Chromosome 2q32-q33 Deletion Syndrome

Mendelian MONDO:0012864 Pathograph 27 Show in embeddings browser hereditary disease chromosomal disorder

Chromosome 2q32-q33 deletion syndrome is a contiguous-gene microdeletion disorder caused by interstitial deletions of chromosome 2q32-q33 that include SATB2 and several neighbouring dosage-sensitive genes (e.g., GLS, MYO1B, TMEFF2, PGAP1). It is characterized by severe developmental delay / intellectual disability with absent or severely limited speech, growth retardation, craniofacial dysmorphism, feeding difficulties, thin and sparse hair, cleft or high-arched palate, and dental anomalies, with a recurrent behavioural phenotype and skeletal/bone fragility. SATB2 haploinsufficiency is the major dosage-sensitive driver of the cognitive and palatal phenotype, while loss of the adjacent genes is thought to contribute to the more complex behavioural and ectodermal features. Because alterations of SATB2 by any mechanism (contiguous deletion, intragenic deletion/duplication, translocation, or point mutation) produce a convergent clinically recognizable phenotype, this deletion syndrome is now lumped with point-mutation cases under the umbrella term SATB2-associated syndrome (Glass syndrome, OMIM 612313).

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1
Inheritance
6
Pathophys.
24
Phenotypes
27
Pathograph
2
Genes
10
Medical Actions
1
Differentials
9
References
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Inheritance

1
Autosomal dominant inheritance HP:0000006
The deletion acts in an autosomal dominant fashion through haploinsufficiency and almost always arises de novo; rare recurrence occurs through parental mosaicism.
autosomal dominant inheritance
Show evidence (1 reference)
PMID:29023086 SUPPORT Human Clinical
"SAS is an autosomal dominant disorder. Almost all probands with SAS reported to date have the disorder as the result of a de novo genetic event."
GeneReviews establishes autosomal dominant inheritance with a predominantly de novo occurrence for SATB2-associated syndrome, which subsumes the 2q32-q33 deletion form.
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Pathophysiology

