Schinzel-Giedion syndrome

Mendelian MONDO:0010010 Pathograph 30 Show in embeddings browser hereditary disease developmental disorder

Schinzel-Giedion syndrome is a severe autosomal dominant multisystem developmental disorder caused by de novo missense variants in the degron region of SETBP1. These variants impair normal SETBP1 protein degradation, leading to toxic accumulation of an epigenetic transcriptional regulator. Dysregulated SETBP1 activity rewires developmental gene-expression programs, impairs neurogenesis and neuronal migration, and underlies the syndrome's severe developmental delay, progressive brain disease, seizures, craniofacial abnormalities, and visceral malformations.

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Classifications

Harrison's Part
GENETICS ENVIRONMENT DISEASE NEUROLOGIC KIDNEY URINARY TRACT
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Mappings

MONDO
MONDO:0010010 Schinzel-Giedion syndrome
skos:exactMatch MONDO
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Inheritance

1
Autosomal dominant inheritance HP:0000006
Schinzel-Giedion syndrome is an autosomal dominant disorder typically caused by spontaneous de novo heterozygous gain-of-function variants in SETBP1.
Autosomal dominant inheritance
Show evidence (1 reference)
PMID:38452171 SUPPORT REVIEW SYNTHESIS Human clinical
"Classic and atypical SGS are autosomal dominant disorders typically caused by a de novo SETBP1 pathogenic variant."
GeneReviews directly supports dominant inheritance with typically de novo SETBP1 pathogenic variants.
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Subtypes

2
Classic Schinzel-Giedion syndrome
Canonical Schinzel-Giedion syndrome caused by heterozygous de novo gain-of-function variants within (or immediately adjacent to) the 12-base-pair exon 4 SETBP1 mutational hot spot encoding the canonical degron, presenting with severe global neurodevelopmental impairment, characteristic craniofacial and visceral malformations, and predisposition to neuroepithelial neoplasia.
Show evidence (2 references)
PMID:38452171 SUPPORT REVIEW SYNTHESIS Human clinical
"The diagnosis of classic SGS can be established in a proband based on published clinical diagnostic criteria, or the molecular diagnosis can be established in a proband with suggestive findings and a heterozygous SETBP1 pathogenic gain-of-function variant within the mutational hot spot (i.e., a..."
Defines classic Schinzel-Giedion syndrome by clinical diagnostic criteria and pathogenic gain-of-function variants within the exon 4 canonical degron hot spot.
PMID:38711130 SUPPORT Human clinical
"Here, we describe a case of typical SGS caused by a novel heterozygous missense variant, D874V, adjacent to the degron."
Documents that missense variants immediately adjacent to the canonical degron can also produce canonical (classic) SGS.
Atypical Schinzel-Giedion syndrome
Atypical Schinzel-Giedion syndrome caused by heterozygous pathogenic SETBP1 variants in proximity to, but outside, the canonical exon 4 degron hot spot, characterized by a variable clinical spectrum overlapping classic SGS but without documented risk for neuroepithelial neoplasia to date.
Show evidence (2 references)
PMID:38452171 SUPPORT REVIEW SYNTHESIS Human clinical
"To date, more than 50 individuals have been reported with molecularly confirmed classic SGS. Atypical SGS, reported in five individuals to date, is caused by pathogenic SETBP1 variants in proximity to – but not within – the mutational hot spot."
Defines atypical Schinzel-Giedion syndrome as caused by pathogenic SETBP1 variants adjacent to but outside the mutational hot spot.
PMID:38452171 SUPPORT REVIEW SYNTHESIS Human clinical
"The broad spectrum of clinical features of variable severity partially overlaps with classic SGS; however, this spectrum does not include risk for neuroepithelial neoplasia to date."
Distinguishes atypical SGS by its variable clinical severity and absence of documented neuroepithelial neoplasia risk to date.
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Pathophysiology

5
Impaired SETBP1 degron-dependent degradation
Classical Schinzel-Giedion syndrome is caused by missense variants within or immediately adjacent to the exon 4 canonical degron of SETBP1 (amino acids 868 to 871), which disrupt ubiquitin-proteasome degradation and produce toxic accumulation of SETBP1 protein.
SETBP1 hgnc:15573 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves SETBP1 (hgnc:15573). hgnc:15573 is a gene from the HUGO Gene Nomenclature Committee.
Downstream
Aberrant developmental gene transcription Excess stabilized SETBP1 protein alters epigenetic and transcriptional control over developmental gene networks
Show evidence (3 references)
PMID:37872881 SUPPORT BACKGROUND Human clinical
"SETBP1 variants causing classical SGS cluster at the degron, disrupting SETBP1 protein degradation and resulting in toxic accumulation, while those located outside cause milder atypical SGS."
Directly states the core degron-disruption mechanism of classical SGS and contrasts it with variants outside the canonical degron in atypical SGS.
PMID:38711130 SUPPORT Human clinical
"Here, we describe a case of typical SGS caused by a novel heterozygous missense variant, D874V, adjacent to the degron."
Shows that missense variants immediately adjacent to the canonical degron can also produce canonical SGS.
PMID:38452171 SUPPORT REVIEW SYNTHESIS Human clinical
"The diagnosis of classic SGS can be established in a proband based on published clinical diagnostic criteria, or the molecular diagnosis can be established in a proband with suggestive findings and a heterozygous SETBP1 pathogenic gain-of-function variant within the mutational hot spot (i.e., a..."
GeneReviews directly establishes that classic SGS is caused by heterozygous pathogenic gain-of-function variants within the 12-bp exon 4 canonical degron hotspot of SETBP1.
Aberrant developmental gene transcription
SETBP1 acts as an epigenetic hub at AT-rich promoter regions through recruitment of the HCF1/KMT2A/PHF8 chromatin-modifying complex, organizes higher-order chromatin interactions with the nuclear lamina, and modulates intracellular signaling pathways such as AKT; excess SETBP1 protein dysregulates developmental gene-expression programs in neural and visceral progenitors.
SETBP1 hgnc:15573 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves SETBP1 (hgnc:15573). hgnc:15573 is a gene from the HUGO Gene Nomenclature Committee.
regulation of transcription by RNA polymerase II GO:0006357 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal regulation of transcription by RNA polymerase II (GO:0006357). GO:0006357 is a biological process from the Gene Ontology.
Downstream
Impaired neurogenesis and neuronal migration Dysregulated SETBP1 transcriptional networks disrupt cortical neurogenesis and neuronal migration
Disrupted visceral and craniofacial morphogenesis Deregulated SETBP1 target genes perturb kidney, skeletal, and craniofacial organogenesis
Neuroepithelial neoplasia Gain-of-function SETBP1 transcriptional and signaling dysregulation predisposes individuals with classic SGS to neuroepithelial neoplasia
Show evidence (4 references)
PMID:29875417 SUPPORT In vitro / ex vivo
"Here we show that SETBP1 binds to gDNA in AT-rich promoter regions, causing activation of gene expression through recruitment of a HCF1/KMT2A/PHF8 epigenetic complex."
Directly supports SETBP1 as a DNA-binding transcriptional and epigenetic regulator recruiting HCF1/KMT2A/PHF8.
PMID:29875417 SUPPORT In vitro / ex vivo
"Gene ontology analysis of deregulated SETBP1 target genes indicates that they are also key controllers of visceral organ development and brain morphogenesis."
Links dysregulated SETBP1 target gene networks to both brain morphogenesis and visceral organ development.
PMID:39825586 SUPPORT In vitro / ex vivo
"We find that extremes of SETBP1 protein dose reciprocally influence important signalling molecules such as AKT, suggesting that the SETBP1 protein operates within a narrow dosage range and that extreme doses are detrimental."
Demonstrates that elevated SETBP1 protein dosage perturbs downstream signaling pathways including AKT in human neural progenitor models.
+ 1 more reference
Impaired neurogenesis and neuronal migration
Pathogenic SETBP1 accumulation disrupts cortical neurogenesis, delays neuronal migration, and alters cell-type-specific transcriptional regulatory networks in cerebral cortex excitatory neurons and other neural cell types.
neuron differentiation GO:0030182 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal neuron differentiation (GO:0030182). GO:0030182 is a biological process from the Gene Ontology.
brain UBERON:0000955 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in brain (UBERON:0000955). UBERON:0000955 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Severe neurodevelopmental impairment Impaired neurogenesis and cortical circuit assembly lead to profound neurodevelopmental disability
Seizure Perturbed cortical neuron development and migration predispose to early-onset, often treatment-refractory seizures
Brain atrophy Persistent postnatal transcriptional dysregulation in cortical neurons leads to progressive cerebral atrophy
Ventriculomegaly Impaired brain morphogenesis and cerebral volume loss result in ventricular dilation
Show evidence (2 references)
PMID:29875417 SUPPORT Model organism
"In line with these findings, in utero brain electroporation of mutated SETBP1 causes impairment of mouse neurogenesis with a profound delay in neuronal migration."
Directly supports impaired neurogenesis and delayed neuronal migration downstream of mutant SETBP1 in vivo.
PMID:37872881 SUPPORT Model organism
"Setbp1 was differentially expressed in excitatory neurons, but known SETBP1 targets were differentially expressed and regulated in many cell types. Our findings suggest molecular drivers underlying neurodevelopmental phenotypes in classical SGS also drive atypical SGS, persist after birth, and..."
Demonstrates cell-type-specific dysregulation of SETBP1 targets in cerebral cortex excitatory neurons and other cell types.
Disrupted visceral and craniofacial morphogenesis
Deregulation of SETBP1 target genes governing organogenesis and persistent cell-type-specific transcriptional rewiring in the kidney and developing tissues disrupt urogenital, cardiac, craniofacial, and skeletal morphogenesis.
anatomical structure morphogenesis GO:0009653 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal anatomical structure morphogenesis (GO:0009653). GO:0009653 is a biological process from the Gene Ontology. kidney development GO:0001822 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal kidney development (GO:0001822). GO:0001822 is a biological process from the Gene Ontology. urogenital system development GO:0001655 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal urogenital system development (GO:0001655). GO:0001655 is a biological process from the Gene Ontology. heart development GO:0007507 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal heart development (GO:0007507). GO:0007507 is a biological process from the Gene Ontology. skeletal system development GO:0001501 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal skeletal system development (GO:0001501). GO:0001501 is a biological process from the Gene Ontology.
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. heart UBERON:0000948 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in heart (UBERON:0000948). UBERON:0000948 is an anatomical location from the Uberon multi-species anatomy ontology. skull UBERON:0003129 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in skull (UBERON:0003129). UBERON:0003129 is an anatomical location from the Uberon multi-species anatomy ontology. face UBERON:0001456 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in face (UBERON:0001456). UBERON:0001456 is an anatomical location from the Uberon multi-species anatomy ontology. skeletal system UBERON:0001434 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in skeletal system (UBERON:0001434). UBERON:0001434 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Hydronephrosis Disrupted renal and urinary tract morphogenesis leads to congenital hydronephrosis
Recurrent pyelonephritis Congenital urinary tract malformations and hydronephrosis predispose to recurrent pyelonephritis
Chronic kidney disease Persistent SETBP1-driven renal regulatory rewiring and structural urinary tract abnormalities lead to chronic kidney disease
Congenital heart defects Disrupted cardiac morphogenesis results in congenital heart defects
Genital anomalies Perturbed urogenital morphogenesis causes congenital genital anomalies
Midface retrusion Abnormal craniofacial morphogenesis produces characteristic midface retrusion
Choanal stenosis Abnormal midface and craniofacial morphogenesis leads to choanal stenosis
Talipes equinovarus Altered limb and skeletal morphogenesis results in congenital clubfoot
Recurrent infections Multisystem anatomical and functional abnormalities predispose affected individuals to recurrent infections
Show evidence (3 references)
PMID:29875417 SUPPORT In vitro / ex vivo
"Gene ontology analysis of deregulated SETBP1 target genes indicates that they are also key controllers of visceral organ development and brain morphogenesis."
Establishes that SETBP1 target genes directly control visceral organ development and morphogenesis.
PMID:37872881 SUPPORT Model organism
"Our findings suggest molecular drivers underlying neurodevelopmental phenotypes in classical SGS also drive atypical SGS, persist after birth, and are present in the kidney. Our results indicate SETBP1's role as an epigenetic hub leads to cell-type-specific differences in TF activity, gene..."
Identifies persistent SETBP1-driven regulatory rewiring in the kidney underlying renal pathology in SGS models.
PMID:38452171 SUPPORT REVIEW SYNTHESIS Human clinical
"Structural malformations can involve the heart, skeleton, kidney and urinary tract, genitalia, and brain."
GeneReviews summarizes the multi-organ craniofacial, cardiac, renal, genital, and skeletal malformations characteristic of classic SGS.
Severe neurodevelopmental impairment
Downstream organism-level consequences of dysregulated SETBP1 activity in the developing central nervous system include severe global developmental delay, moderate-to-profound intellectual disability, motor tone abnormalities, dysautonomia, sensory deficits, sleep disturbance, and feeding intolerance.
Downstream
Developmental delay Global neurodevelopmental impairment manifests clinically as severe developmental delay
Intellectual disability Global neurodevelopmental impairment results in moderate-to-profound intellectual disability
Hypotonia Global neurodevelopmental impairment is accompanied by muscular hypotonia
Spasticity Global neurodevelopmental impairment is accompanied by limb spasticity
Dysautonomia Global neurodevelopmental impairment is accompanied by autonomic nervous system dysfunction
Hearing impairment Global neurodevelopmental impairment is accompanied by hearing loss
Cerebral visual impairment Global neurodevelopmental impairment is accompanied by cerebral visual impairment
Feeding difficulties Severe neurologic and gastrointestinal motility dysfunction is associated with feeding intolerance and poor weight gain
Sleep disturbance Central nervous system dysfunction in SGS is accompanied by sleep disturbance
Show evidence (1 reference)
PMID:38452171 SUPPORT REVIEW SYNTHESIS Human clinical
"Classic Schinzel-Giedion syndrome (SGS), an ultra-rare multisystem disorder caused by gain-of-function pathogenic variants in a SETBP1 mutational hot spot, is characterized by global neurodevelopmental impairment leading to moderate-to-profound intellectual disability, epilepsy (often refractory..."
Directly links the disease mechanism to severe human neurodevelopmental, motor, autonomic, and sensory impairment.
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Pathograph

Use Group by to collapse related nodes into one box. Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Schinzel-Giedion 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

