.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:40991760
    reference_title: Zhu-Tokita-Takenouchi-Kim Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Behavioral issues and seizures are reported in more than half of affected
      individuals.
    explanation: >-
      GeneReviews supports the association and reports that it occurs in more
      than half of affected individuals without fixing an upper frequency bound.
- name: Atypical behavior
  category: Neurologic
  description: >-
    Behavioral issues occur in more than half of reported affected individuals.
  phenotype_term:
    preferred_term: Atypical behavior
    term:
      id: HP:0000708
      label: Atypical behavior
  evidence:
  - reference: PMID:40991760
    reference_title: Zhu-Tokita-Takenouchi-Kim Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Behavioral issues and seizures are reported in more than half of affected
      individuals.
    explanation: >-
      GeneReviews supports the association and reports that it occurs in more
      than half of affected individuals without fixing an upper frequency bound.
- name: Facial dysmorphism
  category: Craniofacial
  description: >-
    Characteristic facial dysmorphism is part of the congenital anomaly pattern
    described in ZTTK syndrome.
  phenotype_term:
    preferred_term: Abnormality of the face
    term:
      id: HP:0000271
      label: Abnormality of the face
  evidence:
  - reference: PMID:40991760
    reference_title: Zhu-Tokita-Takenouchi-Kim Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Characteristic facial features include facial asymmetry, prominent
      forehead, horizontal eyebrows, ptosis, downslanted palpebral fissures,
      epicanthal folds, deep-set eyes, midface retrusion, depressed or other
      abnormality of the nasal bridge, low-set ears that may be posteriorly
      rotated, short and/or smooth philtrum, thin vermilion of the upper lip,
      bifid uvula, and high palate.
    explanation: >-
      The current clinical review directly enumerates the characteristic facial
      phenotype.
- name: Prominent forehead
  category: Craniofacial
  description: A prominent forehead is a characteristic facial feature.
  phenotype_term:
    preferred_term: Prominent forehead
    term:
      id: HP:0011220
      label: Prominent forehead
  evidence:
  - reference: PMID:40991760
    reference_title: Zhu-Tokita-Takenouchi-Kim Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Characteristic facial features include facial asymmetry, prominent
      forehead, horizontal eyebrows, ptosis, downslanted palpebral fissures,
      epicanthal folds, deep-set eyes, midface retrusion, depressed or other
      abnormality of the nasal bridge, low-set ears that may be posteriorly
      rotated, short and/or smooth philtrum, thin vermilion of the upper lip,
      bifid uvula, and high palate.
    explanation: GeneReviews directly lists prominent forehead.
- name: Ptosis
  category: Ophthalmologic
  description: Ptosis is a characteristic periocular feature.
  phenotype_term:
    preferred_term: Ptosis
    term:
      id: HP:0000508
      label: Ptosis
  evidence:
  - reference: PMID:40991760
    reference_title: Zhu-Tokita-Takenouchi-Kim Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Characteristic facial features include facial asymmetry, prominent
      forehead, horizontal eyebrows, ptosis, downslanted palpebral fissures,
      epicanthal folds, deep-set eyes, midface retrusion, depressed or other
      abnormality of the nasal bridge, low-set ears that may be posteriorly
      rotated, short and/or smooth philtrum, thin vermilion of the upper lip,
      bifid uvula, and high palate.
    explanation: GeneReviews directly lists ptosis.
- name: Downslanted palpebral fissures
  category: Craniofacial
  description: Downslanted palpebral fissures are a characteristic facial feature.
  phenotype_term:
    preferred_term: Downslanted palpebral fissures
    term:
      id: HP:0000494
      label: Downslanted palpebral fissures
  evidence:
  - reference: PMID:40991760
    reference_title: Zhu-Tokita-Takenouchi-Kim Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Characteristic facial features include facial asymmetry, prominent
      forehead, horizontal eyebrows, ptosis, downslanted palpebral fissures,
      epicanthal folds, deep-set eyes, midface retrusion, depressed or other
      abnormality of the nasal bridge, low-set ears that may be posteriorly
      rotated, short and/or smooth philtrum, thin vermilion of the upper lip,
      bifid uvula, and high palate.
    explanation: GeneReviews directly lists downslanted palpebral fissures.
- name: High palate
  category: Craniofacial
  description: A high palate is part of the characteristic craniofacial phenotype.
  phenotype_term:
    preferred_term: High palate
    term:
      id: HP:0000218
      label: High palate
  evidence:
  - reference: PMID:40991760
    reference_title: Zhu-Tokita-Takenouchi-Kim Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Characteristic facial features include facial asymmetry, prominent
      forehead, horizontal eyebrows, ptosis, downslanted palpebral fissures,
      epicanthal folds, deep-set eyes, midface retrusion, depressed or other
      abnormality of the nasal bridge, low-set ears that may be posteriorly
      rotated, short and/or smooth philtrum, thin vermilion of the upper lip,
      bifid uvula, and high palate.
    explanation: GeneReviews directly lists high palate.
- name: Brain malformation
  category: Neurologic
  description: >-
    Structural brain malformations are part of the recognized congenital
    anomaly spectrum in ZTTK syndrome.
  phenotype_term:
    preferred_term: Brain malformation
    term:
      id: HP:0012443
      label: Abnormal brain morphology
  evidence:
  - reference: PMID:27545680
    reference_title: >-
      De Novo Mutations in SON Disrupt RNA Splicing of Genes Essential for Brain
      Development and Metabolism, Causing an Intellectual-Disability Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we report on an ID syndrome caused by de novo heterozygous
      loss-of-function (LoF) mutations in SON. The syndrome is characterized by
      ID and/or DD, malformations of the cerebral cortex, epilepsy, vision
      problems, musculoskeletal abnormalities, and congenital malformations.
    explanation: >-
      The original human cohort directly reports malformations of the cerebral
      cortex.
- name: Musculoskeletal abnormalities
  category: Musculoskeletal
  description: >-
    Musculoskeletal abnormalities are part of the multisystem congenital
    anomaly pattern in ZTTK syndrome.
  phenotype_term:
    preferred_term: Musculoskeletal abnormality
    term:
      id: HP:0033127
      label: Abnormality of the musculoskeletal system
  evidence:
  - reference: PMID:27545680
    reference_title: >-
      De Novo Mutations in SON Disrupt RNA Splicing of Genes Essential for Brain
      Development and Metabolism, Causing an Intellectual-Disability Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we report on an ID syndrome caused by de novo heterozygous
      loss-of-function (LoF) mutations in SON. The syndrome is characterized by
      ID and/or DD, malformations of the cerebral cortex, epilepsy, vision
      problems, musculoskeletal abnormalities, and congenital malformations.
    explanation: >-
      The original human cohort directly reports musculoskeletal abnormalities.
- name: Kidney abnormalities
  category: Genitourinary
  frequency: FREQUENT
  description: >-
    Structural kidney anomalies are a recurrent multisystem manifestation and
    include horseshoe kidney, unilateral renal hypoplasia, and renal cysts.
  phenotype_term:
    preferred_term: Abnormality of the kidney
    term:
      id: HP:0000077
      label: Abnormality of the kidney
  evidence:
  - reference: PMID:31005274
    reference_title: >-
      SON haploinsufficiency causes impaired pre-mRNA splicing of CAKUT genes and
      heterogeneous renal phenotypes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Detailed phenotyping of 14 patients with SON haploinsufficiency identified
      kidney anomalies in 8 patients, including horseshoe kidney, unilateral
      renal hypoplasia, and renal cysts.
    explanation: >-
      The study directly documents kidney anomalies in 8 of 14 examined patients,
      supporting both the association and FREQUENT band.
- name: Horseshoe kidney
  category: Genitourinary
  description: Horseshoe kidney is one of the reported structural renal anomalies.
  phenotype_term:
    preferred_term: Horseshoe kidney
    term:
      id: HP:0000085
      label: Horseshoe kidney
  evidence:
  - reference: PMID:31005274
    reference_title: >-
      SON haploinsufficiency causes impaired pre-mRNA splicing of CAKUT genes and
      heterogeneous renal phenotypes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Detailed phenotyping of 14 patients with SON haploinsufficiency identified
      kidney anomalies in 8 patients, including horseshoe kidney, unilateral
      renal hypoplasia, and renal cysts.
    explanation: The renal cohort directly reports horseshoe kidney.
- name: Renal hypoplasia
  category: Genitourinary
  description: Unilateral renal hypoplasia is a reported structural renal anomaly.
  phenotype_term:
    preferred_term: Renal hypoplasia
    term:
      id: HP:0000089
      label: Renal hypoplasia
  evidence:
  - reference: PMID:31005274
    reference_title: >-
      SON haploinsufficiency causes impaired pre-mRNA splicing of CAKUT genes and
      heterogeneous renal phenotypes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Detailed phenotyping of 14 patients with SON haploinsufficiency identified
      kidney anomalies in 8 patients, including horseshoe kidney, unilateral
      renal hypoplasia, and renal cysts.
    explanation: The renal cohort directly reports unilateral renal hypoplasia.
- name: Renal cyst
  category: Genitourinary
  description: Renal cysts occur within the heterogeneous structural renal phenotype.
  phenotype_term:
    preferred_term: Renal cyst
    term:
      id: HP:0000107
      label: Renal cyst
  evidence:
  - reference: PMID:31005274
    reference_title: >-
      SON haploinsufficiency causes impaired pre-mRNA splicing of CAKUT genes and
      heterogeneous renal phenotypes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Detailed phenotyping of 14 patients with SON haploinsufficiency identified
      kidney anomalies in 8 patients, including horseshoe kidney, unilateral
      renal hypoplasia, and renal cysts.
    explanation: The renal cohort directly reports renal cysts.
- name: Short stature
  category: Growth
  description: Short stature is a common growth manifestation of ZTTK syndrome.
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: PMID:40991760
    reference_title: Zhu-Tokita-Takenouchi-Kim Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Skeletal and ocular abnormalities, short stature, and genitourinary and
      kidney manifestations are common.
    explanation: GeneReviews directly identifies short stature as common.
- name: Eye abnormality
  category: Ophthalmologic
  description: Ocular abnormalities are a common multisystem manifestation.
  phenotype_term:
    preferred_term: Abnormality of the eye
    term:
      id: HP:0000478
      label: Abnormality of the eye
  evidence:
  - reference: PMID:40991760
    reference_title: Zhu-Tokita-Takenouchi-Kim Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Skeletal and ocular abnormalities, short stature, and genitourinary and
      kidney manifestations are common.
    explanation: GeneReviews directly identifies ocular abnormalities as common.
- name: Genitourinary abnormality
  category: Genitourinary
  description: Genitourinary manifestations are common in ZTTK syndrome.