6
Contiguous-gene 2q32-q33 haploinsufficiency
Interstitial deletion of chromosome 2q32-q33 removes one copy of a contiguous block of genes. The commonly deleted region contains SATB2 plus neighbouring dosage-sensitive genes (GLS, MYO1B, TMEFF2, PGAP1, among others), so the phenotype reflects combined haploinsufficiency, with SATB2 loss as the major driver of the cognitive and craniofacial/palatal features.
SATB2 hgnc:21637 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves SATB2 (hgnc:21637). hgnc:21637 is a gene from the HUGO Gene Nomenclature Committee. GLS hgnc:4331 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves GLS (hgnc:4331). hgnc:4331 is a gene from the HUGO Gene Nomenclature Committee. MYO1B hgnc:7596 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves MYO1B (hgnc:7596). hgnc:7596 is a gene from the HUGO Gene Nomenclature Committee. TMEFF2 hgnc:11867 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves TMEFF2 (hgnc:11867). hgnc:11867 is a gene from the HUGO Gene Nomenclature Committee. PGAP1 hgnc:25712 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves PGAP1 (hgnc:25712). hgnc:25712 is a gene from the HUGO Gene Nomenclature Committee.
Downstream
SATB2 haploinsufficiency Loss of one SATB2 copy is the major dosage-sensitive driver of the cognitive and palatal phenotype.
Additional contiguous-gene contribution to the behavioural and ectodermal phenotype Loss of adjacent genes (GLS, MYO1B, TMEFF2) and ectodermal features are attributed to the broader deletion beyond SATB2.
Show evidence (2 references)
PMID:19668335 SUPPORT Human Clinical
"The commonly deleted region contains at least seven genes."
Establishes that 2q32q33 microdeletion syndrome is a contiguous-gene disorder involving multiple genes, not a single-gene defect.
PMID:26811410 SUPPORT Human Clinical
"The deletion encompassed 22 known OMIM genes, including GLS, MYO1B, TMEFF2, PGAP1 and SATB2."
A molecularly characterized 8.6 Mb 2q32.2q33.1 deletion documents the contiguous block of dosage-sensitive genes that includes SATB2.
SATB2 haploinsufficiency
SATB2 encodes a nuclear-matrix-attachment-region-binding transcription factor that activates transcription of multiple genes and shapes higher-order chromatin structure. A 50% reduction in functional SATB2 protein (haploinsufficiency) disrupts the dosage-sensitive developmental programs SATB2 controls in the palate, cortex, and skeleton.
SATB2 hgnc:21637 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves SATB2 (hgnc:21637). hgnc:21637 is a gene from the HUGO Gene Nomenclature Committee.
transcriptional regulation GO:0006357 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased transcriptional regulation, annotated with regulation of transcription by RNA polymerase II (GO:0006357). GO:0006357 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Craniofacial and palatal developmental dysregulation Reduced SATB2 dosage disrupts midline craniofacial patterning and palate formation.
Cortical neuron specification defect Reduced SATB2 dosage impairs specification of upper-layer cortical projection neurons.
Osteoblast differentiation defect and bone fragility Reduced SATB2 dosage impairs osteoblast differentiation and bone mineralization.
Show evidence (2 references)
PMID:19668335 SUPPORT Human Clinical
"Haploinsufficiency of one of these genes, SATB2, a DNA-binding protein that regulates gene expression, has been implicated as causative in the cleft or high palate of individuals with 2q32q33 microdeletion syndrome."
Identifies SATB2 haploinsufficiency as the gene-level mechanism driving the core craniofacial features of the deletion syndrome.
PMID:28151491 SUPPORT Human Clinical
"SATB2 haploinsufficiency is a common cause of syndromic intellectual disability."
Confirms haploinsufficiency as the shared pathogenic mechanism producing syndromic intellectual disability.
Craniofacial and palatal developmental dysregulation
SATB2 controls midline craniofacial patterning, jaw growth, and palate formation. Its loss disrupts roof-of-mouth development, producing cleft or high-arched palate, micrognathia, dental anomalies, and facial dysmorphism.
osteoblast CL:0000062 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves osteoblast (CL:0000062). CL:0000062 is a cell type from the Cell Ontology.
palate development GO:0060021 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased palate development, annotated with roof of mouth development (GO:0060021). GO:0060021 is a biological process from the Gene Ontology. ↓ DECREASED embryonic cranial skeleton morphogenesis GO:0048701 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased embryonic cranial skeleton morphogenesis (GO:0048701). GO:0048701 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Cleft palate Failure of palatal shelf fusion produces cleft palate.
High palate Disrupted palatal morphogenesis produces a high-arched palate when overt clefting is absent.
Abnormal facial shape Disturbed craniofacial patterning produces the characteristic facial dysmorphism.
Micrognathia Impaired SATB2-dependent jaw growth and distal mandibular patterning produces micrognathia.
Abnormality of the dentition Disrupted craniofacial/odontogenic development produces dental crowding and abnormally shaped teeth.
Show evidence (2 references)
PMID:24301056 SUPPORT Human Clinical
"In humans, chromosomal translocations and deletions of 2q33.1 leading to SATB2 haploinsufficiency are associated with cleft palate (CP), facial dysmorphism and intellectual disability (ID)."
Directly links SATB2 haploinsufficiency from 2q33.1 deletions to cleft palate and facial dysmorphism.
PMID:27774744 SUPPORT Model Organism
"At birth, mice lacking Satb2 have severely reduced jaw length and die from cleft palate"