22
Cardiovascular 1
Congenital heart defects Abnormal heart morphology HP:0001627 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal heart morphology (HP:0001627). HP:0001627 is a phenotype from the Human Phenotype Ontology.
Coarse binding: source unspecified
Show evidence (2 references)
PMID:38452171 SUPPORT REVIEW SYNTHESIS Human clinical
"Structural malformations can involve the heart, skeleton, kidney and urinary tract, genitalia, and brain."
GeneReviews directly lists congenital heart defects as a typical congenital malformation in classic SGS.
PMID:38711130 SUPPORT Human clinical
"The female patient was diagnosed in the neonatal period and presented with characteristic facial phenotype (midface retraction, prominent forehead, and low-set ears), bilateral symmetrical talipes equinovarus, overlapping toes, and severe bilateral hydronephrosis accompanied by congenital heart..."
Confirms congenital heart disease in a neonate with canonical SGS.
Digestive 1
Feeding difficulties HP:0011968 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Feeding difficulties (HP:0011968). HP:0011968 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38452171 SUPPORT REVIEW SYNTHESIS Human clinical
"Other findings can include poor weight gain often associated with gastroesophageal reflux disease, chronic vomiting, constipation, gastroparesis, and/or feeding intolerance."
GeneReviews documents feeding intolerance and gastrointestinal motility issues associated with poor weight gain in classic SGS.
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 (2 references)
PMID:38452171 SUPPORT REVIEW SYNTHESIS Human clinical
"Classic Schinzel-Giedion syndrome (SGS), an ultra-rare multisystem disorder caused by gain-of-function pathogenic variants in a SETBP1 mutational hot spot, is characterized by global neurodevelopmental impairment leading to moderate-to-profound intellectual disability, epilepsy (often refractory..."
GeneReviews identifies hearing loss as a characteristic manifestation of classic SGS.
PMID:36147799 SUPPORT Human clinical
"Six months after birth, the patient had an epileptic seizure and experienced persistent neurodevelopmental delay with auditory and visual abnormalities."
Confirms auditory abnormalities during infancy in a longitudinally followed SGS patient.
Eye 1
Cerebral visual impairment HP:0100704 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cerebral visual impairment (HP:0100704). HP:0100704 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38452171 SUPPORT REVIEW SYNTHESIS Human clinical
"Classic Schinzel-Giedion syndrome (SGS), an ultra-rare multisystem disorder caused by gain-of-function pathogenic variants in a SETBP1 mutational hot spot, is characterized by global neurodevelopmental impairment leading to moderate-to-profound intellectual disability, epilepsy (often refractory..."
GeneReviews directly lists cerebral visual impairment as a characteristic feature of classic SGS.
Genitourinary 4
Hydronephrosis HP:0000126 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hydronephrosis (HP:0000126). HP:0000126 is a phenotype from the Human Phenotype Ontology.
Sequelae: Recurrent pyelonephritis Chronic kidney disease
Show evidence (2 references)
PMID:38711130 SUPPORT Human clinical
"The female patient was diagnosed in the neonatal period and presented with characteristic facial phenotype (midface retraction, prominent forehead, and low-set ears), bilateral symmetrical talipes equinovarus, overlapping toes, and severe bilateral hydronephrosis accompanied by congenital heart..."
Provides direct human clinical support for severe bilateral hydronephrosis as a canonical SGS manifestation.
PMID:36147799 SUPPORT Human clinical
"Color Doppler ultrasonography at 18 months revealed hydronephrosis and bilateral widening of the lateral ventricles."
Confirms hydronephrosis on follow-up ultrasonography in an infant with molecularly confirmed SGS.
Recurrent pyelonephritis HP:0012787 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent pyelonephritis (HP:0012787). HP:0012787 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38452171 SUPPORT REVIEW SYNTHESIS Human clinical
"Agents/circumstances to avoid: Nephrotoxic drugs such as nonsteroidal anti-inflammatory drugs and vancomycin should be used with caution due to high frequency of chronic renal impairment from recurrent pyelonephritis and structural renal anomalies."
GeneReviews directly documents recurrent pyelonephritis as a renal complication in SGS.
Chronic kidney disease HP:0012622 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Chronic kidney disease (HP:0012622). HP:0012622 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38452171 SUPPORT REVIEW SYNTHESIS Human clinical
"Agents/circumstances to avoid: Nephrotoxic drugs such as nonsteroidal anti-inflammatory drugs and vancomycin should be used with caution due to high frequency of chronic renal impairment from recurrent pyelonephritis and structural renal anomalies."
GeneReviews directly documents chronic kidney disease as a renal manifestation of SGS.
Genital anomalies Abnormality of the genital system HP:0000078 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormality of the genital system (HP:0000078). HP:0000078 is a phenotype from the Human Phenotype Ontology.
Coarse binding: source unspecified
Show evidence (2 references)
PMID:38452171 SUPPORT REVIEW SYNTHESIS Human clinical
"Structural malformations can involve the heart, skeleton, kidney and urinary tract, genitalia, and brain."
GeneReviews identifies genital anomalies as a characteristic congenital malformation of classic SGS.
PMID:36147799 SUPPORT Human clinical
"The neonate had a characteristic midface retraction, abnormal electroencephalogram waveforms, and genital abnormalities."
Confirms neonatal genital abnormalities in a molecularly confirmed SGS case where the abstract does not specify a narrower genital subterm.
Head and Neck 2
Midface retrusion HP:0011800 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Midface retrusion (HP:0011800). HP:0011800 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:38711130 SUPPORT Human clinical
"The female patient was diagnosed in the neonatal period and presented with characteristic facial phenotype (midface retraction, prominent forehead, and low-set ears), bilateral symmetrical talipes equinovarus, overlapping toes, and severe bilateral hydronephrosis accompanied by congenital heart..."
Confirms neonatal midface retraction in canonical SGS.
PMID:36147799 SUPPORT Human clinical
"The neonate had a characteristic midface retraction, abnormal electroencephalogram waveforms, and genital abnormalities."
Confirms characteristic midface retraction in a neonate with SGS.
Choanal stenosis HP:0000452 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Choanal stenosis (HP:0000452). HP:0000452 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38452171 SUPPORT REVIEW SYNTHESIS Human clinical
"Other features may include neuroepithelial neoplasia, severely disrupted sleep, choanal stenosis, inguinal hernia, sensitive skin, and increased risk of infection."
GeneReviews directly lists choanal stenosis as an associated clinical manifestation of SGS.
Immune 1
Recurrent infections HP:0002719 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent infections (HP:0002719). HP:0002719 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38452171 SUPPORT REVIEW SYNTHESIS Human clinical
"Other features may include neuroepithelial neoplasia, severely disrupted sleep, choanal stenosis, inguinal hernia, sensitive skin, and increased risk of infection."
GeneReviews directly documents recurrent infections as an associated clinical feature of SGS.
Limbs 1
Talipes equinovarus HP:0001762 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Talipes equinovarus (HP:0001762). HP:0001762 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38711130 SUPPORT Human clinical
"The female patient was diagnosed in the neonatal period and presented with characteristic facial phenotype (midface retraction, prominent forehead, and low-set ears), bilateral symmetrical talipes equinovarus, overlapping toes, and severe bilateral hydronephrosis accompanied by congenital heart..."
Documents bilateral symmetrical talipes equinovarus in a neonate with canonical SGS.
Musculoskeletal 2
Hypotonia HP:0001252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypotonia (HP:0001252). HP:0001252 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38452171 SUPPORT REVIEW SYNTHESIS Human clinical
"Classic Schinzel-Giedion syndrome (SGS), an ultra-rare multisystem disorder caused by gain-of-function pathogenic variants in a SETBP1 mutational hot spot, is characterized by global neurodevelopmental impairment leading to moderate-to-profound intellectual disability, epilepsy (often refractory..."
GeneReviews directly lists hypotonia among the core neurologic features of classic SGS.
Spasticity HP:0001257 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Spasticity (HP:0001257). HP:0001257 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38452171 SUPPORT REVIEW SYNTHESIS Human clinical
"Classic Schinzel-Giedion syndrome (SGS), an ultra-rare multisystem disorder caused by gain-of-function pathogenic variants in a SETBP1 mutational hot spot, is characterized by global neurodevelopmental impairment leading to moderate-to-profound intellectual disability, epilepsy (often refractory..."
GeneReviews directly supports spasticity as a clinical feature of classic SGS.
Nervous System 7
Developmental delay Global developmental delay HP:0001263 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:37872881 SUPPORT BACKGROUND Human clinical
"The most notable phenotypes involve severe developmental delay, progressive brain atrophy, and drug-resistant seizures."
Summarizes severe developmental delay as a hallmark phenotype of SGS.
PMID:38452171 SUPPORT REVIEW SYNTHESIS Human clinical
"Classic Schinzel-Giedion syndrome (SGS), an ultra-rare multisystem disorder caused by gain-of-function pathogenic variants in a SETBP1 mutational hot spot, is characterized by global neurodevelopmental impairment leading to moderate-to-profound intellectual disability, epilepsy (often refractory..."
Provides direct human clinical support for severe global neurodevelopmental impairment in SGS.
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 (2 references)
PMID:37872881 SUPPORT BACKGROUND Human clinical
"The most notable phenotypes involve severe developmental delay, progressive brain atrophy, and drug-resistant seizures."
Summarizes drug-resistant seizures as a hallmark neurologic phenotype of SGS.
PMID:38452171 SUPPORT REVIEW SYNTHESIS Human clinical
"Classic Schinzel-Giedion syndrome (SGS), an ultra-rare multisystem disorder caused by gain-of-function pathogenic variants in a SETBP1 mutational hot spot, is characterized by global neurodevelopmental impairment leading to moderate-to-profound intellectual disability, epilepsy (often refractory..."
Provides direct human clinical support for treatment-refractory epilepsy in SGS.
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:38452171 SUPPORT REVIEW SYNTHESIS Human clinical
"Classic Schinzel-Giedion syndrome (SGS), an ultra-rare multisystem disorder caused by gain-of-function pathogenic variants in a SETBP1 mutational hot spot, is characterized by global neurodevelopmental impairment leading to moderate-to-profound intellectual disability, epilepsy (often refractory..."
GeneReviews directly supports moderate-to-profound intellectual disability in humans with SGS.
Brain atrophy HP:0012444 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Brain atrophy (HP:0012444). HP:0012444 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37872881 SUPPORT BACKGROUND Human clinical
"The most notable phenotypes involve severe developmental delay, progressive brain atrophy, and drug-resistant seizures."
Supports progressive brain atrophy as a hallmark feature of SGS.
Ventriculomegaly HP:0002119 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ventriculomegaly (HP:0002119). HP:0002119 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36147799 SUPPORT Human clinical
"Color Doppler ultrasonography at 18 months revealed hydronephrosis and bilateral widening of the lateral ventricles."
Documents bilateral lateral ventricular dilation in an infant with molecularly confirmed SGS.
Dysautonomia Abnormal autonomic nervous system physiology HP:0012332 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal autonomic nervous system physiology (HP:0012332). HP:0012332 is a phenotype from the Human Phenotype Ontology.
Coarse binding: source unspecified
Show evidence (1 reference)
PMID:38452171 SUPPORT REVIEW SYNTHESIS Human clinical
"Classic Schinzel-Giedion syndrome (SGS), an ultra-rare multisystem disorder caused by gain-of-function pathogenic variants in a SETBP1 mutational hot spot, is characterized by global neurodevelopmental impairment leading to moderate-to-profound intellectual disability, epilepsy (often refractory..."
GeneReviews directly lists dysautonomia among the core neurologic manifestations of classic SGS without specifying a narrower HPO subterm in the abstract summary.
Sleep disturbance HP:0002360 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sleep disturbance (HP:0002360). HP:0002360 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38452171 SUPPORT REVIEW SYNTHESIS Human clinical
"Other features may include neuroepithelial neoplasia, severely disrupted sleep, choanal stenosis, inguinal hernia, sensitive skin, and increased risk of infection."
GeneReviews directly documents sleep disturbance as an associated clinical feature of SGS.
Neoplasm 1
Neuroepithelial neoplasia Neoplasm of the nervous system HP:0004375 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Neoplasm of the nervous system (HP:0004375). HP:0004375 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:38452171 SUPPORT REVIEW SYNTHESIS Human clinical
"Other features may include neuroepithelial neoplasia, severely disrupted sleep, choanal stenosis, inguinal hernia, sensitive skin, and increased risk of infection."
GeneReviews directly lists neuroepithelial neoplasia as a clinical manifestation of classic SGS.
PMID:38452171 SUPPORT REVIEW SYNTHESIS Human clinical
"The broad spectrum of clinical features of variable severity partially overlaps with classic SGS; however, this spectrum does not include risk for neuroepithelial neoplasia to date."
GeneReviews specifies that neuroepithelial neoplasia risk is restricted to classic SGS rather than atypical SGS to date.
PMID:38452171 SUPPORT REVIEW SYNTHESIS Human clinical
"In individuals with classic SGS, age-related surveillance for occurrence of neoplasia includes liver ultrasound and serum alpha-fetoprotein levels, renal ultrasound examination, pelvic MRI for sacrococcygeal teratoma, and monitoring for clinical signs of leukemia."
Outlines the neoplasia spectrum and surveillance protocol in classic SGS.
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Genetic Associations

1
SETBP1 (Degron-region gain-of-stability missense variants)
Gene: SETBP1 hgnc:15573 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is SETBP1 (hgnc:15573). hgnc:15573 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: DE_NOVO
Autosomal dominant inheritance
Show evidence (3 references)
PMID:38452171 SUPPORT REVIEW SYNTHESIS Human clinical
"Classic Schinzel-Giedion syndrome (SGS), an ultra-rare multisystem disorder caused by gain-of-function pathogenic variants in a SETBP1 mutational hot spot, is characterized by global neurodevelopmental impairment leading to moderate-to-profound intellectual disability, epilepsy (often refractory..."
Provides direct human clinical support for the characteristic SETBP1 gain-of-function variant class in classical SGS.
PMID:36147799 SUPPORT Human clinical
"Whole-exome sequencing revealed a heterozygous de novo variant (c.2605A > G:p.S869G) in exon 4 degradation sequence in SETBP1."
Identifies a de novo heterozygous SETBP1 missense variant within the exon 4 degron sequence in a neonate with SGS.
CGGV:assertion_71885c03-b578-4baf-a17c-4817349eaf36-2021-02-16T170000.000Z SUPPORT Other
"SETBP1 | HGNC:15573 | Schinzel-Giedion syndrome | MONDO:0010010 | AD | Definitive"
ClinGen classifies the SETBP1-Schinzel-Giedion syndrome gene-disease relationship as definitive with autosomal dominant inheritance.
💊

Medical Actions

3
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
Current management is supportive and coordinates multidisciplinary specialists for seizure control, nutritional and feeding support, physical and occupational therapy, hearing and visual rehabilitation, urologic and nephrologic management of hydronephrosis, and oncologic surveillance.
Target Phenotypes: Global developmental delay HP:0001263 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology. Seizure HP:0001250 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology. Hydronephrosis HP:0000126 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Hydronephrosis (HP:0000126). HP:0000126 is a phenotype from the Human Phenotype Ontology. Feeding difficulties HP:0011968 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Feeding difficulties (HP:0011968). HP:0011968 is a phenotype from the Human Phenotype Ontology. Hearing impairment HP:0000365 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Hearing impairment (HP:0000365). HP:0000365 is a phenotype from the Human Phenotype Ontology. Cerebral visual impairment HP:0100704 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Cerebral visual impairment (HP:0100704). HP:0100704 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38452171 SUPPORT REVIEW SYNTHESIS Human clinical
"Supportive treatment to improve quality of life, maximize function, and reduce complications can include multidisciplinary care by specialists in pediatrics, neurology, physiatry, occupational and physical therapy, speech-language pathology, psychiatry, ophthalmology, ENT, surgery, pulmonology,..."
GeneReviews directly supports multidisciplinary supportive management as the standard of care across affected organ systems.
Avoidance of nephrotoxic agents
Category: Therapeutic Action: Preventive InterventionNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Preventive Intervention (NCIT:C15843). NCIT:C15843 is a clinical intervention from the NCI Thesaurus. NCIT:C15843
Agent: Nonsteroidal Antiinflammatory Drug NCIT:C257 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses Nonsteroidal Antiinflammatory Drug (NCIT:C257). NCIT:C257 is a therapeutic agent from the NCI Thesaurus. vancomycin CHEBI:28001 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses vancomycin (CHEBI:28001). CHEBI:28001 is a therapeutic agent from Chemical Entities of Biological Interest.
Because individuals with Schinzel-Giedion syndrome frequently have structural kidney abnormalities, recurrent pyelonephritis, and/or chronic kidney disease, nephrotoxic medications such as nonsteroidal anti-inflammatory drugs (NSAIDs) and vancomycin should be avoided whenever possible.
Target Phenotypes: Hydronephrosis HP:0000126 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Hydronephrosis (HP:0000126). HP:0000126 is a phenotype from the Human Phenotype Ontology. Recurrent pyelonephritis HP:0012787 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Recurrent pyelonephritis (HP:0012787). HP:0012787 is a phenotype from the Human Phenotype Ontology. Chronic kidney disease HP:0012622 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Chronic kidney disease (HP:0012622). HP:0012622 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38452171 SUPPORT REVIEW SYNTHESIS Human clinical
"Agents/circumstances to avoid: Nephrotoxic drugs such as nonsteroidal anti-inflammatory drugs and vancomycin should be used with caution due to high frequency of chronic renal impairment from recurrent pyelonephritis and structural renal anomalies."
GeneReviews explicitly recommends avoiding nephrotoxic agents including NSAIDs and vancomycin in individuals with SGS due to structural kidney abnormalities, recurrent pyelonephritis, and chronic kidney disease.
Genetic counseling
Category: Counseling / Informational Action: Genetic CounselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Genetic Counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. NCIT:C15240
Genetic counseling is indicated for families of affected probands to discuss de novo autosomal dominant inheritance, low recurrence risk (accounting for rare parental germline mosaicism), and options for prenatal or preimplantation genetic testing once the familial SETBP1 variant is known.
Show evidence (1 reference)
PMID:38452171 SUPPORT REVIEW SYNTHESIS Human clinical
"Once the SETBP1 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible."
Supports reproductive genetic counseling and prenatal or preimplantation testing once a pathogenic SETBP1 variant is identified.
🔬

Biochemical Markers

1
Serum alpha-fetoprotein (Monitored longitudinally for tumor surveillance)
Context: Serial serum alpha-fetoprotein measurement is used alongside imaging for age-related surveillance of hepatoblastoma and sacrococcygeal teratoma in classic Schinzel-Giedion syndrome.
Show evidence (1 reference)
PMID:38452171 SUPPORT REVIEW SYNTHESIS Human clinical
"In individuals with classic SGS, age-related surveillance for occurrence of neoplasia includes liver ultrasound and serum alpha-fetoprotein levels, renal ultrasound examination, pelvic MRI for sacrococcygeal teratoma, and monitoring for clinical signs of leukemia."
GeneReviews specifies serum alpha-fetoprotein monitoring as part of routine neoplasia surveillance in classic SGS.
🔬

Diagnosis

3
SETBP1 molecular genetic testing (Confirmatory)
Diagnosis is established via clinical diagnostic criteria or confirmed by molecular genetic testing identifying a heterozygous pathogenic SETBP1 variant in the exon 4 canonical degron region.
Genetic Testing NCIT:C15709 NCI Thesaurus (NCIT)
Results: Identification of a heterozygous de novo pathogenic gain-of-function variant within or adjacent to the SETBP1 exon 4 degron mutational hotspot.
Show evidence (2 references)
PMID:38452171 SUPPORT REVIEW SYNTHESIS Human clinical
"The diagnosis of classic SGS can be established in a proband based on published clinical diagnostic criteria, or the molecular diagnosis can be established in a proband with suggestive findings and a heterozygous SETBP1 pathogenic gain-of-function variant within the mutational hot spot (i.e., a..."
GeneReviews defines the clinical and molecular diagnostic criteria for classic SGS.
PMID:36147799 SUPPORT Human clinical
"The clinical manifestations of neonatal SGS are atypical, and genetic testing is crucial for diagnosis."
Emphasizes the essential role of molecular genetic testing for diagnosing SGS in the neonatal period.
Renal, hepatic, and cranial ultrasonography (Diagnostic and longitudinal surveillance)
Renal, hepatic, and cranial ultrasonography are used to evaluate congenital renal and ventricular anomalies and to conduct age-related surveillance for hepatoblastoma in classic Schinzel-Giedion syndrome.
Ultrasound Imaging NCIT:C17230 NCI Thesaurus (NCIT)
Results: Detection of congenital or progressive hydronephrosis, ventriculomegaly, and age-related hepatic screening for hepatoblastoma.
Show evidence (2 references)
PMID:38452171 SUPPORT REVIEW SYNTHESIS Human clinical
"In individuals with classic SGS, age-related surveillance for occurrence of neoplasia includes liver ultrasound and serum alpha-fetoprotein levels, renal ultrasound examination, pelvic MRI for sacrococcygeal teratoma, and monitoring for clinical signs of leukemia."
Supports routine liver and renal ultrasound in the diagnostic and oncologic surveillance of classic SGS.
PMID:36147799 SUPPORT Human clinical
"Color Doppler ultrasonography at 18 months revealed hydronephrosis and bilateral widening of the lateral ventricles."
Demonstrates the diagnostic utility of ultrasonography for tracking hydronephrosis and ventricular dilation in SGS.
Pelvic MRI surveillance (Longitudinal tumor surveillance)
Pelvic magnetic resonance imaging is used for age-related neoplasia surveillance to detect sacrococcygeal teratoma in classic Schinzel-Giedion syndrome.
Magnetic Resonance Imaging NCIT:C16809 NCI Thesaurus (NCIT)
Results: Age-related pelvic surveillance for sacrococcygeal teratoma in individuals with classic Schinzel-Giedion syndrome.
Show evidence (1 reference)
PMID:38452171 SUPPORT REVIEW SYNTHESIS Human clinical
"In individuals with classic SGS, age-related surveillance for occurrence of neoplasia includes liver ultrasound and serum alpha-fetoprotein levels, renal ultrasound examination, pelvic MRI for sacrococcygeal teratoma, and monitoring for clinical signs of leukemia."
GeneReviews specifies pelvic MRI as part of routine age-related surveillance for sacrococcygeal teratoma in classic SGS.
📈

Progression

2
Neonatal
Age: Birth / neonatal period
Presentation at birth with distinctive craniofacial dysmorphism (midface retrusion, prominent forehead, hypertelorism), skeletal anomalies (talipes equinovarus), congenital heart defects, and congenital hydronephrosis.
Show evidence (2 references)
PMID:38711130 SUPPORT Human clinical
"The female patient was diagnosed in the neonatal period and presented with characteristic facial phenotype (midface retraction, prominent forehead, and low-set ears), bilateral symmetrical talipes equinovarus, overlapping toes, and severe bilateral hydronephrosis accompanied by congenital heart..."
Documents neonatal presentation with characteristic craniofacial features, clubfoot, congenital heart disease, and severe bilateral hydronephrosis.
PMID:36147799 SUPPORT Human clinical
"A male Chinese neonate with dysmorphic facial features, nervous system disorders, and organ malformations at birth was examined in this study and long-term followed-up."
Confirms congenital and neonatal onset of craniofacial, neurologic, and visceral anomalies at birth.
Infantile
Age: Infancy to early childhood
Progressive neurodegeneration, infantile-onset refractory seizures, severe feeding difficulties, ventriculomegaly, and elevated risk of embryonal or neuroepithelial tumors; affected individuals with classic SGS rarely survive past infancy or early childhood.
Show evidence (3 references)
PMID:36147799 SUPPORT Human clinical
"Six months after birth, the patient had an epileptic seizure and experienced persistent neurodevelopmental delay with auditory and visual abnormalities. Color Doppler ultrasonography at 18 months revealed hydronephrosis and bilateral widening of the lateral ventricles. The patient died suddenly..."
Illustrates infantile progression with seizure onset at 6 months, persistent neurodevelopmental delay, progressive ventriculomegaly, and death at 20.5 months.
PMID:38452171 SUPPORT REVIEW SYNTHESIS Human clinical
"Other features may include neuroepithelial neoplasia, severely disrupted sleep, choanal stenosis, inguinal hernia, sensitive skin, and increased risk of infection."
Highlights neuroepithelial neoplasia and increased infection risk in classic SGS.
PMID:25217958 SUPPORT Human clinical
"In contrast to the likely loss-of-function, mutations, gain-of-function mutations cluster within a 12 amino domain and result in a more severe DD with multiple congenital abnormalities and death in infancy48,49."
Supports severe developmental delay, multiple congenital anomalies, and infantile mortality in gain-of-function SETBP1 hotspot mutations.
📊