  phenotype_term:
    preferred_term: Abnormality of the genitourinary system
    term:
      id: HP:0000119
      label: Abnormality of the genitourinary system
  evidence:
  - reference: PMID:40991760
    reference_title: Zhu-Tokita-Takenouchi-Kim Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Skeletal and ocular abnormalities, short stature, and genitourinary and
      kidney manifestations are common.
    explanation: GeneReviews directly identifies genitourinary manifestations as common.
- name: Hematologic abnormality
  category: Hematologic
  description: Hematologic abnormalities occur within the variable multisystem phenotype.
  phenotype_term:
    preferred_term: Abnormality of blood and blood-forming tissues
    term:
      id: HP:0001871
      label: Abnormality of blood and blood-forming tissues
  evidence:
  - reference: PMID:40991760
    reference_title: Zhu-Tokita-Takenouchi-Kim Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hematologic, cardiac, immune, gastrointestinal, and hearing abnormalities
      have also been reported.
    explanation: GeneReviews directly includes hematologic abnormalities.
- name: Cardiovascular system abnormality
  category: Cardiovascular
  description: >-
    Cardiac abnormalities occur within the variable multisystem phenotype.
  phenotype_term:
    preferred_term: Abnormality of the cardiovascular system
    term:
      id: HP:0001626
      label: Abnormality of the cardiovascular system
  evidence:
  - reference: PMID:40991760
    reference_title: Zhu-Tokita-Takenouchi-Kim Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hematologic, cardiac, immune, gastrointestinal, and hearing abnormalities
      have also been reported.
    explanation: >-
      GeneReviews directly reports generic cardiac abnormalities without
      specifying a structural subtype.
- name: Immune system abnormality
  category: Immunologic
  description: Immune abnormalities occur within the variable multisystem phenotype.
  phenotype_term:
    preferred_term: Abnormality of the immune system
    term:
      id: HP:0002715
      label: Abnormality of the immune system
  evidence:
  - reference: PMID:40991760
    reference_title: Zhu-Tokita-Takenouchi-Kim Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hematologic, cardiac, immune, gastrointestinal, and hearing abnormalities
      have also been reported.
    explanation: GeneReviews directly includes immune abnormalities.
- name: Gastrointestinal abnormality
  category: Gastrointestinal
  description: Gastrointestinal abnormalities occur within the variable multisystem phenotype.
  phenotype_term:
    preferred_term: Abnormality of the digestive system
    term:
      id: HP:0025031
      label: Abnormality of the digestive system
  evidence:
  - reference: PMID:40991760
    reference_title: Zhu-Tokita-Takenouchi-Kim Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hematologic, cardiac, immune, gastrointestinal, and hearing abnormalities
      have also been reported.
    explanation: GeneReviews directly includes gastrointestinal abnormalities.
- name: Hearing impairment
  category: Otologic
  description: Hearing abnormalities are part of the reported multisystem phenotype.
  phenotype_term:
    preferred_term: Hearing impairment
    term:
      id: HP:0000365
      label: Hearing impairment
  evidence:
  - reference: PMID:40991760
    reference_title: Zhu-Tokita-Takenouchi-Kim Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hematologic, cardiac, immune, gastrointestinal, and hearing abnormalities
      have also been reported.
    explanation: GeneReviews directly includes hearing abnormalities in the phenotype.
biochemical: []
genetic:
- name: SON
  gene_term:
    preferred_term: SON
    term:
      id: hgnc:11183
      label: SON
  association: Heterozygous loss-of-function causal gene
  presence: Positive
  variant_origin: GERMLINE
  evidence:
  - reference: PMID:34521999
    reference_title: >-
      Establishing the phenotypic spectrum of ZTTK syndrome by analysis of 52
      individuals with variants in SON.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In total, loss-of-function variants were detected in 49 individuals (de
      novo in 47, inheritance unknown in 2), and in 3, a missense variant was
      observed (2 de novo, 1 inheritance unknown).
    explanation: >-
      The cohort establishes the predominant loss-of-function variant class and
      de novo origin in molecularly characterized individuals.
  - reference: CGGV:assertion_b7e86b1d-154a-40b5-b454-fad392f87782-2025-11-10T170000.000Z
    reference_title: "SON / ZTTK syndrome (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "SON | HGNC:11183 | ZTTK syndrome | MONDO:0014936 | AD | Definitive"
    explanation: ClinGen classifies the SON-ZTTK syndrome gene-disease relationship as definitive with autosomal dominant inheritance.
environmental: []
treatments:
- name: Supportive multidisciplinary care
  description: >-
    No therapy directly corrects SON deficiency. Management is supportive and
    individualized across developmental, neurologic, nutritional, renal,
    cardiac, musculoskeletal, ophthalmologic, hearing, immune, and other
    manifestations.
  treatment_term:
    preferred_term: Supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:40991760
    reference_title: Zhu-Tokita-Takenouchi-Kim Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      None of the treatments available directly address SON deficiency.
      Supportive measures include developmental and educational support;
      standard treatment for seizures and movement disorder; treatment of
      craniosynostosis per craniofacial team; treatment of musculoskeletal
      manifestations per orthopedist; treatment of refractive errors and
      strabismus per ophthalmologist; low vision services as needed; nutritional
      support for feeding issues; treatment of growth hormone deficiency per
      endocrinologist; treatment of genitourinary and kidney manifestations per
      nephrologist and/or urologist; treatment of hematologic disorders per
      hematologist; surgical and/or medical treatment for cardiac anomalies;
      treat infections aggressively; in those with immune deficiency irradiated
      blood products are recommended; standard treatment of recurrent otitis
      media; management of bowel dysfunction and other gastrointestinal issues
      per gastroenterologist; hearing aids may be helpful; family and social work
      support.
    explanation: >-
      GeneReviews states that care is supportive rather than disease-modifying
      and enumerates the affected systems requiring individualized management.
- name: Kidney ultrasound surveillance
  description: Kidney ultrasound is recommended annually or as clinically needed.
  treatment_term:
    preferred_term: Supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:40991760
    reference_title: Zhu-Tokita-Takenouchi-Kim Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Surveillance: Assess developmental progress, educational needs, behavioral
      issues, neurologic manifestations, musculoskeletal evaluation, growth,
      nutrition, gastrointestinal and hematologic issues, and for recurrent
      infections at each visit; ophthalmologic evaluation per ophthalmologist;
      endocrine evaluation in those with growth hormone deficiency; kidney
      ultrasound annually or as needed; audiology evaluation annually; assess
      family and social work needs at each visit.
    explanation: GeneReviews directly recommends the renal surveillance schedule.
- name: Annual audiology surveillance
  description: Audiology evaluation is recommended annually.
  treatment_term:
    preferred_term: Supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:40991760
    reference_title: Zhu-Tokita-Takenouchi-Kim Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Surveillance: Assess developmental progress, educational needs, behavioral
      issues, neurologic manifestations, musculoskeletal evaluation, growth,
      nutrition, gastrointestinal and hematologic issues, and for recurrent
      infections at each visit; ophthalmologic evaluation per ophthalmologist;
      endocrine evaluation in those with growth hormone deficiency; kidney
      ultrasound annually or as needed; audiology evaluation annually; assess
      family and social work needs at each visit.
    explanation: GeneReviews directly recommends annual audiology evaluation.
- name: Ophthalmologic surveillance
  description: Ophthalmologic evaluation is scheduled by the treating ophthalmologist.
  treatment_term:
    preferred_term: Supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:40991760
    reference_title: Zhu-Tokita-Takenouchi-Kim Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Surveillance: Assess developmental progress, educational needs, behavioral
      issues, neurologic manifestations, musculoskeletal evaluation, growth,
      nutrition, gastrointestinal and hematologic issues, and for recurrent
      infections at each visit; ophthalmologic evaluation per ophthalmologist;
      endocrine evaluation in those with growth hormone deficiency; kidney
      ultrasound annually or as needed; audiology evaluation annually; assess
      family and social work needs at each visit.
    explanation: GeneReviews directly recommends specialist-directed eye surveillance.
- name: Endocrine surveillance for growth hormone deficiency
  description: Endocrine evaluation is recommended when growth hormone deficiency is present.
  treatment_term:
    preferred_term: Supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:40991760
    reference_title: Zhu-Tokita-Takenouchi-Kim Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Surveillance: Assess developmental progress, educational needs, behavioral
      issues, neurologic manifestations, musculoskeletal evaluation, growth,
      nutrition, gastrointestinal and hematologic issues, and for recurrent
      infections at each visit; ophthalmologic evaluation per ophthalmologist;
      endocrine evaluation in those with growth hormone deficiency; kidney
      ultrasound annually or as needed; audiology evaluation annually; assess
      family and social work needs at each visit.
    explanation: >-
      GeneReviews directly recommends endocrine follow-up when growth hormone
      deficiency is present.
diagnosis:
- name: Characteristic features and molecular genetic testing
  description: >-
    The diagnosis is established in a proband with characteristic features and a
    heterozygous pathogenic variant in SON identified by molecular genetic
    testing.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: NCIT:C19770
      label: Molecular Analysis
  evidence:
  - reference: PMID:40991760
    reference_title: Zhu-Tokita-Takenouchi-Kim Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The diagnosis of ZTTK syndrome is established in a proband with
      characteristic features and a heterozygous pathogenic variant in SON
      identified by molecular genetic testing.
    explanation: >-
      GeneReviews directly states the molecular diagnostic criterion.
differential_diagnoses: []
clinical_trials: []
datasets: []
notes: >-
  This entry emphasizes the established loss-of-function spliceopathy and
  representative, source-backed manifestations across major organ systems.
  Clinical expressivity is highly variable. Causal edges use
  INDIRECT_UNKNOWN_INTERMEDIATES with partial support where a SON-to-phenotype
  relationship is established but the intervening developmental mechanism is
  unresolved. The pathogenic mechanism of rare SON missense variants and robust
  genotype-phenotype correlations remain uncertain, and no disease-modifying
  therapy currently addresses SON deficiency.
📚