Mouse knockout data establish the dosage-sensitive role of SATB2 in jaw growth and palate closure underlying the human craniofacial phenotype.
Cortical neuron specification defect
SATB2 specifies upper-layer cortico-cortical projection neurons and the formation of callosal axonal projections. Its loss misroutes these neurons, providing a mechanism for the severe intellectual disability and the profound speech/language impairment.
cortical upper-layer projection neuron CL:0000540 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cortical upper-layer projection neuron, annotated with neuron (CL:0000540). CL:0000540 is a cell type from the Cell Ontology.
cerebral cortex neuron differentiation GO:0021895 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased cerebral cortex neuron differentiation (GO:0021895). GO:0021895 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Intellectual disability Defective cortical neuron specification produces intellectual disability.
Global developmental delay Disrupted neurodevelopment presents as global developmental delay.
Delayed speech and language development Cortical/speech-network involvement produces severely impaired speech and language development.
Absent speech The most severe end of the speech phenotype is absent speech.
Show evidence (2 references)
PMID:27774744 SUPPORT Model Organism
"In mice, studies have found a critical role for Satb2 in brain development, particularly in the specification of cortical upper layer neurons"
Mouse data establish SATB2's role in specifying upper-layer cortical neurons, the developmental basis for the cognitive phenotype.
PMID:24301056 SUPPORT Model Organism
"Vertebrate animal models have shown that Satb2 has a crucial role in craniofacial patterning and osteoblast differentiation, as well as in determining the fates of neuronal projections in the developing neocortex."
Confirms the conserved role of SATB2 in determining cortical neuronal projection fates relevant to the neurodevelopmental phenotype.
Osteoblast differentiation defect and bone fragility
SATB2 promotes osteoblast differentiation and bone mineralization (in part by regulating osteogenic transcription). Its haploinsufficiency reduces bone mineral density and, particularly with alleles that escape nonsense-mediated decay, produces increased bone turnover, fractures, tibial bowing, and scoliosis.
osteoblast CL:0000062 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves osteoblast (CL:0000062). CL:0000062 is a cell type from the Cell Ontology.
osteoblast differentiation GO:0001649 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased osteoblast differentiation (GO:0001649). GO:0001649 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Reduced bone mineral density Impaired osteoblast function reduces bone mineral density.
Increased susceptibility to fractures Low bone mass and increased bone turnover predispose to fractures.
Tibial bowing Mechanically weakened bone produces progressive tibial bowing.
Scoliosis Skeletal fragility and vertebral involvement contribute to scoliosis.
Show evidence (2 references)
PMID:35241104 SUPPORT Human Clinical
"We conclude that SATB2 pathogenic variants are responsible for skeletal demineralization and osteoporosis. We found increased levels of bone formation markers, supporting the key role of SATB2 in osteoblast differentiation."
A prospective cohort links SATB2 loss to skeletal demineralization and osteoporosis via osteoblast dysfunction.
PMID:27774744 SUPPORT Model Organism
"loss of Satb2 leads to reduced levels of bone mineralization, resulting in short and brittle limb bones"
Mouse data establish the osteogenic role of SATB2 underlying the human bone fragility phenotype.
Additional contiguous-gene contribution to the behavioural and ectodermal phenotype
Beyond SATB2, loss of neighbouring genes is thought to shape the more complex behavioural phenotype (with the glutaminase gene GLS and MYO1B/TMEFF2 proposed as candidates), while thin skin and sparse hair in patients with larger deletions are attributed to loss of additional, as-yet-undefined ectodermal genes.
GLS hgnc:4331 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves GLS (hgnc:4331). hgnc:4331 is a gene from the HUGO Gene Nomenclature Committee. MYO1B hgnc:7596 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves MYO1B (hgnc:7596). hgnc:7596 is a gene from the HUGO Gene Nomenclature Committee. TMEFF2 hgnc:11867 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves TMEFF2 (hgnc:11867). hgnc:11867 is a gene from the HUGO Gene Nomenclature Committee.
Downstream
Autistic behavior Combined gene loss contributes to autistic features within the behavioural spectrum.
Aggressive behavior The recurrent behavioural pattern includes aggression and self-injury.
Sleep disturbance Sleeping problems are part of the recurrent behavioural phenotype.
Sparse hair Thin, sparse hair is an ectodermal feature attributed to broader 2q32-q33 deletion beyond SATB2.
Show evidence (2 references)
PMID:26811410 SUPPORT Human Clinical
"it is our opinion that the SATB2 gene is also crucial to the behavioural problems noted in this current proband and that deletion of the GLS, MYO1B, and TMEFF2 genes presumably contributes to the more complex behavioural characteristics observed"
Supports a contiguous-gene contribution beyond SATB2 to the complex behavioural phenotype.
PMID:19668335 SUPPORT Human Clinical
"Only one of the subjects presented here had a cleft palate, suggesting reduced penetrance for this feature."
Intragenic SATB2 deletions show reduced penetrance of cleft palate, consistent with variable expressivity and contributions of additional loci to the full deletion phenotype.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Chromosome 2q32-q33 Deletion 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