Prevalence

2
Published literature
Cases/families reported in the literature Ultra-rare Classic
More than 50 molecularly confirmed individuals with classic Schinzel-Giedion syndrome carrying pathogenic variants within the SETBP1 exon 4 degron hotspot have been reported in the published literature.
Show evidence (2 references)
PMID:38452171 SUPPORT REVIEW SYNTHESIS Human clinical
"To date, more than 50 individuals have been reported with molecularly confirmed classic SGS. Atypical SGS, reported in five individuals to date, is caused by pathogenic SETBP1 variants in proximity to – but not within – the mutational hot spot."
GeneReviews summarizes the published case counts for molecularly confirmed classic and atypical Schinzel-Giedion syndrome.
PMID:38452171 SUPPORT REVIEW SYNTHESIS Human clinical
"Classic Schinzel-Giedion syndrome (SGS), an ultra-rare multisystem disorder caused by gain-of-function pathogenic variants in a SETBP1 mutational hot spot, is characterized by global neurodevelopmental impairment leading to moderate-to-profound intellectual disability, epilepsy (often refractory..."
Directly establishes classic Schinzel-Giedion syndrome as an ultra-rare multisystem disorder.
Published literature
Cases/families reported in the literature Ultra-rare Atypical
Five individuals have been reported with atypical Schinzel-Giedion syndrome caused by SETBP1 variants adjacent to the canonical degron hotspot.
Show evidence (1 reference)
PMID:38452171 SUPPORT REVIEW SYNTHESIS Human clinical
"To date, more than 50 individuals have been reported with molecularly confirmed classic SGS. Atypical SGS, reported in five individuals to date, is caused by pathogenic SETBP1 variants in proximity to – but not within – the mutational hot spot."
GeneReviews documents five published individuals with atypical Schinzel-Giedion syndrome.
⚖️

Clinical Burden

High
Classic Schinzel-Giedion syndrome imposes a very high clinical burden due to moderate-to-profound intellectual disability, drug-resistant epilepsy, feeding intolerance and poor weight gain, progressive brain atrophy, multiorgan congenital malformations (including severe hydronephrosis and cardiac defects), neuroepithelial tumor predisposition, and premature mortality in infancy.
Show evidence (2 references)
PMID:38452171 SUPPORT REVIEW SYNTHESIS Human clinical
"Classic Schinzel-Giedion syndrome (SGS), an ultra-rare multisystem disorder caused by gain-of-function pathogenic variants in a SETBP1 mutational hot spot, is characterized by global neurodevelopmental impairment leading to moderate-to-profound intellectual disability, epilepsy (often refractory..."
Establishes the severe multisystem neurologic and sensory disability characteristic of classic SGS.
PMID:25217958 SUPPORT Human clinical
"In contrast to the likely loss-of-function, mutations, gain-of-function mutations cluster within a 12 amino domain and result in a more severe DD with multiple congenital abnormalities and death in infancy48,49."
Establishes multiple congenital abnormalities and infantile mortality in gain-of-function SETBP1 hotspot mutations.
🔀

Differential Diagnoses

1

Conditions with similar clinical presentations that must be differentiated from Schinzel-Giedion syndrome:

intellectual disability, autosomal dominant 29 MONDO:0014482
Overlapping Features SETBP1 haploinsufficiency disorder (MRD29) is an allelic disorder caused by heterozygous loss-of-function or nonsense SETBP1 variants; it overlaps genetically with SGS but presents with speech apraxia and a milder neurodevelopmental phenotype without the canonical degron-mediated protein accumulation and severe visceral malformations of SGS.
Distinguishing Features
  • Classical degron-region gain-of-stability missense variants with severe multisystem malformations and refractory epilepsy favor Schinzel-Giedion syndrome.
  • Truncating or haploinsufficiency variants with expressive speech impairment, milder developmental delay, and absence of severe congenital visceral anomalies favor intellectual disability, autosomal dominant 29.
Show evidence (3 references)
PMID:38585550 SUPPORT BACKGROUND Human clinical
"SETBP1 gene variants that decrease or eliminate protein activity have been associated with phenotypes characterized by speech apraxia and intellectual disabilities. This condition, distinctly separated from Schinzel-Giedion syndrome, is referred to as autosomal dominant mental retardation 29 (ADR29)."
Directly distinguishes SETBP1 loss-of-function variants causing autosomal dominant intellectual disability 29 (MRD29/ADR29) from Schinzel-Giedion syndrome.
PMID:34807554 SUPPORT REVIEW SYNTHESIS Human clinical
"The diagnosis of SETBP1-HD is established in a proband with suggestive findings and a heterozygous pathogenic loss-of-function variant in SETBP1 identified by molecular genetic testing."
Establishes that SETBP1 haploinsufficiency disorder is defined by heterozygous loss-of-function SETBP1 variants, contrasting with the gain-of-function degron variants of SGS.
PMID:25217958 SUPPORT Human clinical
"In contrast to the likely loss-of-function, mutations, gain-of-function mutations cluster within a 12 amino domain and result in a more severe DD with multiple congenital abnormalities and death in infancy48,49."
Distinguishes milder loss-of-function SETBP1 phenotypes from severe gain-of-function degron-hotspot SGS.
{ }