References & Deep Research

References

1
PMID:40991760
Zhu-Tokita-Takenouchi-Kim Syndrome.
No top-level findings curated for this source.

Deep Research

1
Asta ▸
Asta Literature Retrieval: Pathophysiology and clinical mechanisms of ZTTK syndrome. Core disease mechanisms, molecular and cellular pathways, i...
Asta Scientific Corpus Retrieval 20 citations 2026-04-14T16:27:15.664887

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of ZTTK syndrome. Core disease mechanisms, molecular and cellular pathways, i...

This report is retrieval-only and is generated directly from Asta results.

  • Papers retrieved: 20
  • Snippets retrieved: 20

Relevant Papers

[1] Knockdown of Son, a mouse homologue of the ZTTK syndrome gene, causes neuronal migration defects and dendritic spine dysgenesis

  • Authors: M. Ueda, Tohru Matsuki, M. Fukada, S. Eda, Akie Toya et al.
  • Year: 2020
  • Venue: Unknown venue
  • URL: https://www.semanticscholar.org/paper/609f724952969a82fed78d27881321d1c78c4799
  • DOI: 10.21203/rs.3.rs-17672/v1
  • Summary: The results strongly suggest that the neural abnormalities in ZTTK syndrome are caused by SON haploinsufficiency independent of the types of mutation that results in functional or dysfunctional proteins.
  • Evidence snippets:
  • Snippet 1 (score: 0.430) > Recent genetic studies identi ed 31 individuals exhibiting intellectual disability (ID) and/or developmental delay with de novo heterozygous mutations in SON, which was established as Zhu-Tokita-Takenouchi-Kim (ZTTK) syndrome [1][2][3][4][5][6]. ZTTK syndrome was further characterized as a congenital anomaly syndrome of ID, brain malformation, facial dysmorphism, musculoskeletal abnormalities, and less common visceral malformations [1,2,4]. The mutations found to be associated with ZTTK syndrome are mostly frameshift mutations and nonsense substitutions generating a premature termination codon [1][2][3][4][5][6], and transcripts of the mutant gene seem to be degraded due to nonsense-mediated mRNA decay (NMD) [1]; this has made ZTTK syndrome to be regarded as an entity caused by SON haploinsu ciency. > SON is a ubiquitously expressed and evolutionarily conserved gene in vertebrates and is located on the human chromosome region 21q22.11 [4]. It encodes the DNA-and RNA-binding protein SON, which functions in RNA splicing as well as gene repression [7][8][9][10][11][12]. A wide variety of genes are, thus, under the control of SON, and SON has been reported to be involved in cell cycle regulation and stem cell maintenance [7][8][9][10][11]. However, the functional signi cance of SON in neural development is largely unknown, and the pathological consequence of SON haploinsu ciency underlying the neural phenotypes of ZTTK syndrome, such as ID and brain malformation, remains undetermined. In this report, we revealed through knockdown experiments in the developing mouse brain that Son insu ciency caused neuronal migration abnormalities and dendritic spine dysgenesis. Rescue experiments that induced the expression of human wild-type SON protein and truncated SON proteins encoded by disease-associated mutant SON genes provided further information relevant to the pathophysiology of ZTTK syndrome.

[2] Changes in Serum Proteomic Profiles at Different Stages of Pregnancy Toxemia in Goats

  • Authors: M. Uzti̇mür, C. N. Ünal, Gurler Akpinar
  • Year: 2025
  • Venue: Journal of Veterinary Internal Medicine
  • URL: https://www.semanticscholar.org/paper/4b9c488b5dbd65d7b26fd2ad9aed70e8c4b59942
  • DOI: 10.1111/jvim.70139
  • PMID: 40492724
  • PMCID: 12150350
  • Summary: Understanding the serum proteome profiles of goats with pregnancy toxemia might help identify the proteomes and pathways responsible for the development of this disease and improve diagnosis and treatment.
  • Evidence snippets:
  • Snippet 1 (score: 0.423) > The pathophysiology and progression of this disease are not fully understood. > Traditional biomedical research has focused on the analysis of single genes, proteins, metabolites, or metabolic pathways in diseases. This molecular reductionist approach is based on the assumption that identifying genetic variations and molecular components will lead to new treatments for diseases [13][14][15][16]. However, many diseases are complex and multifactorial, and in order to determine the phenotype of such diseases, it is necessary to understand the changes that occur in more than one gene, pathway, protein, or metabolite at the cellular, tissue, and organismal levels [17][18][19]. Therefore, in recent years, proteomics, as one field of multi-omics technologies, has helped in evaluating the complex pathogenetic mechanisms of different diseases from a broad perspective and has made substantial contributions [20,21]. In veterinary medicine, proteomic analysis of metabolic diseases such as ketosis [16], hypocalcemia [22], and fatty liver [23] in dairy cows has contributed valuable insights for the definition of new pathophysiological pathways and new diagnosis and treatment protocols for these diseases. The proteomic approach can contribute importantly to a broad and detailed understanding of the changes that occur at the organismal level associated with the increase in BHBA concentration in goats with pregnancy toxemia. Our aim was to evaluate the serum protein profiles of goats with SPT or CPT using proteomic techniques to determine the proteomic profiles of these animals and to identify the relevant pathophysiological mechanisms.