24
Cardiovascular 1
Abnormal heart morphology OCCASIONAL 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.
Show evidence (1 reference)
PMID:29023086 SUPPORT Human Clinical
"In those with a larger deletion involving SATB2 and adjacent genes, cardiovascular, genitourinary, and ectodermal findings may also be present."
GeneReviews attributes cardiovascular findings to larger contiguous deletions.
Digestive 1
Feeding difficulties FREQUENT 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:40474278 SUPPORT Human Clinical
"Early and persistent feeding difficulties were found in 55% of the children."
Cohort data document feeding difficulties in a majority of children.
Eye 1
Strabismus HP:0000486 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Strabismus (HP:0000486). HP:0000486 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29023086 SUPPORT Human Clinical
"Other finding can include pre- and postnatal growth restriction, feeding issues, and eye anomalies (strabismus, refractive error)."
GeneReviews lists strabismus among the eye anomalies.
Head and Neck 6
Drooling VERY_FREQUENT HP:0002307 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Drooling (HP:0002307). HP:0002307 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28151491 SUPPORT Human Clinical
"Recurrent clinical features included neurodevelopmental impairment (19/19), absent/near absent speech (16/19), normal somatic growth (17/19), cleft palate (9/19), drooling (12/19), and dental anomalies (8/19)."
Drooling in 12/19 (63%) supports a very frequent oral-motor phenotype.
Cleft palate FREQUENT HP:0000175 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cleft palate (HP:0000175). HP:0000175 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28151491 SUPPORT Human Clinical
"Recurrent clinical features included neurodevelopmental impairment (19/19), absent/near absent speech (16/19), normal somatic growth (17/19), cleft palate (9/19), drooling (12/19), and dental anomalies (8/19)."
Cleft palate in 9/19 (47%) supports a frequent palatal phenotype.
High palate HP:0000218 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is High palate (HP:0000218). HP:0000218 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:19668335 SUPPORT Human Clinical
"Clinical features of this syndrome include severe mental retardation, growth retardation, dysmorphic features, thin and sparse hair, feeding difficulties and cleft or high palate."
The defining clinical description includes cleft or high palate.
Abnormality of the dentition VERY_FREQUENT HP:0000164 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormality of the dentition (HP:0000164). HP:0000164 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40474278 SUPPORT Human Clinical
"An anomaly of RS spectrum was found in half the cases, and dental malformations were described in 90%."
Dental malformations in 90% support a very frequent dental phenotype.
Abnormal facial shape HP:0001999 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal facial shape (HP:0001999). HP:0001999 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:24301056 SUPPORT Human Clinical
"In humans, chromosomal translocations and deletions of 2q33.1 leading to SATB2 haploinsufficiency are associated with cleft palate (CP), facial dysmorphism and intellectual disability (ID)."
Facial dysmorphism is a recognized feature of SATB2 haploinsufficiency from 2q33.1 deletions.
Micrognathia HP:0000347 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Micrognathia (HP:0000347). HP:0000347 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:27774744 SUPPORT Human Clinical
"Behavioral abnormalities, facial dysmorphism, cleft palate, micrognathia, dental anomalies, and musculoskeletal changes have also been reported consistently in all etiological subgroups"
Micrognathia is reported consistently across all etiological subgroups of SATB2-associated syndrome, including the deletion form.
PMID:27774744 SUPPORT Model Organism
"The SAS phenotype also includes craniofacial anomalies that include micrognathia and cleft palate. Similarly, Satb2 knock‐out mice display hypoplasia of the distal jaw skeleton."
Satb2 knockout mice recapitulate distal jaw hypoplasia, the developmental basis for the human micrognathia phenotype.
Integument 1
Sparse hair HP:0008070 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sparse hair (HP:0008070). HP:0008070 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26811410 SUPPORT Human Clinical
"Individuals with deletions of 2q32q33 and who present with learning difficulties, growth retardation, dysmorphic features, thin and sparse hair, feeding difficulties, and high or cleft palate have been classified as having a new microdeletion syndrome."
Thin and sparse hair is part of the defining phenotype of the 2q32q33 deletion syndrome.
Limbs 1
Tibial bowing HP:0002982 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Tibial bowing (HP:0002982). HP:0002982 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:27409069 SUPPORT Human Clinical
"We report a SATB2 mutation (c.2018dupA; p.(H673fs)) in a 15-year-old patient whose SATB2-associated syndrome phenotype is accompanied by osteoporosis, fractures, progressive tibial bowing, and scoliosis."
Documents progressive tibial bowing within the bone phenotype.
Musculoskeletal 3
Hypotonia FREQUENT 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:27774744 SUPPORT Human Clinical
"hypotonia (53%), thin skin or reduced subcutaneous fat (53%), cleft palate (47%), brain MRI abnormalities (45%), and dental crowding (44%)"
Hypotonia is documented in 53% of patients with large deletions.
Reduced bone mineral density FREQUENT HP:0004349 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Reduced bone mineral density (HP:0004349). HP:0004349 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35241104 SUPPORT Human Clinical
"Skeletal demineralization (16/17, 94%) and cortical thinning of vertebrae (15/17) were the most frequent radiological features at the spine."
Skeletal demineralization in 94% supports a frequent low-bone-mass phenotype.
Scoliosis HP:0002650 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Scoliosis (HP:0002650). HP:0002650 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29023086 SUPPORT Human Clinical
"Skeletal anomalies can include scoliosis, tibial bowing, and joint contractures."
GeneReviews lists scoliosis among the skeletal anomalies.
Nervous System 8
Intellectual disability VERY_FREQUENT 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:29023086 SUPPORT Human Clinical
"SATB2-associated syndrome (SAS) is a multisystem disorder in which all affected individuals have developmental delay / intellectual disability that can range from mild to profound but is most commonly moderate to profound."
GeneReviews documents intellectual disability in all affected individuals.
Global developmental delay VERY_FREQUENT 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 (1 reference)
PMID:29023086 SUPPORT Human Clinical
"SATB2-associated syndrome (SAS) is a multisystem disorder in which all affected individuals have developmental delay / intellectual disability that can range from mild to profound but is most commonly moderate to profound."
GeneReviews documents developmental delay in all affected individuals.
Delayed speech and language development VERY_FREQUENT HP:0000750 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Delayed speech and language development (HP:0000750). HP:0000750 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40474278 SUPPORT Human Clinical
"A major language delay was described in all patients; 65% had a vocabulary of 10 words or less."
Cohort data document major language delay in all patients.
Absent speech VERY_FREQUENT HP:0001344 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Absent speech (HP:0001344). HP:0001344 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28151491 SUPPORT Human Clinical
"Recurrent clinical features included neurodevelopmental impairment (19/19), absent/near absent speech (16/19), normal somatic growth (17/19), cleft palate (9/19), drooling (12/19), and dental anomalies (8/19)."
Absent or near-absent speech in 16/19 supports a very frequent severe speech phenotype.
Autistic behavior HP:0000729 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Autistic behavior (HP:0000729). HP:0000729 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28151491 SUPPORT Human Clinical
"The behavioral phenotype appeared to show the most marked discrepancy within the cohort, with both severe autistic features and friendly/happy personalities being recurrently reported."
Severe autistic features are recurrently reported within the behavioural phenotype.
Aggressive behavior HP:0000718 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Aggressive behavior (HP:0000718). HP:0000718 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26811410 SUPPORT Human Clinical
"A specific behavioural pattern, with hyperactivity and motor restlessness, chaotic behaviour, a happy personality but with periods of aggression and anxiety, sleeping problems and self-mutilation, has also been reported in some of these patients."
Aggression and self-injury are described within the recurrent behavioural pattern.
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:26811410 SUPPORT Human Clinical
"A specific behavioural pattern, with hyperactivity and motor restlessness, chaotic behaviour, a happy personality but with periods of aggression and anxiety, sleeping problems and self-mutilation, has also been reported in some of these patients."
Sleeping problems are part of the recurrent behavioural phenotype.
Seizure OCCASIONAL HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29023086 SUPPORT Human Clinical
"While only about 20% of affected individuals have clinical seizures, a subset of affected individuals have electrical status epilepticus in sleep."
GeneReviews documents clinical seizures in about 20% of patients.
Growth 1
Growth delay FREQUENT HP:0001510 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Growth delay (HP:0001510). HP:0001510 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:27774744 SUPPORT Human Clinical
"feeding difficulties (76%), pre‐ or postnatal growth retardation (71%), hypotonia (53%), thin skin or reduced subcutaneous fat (53%), cleft palate (47%), brain MRI abnormalities (45%), and dental crowding (44%)"
The review's tabulation of large-deletion features documents pre- or postnatal growth retardation in 71% of patients, supporting a frequent growth-delay phenotype.
Other 1
Increased susceptibility to fractures FREQUENT HP:0002659 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Increased susceptibility to fractures (HP:0002659). HP:0002659 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35241104 SUPPORT Human Clinical
"Vertebral compression fractures affected 6/17 patients (35%)."
Vertebral compression fractures in 35% support a frequent fracture susceptibility.
🧬