Source YAML

click to show 
name: Schinzel-Giedion syndrome
creation_date: '2026-04-11T19:38:25Z'
category: Mendelian
description: >-
  Schinzel-Giedion syndrome is a severe autosomal dominant multisystem
  developmental disorder caused by de novo missense variants in the degron
  region of SETBP1. These variants impair normal SETBP1 protein degradation,
  leading to toxic accumulation of an epigenetic transcriptional regulator.
  Dysregulated SETBP1 activity rewires developmental gene-expression programs,
  impairs neurogenesis and neuronal migration, and underlies the syndrome's
  severe developmental delay, progressive brain disease, seizures, craniofacial
  abnormalities, and visceral malformations.
disease_term:
  preferred_term: Schinzel-Giedion syndrome
  term:
    id: MONDO:0010010
    label: Schinzel-Giedion syndrome
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0010010
      label: Schinzel-Giedion syndrome
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
parents:
- hereditary disease
- developmental disorder
synonyms:
- Schinzel-Giedion midface-retraction syndrome
- SETBP1-related Schinzel-Giedion syndrome
has_subtypes:
- name: Classic
  display_name: Classic Schinzel-Giedion syndrome
  description: >-
    Canonical Schinzel-Giedion syndrome caused by heterozygous de novo
    gain-of-function variants within (or immediately adjacent to) the 12-base-pair
    exon 4 SETBP1 mutational hot spot encoding the canonical degron, presenting
    with severe global neurodevelopmental impairment, characteristic craniofacial
    and visceral malformations, and predisposition to neuroepithelial neoplasia.
  evidence:
  - reference: PMID:38452171
    reference_title: Schinzel-Giedion Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      The diagnosis of classic SGS can be established in a proband based on published clinical diagnostic criteria, or the molecular diagnosis can be established in a proband with suggestive findings and a heterozygous SETBP1 pathogenic gain-of-function variant within the mutational hot spot (i.e., a 12-base-pair region in exon 4 encoding a canonical degron).
    explanation: >-
      Defines classic Schinzel-Giedion syndrome by clinical diagnostic criteria
      and pathogenic gain-of-function variants within the exon 4 canonical degron
      hot spot.
  - reference: PMID:38711130
    reference_title: "Novel SETBP1 D874V adjacent to the degron causes canonical schinzel-giedion syndrome: a case report and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we describe a case of typical SGS caused by a novel heterozygous missense variant, D874V, adjacent to the degron.
    explanation: >-
      Documents that missense variants immediately adjacent to the canonical
      degron can also produce canonical (classic) SGS.
- name: Atypical
  display_name: Atypical Schinzel-Giedion syndrome
  description: >-
    Atypical Schinzel-Giedion syndrome caused by heterozygous pathogenic SETBP1
    variants in proximity to, but outside, the canonical exon 4 degron hot spot,
    characterized by a variable clinical spectrum overlapping classic SGS but
    without documented risk for neuroepithelial neoplasia to date.
  evidence:
  - reference: PMID:38452171
    reference_title: Schinzel-Giedion Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      To date, more than 50 individuals have been reported with molecularly confirmed classic SGS. Atypical SGS, reported in five individuals to date, is caused by pathogenic SETBP1 variants in proximity to – but not within – the mutational hot spot.
    explanation: >-
      Defines atypical Schinzel-Giedion syndrome as caused by pathogenic SETBP1
      variants adjacent to but outside the mutational hot spot.
  - reference: PMID:38452171
    reference_title: Schinzel-Giedion Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      The broad spectrum of clinical features of variable severity partially overlaps with classic SGS; however, this spectrum does not include risk for neuroepithelial neoplasia to date.
    explanation: >-
      Distinguishes atypical SGS by its variable clinical severity and absence of
      documented neuroepithelial neoplasia risk to date.
classifications:
  harrisons_chapter:
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
  - classification_value: NEUROLOGIC
  - classification_value: KIDNEY_URINARY_TRACT
prevalence:
- subtype: Classic
  population: Published literature
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    More than 50 molecularly confirmed individuals with classic Schinzel-Giedion
    syndrome carrying pathogenic variants within the SETBP1 exon 4 degron hotspot
    have been reported in the published literature.
  evidence:
  - reference: PMID:38452171
    reference_title: Schinzel-Giedion Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      To date, more than 50 individuals have been reported with molecularly confirmed classic SGS. Atypical SGS, reported in five individuals to date, is caused by pathogenic SETBP1 variants in proximity to – but not within – the mutational hot spot.
    explanation: >-
      GeneReviews summarizes the published case counts for molecularly confirmed
      classic and atypical Schinzel-Giedion syndrome.
  - reference: PMID:38452171
    reference_title: Schinzel-Giedion Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Classic Schinzel-Giedion syndrome (SGS), an ultra-rare multisystem disorder caused by gain-of-function pathogenic variants in a SETBP1 mutational hot spot, is characterized by global neurodevelopmental impairment leading to moderate-to-profound intellectual disability, epilepsy (often refractory to treatment), hypotonia, spasticity, dysautonomia, hearing loss, and cerebral visual impairment.
    explanation: >-
      Directly establishes classic Schinzel-Giedion syndrome as an ultra-rare
      multisystem disorder.
- subtype: Atypical
  population: Published literature
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Five individuals have been reported with atypical Schinzel-Giedion syndrome
    caused by SETBP1 variants adjacent to the canonical degron hotspot.
  evidence:
  - reference: PMID:38452171
    reference_title: Schinzel-Giedion Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      To date, more than 50 individuals have been reported with molecularly confirmed classic SGS. Atypical SGS, reported in five individuals to date, is caused by pathogenic SETBP1 variants in proximity to – but not within – the mutational hot spot.
    explanation: >-
      GeneReviews documents five published individuals with atypical
      Schinzel-Giedion syndrome.
progression:
- phase: Neonatal
  age_range: Birth / neonatal period
  notes: >-
    Presentation at birth with distinctive craniofacial dysmorphism (midface
    retrusion, prominent forehead, hypertelorism), skeletal anomalies (talipes
    equinovarus), congenital heart defects, and congenital hydronephrosis.
  evidence:
  - reference: PMID:38711130
    reference_title: "Novel SETBP1 D874V adjacent to the degron causes canonical schinzel-giedion syndrome: a case report and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The female patient was diagnosed in the neonatal period and presented with characteristic facial phenotype (midface retraction, prominent forehead, and low-set ears), bilateral symmetrical talipes equinovarus, overlapping toes, and severe bilateral hydronephrosis accompanied by congenital heart disease, consistent with canonical SGS.
    explanation: >-
      Documents neonatal presentation with characteristic craniofacial features,
      clubfoot, congenital heart disease, and severe bilateral hydronephrosis.
  - reference: PMID:36147799
    reference_title: "Detection of a novel SETBP1 variant in a Chinese neonate with Schinzel-Giedion syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A male Chinese neonate with dysmorphic facial features, nervous system disorders, and organ malformations at birth was examined in this study and long-term followed-up.
    explanation: >-
      Confirms congenital and neonatal onset of craniofacial, neurologic, and
      visceral anomalies at birth.
- phase: Infantile
  age_range: Infancy to early childhood
  notes: >-
    Progressive neurodegeneration, infantile-onset refractory seizures, severe
    feeding difficulties, ventriculomegaly, and elevated risk of embryonal or
    neuroepithelial tumors; affected individuals with classic SGS rarely survive
    past infancy or early childhood.
  evidence:
  - reference: PMID:36147799
    reference_title: "Detection of a novel SETBP1 variant in a Chinese neonate with Schinzel-Giedion syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Six months after birth, the patient had an epileptic seizure and experienced persistent neurodevelopmental delay with auditory and visual abnormalities. Color Doppler ultrasonography at 18 months revealed hydronephrosis and bilateral widening of the lateral ventricles. The patient died suddenly 20.5 months after birth.
    explanation: >-
      Illustrates infantile progression with seizure onset at 6 months,
      persistent neurodevelopmental delay, progressive ventriculomegaly, and
      death at 20.5 months.
  - reference: PMID:38452171
    reference_title: Schinzel-Giedion Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Other features may include neuroepithelial neoplasia, severely disrupted sleep, choanal stenosis, inguinal hernia, sensitive skin, and increased risk of infection.
    explanation: >-
      Highlights neuroepithelial neoplasia and increased infection risk in
      classic SGS.
  - reference: PMID:25217958
    reference_title: "Refining analyses of copy number variation identifies specific genes associated with developmental delay."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In contrast to the likely loss-of-function, mutations, gain-of-function mutations cluster within a 12 amino domain and result in a more severe DD with multiple congenital abnormalities and death in infancy48,49.
    explanation: >-
      Supports severe developmental delay, multiple congenital anomalies, and
      infantile mortality in gain-of-function SETBP1 hotspot mutations.
clinical_burden:
  burden_level: HIGH
  rationale: >-
    Classic Schinzel-Giedion syndrome imposes a very high clinical burden due to
    moderate-to-profound intellectual disability, drug-resistant epilepsy,
    feeding intolerance and poor weight gain, progressive brain atrophy,
    multiorgan congenital malformations (including severe hydronephrosis and
    cardiac defects), neuroepithelial tumor predisposition, and premature
    mortality in infancy.
  evidence:
  - reference: PMID:38452171
    reference_title: Schinzel-Giedion Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Classic Schinzel-Giedion syndrome (SGS), an ultra-rare multisystem disorder caused by gain-of-function pathogenic variants in a SETBP1 mutational hot spot, is characterized by global neurodevelopmental impairment leading to moderate-to-profound intellectual disability, epilepsy (often refractory to treatment), hypotonia, spasticity, dysautonomia, hearing loss, and cerebral visual impairment.
    explanation: >-
      Establishes the severe multisystem neurologic and sensory disability
      characteristic of classic SGS.
  - reference: PMID:25217958
    reference_title: "Refining analyses of copy number variation identifies specific genes associated with developmental delay."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In contrast to the likely loss-of-function, mutations, gain-of-function mutations cluster within a 12 amino domain and result in a more severe DD with multiple congenital abnormalities and death in infancy48,49.
    explanation: >-
      Establishes multiple congenital abnormalities and infantile mortality in
      gain-of-function SETBP1 hotspot mutations.
inheritance:
- name: Autosomal dominant inheritance
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    Schinzel-Giedion syndrome is an autosomal dominant disorder typically caused
    by spontaneous de novo heterozygous gain-of-function variants in SETBP1.
  evidence:
  - reference: PMID:38452171
    reference_title: Schinzel-Giedion Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Classic and atypical SGS are autosomal dominant disorders typically caused by a de novo SETBP1 pathogenic variant.
    explanation: >-
      GeneReviews directly supports dominant inheritance with typically de novo
      SETBP1 pathogenic variants.
pathophysiology:
- name: Impaired SETBP1 degron-dependent degradation
  description: >-
    Classical Schinzel-Giedion syndrome is caused by missense variants within or
    immediately adjacent to the exon 4 canonical degron of SETBP1 (amino acids
    868 to 871), which disrupt ubiquitin-proteasome degradation and produce toxic
    accumulation of SETBP1 protein.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: SETBP1
    term:
      id: hgnc:15573
      label: SETBP1
  evidence:
  - reference: PMID:37872881
    reference_title: "Cell-type-specific gene expression and regulation in the cerebral cortex and kidney of atypical Setbp1(S858R) Schinzel Giedion Syndrome mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      SETBP1 variants causing classical SGS cluster at the degron, disrupting SETBP1 protein degradation and resulting in toxic accumulation, while those located outside cause milder atypical SGS.
    explanation: >-
      Directly states the core degron-disruption mechanism of classical SGS and
      contrasts it with variants outside the canonical degron in atypical SGS.
  - reference: PMID:38711130
    reference_title: "Novel SETBP1 D874V adjacent to the degron causes canonical schinzel-giedion syndrome: a case report and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we describe a case of typical SGS caused by a novel heterozygous missense variant, D874V, adjacent to the degron.
    explanation: >-
      Shows that missense variants immediately adjacent to the canonical degron
      can also produce canonical SGS.
  - reference: PMID:38452171
    reference_title: Schinzel-Giedion Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      The diagnosis of classic SGS can be established in a proband based on published clinical diagnostic criteria, or the molecular diagnosis can be established in a proband with suggestive findings and a heterozygous SETBP1 pathogenic gain-of-function variant within the mutational hot spot (i.e., a 12-base-pair region in exon 4 encoding a canonical degron).
    explanation: >-
      GeneReviews directly establishes that classic SGS is caused by heterozygous
      pathogenic gain-of-function variants within the 12-bp exon 4 canonical
      degron hotspot of SETBP1.
  downstream:
  - target: Aberrant developmental gene transcription
    description: Excess stabilized SETBP1 protein alters epigenetic and transcriptional control over developmental gene networks
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:29875417
      reference_title: "SETBP1 induces transcription of a network of development genes by acting as an epigenetic hub."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Here we show that SETBP1 binds to gDNA in AT-rich promoter regions, causing activation of gene expression through recruitment of a HCF1/KMT2A/PHF8 epigenetic complex.
      explanation: >-
        Demonstrates that SETBP1 directly binds AT-rich promoters and recruits
        the HCF1/KMT2A/PHF8 chromatin-modifying complex to activate
        developmental gene expression.
- name: Aberrant developmental gene transcription
  description: >-
    SETBP1 acts as an epigenetic hub at AT-rich promoter regions through
    recruitment of the HCF1/KMT2A/PHF8 chromatin-modifying complex, organizes
    higher-order chromatin interactions with the nuclear lamina, and modulates
    intracellular signaling pathways such as AKT; excess SETBP1 protein
    dysregulates developmental gene-expression programs in neural and visceral
    progenitors.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: SETBP1
    term:
      id: hgnc:15573
      label: SETBP1
  biological_processes:
  - preferred_term: regulation of transcription by RNA polymerase II
    modifier: ABNORMAL
    term:
      id: GO:0006357
      label: regulation of transcription by RNA polymerase II
  evidence:
  - reference: PMID:29875417
    reference_title: "SETBP1 induces transcription of a network of development genes by acting as an epigenetic hub."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Here we show that SETBP1 binds to gDNA in AT-rich promoter regions, causing activation of gene expression through recruitment of a HCF1/KMT2A/PHF8 epigenetic complex.
    explanation: >-
      Directly supports SETBP1 as a DNA-binding transcriptional and epigenetic
      regulator recruiting HCF1/KMT2A/PHF8.
  - reference: PMID:29875417
    reference_title: "SETBP1 induces transcription of a network of development genes by acting as an epigenetic hub."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Gene ontology analysis of deregulated SETBP1 target genes indicates that they are also key controllers of visceral organ development and brain morphogenesis.
    explanation: >-
      Links dysregulated SETBP1 target gene networks to both brain morphogenesis
      and visceral organ development.
  - reference: PMID:39825586
    reference_title: "Reciprocal and non-reciprocal effects of clinically relevant SETBP1 protein dosage changes."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We find that extremes of SETBP1 protein dose reciprocally influence important signalling molecules such as AKT, suggesting that the SETBP1 protein operates within a narrow dosage range and that extreme doses are detrimental.
    explanation: >-
      Demonstrates that elevated SETBP1 protein dosage perturbs downstream
      signaling pathways including AKT in human neural progenitor models.
  - reference: PMID:39825586
    reference_title: "Reciprocal and non-reciprocal effects of clinically relevant SETBP1 protein dosage changes."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We identified SETBP1 nuclear bodies as interacting with the nuclear lamina and suggest that SETBP1 may organize higher order chromatin structure via links to the nuclear envelope.
    explanation: >-
      Supports a role for SETBP1 nuclear bodies in higher-order chromatin
      organization at the nuclear lamina.
  downstream:
  - target: Impaired neurogenesis and neuronal migration
    description: Dysregulated SETBP1 transcriptional networks disrupt cortical neurogenesis and neuronal migration
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:29875417
      reference_title: "SETBP1 induces transcription of a network of development genes by acting as an epigenetic hub."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        In line with these findings, in utero brain electroporation of mutated SETBP1 causes impairment of mouse neurogenesis with a profound delay in neuronal migration.
      explanation: >-
        Directly links mutated SETBP1 transcriptional dysregulation to impaired
        neurogenesis and delayed neuronal migration in vivo.
  - target: Disrupted visceral and craniofacial morphogenesis
    description: Deregulated SETBP1 target genes perturb kidney, skeletal, and craniofacial organogenesis
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:29875417
      reference_title: "SETBP1 induces transcription of a network of development genes by acting as an epigenetic hub."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Gene ontology analysis of deregulated SETBP1 target genes indicates that they are also key controllers of visceral organ development and brain morphogenesis.
      explanation: >-
        Demonstrates that deregulated SETBP1 target genes directly govern
        visceral organ development.
  - target: Neuroepithelial neoplasia
    description: Gain-of-function SETBP1 transcriptional and signaling dysregulation predisposes individuals with classic SGS to neuroepithelial neoplasia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:38452171
      reference_title: Schinzel-Giedion Syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        Other features may include neuroepithelial neoplasia, severely disrupted sleep, choanal stenosis, inguinal hernia, sensitive skin, and increased risk of infection.
      explanation: >-
        Supports the downstream clinical predisposition to neuroepithelial
        neoplasia in classic SGS.
    - reference: PMID:38452171
      reference_title: Schinzel-Giedion Syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        The broad spectrum of clinical features of variable severity partially overlaps with classic SGS; however, this spectrum does not include risk for neuroepithelial neoplasia to date.
      explanation: >-
        Confirms that neuroepithelial neoplasia predisposition is a feature of
        classic SGS caused by canonical degron hotspot variants.
- name: Impaired neurogenesis and neuronal migration
  description: >-
    Pathogenic SETBP1 accumulation disrupts cortical neurogenesis, delays
    neuronal migration, and alters cell-type-specific transcriptional regulatory
    networks in cerebral cortex excitatory neurons and other neural cell types.
  biological_scale: CELLULAR
  locations:
  - preferred_term: brain
    term:
      id: UBERON:0000955
      label: brain
  biological_processes:
  - preferred_term: neuron differentiation
    modifier: ABNORMAL
    term:
      id: GO:0030182
      label: neuron differentiation
  evidence:
  - reference: PMID:29875417
    reference_title: "SETBP1 induces transcription of a network of development genes by acting as an epigenetic hub."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      In line with these findings, in utero brain electroporation of mutated SETBP1 causes impairment of mouse neurogenesis with a profound delay in neuronal migration.
    explanation: >-
      Directly supports impaired neurogenesis and delayed neuronal migration
      downstream of mutant SETBP1 in vivo.
  - reference: PMID:37872881
    reference_title: "Cell-type-specific gene expression and regulation in the cerebral cortex and kidney of atypical Setbp1(S858R) Schinzel Giedion Syndrome mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Setbp1 was differentially expressed in excitatory neurons, but known SETBP1 targets were differentially expressed and regulated in many cell types. Our findings suggest molecular drivers underlying neurodevelopmental phenotypes in classical SGS also drive atypical SGS, persist after birth, and are present in the kidney.
    explanation: >-
      Demonstrates cell-type-specific dysregulation of SETBP1 targets in
      cerebral cortex excitatory neurons and other cell types.
  downstream:
  - target: Severe neurodevelopmental impairment
    description: Impaired neurogenesis and cortical circuit assembly lead to profound neurodevelopmental disability
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:37872881
      reference_title: "Cell-type-specific gene expression and regulation in the cerebral cortex and kidney of atypical Setbp1(S858R) Schinzel Giedion Syndrome mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Setbp1 was differentially expressed in excitatory neurons, but known SETBP1 targets were differentially expressed and regulated in many cell types. Our findings suggest molecular drivers underlying neurodevelopmental phenotypes in classical SGS also drive atypical SGS, persist after birth, and are present in the kidney.
      explanation: >-
        Links cortical neuronal transcriptional dysregulation to the
        neurodevelopmental impairment of SGS.
  - target: Seizure
    description: Perturbed cortical neuron development and migration predispose to early-onset, often treatment-refractory seizures
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:37872881
      reference_title: "Cell-type-specific gene expression and regulation in the cerebral cortex and kidney of atypical Setbp1(S858R) Schinzel Giedion Syndrome mice."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      snippet: >-
        The most notable phenotypes involve severe developmental delay, progressive brain atrophy, and drug-resistant seizures.
      explanation: >-
        Identifies drug-resistant seizures as a primary downstream neurologic
        manifestation of SGS cortical pathology.
    - reference: PMID:38452171
      reference_title: Schinzel-Giedion Syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        Classic Schinzel-Giedion syndrome (SGS), an ultra-rare multisystem disorder caused by gain-of-function pathogenic variants in a SETBP1 mutational hot spot, is characterized by global neurodevelopmental impairment leading to moderate-to-profound intellectual disability, epilepsy (often refractory to treatment), hypotonia, spasticity, dysautonomia, hearing loss, and cerebral visual impairment.
      explanation: >-
        Confirms treatment-refractory epilepsy as a core clinical consequence in
        classic SGS.
  - target: Brain atrophy
    description: Persistent postnatal transcriptional dysregulation in cortical neurons leads to progressive cerebral atrophy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:37872881
      reference_title: "Cell-type-specific gene expression and regulation in the cerebral cortex and kidney of atypical Setbp1(S858R) Schinzel Giedion Syndrome mice."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      snippet: >-
        The most notable phenotypes involve severe developmental delay, progressive brain atrophy, and drug-resistant seizures.
      explanation: >-
        Identifies progressive brain atrophy as a hallmark neurologic
        consequence of SGS.
  - target: Ventriculomegaly
    description: Impaired brain morphogenesis and cerebral volume loss result in ventricular dilation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:36147799
      reference_title: "Detection of a novel SETBP1 variant in a Chinese neonate with Schinzel-Giedion syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Color Doppler ultrasonography at 18 months revealed hydronephrosis and bilateral widening of the lateral ventricles.
      explanation: >-
        Documents bilateral lateral ventricular dilation in an infant with SGS.
- name: Disrupted visceral and craniofacial morphogenesis
  description: >-
    Deregulation of SETBP1 target genes governing organogenesis and persistent
    cell-type-specific transcriptional rewiring in the kidney and developing
    tissues disrupt urogenital, cardiac, craniofacial, and skeletal
    morphogenesis.
  biological_scale: TISSUE
  locations:
  - preferred_term: kidney
    term:
      id: UBERON:0002113
      label: kidney
  - preferred_term: heart
    term:
      id: UBERON:0000948
      label: heart
  - preferred_term: skull
    term:
      id: UBERON:0003129
      label: skull
  - preferred_term: face
    term:
      id: UBERON:0001456
      label: face
  - preferred_term: skeletal system
    term:
      id: UBERON:0001434
      label: skeletal system
  biological_processes:
  - preferred_term: anatomical structure morphogenesis
    modifier: ABNORMAL
    term:
      id: GO:0009653
      label: anatomical structure morphogenesis
  - preferred_term: kidney development
    modifier: ABNORMAL
    term:
      id: GO:0001822
      label: kidney development
  - preferred_term: urogenital system development
    modifier: ABNORMAL
    term:
      id: GO:0001655
      label: urogenital system development
  - preferred_term: heart development
    modifier: ABNORMAL
    term:
      id: GO:0007507
      label: heart development
  - preferred_term: skeletal system development
    modifier: ABNORMAL
    term:
      id: GO:0001501
      label: skeletal system development
  evidence:
  - reference: PMID:29875417
    reference_title: "SETBP1 induces transcription of a network of development genes by acting as an epigenetic hub."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Gene ontology analysis of deregulated SETBP1 target genes indicates that they are also key controllers of visceral organ development and brain morphogenesis.
    explanation: >-
      Establishes that SETBP1 target genes directly control visceral organ
      development and morphogenesis.
  - reference: PMID:37872881