[3] A Journey through Huntington's Disease: Exploring Genetics, Neurobiology, and Therapeutic Advances

  • Authors: Sandeep Dey, Shreyas Katta, S. Suresh, Janhvi Mishra
  • Year: 2024
  • Venue: International Journal For Multidisciplinary Research
  • URL: https://www.semanticscholar.org/paper/735574648bec278cf15dc25fd5f1d735afaf6ae6
  • DOI: 10.36948/ijfmr.2024.v06i03.19194
  • Summary: The clinical features, ethics, and neurobiology of HD are discussed and the exciting approaches being employed today to advance understanding of underlying mechanisms in an effort to develop therapies that would delay the onset and slow progression of this disease are reviewed.
  • Evidence snippets:
  • Snippet 1 (score: 0.412) > Also, we present a modern view on the molecular biology of HD as a representative of the group of polyglutamine diseases, with an emphasis on conformational changes of mutant huntingtin, disturbances in its cellular processing, and proteolytic stress in degenerating neurons. > The main pathogenetic mechanisms of neurodegeneration in HD are discussed in detail, such as autophagy, impaired mitochondrial biogenesis, lysosomal dysfunction, organelle and protein transport, inflammation, oxidative stress, and transcription factor modulation. However, other unravelling mechanisms are still unknown. This practical and brief review summarises some of the currently known functions of the wild-type huntingtin protein and the recent findings related to the mechanisms involved in HD pathogenesis. Cellular mechanisms implicated in HD pathogenesis: The major mechanisms associated with HD pathogenesis are depicted here. The schematic shows a presynaptic neuron and a postsynaptic neuron flanked by two astrocytes. Huntingtin gene(HTT) itself is depicted as a "solenoid," based on the presumed folding due to its HEAT repeats. The mechanisms depicted are multimerization of mHtt-containing complexes, transcriptional modulation, ER-Golgi stress pathways, mitochondria and energy homeostasis, microtubular dynamics, endocytic and vesicular trafficking dynamics, autophagy, and synaptic signalling mechanisms. mHTT(mutant HTT protein). Traditionally, therapeutic approaches to HD have included compounds developed for psychiatric indications based on the affected neuronal circuitry: the frontal and motor corticostriatal circuits. None of these were initially developed for the treatment of HD. In this review we focus on the cellular and biological pathways affected by mutant HTT (mHTT) and the current status of associated drug discovery efforts. We also emphasise the need for further clinical research to validate existing hypotheses, which are mostly derived from animal studies and postmortem human tissues. It is generally accepted that most candidate therapeutics fail due to lack of efficacy in pivotal clinical studies.

[4] 18O-assisted dynamic metabolomics for individualized diagnostics and treatment of human diseases

  • Authors: E. Nemutlu, Song Zhang, N. Juranic, A. Terzic, S. Macura et al.
  • Year: 2012
  • Venue: Croatian Medical Journal
  • URL: https://www.semanticscholar.org/paper/880f053c7f060db4b990e447d0a22c4b69372ddb
  • DOI: 10.3325/cmj.2012.53.529
  • PMID: 23275318
  • PMCID: 3541579
  • Citations: 28
  • Summary: The potential use of dynamic phosphometabolomic platform for disease diagnostics currently under development at Mayo Clinic is described and discussed briefly.
  • Evidence snippets:
  • Snippet 1 (score: 0.410) > Living cells represent an integrated and interacting network of genes, transcripts, proteins, small signaling molecules, and metabolites that define cellular phenotype and function. Traditionally the focus of biomedical research was on individual genes, single protein targets, single metabolites, and metabolic or signaling pathways. This "molecular reductionist" paradigm was based on the assumption that identifying genetic variations and molecular components would lead to discovery of cures for human diseases. However, most of diseases are complex and multi-factorial and the disease phenotype is determined by the alterations of multiple genes, pathways, proteins and metabolites (at cellular, tissue, and organismal levels). Therefore, an integrated "omics" approach is more viable direction for uncovering alterations in metabolic networks, disease mechanisms, and mechanisms of drug effects. > Recent advent of large-scale metabolomics and fluxomic (metabolite dynamics and metabolic flux analysis) completed the "omics revolution" (Figure 1), where genomics, transcriptomics, proteomics, metabolomics, and fluxomics all together complement phenotype determination of living organism. Such integrated "omics" cascades provide a framework for advances in system and network biology, integrative physiology, and system medicine as well as system pharmacology and regenerative medicine. Noteworthy is the "reverse omic" approach or "metabolomicsinformed pharmacogenomics, " where discovery of specific metabolite changes have led to discovery of genetic alterations (2). Therefore, bringing new "omics" technologies to clinical practice will improve disease diagnostics and treatment by targeting drugs and procedures for each unique transcriptomic and metabolomic profiles.

[5] Chemotherapy and Mechanisms of Resistance in Breast Cancer

  • Authors: A. Oliveira, R. E. Santos, F. F. O. Rodrigues
  • Year: 2012
  • Venue: Unknown venue
  • URL: https://www.semanticscholar.org/paper/502a86d8bcd7208be6f539fcceba631f82f25a7d
  • DOI: 10.5772/24629
  • Summary: The addition of adjuvant polychemotherapy in advanced breast cancer showed gain by controlling survival of micrometastases in patients with lymph nodes affected by cancer or not.
  • Evidence snippets:
  • Snippet 1 (score: 0.404) > The main reasons responsible for treatment failure in cancer patients are the mechanisms of drug resistance and emergence of disseminated disease (Terek et al, 2003). We identified two types of resistance most relevant to BC: primary resistance, which corresponds to the clinical situation where the patient showed no response to therapy, and secondary or acquired resistance in which, initially, there is an observed response and a subsequent failure of the treatment regimen (Kroger et al, 1999). Several mechanisms may cause the phenotype of multidrug resistance to chemotherapy drugs and are well characterized in in vitro experiments, including alterations in systemic pharmacology (pharmacokinetics and metabolism), extracellular mechanisms (tumor environment, multicellular drug resistance), and cellular mechanisms (cellular pharmacology, activation and inactivation of drugs, modification of specific targets and regulatory pathways of apoptosis) (Leonessa et al, 2003, Riddick et al, 2005. Identification of factors that affect cell metabolism, which are related to drug resistance, will enable the identification of which patients are at particular risk of treatment failure. Among the biochemical and molecular mechanisms of drug resistance, we stress: changes in the activity of topoisomerase II, alterations in the DNA repair mechanism, overexpression of P-glycoprotein; high intracellular concentrations of enzymes purification of cellular metabolism -among them enzymes the family of glutathione S-transferases (GSTs) and changes in the mechanisms of signaling via c-Jun N-terminal kinase 1 (JNK1) -and "apoptosis signal-regulating kinase (ASK1) required for activation of the" mitogenactivated protein (MAP kinases) in apoptosis and cellular restoration. These pathways are also mediated by proteins encoded by genes of GSTs (O'Brien, Tew, 1996;Burg, Mulder, 2002, L'Ecuyer et al, 2004). Different response rates to particular chemotherapy regimens, as observed in patient groups with the same biological characteristics and stage, suggest the existence of different mechanisms of drug resistance, probably induced by genetic alterations (Hayes, Pulford, 1995;O'Brien , Tew, 1996;Pakunlu et al, 2003). Among the mechanisms of purification of cellular metabolism involved in the

[6] Knockdown of Son, a mouse homologue of the ZTTK syndrome gene, causes neuronal migration defects and dendritic spine abnormalities

  • Authors: M. Ueda, Tohru Matsuki, M. Fukada, S. Eda, Akie Toya et al.
  • Year: 2020
  • Venue: Molecular Brain
  • URL: https://www.semanticscholar.org/paper/976a2685a1dc9775c2b442d6106ba2240ee3558c
  • DOI: 10.1186/s13041-020-00622-4
  • PMID: 32448361
  • PMCID: 7245844
  • Citations: 18
  • Influential citations: 1
  • Summary: The results support that the neural abnormalities in ZTTK syndrome are caused by SON haploinsufficiency independent of the types of mutation that results in functional or dysfunctional proteins.
  • Evidence snippets:
  • Snippet 1 (score: 0.400) > Recent genetic studies identified 31 individuals exhibiting intellectual disability (ID) and/or developmental delay with de novo heterozygous mutations in SON, which was established as Zhu-Tokita-Takenouchi-Kim (ZTTK) syndrome [1][2][3][4][5][6]. ZTTK syndrome was further characterized as a congenital anomaly syndrome of ID, brain malformation, facial dysmorphism, musculoskeletal abnormalities, and less common visceral malformations [1,2,4]. The mutations found to be associated with ZTTK syndrome are mostly frameshift mutations and nonsense substitutions generating a premature termination codon [1][2][3][4][5][6], and transcripts of the mutant gene seem to be degraded due to nonsensemediated mRNA decay (NMD) [1]; this has made ZTTK syndrome to be regarded as an entity caused by SON haploinsufficiency. > SON is a ubiquitously expressed and evolutionarily conserved gene in vertebrates and is located on the human chromosome region 21q22.11 [4]. It encodes the DNA-and RNA-binding protein SON, which functions in RNA splicing as well as gene repression [7][8][9][10][11][12][13]. A wide variety of genes are, thus, under the control of SON, and SON has been reported to be involved in cell cycle regulation and stem cell maintenance [7][8][9][10][11][12]. However, the functional significance of SON in neural development is largely unknown, and the pathological consequence of SON haploinsufficiency underlying the neural phenotypes of ZTTK syndrome, such as ID and brain malformation, remains undetermined. In this report, we revealed through knockdown experiments in the developing mouse brain that Son insufficiency caused neuronal migration abnormalities and reduced spine density. Rescue experiments that induced the expression of human wild-type SON protein and truncated SON proteins encoded by disease-associated mutant SON genes provided further information relevant to the pathophysiology of ZTTK syndrome.