Genetic Associations

2
2q32-q33 contiguous-gene deletion (Causal chromosomal deletion)
Show evidence (2 references)
PMID:26811410 SUPPORT Human Clinical
"Chromosomal abnormalities involving 2q32q33 deletions are very rare and present with a specific phenotype."
Establishes the causal 2q32q33 deletion and its recognizable phenotype.
PMID:19668335 SUPPORT Human Clinical
"Our results suggest that deletion of SATB2 is responsible for several of the clinical features associated with 2q32q33 microdeletion syndrome."
Pinpoints SATB2 within the deletion as responsible for several core features.
SATB2 haploinsufficiency (Major dosage-sensitive driver gene)
Gene: SATB2 hgnc:21637 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is SATB2 (hgnc:21637). hgnc:21637 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (1 reference)
PMID:27409069 SUPPORT Human Clinical
"Haploinsufficiency of SATB2 causes cleft palate, intellectual disability with deficient speech, facial and dental abnormalities, and other variable features known collectively as SATB2-associated syndrome."
Summarizes SATB2 haploinsufficiency as the driver of the recognizable phenotype.
💊

Medical Actions

10
Supportive and 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
Management is supportive and multidisciplinary, with standard treatment of developmental delay/intellectual disability, neurobehavioural issues, palatal, dental, skeletal, and ophthalmologic manifestations.
Show evidence (1 reference)
PMID:27774744 SUPPORT Human Clinical
"The multisystemic nature of this syndrome demands a multisystemic approach and we propose evaluation and management guidelines."
The review frames a multisystem, supportive management approach.
Genetic counseling
Action: Genetic CounselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Genetic Counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. NCIT:C15240
Genetic counseling addresses the de novo nature of most cases and the small recurrence risk from parental mosaicism.
Show evidence (1 reference)
PMID:29023086 SUPPORT Human Clinical
"SAS is an autosomal dominant disorder. Almost all probands with SAS reported to date have the disorder as the result of a de novo genetic event."
The inheritance pattern and de novo nature underpin genetic counseling.
Speech therapy and augmentative communication
Action: speech therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is speech therapy, annotated with Speech Language Therapy (NCIT:C159273). NCIT:C159273 is a clinical intervention from the NCI Thesaurus. Ontology label: Speech Language Therapy NCIT:C159273
Early speech therapy and augmentative/alternative communication are central given the near-universal severe speech impairment.
Show evidence (1 reference)
PMID:40474278 SUPPORT Human Clinical
"A major language delay was described in all patients; 65% had a vocabulary of 10 words or less."
The universal severe language phenotype supports early speech-language intervention.
Feeding and nutritional therapy
Action: dietary interventionNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is dietary intervention (NCIT:C15447). NCIT:C15447 is a clinical intervention from the NCI Thesaurus. Ontology label: Dietary Intervention NCIT:C15447
Feeding therapy, swallowing evaluation, and nutritional support address the common early feeding difficulties; gastrostomy may be required when feeding issues persist.
Show evidence (1 reference)
PMID:40474278 SUPPORT Human Clinical
"Early and persistent feeding difficulties were found in 55% of the children."
Frequent feeding difficulties support feeding/nutritional intervention.
Physical therapy
Action: physical therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is physical therapy (NCIT:C15302). NCIT:C15302 is a clinical intervention from the NCI Thesaurus. Ontology label: Physical Therapy NCIT:C15302
Physical therapy addresses hypotonia and motor delay.
Show evidence (1 reference)
PMID:27774744 SUPPORT Human Clinical
"Physical and occupational therapies assessment is equally indicated, with therapy provided as necessary."
The review recommends physical therapy as part of management.
Occupational therapy
Action: occupational therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is occupational therapy (NCIT:C121351). NCIT:C121351 is a clinical intervention from the NCI Thesaurus. Ontology label: Occupational Therapy NCIT:C121351
Occupational therapy supports adaptive and fine-motor skills.
Show evidence (1 reference)
PMID:27774744 SUPPORT Human Clinical
"Physical and occupational therapies assessment is equally indicated, with therapy provided as necessary."
The review recommends occupational therapy as part of management.
Early intervention and educational support
Action: early intervention servicesNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is early intervention services, annotated with Early Intervention (NCIT:C159524). NCIT:C159524 is a clinical intervention from the NCI Thesaurus. Ontology label: Early Intervention NCIT:C159524
Early-intervention programs and individualized education plans support development given the universal cognitive and speech involvement.
Show evidence (1 reference)
PMID:29023086 SUPPORT Human Clinical
"Standard treatment for developmental delay / intellectual disability, neurobehavioral issues, cleft palate, micrognathia, dental anomalies, scoliosis, tibial bowing, joint contractures, spasticity, epilepsy, undescended testes, inguinal hernia, hypospadias, refractive error, strabismus, and..."
GeneReviews recommends standard developmental treatment for the cognitive phenotype.
Behavioral and mental-health support
Action: cognitive and behavioral interventionNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is cognitive and behavioral intervention, annotated with Behavioral Intervention (NCIT:C15184). NCIT:C15184 is a clinical intervention from the NCI Thesaurus. Ontology label: Behavioral Intervention NCIT:C15184
Behavioural interventions and mental-health support address the recurrent behavioural phenotype (aggression, self-injury, hyperactivity, sleep problems).
Show evidence (1 reference)
PMID:27774744 SUPPORT Human Clinical
"From the neurodevelopmental perspective, medical management of behavioral issues could be required with further psychological mental health support."
The review recommends behavioural and mental-health management.
Antiepileptic drug therapy
Action: anticonvulsant agent therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is anticonvulsant agent therapy, annotated with Anticonvulsant Therapy (NCIT:C64172). NCIT:C64172 is a clinical intervention from the NCI Thesaurus. Ontology label: Anticonvulsant Therapy NCIT:C64172
Anticonvulsant therapy is indicated when clinical seizures occur (about 20% of patients).
Show evidence (1 reference)
PMID:29023086 SUPPORT Human Clinical
"While only about 20% of affected individuals have clinical seizures, a subset of affected individuals have electrical status epilepticus in sleep."
Clinical seizures in a subset support antiepileptic management when present.
Bone-directed therapy and bisphosphonates
Action: bisphosphonate agent therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is bisphosphonate agent therapy, annotated with Bisphosphonate Therapy (NCIT:C198585). NCIT:C198585 is a clinical intervention from the NCI Thesaurus. Ontology label: Bisphosphonate Therapy NCIT:C198585
Bone health management includes optimizing physical activity and calcium / vitamin D, with bisphosphonates or denosumab and bone-turnover surveillance to prevent fractures and progressive deformity.
Show evidence (1 reference)
PMID:27409069 SUPPORT Human Clinical
"We propose surveillance and treatment with osteoclast inhibitors to prevent fractures and to slow progressive bone deformities."
Osteoclast-inhibitor therapy (bisphosphonates) is proposed for the bone phenotype.
🔬