    reference_title: "Cell-type-specific gene expression and regulation in the cerebral cortex and kidney of atypical Setbp1(S858R) Schinzel Giedion Syndrome mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Our findings suggest molecular drivers underlying neurodevelopmental phenotypes in classical SGS also drive atypical SGS, persist after birth, and are present in the kidney. Our results indicate SETBP1's role as an epigenetic hub leads to cell-type-specific differences in TF activity, gene targeting, and regulatory rewiring.
    explanation: >-
      Identifies persistent SETBP1-driven regulatory rewiring in the kidney
      underlying renal pathology in SGS models.
  - reference: PMID:38452171
    reference_title: Schinzel-Giedion Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Structural malformations can involve the heart, skeleton, kidney and urinary tract, genitalia, and brain.
    explanation: >-
      GeneReviews summarizes the multi-organ craniofacial, cardiac, renal,
      genital, and skeletal malformations characteristic of classic SGS.
  downstream:
  - target: Hydronephrosis
    description: Disrupted renal and urinary tract morphogenesis leads to congenital hydronephrosis
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:38452171
      reference_title: Schinzel-Giedion Syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        Structural malformations can involve the heart, skeleton, kidney and urinary tract, genitalia, and brain.
      explanation: >-
        Supports kidney and urinary tract malformations as core visceral
        anomalies in SGS.
    - reference: PMID:38711130
      reference_title: "Novel SETBP1 D874V adjacent to the degron causes canonical schinzel-giedion syndrome: a case report and review of the literature."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The female patient was diagnosed in the neonatal period and presented with characteristic facial phenotype (midface retraction, prominent forehead, and low-set ears), bilateral symmetrical talipes equinovarus, overlapping toes, and severe bilateral hydronephrosis accompanied by congenital heart disease, consistent with canonical SGS.
      explanation: >-
        Documents congenital severe bilateral hydronephrosis in canonical SGS.
  - target: Recurrent pyelonephritis
    description: Congenital urinary tract malformations and hydronephrosis predispose to recurrent pyelonephritis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:38452171
      reference_title: Schinzel-Giedion Syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        Agents/circumstances to avoid: Nephrotoxic drugs such as nonsteroidal anti-inflammatory drugs and vancomycin should be used with caution due to high frequency of chronic renal impairment from recurrent pyelonephritis and structural renal anomalies.
      explanation: >-
        Documents recurrent pyelonephritis alongside structural kidney
        abnormalities in SGS.
  - target: Chronic kidney disease
    description: Persistent SETBP1-driven renal regulatory rewiring and structural urinary tract abnormalities lead to chronic kidney disease
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:38452171
      reference_title: Schinzel-Giedion Syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        Agents/circumstances to avoid: Nephrotoxic drugs such as nonsteroidal anti-inflammatory drugs and vancomycin should be used with caution due to high frequency of chronic renal impairment from recurrent pyelonephritis and structural renal anomalies.
      explanation: >-
        Documents chronic kidney disease as a renal complication in SGS.
  - target: Congenital heart defects
    description: Disrupted cardiac morphogenesis results in congenital heart defects
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:38452171
      reference_title: Schinzel-Giedion Syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        Structural malformations can involve the heart, skeleton, kidney and urinary tract, genitalia, and brain.
      explanation: >-
        Directly supports congenital heart defects as a core visceral
        malformation in SGS.
  - target: Genital anomalies
    description: Perturbed urogenital morphogenesis causes congenital genital anomalies
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:38452171
      reference_title: Schinzel-Giedion Syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        Structural malformations can involve the heart, skeleton, kidney and urinary tract, genitalia, and brain.
      explanation: >-
        Directly supports genital anomalies as a core congenital malformation in
        SGS.
  - target: Midface retrusion
    description: Abnormal craniofacial morphogenesis produces characteristic midface retrusion
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:38711130
      reference_title: "Novel SETBP1 D874V adjacent to the degron causes canonical schinzel-giedion syndrome: a case report and review of the literature."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The female patient was diagnosed in the neonatal period and presented with characteristic facial phenotype (midface retraction, prominent forehead, and low-set ears), bilateral symmetrical talipes equinovarus, overlapping toes, and severe bilateral hydronephrosis accompanied by congenital heart disease, consistent with canonical SGS.
      explanation: >-
        Documents characteristic neonatal midface retraction in canonical SGS.
  - target: Choanal stenosis
    description: Abnormal midface and craniofacial morphogenesis leads to choanal stenosis
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:38452171
      reference_title: Schinzel-Giedion Syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        Other features may include neuroepithelial neoplasia, severely disrupted sleep, choanal stenosis, inguinal hernia, sensitive skin, and increased risk of infection.
      explanation: >-
        Supports choanal stenosis as an upper-airway craniofacial manifestation
        of SGS.
  - target: Talipes equinovarus
    description: Altered limb and skeletal morphogenesis results in congenital clubfoot
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:38711130
      reference_title: "Novel SETBP1 D874V adjacent to the degron causes canonical schinzel-giedion syndrome: a case report and review of the literature."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The female patient was diagnosed in the neonatal period and presented with characteristic facial phenotype (midface retraction, prominent forehead, and low-set ears), bilateral symmetrical talipes equinovarus, overlapping toes, and severe bilateral hydronephrosis accompanied by congenital heart disease, consistent with canonical SGS.
      explanation: >-
        Documents congenital bilateral talipes equinovarus in canonical SGS.
  - target: Recurrent infections
    description: Multisystem anatomical and functional abnormalities predispose affected individuals to recurrent infections
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:38452171
      reference_title: Schinzel-Giedion Syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        Other features may include neuroepithelial neoplasia, severely disrupted sleep, choanal stenosis, inguinal hernia, sensitive skin, and increased risk of infection.
      explanation: >-
        Supports recurrent infections as a recognized clinical complication of
        SGS.
- name: Severe neurodevelopmental impairment
  description: >-
    Downstream organism-level consequences of dysregulated SETBP1 activity in the
    developing central nervous system include severe global developmental delay,
    moderate-to-profound intellectual disability, motor tone abnormalities,
    dysautonomia, sensory deficits, sleep disturbance, and feeding intolerance.
  biological_scale: ORGANISM
  evidence:
  - reference: PMID:38452171
    reference_title: Schinzel-Giedion Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Classic Schinzel-Giedion syndrome (SGS), an ultra-rare multisystem disorder caused by gain-of-function pathogenic variants in a SETBP1 mutational hot spot, is characterized by global neurodevelopmental impairment leading to moderate-to-profound intellectual disability, epilepsy (often refractory to treatment), hypotonia, spasticity, dysautonomia, hearing loss, and cerebral visual impairment.
    explanation: >-
      Directly links the disease mechanism to severe human neurodevelopmental,
      motor, autonomic, and sensory impairment.
  downstream:
  - target: Developmental delay
    description: Global neurodevelopmental impairment manifests clinically as severe developmental delay
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:38452171
      reference_title: Schinzel-Giedion Syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        Classic Schinzel-Giedion syndrome (SGS), an ultra-rare multisystem disorder caused by gain-of-function pathogenic variants in a SETBP1 mutational hot spot, is characterized by global neurodevelopmental impairment leading to moderate-to-profound intellectual disability, epilepsy (often refractory to treatment), hypotonia, spasticity, dysautonomia, hearing loss, and cerebral visual impairment.
      explanation: >-
        Directly supports global neurodevelopmental impairment in classic SGS.
  - target: Intellectual disability
    description: Global neurodevelopmental impairment results in moderate-to-profound intellectual disability
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:38452171
      reference_title: Schinzel-Giedion Syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        Classic Schinzel-Giedion syndrome (SGS), an ultra-rare multisystem disorder caused by gain-of-function pathogenic variants in a SETBP1 mutational hot spot, is characterized by global neurodevelopmental impairment leading to moderate-to-profound intellectual disability, epilepsy (often refractory to treatment), hypotonia, spasticity, dysautonomia, hearing loss, and cerebral visual impairment.
      explanation: >-
        Directly states that global neurodevelopmental impairment leads to
        moderate-to-profound intellectual disability.
  - target: Hypotonia
    description: Global neurodevelopmental impairment is accompanied by muscular hypotonia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:38452171
      reference_title: Schinzel-Giedion Syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        Classic Schinzel-Giedion syndrome (SGS), an ultra-rare multisystem disorder caused by gain-of-function pathogenic variants in a SETBP1 mutational hot spot, is characterized by global neurodevelopmental impairment leading to moderate-to-profound intellectual disability, epilepsy (often refractory to treatment), hypotonia, spasticity, dysautonomia, hearing loss, and cerebral visual impairment.
      explanation: >-
        Lists hypotonia among the core neurologic features of classic SGS.
  - target: Spasticity
    description: Global neurodevelopmental impairment is accompanied by limb spasticity
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:38452171
      reference_title: Schinzel-Giedion Syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        Classic Schinzel-Giedion syndrome (SGS), an ultra-rare multisystem disorder caused by gain-of-function pathogenic variants in a SETBP1 mutational hot spot, is characterized by global neurodevelopmental impairment leading to moderate-to-profound intellectual disability, epilepsy (often refractory to treatment), hypotonia, spasticity, dysautonomia, hearing loss, and cerebral visual impairment.
      explanation: >-
        Lists spasticity among the core neurologic features of classic SGS.
  - target: Dysautonomia
    description: Global neurodevelopmental impairment is accompanied by autonomic nervous system dysfunction
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:38452171
      reference_title: Schinzel-Giedion Syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        Classic Schinzel-Giedion syndrome (SGS), an ultra-rare multisystem disorder caused by gain-of-function pathogenic variants in a SETBP1 mutational hot spot, is characterized by global neurodevelopmental impairment leading to moderate-to-profound intellectual disability, epilepsy (often refractory to treatment), hypotonia, spasticity, dysautonomia, hearing loss, and cerebral visual impairment.
      explanation: >-
        Lists dysautonomia among the core neurologic features of classic SGS.
  - target: Hearing impairment
    description: Global neurodevelopmental impairment is accompanied by hearing loss
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:38452171
      reference_title: Schinzel-Giedion Syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        Classic Schinzel-Giedion syndrome (SGS), an ultra-rare multisystem disorder caused by gain-of-function pathogenic variants in a SETBP1 mutational hot spot, is characterized by global neurodevelopmental impairment leading to moderate-to-profound intellectual disability, epilepsy (often refractory to treatment), hypotonia, spasticity, dysautonomia, hearing loss, and cerebral visual impairment.
      explanation: >-
        Lists hearing loss among the core clinical features of classic SGS.
  - target: Cerebral visual impairment
    description: Global neurodevelopmental impairment is accompanied by cerebral visual impairment
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:38452171
      reference_title: Schinzel-Giedion Syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        Classic Schinzel-Giedion syndrome (SGS), an ultra-rare multisystem disorder caused by gain-of-function pathogenic variants in a SETBP1 mutational hot spot, is characterized by global neurodevelopmental impairment leading to moderate-to-profound intellectual disability, epilepsy (often refractory to treatment), hypotonia, spasticity, dysautonomia, hearing loss, and cerebral visual impairment.
      explanation: >-
        Lists cerebral visual impairment among the core clinical features of
        classic SGS.
  - target: Feeding difficulties
    description: Severe neurologic and gastrointestinal motility dysfunction is associated with feeding intolerance and poor weight gain
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:38452171
      reference_title: Schinzel-Giedion Syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        Other findings can include poor weight gain often associated with gastroesophageal reflux disease, chronic vomiting, constipation, gastroparesis, and/or feeding intolerance.
      explanation: >-
        Documents feeding intolerance, gastroparesis, and poor weight gain in
        classic SGS.
  - target: Sleep disturbance
    description: Central nervous system dysfunction in SGS is accompanied by sleep disturbance
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:38452171
      reference_title: Schinzel-Giedion Syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        Other features may include neuroepithelial neoplasia, severely disrupted sleep, choanal stenosis, inguinal hernia, sensitive skin, and increased risk of infection.
      explanation: >-
        Documents sleep disturbance as an associated clinical finding in SGS.
phenotypes:
- name: Developmental delay
  category: Neurologic
  diagnostic: true
  description: >-
    Severe global developmental delay is one of the universal core features of
    Schinzel-Giedion syndrome.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:37872881
    reference_title: "Cell-type-specific gene expression and regulation in the cerebral cortex and kidney of atypical Setbp1(S858R) Schinzel Giedion Syndrome mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      The most notable phenotypes involve severe developmental delay, progressive brain atrophy, and drug-resistant seizures.
    explanation: >-
      Summarizes severe developmental delay as a hallmark phenotype of SGS.
  - reference: PMID:38452171
    reference_title: Schinzel-Giedion Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Classic Schinzel-Giedion syndrome (SGS), an ultra-rare multisystem disorder caused by gain-of-function pathogenic variants in a SETBP1 mutational hot spot, is characterized by global neurodevelopmental impairment leading to moderate-to-profound intellectual disability, epilepsy (often refractory to treatment), hypotonia, spasticity, dysautonomia, hearing loss, and cerebral visual impairment.
    explanation: >-
      Provides direct human clinical support for severe global neurodevelopmental
      impairment in SGS.
- name: Seizure
  category: Neurologic
  diagnostic: true
  description: >-
    Early-onset, often drug-resistant seizures are a prominent neurologic
    complication of Schinzel-Giedion syndrome.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:37872881
    reference_title: "Cell-type-specific gene expression and regulation in the cerebral cortex and kidney of atypical Setbp1(S858R) Schinzel Giedion Syndrome mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      The most notable phenotypes involve severe developmental delay, progressive brain atrophy, and drug-resistant seizures.
    explanation: >-
      Summarizes drug-resistant seizures as a hallmark neurologic phenotype of
      SGS.
  - reference: PMID:38452171
    reference_title: Schinzel-Giedion Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Classic Schinzel-Giedion syndrome (SGS), an ultra-rare multisystem disorder caused by gain-of-function pathogenic variants in a SETBP1 mutational hot spot, is characterized by global neurodevelopmental impairment leading to moderate-to-profound intellectual disability, epilepsy (often refractory to treatment), hypotonia, spasticity, dysautonomia, hearing loss, and cerebral visual impairment.
    explanation: >-
      Provides direct human clinical support for treatment-refractory epilepsy in
      SGS.
- name: Intellectual disability
  category: Neurologic
  description: >-
    Schinzel-Giedion syndrome causes moderate-to-profound intellectual
    disability in affected individuals.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:38452171
    reference_title: Schinzel-Giedion Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Classic Schinzel-Giedion syndrome (SGS), an ultra-rare multisystem disorder caused by gain-of-function pathogenic variants in a SETBP1 mutational hot spot, is characterized by global neurodevelopmental impairment leading to moderate-to-profound intellectual disability, epilepsy (often refractory to treatment), hypotonia, spasticity, dysautonomia, hearing loss, and cerebral visual impairment.
    explanation: >-
      GeneReviews directly supports moderate-to-profound intellectual disability
      in humans with SGS.
- name: Brain atrophy
  category: Neurologic
  description: >-
    Progressive cerebral atrophy is a characteristic neuroimaging finding in
    Schinzel-Giedion syndrome.
  phenotype_term:
    preferred_term: Brain atrophy
    term:
      id: HP:0012444
      label: Brain atrophy
  evidence:
  - reference: PMID:37872881
    reference_title: "Cell-type-specific gene expression and regulation in the cerebral cortex and kidney of atypical Setbp1(S858R) Schinzel Giedion Syndrome mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      The most notable phenotypes involve severe developmental delay, progressive brain atrophy, and drug-resistant seizures.
    explanation: >-
      Supports progressive brain atrophy as a hallmark feature of SGS.
- name: Ventriculomegaly
  category: Neurologic
  description: >-
    Bilateral widening of the lateral ventricles is observed on neuroimaging in
    infants with Schinzel-Giedion syndrome.
  phenotype_term:
    preferred_term: Ventriculomegaly
    term:
      id: HP:0002119
      label: Ventriculomegaly
  evidence:
  - reference: PMID:36147799
    reference_title: "Detection of a novel SETBP1 variant in a Chinese neonate with Schinzel-Giedion syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Color Doppler ultrasonography at 18 months revealed hydronephrosis and bilateral widening of the lateral ventricles.
    explanation: >-
      Documents bilateral lateral ventricular dilation in an infant with
      molecularly confirmed SGS.
- name: Hypotonia
  category: Neurologic
  description: >-
    Muscular hypotonia is a recurrent neurologic manifestation of classic
    Schinzel-Giedion syndrome.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:38452171
    reference_title: Schinzel-Giedion Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Classic Schinzel-Giedion syndrome (SGS), an ultra-rare multisystem disorder caused by gain-of-function pathogenic variants in a SETBP1 mutational hot spot, is characterized by global neurodevelopmental impairment leading to moderate-to-profound intellectual disability, epilepsy (often refractory to treatment), hypotonia, spasticity, dysautonomia, hearing loss, and cerebral visual impairment.
    explanation: >-
      GeneReviews directly lists hypotonia among the core neurologic features of
      classic SGS.
- name: Spasticity
  category: Neurologic
  description: >-
    Limb spasticity frequently accompanies the severe neurodevelopmental
    phenotype of Schinzel-Giedion syndrome.
  phenotype_term:
    preferred_term: Spasticity
    term:
      id: HP:0001257
      label: Spasticity
  evidence:
  - reference: PMID:38452171
    reference_title: Schinzel-Giedion Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Classic Schinzel-Giedion syndrome (SGS), an ultra-rare multisystem disorder caused by gain-of-function pathogenic variants in a SETBP1 mutational hot spot, is characterized by global neurodevelopmental impairment leading to moderate-to-profound intellectual disability, epilepsy (often refractory to treatment), hypotonia, spasticity, dysautonomia, hearing loss, and cerebral visual impairment.
    explanation: >-
      GeneReviews directly supports spasticity as a clinical feature of classic
      SGS.
- name: Dysautonomia
  category: Neurologic
  description: >-
    Autonomic nervous system dysfunction (dysautonomia) is a recognized
    neurologic feature of classic Schinzel-Giedion syndrome.
  phenotype_term:
    preferred_term: Abnormal autonomic nervous system physiology
    term:
      id: HP:0012332
      label: Abnormal autonomic nervous system physiology
    coarse_binding_basis: SOURCE_UNSPECIFIED
  evidence:
  - reference: PMID:38452171
    reference_title: Schinzel-Giedion Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Classic Schinzel-Giedion syndrome (SGS), an ultra-rare multisystem disorder caused by gain-of-function pathogenic variants in a SETBP1 mutational hot spot, is characterized by global neurodevelopmental impairment leading to moderate-to-profound intellectual disability, epilepsy (often refractory to treatment), hypotonia, spasticity, dysautonomia, hearing loss, and cerebral visual impairment.
    explanation: >-
      GeneReviews directly lists dysautonomia among the core neurologic
      manifestations of classic SGS without specifying a narrower HPO subterm in
      the abstract summary.
- name: Sleep disturbance
  category: Neurologic
  description: >-
    Sleep disturbance is a recognized clinical manifestation in individuals with
    Schinzel-Giedion syndrome.
  phenotype_term:
    preferred_term: Sleep disturbance
    term:
      id: HP:0002360
      label: Sleep disturbance
  evidence:
  - reference: PMID:38452171
    reference_title: Schinzel-Giedion Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Other features may include neuroepithelial neoplasia, severely disrupted sleep, choanal stenosis, inguinal hernia, sensitive skin, and increased risk of infection.
    explanation: >-
      GeneReviews directly documents sleep disturbance as an associated clinical
      feature of SGS.
- name: Hearing impairment
  category: Ear
  description: >-
    Auditory abnormalities and hearing loss are common sensory deficits in
    Schinzel-Giedion syndrome.
  phenotype_term:
    preferred_term: Hearing impairment
    term:
      id: HP:0000365
      label: Hearing impairment
  evidence:
  - reference: PMID:38452171
    reference_title: Schinzel-Giedion Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Classic Schinzel-Giedion syndrome (SGS), an ultra-rare multisystem disorder caused by gain-of-function pathogenic variants in a SETBP1 mutational hot spot, is characterized by global neurodevelopmental impairment leading to moderate-to-profound intellectual disability, epilepsy (often refractory to treatment), hypotonia, spasticity, dysautonomia, hearing loss, and cerebral visual impairment.
    explanation: >-
      GeneReviews identifies hearing loss as a characteristic manifestation of
      classic SGS.
  - reference: PMID:36147799
    reference_title: "Detection of a novel SETBP1 variant in a Chinese neonate with Schinzel-Giedion syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Six months after birth, the patient had an epileptic seizure and experienced persistent neurodevelopmental delay with auditory and visual abnormalities.
    explanation: >-
      Confirms auditory abnormalities during infancy in a longitudinally followed
      SGS patient.
- name: Cerebral visual impairment
  category: Ophthalmologic
  description: >-
    Cerebral visual impairment is a characteristic neuro-ophthalmologic feature
    of Schinzel-Giedion syndrome.
  phenotype_term:
    preferred_term: Cerebral visual impairment
    term:
      id: HP:0100704
      label: Cerebral visual impairment
  evidence:
  - reference: PMID:38452171
    reference_title: Schinzel-Giedion Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Classic Schinzel-Giedion syndrome (SGS), an ultra-rare multisystem disorder caused by gain-of-function pathogenic variants in a SETBP1 mutational hot spot, is characterized by global neurodevelopmental impairment leading to moderate-to-profound intellectual disability, epilepsy (often refractory to treatment), hypotonia, spasticity, dysautonomia, hearing loss, and cerebral visual impairment.
    explanation: >-
      GeneReviews directly lists cerebral visual impairment as a characteristic
      feature of classic SGS.
- name: Feeding difficulties
  category: Gastrointestinal
  description: >-
    Feeding intolerance, gastroparesis, gastroesophageal reflux, and poor weight
    gain are common in individuals with classic Schinzel-Giedion syndrome.
  phenotype_term:
    preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
  evidence:
  - reference: PMID:38452171
    reference_title: Schinzel-Giedion Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Other findings can include poor weight gain often associated with gastroesophageal reflux disease, chronic vomiting, constipation, gastroparesis, and/or feeding intolerance.
    explanation: >-
      GeneReviews documents feeding intolerance and gastrointestinal motility
      issues associated with poor weight gain in classic SGS.
- name: Hydronephrosis
  category: Genitourinary
  diagnostic: true
  description: >-
    Congenital or infantile hydronephrosis and kidney malformations are cardinal
    visceral features of Schinzel-Giedion syndrome.
  phenotype_term:
    preferred_term: Hydronephrosis
    term:
      id: HP:0000126
      label: Hydronephrosis
  sequelae:
  - target: Recurrent pyelonephritis
    description: Urinary tract dilation and structural kidney malformations predispose to recurrent upper urinary tract infections
    evidence:
    - reference: PMID:38452171
      reference_title: Schinzel-Giedion Syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        Agents/circumstances to avoid: Nephrotoxic drugs such as nonsteroidal anti-inflammatory drugs and vancomycin should be used with caution due to high frequency of chronic renal impairment from recurrent pyelonephritis and structural renal anomalies.
      explanation: >-
        GeneReviews links structural kidney abnormalities in SGS with recurrent
        pyelonephritis and chronic kidney disease.
  - target: Chronic kidney disease
    description: Severe congenital hydronephrosis and recurrent renal injury can progress to chronic kidney disease
    evidence:
    - reference: PMID:38452171
      reference_title: Schinzel-Giedion Syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        Agents/circumstances to avoid: Nephrotoxic drugs such as nonsteroidal anti-inflammatory drugs and vancomycin should be used with caution due to high frequency of chronic renal impairment from recurrent pyelonephritis and structural renal anomalies.
      explanation: >-
        GeneReviews documents chronic kidney disease alongside structural kidney
        abnormalities and recurrent pyelonephritis in SGS.
  evidence:
  - reference: PMID:38711130