[7] Mitochondrial transplantation as a promising therapy for mitochondrial diseases

  • Authors: Tian-Guang Zhang, Chaoyu Miao
  • Year: 2022
  • Venue: Acta Pharmaceutica Sinica. B
  • URL: https://www.semanticscholar.org/paper/72802097939b0bffc319c93d05128d7e3160e0eb
  • DOI: 10.1016/j.apsb.2022.10.008
  • PMID: 36970208
  • PMCID: 10031255
  • Citations: 84
  • Influential citations: 1
  • Summary: Different techniques used in mitochondrial isolation and delivery, mechanisms of mitochondrial internalization and consequences of mitochondrial transplantation, along with challenges for clinical application are presented.
  • Evidence snippets:
  • Snippet 1 (score: 0.400) > Mitochondria, the vital organelles of eukaryotic cells, are integrators of various cellular metabolic pathways, including oxidative phosphorylation, fatty acid oxidation, urea cycle, Krebs cycle, ketogenesis and gluconeogenesis 1 . Mitochondria are also important in many other essential cellular processes such as calcium homeostasis, lipid metabolism, amino acid metabolism, biosynthesis of heme, and thermogenesis 2 . However, they also have important roles in many pathways which can cause both apoptosis and necrosis 3 . Therefore, the importance of the mitochondrion in the maintenance of cellular homeostasis is well established, meanwhile a large amount of evidence shows that mitochondrial dysfunction is deleterious 4 . > Due to the essential function of mitochondria in the human body, mitochondrial dysfunction causes a great variety of mitochondrial diseases, which can affect almost all the organs in the body and present at any age 4,5 . Mitochondrial diseases are a group of metabolic disorders characterized by energy metabolism dysfunction. The pathophysiology is further complicated by the involvement of genetic mutations in nuclear DNA (nDNA) and mitochondrial DNA (mtDNA) which encode mitochondrial proteins. This means that mitochondrial diseases may result from inheritance for nDNA mutations and maternal inheritance for mtDNA mutations. The estimated minimum prevalence of mitochondrial diseases is 1 in 5000, whereas it could be higher 6 . > As advances in molecular and biochemical methodologies led to a better understanding of the mechanisms of mitochondrial disorders for various diseases, mitochondria have become a major target for research institutions and pharma companies. Pharmacological approaches include dietary supplements such as agents increasing respiratory chain function (coenzyme Q10 and riboflavin), agents inducing mitochondrial biogenesis (AICAR and bezafibrate), antioxidants (vitamin C and vitamin E), mitochondrial substrates (L-carnitine) and so on 7,8 . However, these agents fail to significantly alleviate disease symptoms or effectively slow disease progressions, there has therefore been no satisfactory therapeutic strategy available for mitochondrial diseases so far 9 . In addition, all new drugs under clinical trials for treatment of mitochondrial diseases are unable to cure these diseases permanently 9 .

[8] Future research trends in understanding the mechanisms underlying allergic diseases for improved patient care

  • Authors: H. Breiteneder, Z. Diamant, T. Eiwegger, W. Fokkens, C. Traidl‐Hoffmann et al.
  • Year: 2019
  • Venue: Allergy
  • URL: https://www.semanticscholar.org/paper/e19b0755c4f4903f68377333676edebf9bd73c89
  • DOI: 10.1111/all.13851
  • PMID: 31056763
  • PMCID: 6973012
  • Citations: 90
  • Influential citations: 3
  • Summary: Recent developments in research and patient care and future trends in the discipline are reviewed and topics on food allergy, biologics, small molecules, and novel therapeutic concepts in allergen‐specific immunotherapy for airway disease are highlighted.
  • Evidence snippets:
  • Snippet 1 (score: 0.394) > The past decades have witnessed extensive progress in unraveling cellular and molecular mechanisms of immune regulation in asthma, allergic diseases, organ transplantation, autoimmune diseases, tumor biology, and chronic infections. 1,2 Consequently, a better understanding of the functions, the reciprocal regulation, and the counterbalance of subsets of immune and inflammatory cells but also structural cells-for example, epithelial and vascular cells, airway smooth muscle cells, neuroendocrine system-that interact via various intercellular messengers will indicate avenues for immune interventions and novel treatment modalities of allergic diseases and immunological disorders. It is generally expected that drug development in the next decades will show a significant shift from chemicals to biologicals. > After more than 20 years without any breakthrough drug becoming available for patients, several disciplines including allergology are now experiencing extraordinary times with the recent licensing of several major biological drugs and novel allergen-specific immunotherapy (AIT) vaccines. Several biological modifiers of the immune response targeting intracellular messengers or their receptors have been developed to date. [3][4][5][6][7][8] In addition, a number of promising small molecule drugs and vaccines are in the development pipeline. [9][10][11] This new era is now calling for the development of biomarkers and phenoand endotyping of diseases for customized patient care, which is termed stratified medicine, precision medicine, or personalized medicine. 4 Distinguishing phenotypes of a complex disease covers the observable clinically relevant properties of the disease but does not show a direct relationship to disease etiology and pathophysiology. In a complex condition, such as asthma, different pathogenetic mechanisms can induce similar clinical manifestations; however, they may require different treatment approaches. 12,13 These pathophysiological mechanisms underlying disease subgroups are addressed by the term "endotype." [12][13][14] Classification of complex diseases based on the concept of endotypes provides advantages for epidemiological, genetic, and drug-related studies. Accurate endotyping by using reliable biomarkers reflects the natural history of the disease and aims to predict the response to (targeted) treatments. 15 Recent studies have focused on better understanding

[9] Nasopharyngeal Carcinoma Signaling Pathway: An Update on Molecular Biomarkers

  • Authors: W. Tulalamba, T. Janvilisri
  • Year: 2012
  • Venue: International Journal of Cell Biology
  • URL: https://www.semanticscholar.org/paper/307cb9186444d9dad6e2e3b53763be0de76de186
  • DOI: 10.1155/2012/594681
  • PMID: 22500174
  • PMCID: 3303613
  • Citations: 93
  • Influential citations: 5
  • Summary: The molecular signaling pathways in the NPC are discussed for the holistic view of NPC development and progression and the important insights toward NPC pathogenesis may offer strategies for identification of novel biomarkers for diagnosis and prognosis.
  • Evidence snippets:
  • Snippet 1 (score: 0.392) > In the pregenomic eras, highly integrated and complex circuitry of molecular signaling in NPC pathogenesis was only partially understood. Over the past decade, the knowledge of the molecular mechanisms in NPC carcinogenesis has been rapidly accumulated. Dysregulation and abnormal protein expression of molecules in certain signaling pathways involved in cellular functions including proliferation, adhesion, survival, and apoptosis has been demonstrated in the NPC cells. Detailed information on the complex network in signaling pathway leading to a coordinated pattern of gene expression and regulation in NPC will undoubtedly provide important clues to develop novel prognostic and therapeutic strategies for this cancer. Refining molecular markers into clinically relevant assays may assist in the detection of NPC in asymptomatic patients, as well as stage classification and monitoring disease progression and treatments. Furthermore, selective regulation of particular proteins targeting cancer cell proliferation, invasion, and apoptosis is a hopeful prospect for future anticancer therapy that slow disease progression and improve survival.