Biochemical Markers

4
Osteocalcin (INCREASED)
Context: Bone-formation marker; elevated in SATB2-associated syndrome, consistent with the SATB2-dependent role in osteoblast differentiation and increased bone turnover.
Pathograph Readouts
Readout Of Osteoblast differentiation defect and bone fragility Positive Diagnostic
Elevated osteocalcin reports increased bone turnover/formation arising from the SATB2-dependent osteoblast program.
Show evidence (2 references)
PMID:35241104 SUPPORT Human Clinical
"osteocalcin and serum procollagen type 1 amino-terminal propeptide (P1NP) were both increased. Vitamin D insufficiency was frequent (66.7%)."
The prospective skeletal cohort documents increased osteocalcin as a bone-formation marker.
PMID:27409069 SUPPORT Human Clinical
"Elevations in alkaline phosphatase, urinary N-telopeptide/creatinine ratio, and osteocalcin in the patient indicate increased bone turnover."
A dominant-negative-allele patient shows elevated osteocalcin indicating increased bone turnover.
Procollagen type 1 amino-terminal propeptide (P1NP) (INCREASED)
Context: Bone-formation marker; elevated in the SATB2-associated skeletal phenotype.
Pathograph Readouts
Readout Of Osteoblast differentiation defect and bone fragility Positive Diagnostic
Elevated P1NP reports increased osteoblastic bone-formation activity.
Show evidence (1 reference)
PMID:35241104 SUPPORT Human Clinical
"osteocalcin and serum procollagen type 1 amino-terminal propeptide (P1NP) were both increased. Vitamin D insufficiency was frequent (66.7%)."
The prospective skeletal cohort documents increased P1NP as a bone-formation marker.
Alkaline phosphatase (INCREASED)
Context: Bone-turnover marker reported as elevated in a SATB2-associated syndrome patient with a dominant-negative allele; in a separate skeletal cohort ALP was in the upper-normal range, reflecting variable expression.
Pathograph Readouts
Readout Of Osteoblast differentiation defect and bone fragility Positive Diagnostic
Elevated alkaline phosphatase reports increased bone turnover.
Show evidence (1 reference)
PMID:27409069 SUPPORT Human Clinical
"Elevations in alkaline phosphatase, urinary N-telopeptide/creatinine ratio, and osteocalcin in the patient indicate increased bone turnover."
A dominant-negative-allele patient shows elevated alkaline phosphatase indicating increased bone turnover.
Urinary N-telopeptide/creatinine ratio (INCREASED)
Context: Bone-resorption marker; elevated urinary N-telopeptide/creatinine ratio reflects increased bone turnover in the skeletal phenotype.
Pathograph Readouts
Readout Of Osteoblast differentiation defect and bone fragility Positive Diagnostic
Elevated urinary N-telopeptide reports increased bone resorption / turnover.
Show evidence (1 reference)
PMID:27409069 SUPPORT Human Clinical
"Elevations in alkaline phosphatase, urinary N-telopeptide/creatinine ratio, and osteocalcin in the patient indicate increased bone turnover."
The urinary N-telopeptide/creatinine ratio is elevated, indicating increased bone resorption.
🔬

Diagnosis

2
Chromosomal microarray
Chromosomal microarray defines the 2q32-q33 deletion and its gene content and is the principal diagnostic test for the contiguous-gene deletion.
genetic testing NCIT:C15709 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:29023086 SUPPORT Human Clinical
"a heterozygous non-recurrent deletion at 2q33.1 that includes SATB2"
GeneReviews lists a 2q33.1 deletion including SATB2 as a diagnostic molecular finding, identified by chromosomal microarray.
Molecular genetic testing
Sequencing and deletion/duplication analysis of SATB2 (or a multigene panel / exome) confirms the diagnosis across the spectrum of SATB2 alterations.
molecular genetic testing NCIT:C19770 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:24301056 SUPPORT Human Clinical
"Exome sequencing revealed a de novo nonsense mutation in the SATB2 gene (c.715C>T; p.R239*)."
Molecular sequencing identifies SATB2 alterations in patients without a visible deletion.
📈