    reference_title: "Novel SETBP1 D874V adjacent to the degron causes canonical schinzel-giedion syndrome: a case report and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The female patient was diagnosed in the neonatal period and presented with characteristic facial phenotype (midface retraction, prominent forehead, and low-set ears), bilateral symmetrical talipes equinovarus, overlapping toes, and severe bilateral hydronephrosis accompanied by congenital heart disease, consistent with canonical SGS.
    explanation: >-
      Provides direct human clinical support for severe bilateral hydronephrosis
      as a canonical SGS manifestation.
  - reference: PMID:36147799
    reference_title: "Detection of a novel SETBP1 variant in a Chinese neonate with Schinzel-Giedion syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Color Doppler ultrasonography at 18 months revealed hydronephrosis and bilateral widening of the lateral ventricles.
    explanation: >-
      Confirms hydronephrosis on follow-up ultrasonography in an infant with
      molecularly confirmed SGS.
- name: Recurrent pyelonephritis
  category: Genitourinary
  description: >-
    Recurrent pyelonephritis occurs in individuals with Schinzel-Giedion
    syndrome, often in the setting of congenital urinary tract malformations and
    hydronephrosis.
  phenotype_term:
    preferred_term: Recurrent pyelonephritis
    term:
      id: HP:0012787
      label: Recurrent pyelonephritis
  evidence:
  - reference: PMID:38452171
    reference_title: Schinzel-Giedion Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Agents/circumstances to avoid: Nephrotoxic drugs such as nonsteroidal anti-inflammatory drugs and vancomycin should be used with caution due to high frequency of chronic renal impairment from recurrent pyelonephritis and structural renal anomalies.
    explanation: >-
      GeneReviews directly documents recurrent pyelonephritis as a renal
      complication in SGS.
- name: Chronic kidney disease
  category: Genitourinary
  description: >-
    Chronic kidney disease is a recognized renal complication in individuals with
    Schinzel-Giedion syndrome and motivates avoidance of nephrotoxic medications.
  phenotype_term:
    preferred_term: Chronic kidney disease
    term:
      id: HP:0012622
      label: Chronic kidney disease
  evidence:
  - reference: PMID:38452171
    reference_title: Schinzel-Giedion Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Agents/circumstances to avoid: Nephrotoxic drugs such as nonsteroidal anti-inflammatory drugs and vancomycin should be used with caution due to high frequency of chronic renal impairment from recurrent pyelonephritis and structural renal anomalies.
    explanation: >-
      GeneReviews directly documents chronic kidney disease as a renal
      manifestation of SGS.
- name: Genital anomalies
  category: Genitourinary
  description: >-
    Congenital genital anomalies are among the characteristic urogenital
    malformations of Schinzel-Giedion syndrome.
  phenotype_term:
    preferred_term: Abnormality of the genital system
    term:
      id: HP:0000078
      label: Abnormality of the genital system
    coarse_binding_basis: SOURCE_UNSPECIFIED
  evidence:
  - reference: PMID:38452171
    reference_title: Schinzel-Giedion Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Structural malformations can involve the heart, skeleton, kidney and urinary tract, genitalia, and brain.
    explanation: >-
      GeneReviews identifies genital anomalies as a characteristic congenital
      malformation of classic SGS.
  - reference: PMID:36147799
    reference_title: "Detection of a novel SETBP1 variant in a Chinese neonate with Schinzel-Giedion syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The neonate had a characteristic midface retraction, abnormal electroencephalogram waveforms, and genital abnormalities.
    explanation: >-
      Confirms neonatal genital abnormalities in a molecularly confirmed SGS case
      where the abstract does not specify a narrower genital subterm.
- name: Congenital heart defects
  category: Cardiovascular
  description: >-
    Congenital heart defects frequently accompany the visceral malformation
    spectrum of classic Schinzel-Giedion syndrome.
  phenotype_term:
    preferred_term: Abnormal heart morphology
    term:
      id: HP:0001627
      label: Abnormal heart morphology
    coarse_binding_basis: SOURCE_UNSPECIFIED
  evidence:
  - reference: PMID:38452171
    reference_title: Schinzel-Giedion Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Structural malformations can involve the heart, skeleton, kidney and urinary tract, genitalia, and brain.
    explanation: >-
      GeneReviews directly lists congenital heart defects as a typical congenital
      malformation in classic SGS.
  - reference: PMID:38711130
    reference_title: "Novel SETBP1 D874V adjacent to the degron causes canonical schinzel-giedion syndrome: a case report and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The female patient was diagnosed in the neonatal period and presented with characteristic facial phenotype (midface retraction, prominent forehead, and low-set ears), bilateral symmetrical talipes equinovarus, overlapping toes, and severe bilateral hydronephrosis accompanied by congenital heart disease, consistent with canonical SGS.
    explanation: >-
      Confirms congenital heart disease in a neonate with canonical SGS.
- name: Midface retrusion
  category: Head and Neck
  diagnostic: true
  description: >-
    Midface retrusion accompanied by a prominent forehead and low-set ears forms
    the recognizable craniofacial gestalt of Schinzel-Giedion syndrome.
  phenotype_term:
    preferred_term: Midface retrusion
    term:
      id: HP:0011800
      label: Midface retrusion
  evidence:
  - reference: PMID:38711130
    reference_title: "Novel SETBP1 D874V adjacent to the degron causes canonical schinzel-giedion syndrome: a case report and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The female patient was diagnosed in the neonatal period and presented with characteristic facial phenotype (midface retraction, prominent forehead, and low-set ears), bilateral symmetrical talipes equinovarus, overlapping toes, and severe bilateral hydronephrosis accompanied by congenital heart disease, consistent with canonical SGS.
    explanation: >-
      Confirms neonatal midface retraction in canonical SGS.
  - reference: PMID:36147799
    reference_title: "Detection of a novel SETBP1 variant in a Chinese neonate with Schinzel-Giedion syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The neonate had a characteristic midface retraction, abnormal electroencephalogram waveforms, and genital abnormalities.
    explanation: >-
      Confirms characteristic midface retraction in a neonate with SGS.
- name: Choanal stenosis
  category: Respiratory
  description: >-
    Choanal stenosis is a recognized upper-airway anomaly in individuals with
    Schinzel-Giedion syndrome.
  phenotype_term:
    preferred_term: Choanal stenosis
    term:
      id: HP:0000452
      label: Choanal stenosis
  evidence:
  - reference: PMID:38452171
    reference_title: Schinzel-Giedion Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Other features may include neuroepithelial neoplasia, severely disrupted sleep, choanal stenosis, inguinal hernia, sensitive skin, and increased risk of infection.
    explanation: >-
      GeneReviews directly lists choanal stenosis as an associated clinical
      manifestation of SGS.
- name: Talipes equinovarus
  category: Musculoskeletal
  description: >-
    Congenital talipes equinovarus (clubfoot) is a skeletal anomaly observed in
    individuals with Schinzel-Giedion syndrome.
  phenotype_term:
    preferred_term: Talipes equinovarus
    term:
      id: HP:0001762
      label: Talipes equinovarus
  evidence:
  - reference: PMID:38711130
    reference_title: "Novel SETBP1 D874V adjacent to the degron causes canonical schinzel-giedion syndrome: a case report and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The female patient was diagnosed in the neonatal period and presented with characteristic facial phenotype (midface retraction, prominent forehead, and low-set ears), bilateral symmetrical talipes equinovarus, overlapping toes, and severe bilateral hydronephrosis accompanied by congenital heart disease, consistent with canonical SGS.
    explanation: >-
      Documents bilateral symmetrical talipes equinovarus in a neonate with
      canonical SGS.
- name: Neuroepithelial neoplasia
  category: Neoplasm
  subtype: Classic
  description: >-
    Individuals with classic Schinzel-Giedion syndrome have an increased risk of
    neuroepithelial neoplasia and sacrococcygeal teratoma, requiring age-related
    oncologic surveillance; this risk has not been documented in atypical SGS to
    date.
  phenotype_term:
    preferred_term: Neoplasm of the nervous system
    term:
      id: HP:0004375
      label: Neoplasm of the nervous system
  evidence:
  - reference: PMID:38452171
    reference_title: Schinzel-Giedion Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Other features may include neuroepithelial neoplasia, severely disrupted sleep, choanal stenosis, inguinal hernia, sensitive skin, and increased risk of infection.
    explanation: >-
      GeneReviews directly lists neuroepithelial neoplasia as a clinical
      manifestation of classic SGS.
  - reference: PMID:38452171
    reference_title: Schinzel-Giedion Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      The broad spectrum of clinical features of variable severity partially overlaps with classic SGS; however, this spectrum does not include risk for neuroepithelial neoplasia to date.
    explanation: >-
      GeneReviews specifies that neuroepithelial neoplasia risk is restricted to
      classic SGS rather than atypical SGS to date.
  - reference: PMID:38452171
    reference_title: Schinzel-Giedion Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      In individuals with classic SGS, age-related surveillance for occurrence of neoplasia includes liver ultrasound and serum alpha-fetoprotein levels, renal ultrasound examination, pelvic MRI for sacrococcygeal teratoma, and monitoring for clinical signs of leukemia.
    explanation: >-
      Outlines the neoplasia spectrum and surveillance protocol in classic SGS.
- name: Recurrent infections
  category: Immune
  description: >-
    Recurrent infections are a recognized clinical complication in individuals
    with Schinzel-Giedion syndrome.
  phenotype_term:
    preferred_term: Recurrent infections
    term:
      id: HP:0002719
      label: Recurrent infections
  evidence:
  - reference: PMID:38452171
    reference_title: Schinzel-Giedion Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Other features may include neuroepithelial neoplasia, severely disrupted sleep, choanal stenosis, inguinal hernia, sensitive skin, and increased risk of infection.
    explanation: >-
      GeneReviews directly documents recurrent infections as an associated
      clinical feature of SGS.
biochemical:
- name: Serum alpha-fetoprotein
  biomarker_term:
    preferred_term: Alpha-Fetoprotein
    term:
      id: NCIT:C16278
      label: Alpha-Fetoprotein
  presence: Monitored longitudinally for tumor surveillance
  context: >-
    Serial serum alpha-fetoprotein measurement is used alongside imaging for
    age-related surveillance of hepatoblastoma and sacrococcygeal teratoma in
    classic Schinzel-Giedion syndrome.
  evidence:
  - reference: PMID:38452171
    reference_title: Schinzel-Giedion Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      In individuals with classic SGS, age-related surveillance for occurrence of neoplasia includes liver ultrasound and serum alpha-fetoprotein levels, renal ultrasound examination, pelvic MRI for sacrococcygeal teratoma, and monitoring for clinical signs of leukemia.
    explanation: >-
      GeneReviews specifies serum alpha-fetoprotein monitoring as part of routine
      neoplasia surveillance in classic SGS.
genetic:
- name: SETBP1
  association: Degron-region gain-of-stability missense variants
  relationship_type: CAUSATIVE
  variant_origin: DE_NOVO
  gene_term:
    preferred_term: SETBP1
    term:
      id: hgnc:15573
      label: SETBP1
  inheritance:
  - name: Autosomal dominant inheritance
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
  features: >-
    Heterozygous de novo missense variants clustering in or immediately adjacent
    to the 12-base-pair canonical degron hotspot in exon 4 of SETBP1 (amino acids
    868 to 871; e.g., p.S869G in the degron and p.D874V or p.S867R adjacent to
    the degron).
  gene_disease_validity:
  - validity_classification: DEFINITIVE
    classified_by: CLINGEN
    external_id: CGGV:assertion_71885c03-b578-4baf-a17c-4817349eaf36-2021-02-16T170000.000Z
    notes: >-
      ClinGen Intellectual Disability and Autism Gene Curation Expert Panel
      classified the SETBP1 gene-disease relationship with Schinzel-Giedion
      syndrome (MONDO:0010010) as Definitive under autosomal dominant
      inheritance.
    evidence:
    - reference: CGGV:assertion_71885c03-b578-4baf-a17c-4817349eaf36-2021-02-16T170000.000Z
      reference_title: "SETBP1 / Schinzel-Giedion syndrome (Definitive)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "SETBP1 | HGNC:15573 | Schinzel-Giedion syndrome | MONDO:0010010 | AD | Definitive"
      explanation: >-
        ClinGen assertion directly establishes Definitive gene-disease validity
        for SETBP1 in autosomal dominant Schinzel-Giedion syndrome.
  notes: >-
    Classical Schinzel-Giedion syndrome is caused by de novo missense variants
    in the degron region of SETBP1 that impair protein degradation and increase
    aberrant transcriptional activity.
  evidence:
  - reference: PMID:38452171
    reference_title: Schinzel-Giedion Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Classic Schinzel-Giedion syndrome (SGS), an ultra-rare multisystem disorder caused by gain-of-function pathogenic variants in a SETBP1 mutational hot spot, is characterized by global neurodevelopmental impairment leading to moderate-to-profound intellectual disability, epilepsy (often refractory to treatment), hypotonia, spasticity, dysautonomia, hearing loss, and cerebral visual impairment.
    explanation: >-
      Provides direct human clinical support for the characteristic SETBP1
      gain-of-function variant class in classical SGS.
  - reference: PMID:36147799
    reference_title: "Detection of a novel SETBP1 variant in a Chinese neonate with Schinzel-Giedion syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Whole-exome sequencing revealed a heterozygous de novo variant (c.2605A > G:p.S869G) in exon 4 degradation sequence in SETBP1.
    explanation: >-
      Identifies a de novo heterozygous SETBP1 missense variant within the exon 4
      degron sequence in a neonate with SGS.
  - reference: CGGV:assertion_71885c03-b578-4baf-a17c-4817349eaf36-2021-02-16T170000.000Z
    reference_title: "SETBP1 / Schinzel-Giedion syndrome (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "SETBP1 | HGNC:15573 | Schinzel-Giedion syndrome | MONDO:0010010 | AD | Definitive"
    explanation: >-
      ClinGen classifies the SETBP1-Schinzel-Giedion syndrome gene-disease
      relationship as definitive with autosomal dominant inheritance.
diagnosis:
- name: SETBP1 molecular genetic testing
  diagnosis_term:
    preferred_term: Genetic Testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  presence: Confirmatory
  results: >-
    Identification of a heterozygous de novo pathogenic gain-of-function variant
    within or adjacent to the SETBP1 exon 4 degron mutational hotspot.
  description: >-
    Diagnosis is established via clinical diagnostic criteria or confirmed by
    molecular genetic testing identifying a heterozygous pathogenic SETBP1
    variant in the exon 4 canonical degron region.
  evidence:
  - reference: PMID:38452171
    reference_title: Schinzel-Giedion Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      The diagnosis of classic SGS can be established in a proband based on published clinical diagnostic criteria, or the molecular diagnosis can be established in a proband with suggestive findings and a heterozygous SETBP1 pathogenic gain-of-function variant within the mutational hot spot (i.e., a 12-base-pair region in exon 4 encoding a canonical degron).
    explanation: >-
      GeneReviews defines the clinical and molecular diagnostic criteria for
      classic SGS.
  - reference: PMID:36147799
    reference_title: "Detection of a novel SETBP1 variant in a Chinese neonate with Schinzel-Giedion syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The clinical manifestations of neonatal SGS are atypical, and genetic testing is crucial for diagnosis.
    explanation: >-
      Emphasizes the essential role of molecular genetic testing for diagnosing
      SGS in the neonatal period.
- name: Renal, hepatic, and cranial ultrasonography
  diagnosis_term:
    preferred_term: Ultrasound Imaging
    term:
      id: NCIT:C17230
      label: Ultrasound Imaging
  presence: Diagnostic and longitudinal surveillance
  results: >-
    Detection of congenital or progressive hydronephrosis, ventriculomegaly, and
    age-related hepatic screening for hepatoblastoma.
  description: >-
    Renal, hepatic, and cranial ultrasonography are used to evaluate congenital
    renal and ventricular anomalies and to conduct age-related surveillance for
    hepatoblastoma in classic Schinzel-Giedion syndrome.
  evidence:
  - reference: PMID:38452171
    reference_title: Schinzel-Giedion Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      In individuals with classic SGS, age-related surveillance for occurrence of neoplasia includes liver ultrasound and serum alpha-fetoprotein levels, renal ultrasound examination, pelvic MRI for sacrococcygeal teratoma, and monitoring for clinical signs of leukemia.
    explanation: >-
      Supports routine liver and renal ultrasound in the diagnostic and
      oncologic surveillance of classic SGS.
  - reference: PMID:36147799
    reference_title: "Detection of a novel SETBP1 variant in a Chinese neonate with Schinzel-Giedion syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Color Doppler ultrasonography at 18 months revealed hydronephrosis and bilateral widening of the lateral ventricles.
    explanation: >-
      Demonstrates the diagnostic utility of ultrasonography for tracking
      hydronephrosis and ventricular dilation in SGS.
- name: Pelvic MRI surveillance
  diagnosis_term:
    preferred_term: Magnetic Resonance Imaging
    term:
      id: NCIT:C16809
      label: Magnetic Resonance Imaging
  presence: Longitudinal tumor surveillance
  results: >-
    Age-related pelvic surveillance for sacrococcygeal teratoma in individuals
    with classic Schinzel-Giedion syndrome.
  description: >-
    Pelvic magnetic resonance imaging is used for age-related neoplasia
    surveillance to detect sacrococcygeal teratoma in classic Schinzel-Giedion
    syndrome.
  evidence:
  - reference: PMID:38452171
    reference_title: Schinzel-Giedion Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      In individuals with classic SGS, age-related surveillance for occurrence of neoplasia includes liver ultrasound and serum alpha-fetoprotein levels, renal ultrasound examination, pelvic MRI for sacrococcygeal teratoma, and monitoring for clinical signs of leukemia.
    explanation: >-
      GeneReviews specifies pelvic MRI as part of routine age-related
      surveillance for sacrococcygeal teratoma in classic SGS.
treatments:
- name: Supportive multidisciplinary care
  description: >-
    Current management is supportive and coordinates multidisciplinary
    specialists for seizure control, nutritional and feeding support, physical
    and occupational therapy, hearing and visual rehabilitation, urologic and
    nephrologic management of hydronephrosis, and oncologic surveillance.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_phenotypes:
  - preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  - preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  - preferred_term: Hydronephrosis
    term:
      id: HP:0000126
      label: Hydronephrosis
  - preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
  - preferred_term: Hearing impairment
    term:
      id: HP:0000365
      label: Hearing impairment
  - preferred_term: Cerebral visual impairment
    term:
      id: HP:0100704
      label: Cerebral visual impairment
  evidence:
  - reference: PMID:38452171
    reference_title: Schinzel-Giedion Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Supportive treatment to improve quality of life, maximize function, and reduce complications can include multidisciplinary care by specialists in pediatrics, neurology, physiatry, occupational and physical therapy, speech-language pathology, psychiatry, ophthalmology, ENT, surgery, pulmonology, oncology, urology, nephrology, audiology, gastroenterology, orthopedics, cardiology, and medical genetics.
    explanation: >-
      GeneReviews directly supports multidisciplinary supportive management as
      the standard of care across affected organ systems.
- name: Avoidance of nephrotoxic agents
  description: >-
    Because individuals with Schinzel-Giedion syndrome frequently have
    structural kidney abnormalities, recurrent pyelonephritis, and/or chronic
    kidney disease, nephrotoxic medications such as nonsteroidal
    anti-inflammatory drugs (NSAIDs) and vancomycin should be avoided whenever
    possible.
  treatment_term:
    preferred_term: Preventive Intervention
    term:
      id: NCIT:C15843
      label: Preventive Intervention
    therapeutic_agent:
    - preferred_term: Nonsteroidal Antiinflammatory Drug
      term:
        id: NCIT:C257
        label: Nonsteroidal Antiinflammatory Drug
    - preferred_term: vancomycin
      term:
        id: CHEBI:28001
        label: vancomycin
  action_category: THERAPEUTIC
  target_phenotypes:
  - preferred_term: Hydronephrosis
    term:
      id: HP:0000126
      label: Hydronephrosis
  - preferred_term: Recurrent pyelonephritis
    term:
      id: HP:0012787
      label: Recurrent pyelonephritis
  - preferred_term: Chronic kidney disease
    term:
      id: HP:0012622
      label: Chronic kidney disease
  evidence:
  - reference: PMID:38452171
    reference_title: Schinzel-Giedion Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Agents/circumstances to avoid: Nephrotoxic drugs such as nonsteroidal anti-inflammatory drugs and vancomycin should be used with caution due to high frequency of chronic renal impairment from recurrent pyelonephritis and structural renal anomalies.
    explanation: >-
      GeneReviews explicitly recommends avoiding nephrotoxic agents including
      NSAIDs and vancomycin in individuals with SGS due to structural kidney
      abnormalities, recurrent pyelonephritis, and chronic kidney disease.
- name: Genetic counseling
  description: >-
    Genetic counseling is indicated for families of affected probands to discuss
    de novo autosomal dominant inheritance, low recurrence risk (accounting for
    rare parental germline mosaicism), and options for prenatal or
    preimplantation genetic testing once the familial SETBP1 variant is known.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  action_category: COUNSELING_INFORMATIONAL
  evidence:
  - reference: PMID:38452171
    reference_title: Schinzel-Giedion Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Once the SETBP1 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.
    explanation: >-
      Supports reproductive genetic counseling and prenatal or preimplantation
      testing once a pathogenic SETBP1 variant is identified.
differential_diagnoses:
- name: intellectual disability, autosomal dominant 29
  disease_term:
    preferred_term: intellectual disability, autosomal dominant 29
    term:
      id: MONDO:0014482
      label: intellectual disability, autosomal dominant 29
  description: >-
    SETBP1 haploinsufficiency disorder (MRD29) is an allelic disorder caused by
    heterozygous loss-of-function or nonsense SETBP1 variants; it overlaps
    genetically with SGS but presents with speech apraxia and a milder
    neurodevelopmental phenotype without the canonical degron-mediated protein
    accumulation and severe visceral malformations of SGS.
  distinguishing_features:
  - Classical degron-region gain-of-stability missense variants with severe multisystem malformations and refractory epilepsy favor Schinzel-Giedion syndrome.
  - Truncating or haploinsufficiency variants with expressive speech impairment, milder developmental delay, and absence of severe congenital visceral anomalies favor intellectual disability, autosomal dominant 29.
  evidence:
  - reference: PMID:38585550
    reference_title: "Delayed Bone Age in a Child with a Novel Loss-of-Function Variant in SETBP1 Gene Sheds Light on the Potential Role of SETBP1 Protein in Skeletal Development."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      SETBP1 gene variants that decrease or eliminate protein activity have been associated with phenotypes characterized by speech apraxia and intellectual disabilities. This condition, distinctly separated from Schinzel-Giedion syndrome, is referred to as autosomal dominant mental retardation 29 (ADR29).
    explanation: >-
      Directly distinguishes SETBP1 loss-of-function variants causing autosomal
      dominant intellectual disability 29 (MRD29/ADR29) from Schinzel-Giedion
      syndrome.
  - reference: PMID:34807554
    reference_title: "SETBP1 Haploinsufficiency Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      The diagnosis of SETBP1-HD is established in a proband with suggestive findings and a heterozygous pathogenic loss-of-function variant in SETBP1 identified by molecular genetic testing.
    explanation: >-
      Establishes that SETBP1 haploinsufficiency disorder is defined by
      heterozygous loss-of-function SETBP1 variants, contrasting with the
      gain-of-function degron variants of SGS.
  - reference: PMID:25217958
    reference_title: "Refining analyses of copy number variation identifies specific genes associated with developmental delay."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In contrast to the likely loss-of-function, mutations, gain-of-function mutations cluster within a 12 amino domain and result in a more severe DD with multiple congenital abnormalities and death in infancy48,49.
    explanation: >-
      Distinguishes milder loss-of-function SETBP1 phenotypes from severe
      gain-of-function degron-hotspot SGS.
clinical_trials: []
datasets: []
notes: >-
  Genotype-phenotype correlation in SETBP1-related disorders reflects a strict
  dosage-sensitivity continuum: de novo missense variants within the 12-bp exon 4
  canonical degron (amino acids 868 to 871) cause classic Schinzel-Giedion
  syndrome via impaired ubiquitin-proteasome degradation and toxic SETBP1 protein
  accumulation, missense variants immediately adjacent to the degron (such as
  p.S867R or p.D874V) cause either canonical or milder atypical SGS, and
  heterozygous truncating or deletion variants cause SETBP1 haploinsufficiency
  disorder (MRD29).
references:
- reference: PMID:38452171
  title: "Schinzel-Giedion Syndrome."
  tags:
  - GeneReviews
  findings: []
- reference: PMID:37872881
  title: "Cell-type-specific gene expression and regulation in the cerebral cortex and kidney of atypical Setbp1(S858R) Schinzel Giedion Syndrome mice."
  findings: []
- reference: PMID:29875417
  title: "SETBP1 induces transcription of a network of development genes by acting as an epigenetic hub."
  findings: []
- reference: PMID:38711130
  title: "Novel SETBP1 D874V adjacent to the degron causes canonical schinzel-giedion syndrome: a case report and review of the literature."
  findings: []
- reference: PMID:36147799
  title: "Detection of a novel SETBP1 variant in a Chinese neonate with Schinzel-Giedion syndrome."
  findings: []
- reference: PMID:39825586
  title: "Reciprocal and non-reciprocal effects of clinically relevant SETBP1 protein dosage changes."
  findings: []
- reference: PMID:34807554
  title: "SETBP1 Haploinsufficiency Disorder."
  tags:
  - GeneReviews
  findings: []
- reference: PMID:38585550
  title: "Delayed Bone Age in a Child with a Novel Loss-of-Function Variant in SETBP1 Gene Sheds Light on the Potential Role of SETBP1 Protein in Skeletal Development."
  findings: []
- reference: PMID:25217958
  title: "Refining analyses of copy number variation identifies specific genes associated with developmental delay."
  findings: []
📚