[10] The Expanding Phenotype of ZTTK Syndrome Due to the Heterozygous Variant of SON Gene Focusing on Liver Involvement: Patient Report and Literature Review

  • Authors: A. Pietrobattista, Luca Della Volpe, P. Francalanci, L. Figá Talamanca, L. Monti et al.
  • Year: 2023
  • Venue: Genes
  • URL: https://www.semanticscholar.org/paper/d2a98c42645c17d3239e8b519ea2384456da8af9
  • DOI: 10.3390/genes14030739
  • PMID: 36981010
  • PMCID: 10048019
  • Citations: 1
  • Summary: The report provides new information on this rare condition and suggests the expansion of the ZTTK syndrome phenotype, including possible liver involvement, and recommends screening patients with SON variants specifically for liver involvement from the first years of life.
  • Evidence snippets:
  • Snippet 1 (score: 0.391) > Therefore, the normal LFTs reported in all previously published single cases and series of ZTTK syndrome may not be completely reassuring. Moreover, a pattern of normal biochemical tests in CLDs is not completely unexpected because there are other known disease models which can progress toward PH maintaining normal LFTs. In our case, liver involvement was accidentally detected at age 16 during a follow-up ultrasound that monitored the surgical vesicoureteral reflux correction. A proper ecographic evaluation of the liver requires dedicated pediatric radiological skills as well as a doppler study of the hepatic vascular flows which could be missed during routine studies. > The role of SON as a master regulator of genes that are essential for human neurodevelopmental processes, kidney development, and metabolism has already been revealed through a description of various essential genes that are significantly downregulated upon SON haploinsufficiency, thus potentially impairing normal development and/or functions of multiple organs [3,4]. As such, it is important to identify direct SON targets in cells that are relevant to the observed clinical phenotypes. > Overall, it is still not clear whether hepatic involvement is a possible phenotypic manifestation associated with a mutation of the SON gene or if it is an epiphenomenon in the context of patients with ZTTK syndrome. However, in the absence of other definitive causes, it seems reasonable to include liver disease in a proposal of expanding phenotypes. > Unfortunately, in our case, even if we excluded variants in all genes known to be associated with CLD pathogenesis, we would not be able to investigate whether there was a downregulation of those genes due to SON haploinsufficiency. In this view, the absence of functional studies is the major limitation of our study that prevents us from establishing a direct link between the SON variant and the CLD. At this stage, we can only surmise that this hypothesis is worthy of further consideration as a field of future research mainly focusing on SON and mechanisms of hepatic fibrogenesis.

[11] New Insights into Mitochondria in Health and Diseases

  • Authors: Ya Li, Huhu Zhang, Chunjuan Yu, Xiaolei Dong, Fanghao Yang et al.
  • Year: 2024
  • Venue: International Journal of Molecular Sciences
  • URL: https://www.semanticscholar.org/paper/23002a4ffabfd043f52c664f4d5acab85b8dcac0
  • DOI: 10.3390/ijms25189975
  • PMID: 39337461
  • PMCID: 11432609
  • Citations: 38
  • Summary: This overview outlines the various mechanisms by which mitochondria are involved in numerous illnesses and cellular physiological activities and provides new discoveries regarding the involvement of mitochondria in both disorders and the maintenance of good health.
  • Evidence snippets:
  • Snippet 1 (score: 0.391) > Mitochondria are essential organelles within cells, playing critical roles not only in energy metabolism but also in various cellular activities, such as cell differentiation, signal transduction, and apoptosis. Mitochondrial dysfunction is implicated in a range of diseases, including but not limited to diabetes and its complications, neurodegenerative disorders, myocardial ischemia-reperfusion injury, and heart failure. Therefore, investigating the structure and function of mitochondria as well as the mechanisms underlying mitochondrial dysfunction in disease contexts holds significant scientific and clinical importance. > Basic scientific research: Diseases manifest systemically and exhibit complexity; thus, it is imperative to understand mitochondrial structure at the molecular level along with known pathways while characterizing novel pathways that influence mitochondrial behavior and functionality. For instance, mapping genetic interactions among genes encoding mitochondrial proteins can elucidate interrelations between different aspects of mitochondrial function. The first focused map of mitochondria has been constructed in yeast models, revealing dense and significant connections among localization pathways distributed across various mitochondrial compartments [126]. > Disease diagnosis: A comprehensive understanding of the mechanisms governing mitochondrial dysfunction can facilitate the development of innovative diagnostic tools. By monitoring specific indicators related to mitochondrial function, earlier diagnosis of diseases associated with mitochondrial impairment becomes feasible. Employing nextgeneration sequencing technologies for analyzing the mitochondrial proteome aids in identifying novel proteins and pathways linked to mitochondria while enabling streamlined diagnostics alongside genetic counseling opportunities for patients with mitochondrial diseases [127]. > Drug development: Advancements in our comprehension of how mitochondria contribute to disease processes may promote targeted therapeutic strategies. For example, metformin-a widely used antidiabetic agent-has recently been repurposed as an anticancer drug; its combination with standard epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) significantly improves progression-free survival rates and overall survival outcomes for patients with advanced lung adenocarcinoma [125]. > Personalized medicine: Given that manifestations of mitochondrial dysfunction may vary among individuals, research into mitochondria provides a theoretical foundation for personalized medicine by allowing tailored treatment plans based on individual states of mitochondrial functionality [127].

[12] Human Dermal Fibroblast: A Promising Cellular Model to Study Biological Mechanisms of Major Depression and Antidepressant Drug Response

  • Authors: P. Mesdom, R. Colle, É. Lebigot, S. Trabado, Eric Deflesselle et al.
  • Year: 2020
  • Venue: Current Neuropharmacology
  • URL: https://www.semanticscholar.org/paper/79368e365458486de96794333613c12a6063bf54
  • DOI: 10.2174/1570159X17666191021141057
  • PMID: 31631822
  • PMCID: 7327943
  • Citations: 12
  • Summary: This review highlights the great and still underused potential of HDF, which stands out as a very promising tool in the understanding of MDD and AD mechanisms of action.
  • Evidence snippets:
  • Snippet 1 (score: 0.387) > Background: Human dermal fibroblasts (HDF) can be used as a cellular model relatively easily and without genetic engineering. Therefore, HDF represent an interesting tool to study several human diseases including psychiatric disorders. Despite major depressive disorder (MDD) being the second cause of disability in the world, the efficacy of antidepressant drug (AD) treatment is not sufficient and the underlying mechanisms of MDD and the mechanisms of action of AD are poorly understood. Objective The aim of this review is to highlight the potential of HDF in the study of cellular mechanisms involved in MDD pathophysiology and in the action of AD response. Methods The first part is a systematic review following PRISMA guidelines on the use of HDF in MDD research. The second part reports the mechanisms and molecules both present in HDF and relevant regarding MDD pathophysiology and AD mechanisms of action. Results HDFs from MDD patients have been investigated in a relatively small number of works and most of them focused on the adrenergic pathway and metabolism-related gene expression as compared to HDF from healthy controls. The second part listed an important number of papers demonstrating the presence of many molecular processes in HDF, involved in MDD and AD mechanisms of action. Conclusion The imbalance in the number of papers between the two parts highlights the great and still underused potential of HDF, which stands out as a very promising tool in our understanding of MDD and AD mechanisms of action

[13] Drug repurposing in Rett and Rett-like syndromes: a promising yet underrated opportunity?

  • Authors: Claudia Fuchs, P. A. ‛. ’t Hoen, A. Müller, Friederike Ehrhart, C. V. van Karnebeek
  • Year: 2024
  • Venue: Frontiers in Medicine
  • URL: https://www.semanticscholar.org/paper/b00d0859458647edeebf3cf53f9b39c79311d5ed
  • DOI: 10.3389/fmed.2024.1425038
  • PMID: 39135718
  • PMCID: 11317438
  • Citations: 1
  • Summary: The potential of drug repurposing (DR) as a promising avenue for addressing the unmet medical needs of individuals with RTT and related disorders is explored and Leveraging existing drugs for new therapeutic purposes presents an attractive strategy.
  • Evidence snippets:
  • Snippet 1 (score: 0.386) > Rigorous preclinical and clinical studies are also crucial for better understanding the complex pathophysiology of these syndromes. To date, the precise molecular mechanisms underlying these complex disorders are still not fully understood; hindering the identification and validation of potential drug targets. This specifically applies to CDD and FOXG1-syndrome: both conditions were identified as distinct clinical entities only recently and it is understandable that research efforts initially focused primarily on "classical" RTT. This discrepancy is reflected also in the very different numbers of repurposing studies highlighted in Figure 1. Continued efforts in pre-clinical (identification of valuable cell and animal models etc.) and clinical research (better understanding of the natural history, clinical manifestations, disease progression, biomarkers etc.) will be essential for advancing our understanding and improving outcomes for individuals affected by these syndromes. In particular, better characterizing the shared symptoms and pathways across these entities, will provide valuable insights into the underlying biology and potentially uncover new common mechanisms and targeted therapies. If the disorders demonstrate convergence in their underlying molecular pathways, this provides an opportunity for designing joint DR 10.3389/fmed.2024.1425038 strategies across RTT and RTT-like disorders. This could reduce the time needed for the development of DR and increase the number of patients benefiting from the treatments, resulting in more attractive business models. > Despite promising DR results in preclinical or early-phase clinical trials for RTT and related disorders in our opinion DR is still underrated and underutilized in this kind of disorders. DR holds immense potential for addressing the unmet medical needs and therapeutic challenges posed by such complex NDDs, and recent advancements screening and computational techniques, offer the unique opportunity to predict drug-disease interactions and prioritize candidate compounds for further investigation. By leveraging existing drugs and repurposing them for new indications, this approach offers a pragmatic and efficient strategy to accelerate the development of treatments for individuals affected by these debilitating conditions.