Progression

2
Congenital and early-childhood multisystem presentation
Age: Birth through early childhood
Palatal and feeding difficulties are evident from birth, while developmental delay, severe speech impairment, hypotonia, and behavioural problems emerge in infancy and early childhood.
Show evidence (1 reference)
PMID:40474278 SUPPORT Human Clinical
"Early and persistent feeding difficulties were found in 55% of the children. Communication was abnormal from the first months of life, with poor babbling in 85% of them."
Cohort data confirm an early-onset oral and communication phenotype apparent from the first months of life.
Childhood-to-adulthood skeletal and neurobehavioural course
Age: Childhood through adulthood
Bone fragility (osteopenia/osteoporosis, fractures, tibial bowing, scoliosis) and behavioural manifestations become increasingly relevant with age, and secondary cognitive decline has been documented in at least one long-followed adult, supporting age-dependent surveillance.
Show evidence (1 reference)
PMID:26811410 SUPPORT Human Clinical
"This current patient is also, to our knowledge, the only patient with 2q32q33 microdeletion syndrome with secondary cognitive decline documented by psychometric tests."
A long-followed adult demonstrates that the neurocognitive course can progress over time in this deletion syndrome.
🔀

Differential Diagnoses

1

Conditions with similar clinical presentations that must be differentiated from Chromosome 2q32-q33 Deletion Syndrome:

2q37 deletion syndrome MONDO:0010886
Overlapping Features 2q37 deletion syndrome is another chromosome 2q contiguous-gene deletion with developmental delay, but differs in gene content (HDAC4) and skeletal phenotype (brachydactyly type E).
{ }