References & Deep Research

References

9
PMID:38452171
Schinzel-Giedion Syndrome.
No top-level findings curated for this source.
PMID:37872881
Cell-type-specific gene expression and regulation in the cerebral cortex and kidney of atypical Setbp1(S858R) Schinzel Giedion Syndrome mice.
No top-level findings curated for this source.
PMID:29875417
SETBP1 induces transcription of a network of development genes by acting as an epigenetic hub.
No top-level findings curated for this source.
PMID:38711130
Novel SETBP1 D874V adjacent to the degron causes canonical schinzel-giedion syndrome: a case report and review of the literature.
No top-level findings curated for this source.
PMID:36147799
Detection of a novel SETBP1 variant in a Chinese neonate with Schinzel-Giedion syndrome.
No top-level findings curated for this source.
PMID:39825586
Reciprocal and non-reciprocal effects of clinically relevant SETBP1 protein dosage changes.
No top-level findings curated for this source.
PMID:34807554
SETBP1 Haploinsufficiency Disorder.
No top-level findings curated for this source.
PMID:38585550
Delayed Bone Age in a Child with a Novel Loss-of-Function Variant in SETBP1 Gene Sheds Light on the Potential Role of SETBP1 Protein in Skeletal Development.
No top-level findings curated for this source.
PMID:25217958
Refining analyses of copy number variation identifies specific genes associated with developmental delay.
No top-level findings curated for this source.

Deep Research

1

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

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Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Schinzel-Giedion syndrome. Core disease mechanisms, molecular and cellular...
Asta Scientific Corpus Retrieval 20 citations 2026-04-11T16:00:29.721430

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Schinzel-Giedion syndrome. Core disease mechanisms, molecular and cellular...

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  • Papers retrieved: 20
  • Snippets retrieved: 20

Relevant Papers

[1] Role of Transcriptomics in Precision Oncology

  • Authors: Ruby Srivastava
  • Year: 2024
  • Venue: Reports of Radiotherapy and Oncology
  • URL: https://www.semanticscholar.org/paper/0bd862558bbb7286336111d9dfd232b5f905d3d9
  • DOI: 10.5812/rro-142195
  • Citations: 4
  • Summary: : Transcriptome profiling is one of the most widely used approaches in the field of multiomics research. It plays a crucial role in the prognostic, diagnostic, and predictive treatment of cancer patients. Novel next-generation sequencing (NGS) technologies permit the identification of cancer biomarkers, gene signatures, and their abnormal expression, affecting oncogenic and molecular targets and novel biomarkers for cancer therapies. Multiomics studies have changed the overall understanding o...
  • Evidence snippets:
  • Snippet 1 (score: 0.384) > : Transcriptome profiling is one of the most widely used approaches in the field of multiomics research. It plays a crucial role in the prognostic, diagnostic, and predictive treatment of cancer patients. Novel next-generation sequencing (NGS) technologies permit the identification of cancer biomarkers, gene signatures, and their abnormal expression, affecting oncogenic and molecular targets and novel biomarkers for cancer therapies. Multiomics studies have changed the overall understanding of cancer and opened a precise perspective for tumor diagnostics and therapy. The use of these approaches has strengthened our understanding of disease pathophysiology and classifications at the molecular level, including specific interference with drug mechanisms of action. Still, it has limited added value in the clinical setting. The omics data on precision medicine include the application of data from genes, transcripts, and proteins for diagnosis, monitoring of diseases, risk factor determination, counseling, and development of novel therapeutics. Bioinformatics applications have expanded statistics-based analysis toward deriving molecular pathways and process models for characterizing phenotypes and drug action mechanisms. In this review, we will discuss transcriptomics and interference analysis that allows the identification of predictive biomarkers at the molecular level to test drug response and analyze the molecular process interface of disease progression-relevant pathophysiology and mechanism of action to propose predictive biomarkers.

[2] Modeling psychiatric disorders: from genomic findings to cellular phenotypes

  • Authors: Anna Falk, Vivi M. Heine, A. Harwood, Patrick F. Sullivan, M. Peitz et al.
  • Year: 2016
  • Venue: Molecular Psychiatry
  • URL: https://www.semanticscholar.org/paper/235b41240d78140de7ab06a3ad8a7d0b1bdff1a5
  • DOI: 10.1038/mp.2016.89
  • PMID: 27240529
  • PMCID: 4995546
  • Citations: 77
  • Influential citations: 2
  • Summary: The challenges for modeling of psychiatric disorders, potential solutions and how iPSC technology can be used to develop an analytical framework for the evaluation and therapeutic manipulation of fundamental disease processes are critically reviewed.
  • Evidence snippets:
  • Snippet 1 (score: 0.382) > The key challenge for iPSC-based disease modeling is to identify one or more relevant cellular phenotypes that accurately represent the disease pathophysiology. Increasing numbers of reports have demonstrated that for many diseases specific pathophysiology can be captured in human iPSC-based disease models. These range from cardiovascular disease, 44,45 cancer, 46,47 ocular disease, 48,49 diabetes mellitus 50,51 and neurological disorders of the brain. 52,53 Can the same approach be applied to complex psychiatric disorders? > The problem is that almost all psychiatric disorders are characterized by clinical signs and symptoms, but lack independent verification from objective biomarkers. Thus, how might these clinical phenotypes manifest themselves in terms of cell behavior? The identity of robust cellular 'readouts', which typify any psychiatric disorder, is a crucial unsolved problem and an area of intense study 54 (Table 2). When satisfactorily answered, this will herald a new degree of biological objectivity and quantification for the study of psychiatric disorders. > The aim is to find a single or small number of cell phenotypes or parameters that strongly associate with psychiatric disorders, and establish a cellular profile characteristic of cells derived from the general patient population. Although a consensus set of cellular phenotypes for psychiatric disorder is yet to be established, we can define some of their desired characteristics. First, cellular phenotypes have to relate to the biological pathways identified by genetics. Second, although there are many risk genes in disparate biological pathways, at some level, phenotypes should converge onto a much smaller grouping. Third, phenotypes need to be quantifiable. Finally, to be useful for drug development cellular phenotypes should be reversed by pharmacological treatment, although not necessarily by drugs in current use. > Although human iPSC-based approaches underrepresent the complexity of the human central nervous system, cellular phenotypes are likely to lie more proximal to molecular disease mechanisms than phenotypes seen at the level of a tissue or organism, 55 and thus may bypass compensatory homeostatic (2) Gene expression profiles of SCZ human iPSC neurons identified altered expression of many components of the cyclic AMP and WNT signaling pathways. > (3

[3] New therapeutic targets in rare genetic skeletal diseases

  • Authors: M. Briggs, Peter A. Bell, M. Wright, K. A. Pirog
  • Year: 2015
  • Venue: Expert Opinion on Orphan Drugs
  • URL: https://www.semanticscholar.org/paper/1363107f71ae6d2d60abca471cddf3da5d13644b
  • DOI: 10.1517/21678707.2015.1083853
  • PMID: 26635999
  • PMCID: 4643203
  • Citations: 37
  • Influential citations: 1
  • Summary: An overview of disease mechanisms that are shared amongst groups of different GSDs and potential therapeutic approaches that are under investigation are described to generate critical mass for the identification and validation of novel therapeutic targets and biomarkers.
  • Evidence snippets:
  • Snippet 1 (score: 0.377) > proteins of the cartilage ECM such as type II collagen [50]. However, emerging knowledge suggests that the primary genetic defect may be less important than the cells' response to the expression of the mutant gene product [107]. Moreover, the largely overlooked response of a cell (i.e. chondrocyte) to the abnormal extracellular environment is also important for disease progression as illustrated by several GSDs discussed in this review. > It is important that 'omics'-based approaches and technologies are systematically applied to the study of rare GSDs so that definitive reference profiles and disease signatures are generated for each phenotype. These can then be used in a Systems Biology approach to identify both common and dissimilar pathological signatures and disease mechanisms. This approach is entirely dependent upon relevant in vitro and in vivo models (and also novel 'disease-mechanism phenocopies' [107]) for testing new diagnostic and prognostic tools and for determining the molecular mechanisms that underpin the pathophysiology so that effective therapeutic treatments can be developed and validated. This approach will eventually lead to personalized treatments and care strategies centred on shared disease mechanisms with the use of relevant biomarkers to monitor the efficacy of treatment and disease progression. > It is vital that all relevant stakeholders are involved from the outset in defining the appropriate outcomes of any potential therapeutic regime. The perceptions of a successful therapy can differ widely between the clinical academic community and the relevant patient-support groups and it is vital that there is engagement on all these issues. > In summary, the identification of causative genes and mutations for GSDs over the last 20 years, coupled with the generation and in-depth analysis of a plethora of relevant cell and mouse models, has derived new knowledge on disease mechanisms and suggested potential therapeutic targets. The fast-evolving hypothesis that clinically disparate diseases can share common disease mechanisms is a powerful concept that will generate critical mass for the identification and validation of novel therapeutic targets and biomarkers.

[4] 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: 0.377) > 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.

[5] In vitro systems to study inborn errors of immunity using human induced pluripotent stem cells

  • Authors: Eirini Nikolouli, Janne Reichstein, G. Hansen, N. Lachmann
  • Year: 2022
  • Venue: Frontiers in Immunology
  • URL: https://www.semanticscholar.org/paper/50f330ee9584168734b8cc8a22dc702c4cbe8ec5
  • DOI: 10.3389/fimmu.2022.1024935
  • PMID: 36466870
  • PMCID: 9713844
  • Citations: 1
  • Summary: This review aims to provide an overview of the current available in vitro models used to study IEI and which could lay the foundation for new therapeutic approaches and elaborate in particular on the use of induced pluripotent stem cell-based systems.
  • Evidence snippets:
  • Snippet 1 (score: 0.377) > of drug-resistant pathogens, which can cause lifethreatening infections. In some cases, like in the severe combined immunodeficiency (SCID) syndrome, allogenic hematopoietic stem cell transplantation (HSCT) (or autologous HSC-gene therapy) is the only curative therapy (6,7). However, HSCT always lurks the risk of immunological rejection or development of graft versus host disease with devastating consequences for the patient, pointing towards the need of suitable alternatives. > For these reasons, more targeted therapeutic approaches, which can directly modulate specific cell types or intracellular pathways, are preferred. These approaches include the use of specific inhibitors or biologics (antibodies or recombinant proteins). For the safe use of these emerging therapeutic agents, a detailed study of the pathophysiological mechanisms of the diseases is necessary. Given the rarity of IEI and the technical difficulties (obtaining sufficient samples from children or the low number of affected cells), the study of IEI-related diseases remains challenging. Thus, the development of novel systems to unravel the cellular and molecular mechanisms involved in the pathophysiology of the various IEI is of great importance.

[6] Investigating the role of NPR1 in dilated cardiomyopathy and its potential as a therapeutic target for glucocorticoid therapy

  • Authors: Yaomeng Huang, Tongxin Li, Shichao Gao, Shuyu Li, Xiaoran Zhu et al.
  • Year: 2023
  • Venue: Frontiers in Pharmacology
  • URL: https://www.semanticscholar.org/paper/be229f6f2059faab4c97ec0a04bd055adab9dfe1
  • DOI: 10.3389/fphar.2023.1290253
  • PMID: 38026943
  • PMCID: 10662320
  • Citations: 3
  • Summary: Natriuretic peptide receptor 1 (NPR1) was identified as a core gene associated with DCM through bioinformatics analysis and led to substantial improvements in cardiac and renal function, accompanied by an upregulation of NPR1 expression.
  • Evidence snippets:
  • Snippet 1 (score: 0.373) > Multiple pathways and molecules are involved in this process; however, the detailed underlying mechanisms remain unclear. In recent years, with the development of high-throughput sequencing and gene chip technologies, the use of bioinformatics technology to explore the occurrence, development, and prognosis of diseases has become a hot topic for scholars worldwide (Hwang et al., 2018;Nayor et al., 2019;Rinschen et al., 2019;Sturm et al., 2019;Montaner et al., 2020). > The present study aimed to use bioinformatics technology to screen for DCM-related genes and investigate their mechanisms, with the purpose of revealing the pathogenesis of DCM and seeking treatment methods. The GSE3586 dataset, containing expression profiles related to DCM, was selected from the Gene Expression Omnibus (GEO) database. This study aimed to predict the core genes that may play crucial roles in disease progression at the molecular level through the enrichment of relevant molecular pathways associated with DCM. Furthermore, the phenotype of the core genes was validated to further support the results of the bioinformatics analysis through basic and clinical experiments. Additionally, the role of glucocorticoids in DCM treatment is discussed in this article with the purpose of providing a theoretical and experimental basis for exploring the pathogenesis of DCM and elucidating therapeutic methods. This study also provides a theoretical reference for the interpretation, early diagnosis, and treatment of DCM.

[7] 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: 0.370) > 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

[8] Novel variants in KAT6B spectrum of disorders expand our knowledge of clinical manifestations and molecular mechanisms

  • Authors: M. Yabumoto, Jessica Kianmahd, Meghna Singh, Maria F. Palafox, Angela Wei et al.
  • Year: 2021
  • Venue: Molecular Genetics & Genomic Medicine
  • URL: https://www.semanticscholar.org/paper/3a47a1b1208ba7420900b090d3d7d712ed391719
  • DOI: 10.1002/mgg3.1809
  • PMID: 34519438
  • PMCID: 8580094
  • Citations: 12
  • Influential citations: 2
  • Summary: A range of features previously described for KAT6B‐related syndromes are identified, including concern for keratoconus, sensitivity to light or noise, recurring infections, and fractures in greater numbers than previously reported.
  • Evidence snippets:
  • Snippet 1 (score: 0.369) > Finally, as gene-centric models of disease have started to take hold, understanding the underlying functional mechanisms that are affected can help us elucidate the effect on molecular and cellular phenotypes that are regulated by KAT6B (Klein et al., 2019;Sheikh et al., 2012). We developed a model of KAT6B truncating variants in a human cell line to explore how these variants result in differential regulation of key transcripts. These types of approaches have been performed in a high throughput manner for tumor suppressor genes like BRCA1 (Findlay et al., 2018) and TP53 (Kotler et al., 2018) and can help identify key pathways that are dysregulated by KAT6B-related disorders and could be future targets for translational research. > Here, we analyze 20 clinical cases representing a KAT6B-related clinical spectrum across three domains: their genotype, phenotype, and experience with genetic counseling resources. Furthermore, we developed an in vitro model of KAT6B mutations using CRISPR technology to explore the effect of protein truncation on global transcriptional regulation. Here we demonstrate that the genes that drive core clinical phenotypes are enriched in our in vitro model system. Together, we show that our clinical observations parallel the transcriptional processes in our cell model systems which allow for a further understanding of the mechanisms underlying the KAT6Brelated clinical spectrum.

[9] 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: 0.368) > 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.

[10] Cellular reprogramming and inherited peripheral neuropathies: perspectives and challenges

  • Authors: M. Saporta
  • Year: 2015
  • Venue: Neural Regeneration Research
  • URL: https://www.semanticscholar.org/paper/8c3dabb1b4abf93506e2026564b8a329c0ec37c6
  • DOI: 10.4103/1673-5374.158345
  • PMID: 26199602
  • PMCID: 4498347
  • Citations: 4
  • Summary: iPSC-based models of neuromuscular disorders, including amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA) and inherited peripheral neuropathies, have successfully reproduced pathophysiological findings from previous animal and cellular models and have also identified new disease mechanisms with potential therapeutical implications.
  • Evidence snippets:
  • Snippet 1 (score: 0.368) > Inherited peripheral neuropathies (or Charcot-Marie-Tooth disease, CMT) are a phenotypically and genetically heterogeneous group of disorders, which are currently untreatable. They are the most common inherited neuromuscular disorder, affecting around 1 in every 2,500 people (over 120,000 people in the US). Based on clinical neurophysiological and histopathological features, inherited neuropathies can be divided into two major forms: demyelinating (type 1) and axonal (type 2) CMT (Saporta, 2014). From a biological standpoint, these two major forms of CMT are associated with mutations in different sets of genes, affecting Schwann cell development and myelination (type 1) or peripheral axon physiology (type 2), although some overlap does exist (Figure 1). To date, over 70 genes have been associated with a CMT phenotype, making CMT an attractive natural model to study peripheral nervous system biology. Despite significant advances made in our knowledge of disease mechanisms in CMT, findings from animal models have so far translated poorly in clinical trials, underscoring the need for innovative methods to investigate the pathophysiology of these human disorders. Induced pluripotent stem cells (iPSCs) offer an unlimited source of patient specific, disease-relevant cell lines that can be used as a platform for identification of disease mechanisms, discovery of molecular targets and development of phenotypic screens for drug discovery (Saporta et al., 2011). iPSC-based models of neuromuscular disorders, including amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA) and inherited peripheral neuropathies, have successfully reproduced pathophysiological findings from previous animal and cellular models and have also identified new disease mechanisms with potential therapeutical implications.

[11] 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: 23
  • 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: 0.364) > 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].