[14] Clinical metabolomics in type 2 diabetes mellitus: from pathogenesis to biomarkers

  • Authors: Chuanxin Liu, Hetao Chen, Yujin Ma, Lei Zhang, Lulu Chen et al.
  • Year: 2025
  • Venue: Frontiers in Endocrinology
  • URL: https://www.semanticscholar.org/paper/36f8d26a208b7b96763df2e9aa3211e440031c0e
  • DOI: 10.3389/fendo.2025.1501305
  • PMID: 40070584
  • PMCID: 11893406
  • Citations: 11
  • Summary: The results facilitate understanding the pathophysiology and mechanism of type 2 diabetes mellitus and supports research in accurate diagnosis, risk prediction, curative effect, distinct stages, and prognosis judgment of T2DM.
  • Evidence snippets:
  • Snippet 1 (score: 0.386) > T2DM is a chronic disease characterized by two primary pathophysiological mechanisms: ① a reduction in the mass and function of pancreatic b cells, ranging from 20% to 65%, which leads to impaired insulin secretion; ② insulin resistance, where cells in muscles, fat, and liver tissues fail to respond adequately to insulin (9). Consequently, higher levels of insulin are required to maintain normal blood glucose concentrations by inhibiting hepatic glucose production and promoting glucose uptake in muscle and adipose tissues. Prolonged exposure to elevated levels of circulating insulin leads to the development of insulin resistance in peripheral tissues, and over time, the pancreas fails to produce sufficient insulin to overcome this cellular resistance (10). However, due to the long latent period and absence of obvious symptoms initially, reversing T2DM with drug intervention is difficult after the symptoms are exposed or clinically confirmed in light of clear diagnostic criteria. According to the literature, the pathogenesis and process of metabolic syndromes such as diabetes and its complications are mainly reflected in the metabolite network, and the mechanism changes at the gene level are also found in the network. Studies have shown that some related metabolites in patients with diabetes have changed before the occurrence of obvious organic damage (11). Therefore, it is necessary to scientifically prevent T2DM in the early stages of disease onset. Fortunately, clinical metabolomics were employed to understand the progression pathologies of T2DM and its corresponding complications in detail (12). Studies have demonstrated that metabolomic analysis enables the exploration of metabolic disorders associated with T2DM, thereby deepening our understanding of disease progression (13,14). This approach has the potential to facilitate novel clinical diagnoses and the development of effective treatment strategies. Moreover, identifying specific metabolites may provide promising biomarkers for the early prediction, prevention, and management of hyperglycemia and its complications (15). In recent years, excellent progress has been made in the study of T2DM and its complications through High throughput sequencing method, i.e., a discipline specifically focused on metabolic small molecules. > Clinical metabolomics is a type of systems biology research closely linked to phenotype.

[15] Precision Therapeutics in Lennox–Gastaut Syndrome: Targeting Molecular Pathophysiology in a Developmental and Epileptic Encephalopathy

  • Authors: Debopam Samanta
  • Year: 2025
  • Venue: Children
  • URL: https://www.semanticscholar.org/paper/455479c1bfbea7b90b73c109228f67c813d13888
  • DOI: 10.3390/children12040481
  • PMID: 40310132
  • PMCID: 12025602
  • Citations: 19
  • Influential citations: 1
  • Summary: A narrative review explores precision therapeutic strategies for LGS based on molecular pathophysiology, including channelopathies, receptor and ligand dysfunction, receptor and ligand dysfunction, cell signaling abnormalities, cell signaling abnormalities, synaptopathies, and the repurposing of existing medications with mechanism-specific effects.
  • Evidence snippets:
  • Snippet 1 (score: 0.385) > Lennox–Gastaut syndrome (LGS) is a severe childhood-onset developmental and epileptic encephalopathy characterized by multiple drug-resistant seizure types, cognitive impairment, and distinctive electroencephalographic patterns. Current treatments primarily focus on symptom management through antiseizure medications (ASMs), dietary therapy, epilepsy surgery, and neuromodulation, but often fail to address the underlying pathophysiology or improve cognitive outcomes. As genetic causes are identified in 30–40% of LGS cases, precision therapeutics targeting specific molecular mechanisms are emerging as promising disease-modifying approaches. This narrative review explores precision therapeutic strategies for LGS based on molecular pathophysiology, including channelopathies (SCN2A, SCN8A, KCNQ2, KCNA2, KCNT1, CACNA1A), receptor and ligand dysfunction (GABA/glutamate systems), cell signaling abnormalities (mTOR pathway), synaptopathies (STXBP1, IQSEC2, DNM1), epigenetic dysregulation (CHD2), and CDKL5 deficiency disorder. Treatment modalities discussed include traditional ASMs, dietary therapy, targeted pharmacotherapy, antisense oligonucleotides, gene therapy, and the repurposing of existing medications with mechanism-specific effects. Early intervention with precision therapeutics may not only improve seizure control but could also potentially prevent progression to LGS in susceptible populations. Future directions include developing computable phenotypes for accurate diagnosis, refining molecular subgrouping, enhancing drug development, advancing gene-based therapies, personalizing neuromodulation, implementing adaptive clinical trial designs, and ensuring equitable access to precision therapeutic approaches. While significant challenges remain, integrating biological insights with innovative clinical strategies offers new hope for transforming LGS treatment from symptomatic management to targeted disease modification.

[16] Mitochondrial Dysfunction in Diabetes: Shedding Light on a Widespread Oversight

  • Authors: F. Iheagwam, A. J. Joseph, E. D. Adedoyin, Olawumi Toyin Iheagwam, Samuel Akpoyowvare Ejoh
  • Year: 2025
  • Venue: Pathophysiology
  • URL: https://www.semanticscholar.org/paper/dbf8042761c1a5fc50f8cd894cc498505abac7cb
  • DOI: 10.3390/pathophysiology32010009
  • PMID: 39982365
  • PMCID: 12077258
  • Citations: 25
  • Summary: This review aims to elucidate the complex link between mitochondrial dysfunction and diabetes, covering the spectrum of diabetes types, the role of mitochondria in insulin resistance, highlighting pathophysiological mechanisms, mitochondrial DNA damage, and altered mitochondrial biogenesis and dynamics.
  • Evidence snippets:
  • Snippet 1 (score: 0.385) > The landscape of DM research is continuously evolving, with emerging technologies and approaches offering new insights into the pathophysiology of the disease and potential therapeutic targets. Advancements in omics technologies, encompassing genomes, transcriptomics, proteomics, and metabolomics, have transformed the molecular mechanisms underlying DM [134]. High-throughput sequencing techniques enable comprehensive analysis of genetic variants, gene expression profiles, protein abundance, and metabolite levels associated with DM and its complications [135]. Single-cell omics approaches provide unprecedented resolution and granularity, allowing researchers to dissect cellular heterogeneity and identify novel cell types, subpopulations, and signalling pathways involved in DM pathogenesis. Integrating multi-omics data sets offers a systems-level perspective of DM, unravelling complex networks of molecular interactions and regulatory circuits underlying disease progression [136]. > In addition to omics technologies, advances in imaging modalities, such as MRI, PET, and optical imaging, enable non-invasive visualisation and quantification of metabolic, functional, and structural changes. Molecular imaging probes targeting specific biomarkers and metabolic pathways provide valuable insights into disease mechanisms and treatment responses in preclinical and clinical settings [85]. Despite significant progress in DM research, numerous unanswered questions and knowledge gaps persist, hindering the ability to develop effective prevention and treatment strategies. Key areas requiring further investigation include the role of epigenetics, environmental factors, and the microbiome in DM susceptibility and progression. Moreover, the interaction between environmental cues and genetic predisposition remains incompletely understood, highlighting the need for comprehensive multi-omics studies and large-scale epidemiological analyses to identify gene-environment interactions and modifiable risk factors for DM [137]. Furthermore, the heterogeneity of DM phenotypes and clinical outcomes poses a challenge for personalised medicine approaches, necessitating robust biomarkers and predictive models to stratify patients based on disease subtypes, prognosis, and treatment response [138].