[12] Novel STAG1 Frameshift Mutation in a Patient Affected by a Syndromic Form of Neurodevelopmental Disorder

  • Authors: Ester Di Muro, P. Palumbo, Mario Benvenuto, M. Accadia, M. D. Di Giacomo et al.
  • Year: 2021
  • Venue: Genes
  • URL: https://www.semanticscholar.org/paper/5645cba84a9fd5bc5561d2c0a4217b57929d4b68
  • DOI: 10.3390/genes12081116
  • PMID: 34440290
  • PMCID: 8392311
  • Citations: 14
  • Influential citations: 2
  • Summary: A 5 year old female patient with neurodevelopmental delay, mild intellectual disability, dysmorphic features and congenital anomalies is described, in which next generation sequencing analysis allowed us to identify a novel pathogenic variation c.2769_2770del p.(Ile924Serfs*8) in STAG1 gene, which result to be de novo.
  • Evidence snippets:
  • Snippet 1 (score: 0.362) > Obviously, more patients and genotype-phenotype correlation studies are needed to corroborate these data and to better delineate the clinical spectrum of this rare cohesinopathy. > From a molecular point of view, the variant c.2769_2770del p.(Ile924Serfs*8) detected in our patient was never reported before in medical literature, is absent in public databases, and is thus useful to expand the molecular spectrum of pathogenic alterations of STAG1. > Furthermore, a careful observation of the clinical and molecular features documented in the affected individuals, including ours, suggests that the etiopathogenetic mechanism may be the same, namely STAG1 haploinsufficiency. In fact, although to date very heterogeneous patients from a genetic point of view (carriers of STAG1 deletions, frameshift variants, missense) have been identified, and there does not seem to be a mutational hot spot for the STAG1 gene which has instead emerged for other clinical conditions such as Schinzel-Giedion syndrome (SGS, OMIM 269150) [18], all the patients described share specific clinical features. Therefore, in agreement with other authors [8], we suggest that the clinical manifestations and severity of the STAG1-syndrome does not depend on the nature/type of the gene variant but arises through transcriptional dysregulation due to depletion/defects of cohesin complex. Further functional studies on cellular and/or animal models, and analysis of gene expression profiles are needed to reinforce this emerging evidence on the etiopathogenetic mechanisms and to delineate the key events responsible for the onset of this rare cohesinopaty.

[13] Pharmacogenomic characterization of gemcitabine response – a framework for data integration to enable personalized medicine

  • Authors: Michael Harris, K. Bhuvaneshwar, Thanemozhi Natarajan, L. Sheahan, Difei Wang et al.
  • Year: 2013
  • Venue: Pharmacogenetics and Genomics
  • URL: https://www.semanticscholar.org/paper/1382ddf84b87736a73c2f2f81164ca876c29f4c4
  • DOI: 10.1097/FPC.0000000000000015
  • PMID: 24401833
  • PMCID: 3888473
  • Citations: 16
  • Summary: This in-silico study identified gene variants significantly associated with gemcitabine response that may help to personalize treatment in the clinic and gain insights into drug response mechanisms and to facilitate clinical trial design and regulatory reviews.
  • Evidence snippets:
  • Snippet 1 (score: 0.360) > Understanding the genetic and molecular mechanisms underlying complex diseases such as cancer is extremely challenging. Genome-wide association studies (GWAS) have been extensively used in the past decade to discover important genetic variants. However, the identified SNPs explain only a small proportion of the phenotypic variation, and the predictive power of these SNPs remains low for many complex diseases [10]. To fully elucidate genetic underpinnings of disease a systems biology approach is necessary to characterize variants, mRNA, copy number, proteins, and metabolites, as well as their cellular interactions [11]. Gene set and pathway association analyses are playing an increasingly important role in explaining disease mechanisms through the identification of functional genetic interactions [12]. Many gene-disease association analyses are based on SNP genotype profiling or gene expression studies. However, SNPs can influence many downstream processes including the expression levels of multiple genes and/or protein levels, and variations in expression levels can directly or indirectly impact disease progression and even drug response [13]. An integrative approach combining multiple data types can more accurately capture pathway associations [12] for discovery of clinically actionable variants. > Statistical approaches commonly used to associate variants with disease and/or drug response Fisher's exact test (FET) is commonly used in the association of germline polymorphisms with drug response [14]. The use of probabilistic networks in conjunction with traditional statistical models for mining relationships and associations from genotype-phenotype data is well established [15]. Probabilistic network methods for pharmacogenomics and newer methods such as the Markov Blanket concept may be helpful to better analyze these complex genotype-phenotype associations [16]. Considering the complexity of both cancer prognosis and individual drug response to chemotherapeutics, application of these association methods in conjunction with novel informatics and data integration approaches is necessary to identify clinically relevant variants for validation studies and ultimately testing in the clinic for pharmacogenomics applications.

[14] Renal ciliopathies: promising drug targets and prospects for clinical trials

  • Authors: L. Devlin, Praveen Dhondurao Sudhindar, J. Sayer
  • Year: 2023
  • Venue: Expert Opinion on Therapeutic Targets
  • URL: https://www.semanticscholar.org/paper/ab2155b6e12caba53d57ac0e8ce28860d69ec9fd
  • DOI: 10.1080/14728222.2023.2218616
  • PMID: 37243567
  • Citations: 10
  • Summary: The advances in basic science and clinical research into renal ciliopathies which have yielded promising small compounds and drug targets are reviewed, within both preclinical studies and clinical trials.
  • Evidence snippets:
  • Snippet 1 (score: 0.359) > Although renal ciliopathies can be classified into distinct syndromes, causative mutations in genes encoding proteins involved in the primary cilium or centrosome mean they may share overlapping mechanisms of disease, which may be amenable for therapeutic intervention (Figure 2). Abnormal functioning of proteins involved in ciliogenesis, such as CEP164, can prevent proper cilia formation, which will effect a myriad of downstream ciliary signaling pathways. Additionally, mutations in genes encoding for proteins involved in cargo trafficking or regulation, such as CEP290, will have implications for signal pathway transduction, as well as mutations in components of signaling pathways themselves, such as PKD1. In regard to renal ciliopathies, abnormalities in signaling pathways such as cAMP, Shh, Wnt, mTOR, and AMPK, likely cause misoriented cellular divisions, increased proliferation, increased fluid secretion and subsequent cystogenesis, consequently leading to further kidney damage. Ciliary and centriolar proteins which have roles in DDR and cell cycle regulation may also be driving a renal cystogenesis phenotype alongside increased fibrosis and apoptosis. Increased inflammation and dysfunctional mitochondria are also byproducts of dysregulated signaling pathways have been shown to contribute to the progression of renal ciliopathies. Extensive reviews of mechanisms of renal ciliopathy diseases have recently been performed [23,24]. Importantly, due to the wide range of cellular processes that primary cilia regulate, it is likely that in each syndrome there are multiple pathogenic drivers of disease. In some ways, this is advantageous as it offers many points for potential therapeutic targets. However, the cross talk between pathways and feedback loops introduces complications of changing one pathway without negatively affecting another. Further challenges arise with core biological pathways, such as Shh signaling, in which modification in vitro may be beneficial, but systemic treatment is unrealistic due to the expected severe side effects [18,24,116].

[15] Exploring the molecular mechanisms of subarachnoid hemorrhage and potential therapeutic targets: insights from bioinformatics and drug prediction

  • Authors: Yi Liu, Yang Zhang, Huan Wei, Li Wang, Lishang Liao
  • Year: 2025
  • Venue: Scientific Reports
  • URL: https://www.semanticscholar.org/paper/19a91d9c8cabec6a5a186729d545077e252ecb67
  • DOI: 10.1038/s41598-025-97642-8
  • PMID: 40229542
  • PMCID: 11997208
  • Summary: The findings not only elucidate the molecular mechanisms underlying SAH but also provide robust bioinformatics and experimental evidence supporting IRN as a promising therapeutic candidate, offering novel insights for future intervention strategies in SAH.
  • Evidence snippets:
  • Snippet 1 (score: 0.359) > involved in SAH pathology. As a result, our understanding of the cellular composition and microenvironment in SAH remains incomplete 8 . > Advances in bioinformatics provide powerful tools to analyze large-scale gene expression data and understand complex biological processes. By integrating transcriptomic data with immune cell infiltration analysis, we can gain a deeper understanding of the molecular mechanisms underlying SAH and identify potential key genes as therapeutic targets 9,10 . Previous studies have indicated that inflammation, oxidative stress, and cell death play crucial roles in the development of SAH, processes that are often closely associated with changes in specific cell types and immune responses 11 . > The goal of this study is to explore the molecular mechanisms of SAH, with a focus on immune cell infiltration and its role in disease progression. We aim to identify key genes and signaling pathways associated with SAH and investigate potential therapeutic strategies. Specifically, we will examine Isorhynchophylline (IRN) as a potential treatment for SAH and analyze its effects on relevant targets and signaling pathways. Through a comprehensive understanding of the pathological features of SAH, this study aims to provide valuable insights into future clinical interventions and treatment strategies.

[16] 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: 0.358) > 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

[17] Molecular Mechanisms and Risk Factors for the Pathogenesis of Hydrocephalus

  • Authors: Jing-wen Li, Xinjie Zhang, Jianfeng Guo, Chen Yu, Jun Yang
  • Year: 2022
  • Venue: Frontiers in Genetics
  • URL: https://www.semanticscholar.org/paper/d53bdf5f73f54a6d5a8be8777d23c465a13e9185
  • DOI: 10.3389/fgene.2021.777926
  • PMID: 35047005
  • PMCID: 8762052
  • Citations: 15
  • Influential citations: 2
  • Summary: Some possible fundamental molecular mechanisms and facilitating risk factors involved in the pathogenesis of hydrocephalus are elicited, and knowledge could be used to improve patient care in different ways, such as early precise diagnosis and effective therapeutic regimens.
  • Evidence snippets:
  • Snippet 1 (score: 0.355) > Cwh43 modifies the glycosylphosphatidylinositol-anchored proteins on the ependymal cells, and the mutant Cwh43 is related to iNPH in both humans and mice. The clinical features manifest as late-onset communicating hydrocephalus with symptoms of gait and balance dysfunction (Yang et al., 2021a). > The clinical manifestation and progression, as well as experimental investigations, indicate that hydrocephalus is a complex disease with polygenic involvement, rather than a simple CSF accumulation disorder. Although the current studies have revealed that some genetic mutations are involved in the pathogenesis of hydrocephalus, how these mutations are associated with the disorder of CSF circulation and their pathogenic roles in the pathological progression of hydrocephalus still remain largely unknown. Previous studies indicated that a lot of genetic mutations were relevant to the disorders of ciliary and/or centrosome, resulting in the dysfunction of the glymphatic system. However, how these mutations and their interactions contribute to the pathogenesis of hydrocephalus needs to be further elucidated. Moreover, there is still a lack of basic knowledge on the mechanisms underlying the cognitive functional impairment of hydrocephalus. Therefore, further extensive studies should be conducted to explore the underlying molecular mechanisms of identified and/or unidentified genes in the pathophysiology of hydrocephalus. Based on our knowledge, we propose that the genetic mutations relevant to ciliary and centrosomal proteins and the interaction between glymphatic system and ciliary/ centrosomal structures/functions may be a critical molecular mechanism in the pathophysiology of hydrocephalus. In addition, based on these fundamental molecular mechanisms, it is noteworthy that environmental and other acquired risks or etiological factors are also involved in the facilitation of ventricular enlargement.

[18] Conceptualizing Epigenetics and the Environmental Landscape of Autism Spectrum Disorders

  • Authors: G. Torres, Mervat Mourad, Saba Iqbal, Emmanuel Moses-Fynn, Ashani Pandita et al.
  • Year: 2023
  • Venue: Genes
  • URL: https://www.semanticscholar.org/paper/bf76f0682a8a1986ce889cee1fef818480abc83b
  • DOI: 10.3390/genes14091734
  • PMID: 37761876
  • PMCID: 10531442
  • Citations: 11
  • Summary: The present work reviews recent evolutionary, molecular, and epigenetic mechanisms potentially linked to the etiology of autism, and presents a clinical vignette to describe clusters of maladaptive behaviors frequently diagnosed in autistic patients.
  • Evidence snippets:
  • Snippet 1 (score: 0.353) > Currently, there are hundreds of gene variants associated with the onset of ASD. Thus, the clinical presentation of the disease is highly variable, as one or more behavioral symptoms may be related to other comorbid conditions (e.g., anxiety disorder, seizure disorder) besides autism. In addition, antagonistic pleiotropy and dosage-sensitive genes further fragment the phenotypic characteristics of ASD. Regardless, here, we present a prototypical autism clinical vignette with five behavioral specifiers: cognitive disability; deficits in social-emotional reciprocity; repetitive or stereotyped motor behavior; improper coordinated language communication; and gastrointestinal distress. Underneath this clinical vignette, we microdissected and correlated a particular phenotype of the disease to functionally and anatomically related regions of the brain and bilateral body plan. The structural organization imposed here will not only identify a wide network of cells, but also specific clusters of genes targeting a particular symptom within behaviorally relevant regions. It is expected that such structural organization will help lay a solid foundation in psychiatry and point to more focused approaches to a deeper understanding of ASD and its individualized treatment (Table 2). Autism Spectrum Disorders can be managed with appropriate pharmacotherapy. Selective dopamine (DA) and serotonin (5HT) based drugs are the mainstay of pharmacological treatment [43,44]. Additional neurotransmitter systems (e.g., norepinephrine (NE) and histamine) are also drug targets. It is not known whether the listed drugs regulate epigenetic mechanisms to counteract autistic symptoms. What is broadly known is that atypical, typical and psychoactive drugs act on DA and 5HT signaling pathways within regions of the human brain (e.g., cortex and basal ganglia) that are behaviorally relevant to the pathophysiology of ASD. Attention Deficit Hyperactivity Disorder (ADHD) and Fragile X Syndrome are debilitating neuropsychiatric conditions commonly diagnosed in pediatric populations. Fragile X Syndrome is a monogenic inherited disease leading to cognitive disability and ASD.

[19] Single-nucleus multi-omics identifies shared and distinct pathways in Pick’s and Alzheimer’s disease

  • Authors: Zechuan Shi, Sudeshna Das, S. Morabito, Jennifer T. Stocksdale, Emily Miyoshi et al.
  • Year: 2024
  • Venue: bioRxiv
  • URL: https://www.semanticscholar.org/paper/ca1fba4e0f132d9a309b13c1dc393873bf0de2ad
  • DOI: 10.1101/2024.09.06.611761
  • PMID: 39282421
  • PMCID: 11398495
  • Citations: 3
  • Summary: Comparative studies in AD and PiD reveal critical regulatory changes driving disease progression and identify risk gene associations for PiD, and validated the findings using CRISPR to excise a predicted enhancer region in UBE3A and developed an interactive database, scROAD, to visualize predicted single-cell TF occupancy and regulatory networks.
  • Evidence snippets:
  • Snippet 1 (score: 0.352) > Our differential analyses highlight the utility of our identified promoter-enhancer links in elucidating regulatory mechanisms, and revealed widespread chromatin accessibility and gene expression changes linked to PiD and AD pathology across major cell types. Some of these changes, including the increased chromatin accessibility and dysregulated gene expression involved in synap- tic signaling, apoptotic process, regulation of neuronal activity, cellular response to stress, and cell communication, may represent an attempt of neurons and oligodendrocytes interaction to reestablish homeostasis through necessary attempts to different genes. Some promoter-enhancer connections facilitated increased chromatin accessibility, potentially serving as a compensatory mechanism to mitigate the dysregulation of target genes. Other alterations, including positive regulation of endocytosis, genes responsible for cellular metabolic process, and genes encoding cellular response to unfolded/misfolded protein in astrocytes and microglia, may contribute to glial cell differentiation or immune activation in PiD and AD. Disruptions in the metabolic processes and cellular stress response compromise the balance in the cellular microenvironment and consequently contribute to the progression of PiD and AD. > While the causative molecular mechanisms of PiD remain unknown, our work offers new insights that assist in unraveling the nature of gene regulation in PiD, especially regarding genomic loci with well-described heritable disease risk. We capitalized on the AD and FTD GWAS data to identify genes associated with phenotypic variability between PiD and AD because of similar pathological and clinical traits, such as tauopathies and cognitive decline. GWASs have been widely used to enhance our understanding of polygenic human traits and to reveal clinically relevant risk variants for neurodegeneration. Notably, we identified genetic risk variants that overlapped with specific cell types to narrow down the potential non-coding variants underlying disease susceptibility. Furthermore, our analysis revealed that AD GWAS genes showed a highly significant overlap with differentially expressed genes in PiD cases, suggesting that these associations are not random. This highlights the potential convergent regulatory mechanisms that may be shared between PiD and AD, despite the distinct clinical manifestations.

[20] Can network biology unravel the aetiology of congenital hyperinsulinism?

  • Authors: A. Stevens, K. Cosgrove, R. Padidela, M. Skae, P. Clayton et al.
  • Year: 2013
  • Venue: Orphanet Journal of Rare Diseases
  • URL: https://www.semanticscholar.org/paper/474ed97fdbb2a604459faa0b626a8b7d20ed6bf4
  • DOI: 10.1186/1750-1172-8-21
  • PMID: 23394473
  • PMCID: 3599136
  • Citations: 9
  • Influential citations: 1
  • Summary: A rational argument for the use of computational biology as a valuable resource for identifying new candidate genes which may cause disease and for understanding the complex mechanisms which define the pathophysiology of this rare disease is presented.
  • Evidence snippets:
  • Snippet 1 (score: 0.352) > Congenital Hyperinsulinism (CHI) is a rare disease, but is the most common cause of recurrent hypoglycaemia in infancy [1]. The treatment of CHI can be difficult and involves drugs which may not be successful and often are poorly tolerated. As a potentially life-threatening condition, CHI is associated with lifelong sequelae -including critical brain damage (epilepsy, cerebral palsy and neurological impairment) in up to 40% of cases. To date, nine candidate genes associate with CHI, but for the majority of patientsestimated to be approximately 65%, both the aetiology of the CHI and the mechanisms of disease are unknown. > Our current approach to the classification and treatment of CHI is based largely upon observational correlations between the pathological analysis of candidate gene defects and clinical symptoms of hypoglycaemia [1][2][3]. In this respect, there are similarities between CHI and many other diseases in which numerous mutations in different genes give rise to clinical phenotypes that are essentially indistinguishable from one another. However, under normal physiological conditions, cells function correctly because there is a high degree of interdependency between individual biochemical components (DNA, RNA, proteins and metabolites) and their complex interactions (DNA-protein interactions, protein-protein interactions, metabolic and biochemical pathways, etc.), and tissues function in a co-ordinated manner because there is interplay between different cell types. Diseases rarely result from an abnormality in a single gene, but are in fact the manifestation of disturbances in the multiple networks that integrate cellular processes, and those that link cells with tissues, and tissues with organ systems. As a result, current approaches to molecular diagnosis, however valuable, have shortcomings. These include a lack of sensitivity in identifying preclinical disease, a poor ability to predict prognosis, and ambiguity in defining and resolving a condition where several clinical phenotypes can be observed. All of these inadequacies are evident in CHI, with our current understanding of the causes of disease failing to distinguish transient from persistent disease at the point of presentation and to determine accurately the severity of disease.

Notes

  • This provider combines search_papers_by_relevance with snippet_search.
  • No synthesis or second-stage model call is performed.