[17] Recent advances in modelling of cerebellar ataxia using induced pluripotent stem cells

  • Authors: M. M. Wong, L. Watson, Esther B. E. Becker
  • Year: 2017
  • Venue: Journal of neurology & neuromedicine
  • URL: https://www.semanticscholar.org/paper/0d962652305116e383ab260b9e82d3a5ffe1722f
  • DOI: 10.29245/2572.942X/2017/7.1134
  • PMID: 28825058
  • PMCID: 5558869
  • Citations: 9
  • Summary: This review focuses on recent breakthroughs in generating human iPSC-derived Purkinje cells and highlights the future challenges that will need to be addressed in order to fully exploit these models for the modelling of the molecular mechanisms underlying cerebellar ataxias and the development of effective therapeutics.
  • Evidence snippets:
  • Snippet 1 (score: 0.384) > dominant polyglutamine spinocerebellar ataxias (SCAs) are the most studied forms of ataxias. Despite significant clinical and genetic heterogeneity, emerging evidence points to the existence of common pathogenic mechanisms that may be shared by several genetically distinct forms of cerebellar ataxias (reviewed in5-8). However, it is still unclear how the proposed pathological pathways ultimately result in cerebellar dysfunction and degeneration, predominantly affecting Purkinje cells. > Understanding disease mechanisms is key to treating neurodegenerative disorders. The heterogeneous nature of the cerebellar ataxias combined with the unavailability of human brain tissue and the lack of reliable disease models have, however, hampered our understanding of the molecular disease mechanisms underlying cerebellar ataxias and thus, the development of effective therapies. Although mouse models of several cerebellar ataxias, including FRDA and SCAs, have provided valuable insights into the pathophysiology of these disorders (reviewed in9), many questions remain about the observed species differences in disease phenotypes and the effectiveness of potential drugs in clinical trials. > To help translate research from animal models into novel treatments for ataxia patients, it is essential to validate findings in the relevant affected human cell types, particularly in cerebellar Purkinje cells. The current obstacles might be overcome by exploiting recently developed human induced pluripotent stem cell (iPSC) technology and neuronal differentiation protocols.

[18] Insights in biomarkers complexity and routine clinical practice for the diagnosis of thyroid nodules and cancer

  • Authors: M. G. de Matos, Mafalda Pinto, A. Gonçalves, Sule Canberk, M. J. Bugalho et al.
  • Year: 2025
  • Venue: PeerJ
  • URL: https://www.semanticscholar.org/paper/655de68f1a7e8137dcba8a2046f14dee4f07594d
  • DOI: 10.7717/peerj.18801
  • PMID: 39850836
  • PMCID: 11756370
  • Citations: 4
  • Summary: The knowledge of genetic and molecular biomarkers has achieved a high level of complexity, and the difficulties related to its applicability determine that their implementation in clinical practice is not yet a reality.
  • Evidence snippets:
  • Snippet 1 (score: 0.381) > Knowledge of molecular mechanisms implicated in thyroid carcinogenesis has been attained in recent years. Thyroid neoplasm result from alterations in gene expression patterns, which occur due to a gradual accumulation of genetic and epigenetic events. These changes are associated with specific tumor phenotypes and are implicated in disease etiology. Molecular alterations induce the activation of different signaling pathways, such as the mitogen-activated protein kinase (MAPK), and phosphatidylinositol 3-kinase (PI3K/AKT/mTOR), which are involved in and promote carcinogenesis (Hsiao & Nikiforov, 2014). In a few years, the knowledge of molecular mechanisms implicated in thyroid carcinogenesis changed from understanding signaling pathways and identification of a few genes mutations to the knowledge of the main genes implicated in thyroid carcinogenesis, reviewed by De Leo et al. (2024). Genetic changes in thyroid neoplasms were divided in early/driver molecular alterations and late/progression events. Late/ progression events may be associated with early/driver molecular alterations and represent the evolution from well-differentiated to high-grade and undifferentiated carcinoma, being (Pozdeyev et al., 2018). Most frequent gene mutations present in follicular-cell derived thyroid tumors are BRAF, RAS, and TERTp mutations, associate with clinically relevant clinicopathologic features, as shown in Table 3.

[19] From Data to Cure: A Comprehensive Exploration of Multi-omics Data Analysis for Targeted Therapies

  • Authors: Arnab Mukherjee, S. Abraham, Akshita Singh, S. Balaji, K. Mukunthan
  • Year: 2024
  • Venue: Molecular Biotechnology
  • URL: https://www.semanticscholar.org/paper/04593d2268ccd7c26b5296d8342b468ca84ae7b1
  • DOI: 10.1007/s12033-024-01133-6
  • PMID: 38565775
  • PMCID: 11928429
  • Citations: 69
  • Influential citations: 2
  • Summary: This review navigates the expansive omics landscape, showcasing tailored assays for each molecular layer through genomes to metabolomes, and aims to illuminate the transformative impact of multi-omics in the big data era, shaping the future of biological research.
  • Evidence snippets:
  • Snippet 1 (score: 0.379) > Biological processes and molecular functions arise from intricate interactions among thousands of molecules, constituting inherent complexity. Integration of metabolomics data with other omics data holds significant promise for achieving a holistic understanding of disease mechanisms. Metabolomics, which focuses on the comprehensive analysis of small molecule metabolites within biological systems, provides unique insights into the functional status and metabolic phenotypes associated with various physiological and pathological conditions [160,161]. The integration of omics datasets with computational models and network analysis tools elucidates the complex interplay between genes, proteins, metabolites, and cellular processes underlying disease phenotypes. > Despite recent progress in omics technologies, the underlying genetic factors contributing to numerous metabolic phenotypes remain elusive. Metabolite biomarkers can be integrated with genomics and clinical parameters to enhance diagnostic accuracy or refine disease risk prediction models. Metabolites can also serve as intermediate phenotypes for genetic investigations, offering insights into underlying genetic mechanisms [162]. The integration of metabolomics data with either whole-exome sequencing or WGS-data presents a promising systematic strategy for pinpointing disease-causing variants and holds potential utility within the framework of a specific pathway under investigation [163]. Furthermore, at a more intricate biological and analytical level, metabolomics can be combined with various omic platforms, facilitating a comprehensive understanding of complex biological systems and interactions (Fig. 4). > The alterations in metabolite levels, perturbations in metabolic pathways, and the onset of disease states can be elucidated by assessing the epigenetic alterations. This approach offers molecular insights into the intricate interplay among genetic, epigenetic, and metabolic factors during the disease progression. Through the integration of epigenomic Fig. 4 The workflow for integration of metabolomics with other omics for a holistic understanding of disease progression and metabolomic data, the intricate relationships between epigenetic alterations and metabolic pathways in disease pathogenesis can be uncovered. In recent years, metabolomics and epigenomics have experienced notable advancement as prominent molecular and analytical methodologies for biomarker identification [164,165].

[20] Computational drug discovery approaches identify mebendazole as a candidate treatment for autosomal dominant polycystic kidney disease

  • Authors: P. Brownjohn, A. Zoufir, Daniel J O’Donovan, Saatviga Sudhahar, A. Syme et al.
  • Year: 2024
  • Venue: Frontiers in Pharmacology
  • URL: https://www.semanticscholar.org/paper/a595e78572ca02b8cb2897bfc4a989a2b021b279
  • DOI: 10.3389/fphar.2024.1397864
  • PMID: 38846086
  • PMCID: 11154008
  • Citations: 3
  • Summary: It is determined that the anthelmintic mebendazole was a potent anti-cystic agent in human cellular and in vivo models of ADPKD, and is likely acting through the inhibition of microtubule polymerisation and protein kinase activity.
  • Evidence snippets:
  • Snippet 1 (score: 0.379) > Targets and molecules were ultimately filtered for validation based on biological and chemical insights, and the potential for clinical translation.Earlier this year, Wilk et al., 2023 applied a similar transcriptomic approach to us, in that case making use of publicly available transcriptomic datasets to create Pkd2-specific ADPKD disease signatures, from which signature reversion was sought from the Library of Integrated Network-based Cellular Signatures (LINCs) drug signature database in order to identify drug repurposing candidates.While one group has previously made use of a knowledge graph-based approach to prioritise preclinically active compounds with the highest chance of clinical translation (Malas et al., 2019), to our knowledge, the current study provides the first combined application of transcriptomic and machine-learning approaches to identify and prioritise putative treatments for ADPKD, and further deconvolute potential mechanisms of action for experimental validation. > In summary we report, using computational, in vitro and in vivo approaches, that the anthelmintic drug mebendazole ameliorates disease-relevant phenotypes in cellular and animal models of ADPKD.We further show that this effect is likely primarily due to the inhibitory effect of mebendazole on the polymerisation of microtubules, which underlie cellular processes important in ADPKD, including cell proliferation, transport, and cilia signalling, and extends previous work linking the importance of the microtubule network to ADPKD pathophysiology.We also describe the inhibitory profile of mebendazole on known and novel protein kinase targets, some of which have previously been implicated in ADPKD, suggesting mebendazole may be acting via polypharmacology to impact disease mechanisms.We acknowledge that further experimental efforts will be required to confirm the actions of mebendazole on these putative targets in relevant disease model systems.It would be particularly informative to investigate these mechanisms in dedicated in vivo studies, where the effects of mebendazole on a wider range of ADPKD-relevant cell types and phenotypes could be evaluated.

Notes

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