Source YAML

click to show 
name: Chromosome 2q32-q33 Deletion Syndrome
creation_date: "2026-06-30T00:00:00Z"
synonyms:
- 2q32q33 microdeletion syndrome
- 2q33.1 microdeletion syndrome
- SATB2-associated syndrome (deletion form)
- Glass syndrome
description: >-
  Chromosome 2q32-q33 deletion syndrome is a contiguous-gene microdeletion
  disorder caused by interstitial deletions of chromosome 2q32-q33 that include
  SATB2 and several neighbouring dosage-sensitive genes (e.g., GLS, MYO1B,
  TMEFF2, PGAP1). It is characterized by severe developmental delay / intellectual
  disability with absent or severely limited speech, growth retardation,
  craniofacial dysmorphism, feeding difficulties, thin and sparse hair, cleft or
  high-arched palate, and dental anomalies, with a recurrent behavioural phenotype
  and skeletal/bone fragility. SATB2 haploinsufficiency is the major dosage-sensitive
  driver of the cognitive and palatal phenotype, while loss of the adjacent genes
  is thought to contribute to the more complex behavioural and ectodermal features.
  Because alterations of SATB2 by any mechanism (contiguous deletion, intragenic
  deletion/duplication, translocation, or point mutation) produce a convergent
  clinically recognizable phenotype, this deletion syndrome is now lumped with
  point-mutation cases under the umbrella term SATB2-associated syndrome (Glass
  syndrome, OMIM 612313).
category: Mendelian
parents:
- hereditary disease
- chromosomal disorder
disease_term:
  preferred_term: chromosome 2q32-q33 deletion syndrome
  term:
    id: MONDO:0012864
    label: chromosome 2q32-q33 deletion syndrome
inheritance:
- name: Autosomal dominant inheritance
  description: >-
    The deletion acts in an autosomal dominant fashion through haploinsufficiency
    and almost always arises de novo; rare recurrence occurs through parental
    mosaicism.
  inheritance_term:
    preferred_term: autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:29023086
    reference_title: SATB2-Associated Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      SAS is an autosomal dominant disorder. Almost all probands with SAS
      reported to date have the disorder as the result of a de novo genetic
      event.
    explanation: >-
      GeneReviews establishes autosomal dominant inheritance with a predominantly
      de novo occurrence for SATB2-associated syndrome, which subsumes the
      2q32-q33 deletion form.
progression:
- phase: Congenital and early-childhood multisystem presentation
  age_range: Birth through early childhood
  notes: >-
    Palatal and feeding difficulties are evident from birth, while developmental
    delay, severe speech impairment, hypotonia, and behavioural problems emerge
    in infancy and early childhood.
  evidence:
  - reference: PMID:40474278
    reference_title: "Oral phenotype in SATB2-associated syndrome: cross-sectional study of the French cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Early and persistent feeding difficulties were found in 55% of the
      children. Communication was abnormal from the first months of life, with
      poor babbling in 85% of them.
    explanation: >-
      Cohort data confirm an early-onset oral and communication phenotype
      apparent from the first months of life.
- phase: Childhood-to-adulthood skeletal and neurobehavioural course
  age_range: Childhood through adulthood
  notes: >-
    Bone fragility (osteopenia/osteoporosis, fractures, tibial bowing, scoliosis)
    and behavioural manifestations become increasingly relevant with age, and
    secondary cognitive decline has been documented in at least one long-followed
    adult, supporting age-dependent surveillance.
  evidence:
  - reference: PMID:26811410
    reference_title: Specific behavioural phenotype and secondary cognitive decline as a result of an 8.6 Mb deletion of 2q32.2q33.1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This current patient is also, to our knowledge, the only patient with
      2q32q33 microdeletion syndrome with secondary cognitive decline documented
      by psychometric tests.
    explanation: >-
      A long-followed adult demonstrates that the neurocognitive course can
      progress over time in this deletion syndrome.
pathophysiology:
- name: Contiguous-gene 2q32-q33 haploinsufficiency
  description: >-
    Interstitial deletion of chromosome 2q32-q33 removes one copy of a contiguous
    block of genes. The commonly deleted region contains SATB2 plus neighbouring
    dosage-sensitive genes (GLS, MYO1B, TMEFF2, PGAP1, among others), so the
    phenotype reflects combined haploinsufficiency, with SATB2 loss as the major
    driver of the cognitive and craniofacial/palatal features.
  genes:
  - preferred_term: SATB2
    term:
      id: hgnc:21637
      label: SATB2
  - preferred_term: GLS
    term:
      id: hgnc:4331
      label: GLS
  - preferred_term: MYO1B
    term:
      id: hgnc:7596
      label: MYO1B
  - preferred_term: TMEFF2
    term:
      id: hgnc:11867
      label: TMEFF2
  - preferred_term: PGAP1
    term:
      id: hgnc:25712
      label: PGAP1
  evidence:
  - reference: PMID:19668335
    reference_title: Small deletions of SATB2 cause some of the clinical features of the 2q33.1 microdeletion syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The commonly deleted region contains at least seven genes.
    explanation: >-
      Establishes that 2q32q33 microdeletion syndrome is a contiguous-gene
      disorder involving multiple genes, not a single-gene defect.
  - reference: PMID:26811410
    reference_title: Specific behavioural phenotype and secondary cognitive decline as a result of an 8.6 Mb deletion of 2q32.2q33.1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The deletion encompassed 22 known OMIM genes, including GLS, MYO1B,
      TMEFF2, PGAP1 and SATB2.
    explanation: >-
      A molecularly characterized 8.6 Mb 2q32.2q33.1 deletion documents the
      contiguous block of dosage-sensitive genes that includes SATB2.
  downstream:
  - target: SATB2 haploinsufficiency
    description: >-
      Loss of one SATB2 copy is the major dosage-sensitive driver of the
      cognitive and palatal phenotype.
  - target: Additional contiguous-gene contribution to the behavioural and ectodermal phenotype
    description: >-
      Loss of adjacent genes (GLS, MYO1B, TMEFF2) and ectodermal features are
      attributed to the broader deletion beyond SATB2.
- name: SATB2 haploinsufficiency
  description: >-
    SATB2 encodes a nuclear-matrix-attachment-region-binding transcription factor
    that activates transcription of multiple genes and shapes higher-order
    chromatin structure. A 50% reduction in functional SATB2 protein
    (haploinsufficiency) disrupts the dosage-sensitive developmental programs SATB2
    controls in the palate, cortex, and skeleton.
  genes:
  - preferred_term: SATB2
    term:
      id: hgnc:21637
      label: SATB2
  biological_processes:
  - preferred_term: transcriptional regulation
    modifier: DECREASED
    term:
      id: GO:0006357
      label: regulation of transcription by RNA polymerase II
  evidence:
  - reference: PMID:19668335
    reference_title: Small deletions of SATB2 cause some of the clinical features of the 2q33.1 microdeletion syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Haploinsufficiency of one of these genes, SATB2, a DNA-binding protein
      that regulates gene expression, has been implicated as causative in the
      cleft or high palate of individuals with 2q32q33 microdeletion syndrome.
    explanation: >-
      Identifies SATB2 haploinsufficiency as the gene-level mechanism driving the
      core craniofacial features of the deletion syndrome.
  - reference: PMID:28151491
    reference_title: Clinical and molecular consequences of disease-associated de novo mutations in SATB2.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      SATB2 haploinsufficiency is a common cause of syndromic intellectual
      disability.
    explanation: >-
      Confirms haploinsufficiency as the shared pathogenic mechanism producing
      syndromic intellectual disability.
  downstream:
  - target: Craniofacial and palatal developmental dysregulation
    description: >-
      Reduced SATB2 dosage disrupts midline craniofacial patterning and palate
      formation.
  - target: Cortical neuron specification defect
    description: >-
      Reduced SATB2 dosage impairs specification of upper-layer cortical
      projection neurons.
  - target: Osteoblast differentiation defect and bone fragility
    description: >-
      Reduced SATB2 dosage impairs osteoblast differentiation and bone
      mineralization.
- name: Craniofacial and palatal developmental dysregulation
  description: >-
    SATB2 controls midline craniofacial patterning, jaw growth, and palate
    formation. Its loss disrupts roof-of-mouth development, producing cleft or
    high-arched palate, micrognathia, dental anomalies, and facial dysmorphism.
  cell_types:
  - preferred_term: osteoblast
    term:
      id: CL:0000062
      label: osteoblast
  biological_processes:
  - preferred_term: palate development
    modifier: DECREASED
    term:
      id: GO:0060021
      label: roof of mouth development
  - preferred_term: embryonic cranial skeleton morphogenesis
    modifier: DECREASED
    term:
      id: GO:0048701
      label: embryonic cranial skeleton morphogenesis
  evidence:
  - reference: PMID:24301056
    reference_title: Further delineation of the SATB2 phenotype.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In humans, chromosomal translocations and deletions of 2q33.1 leading to
      SATB2 haploinsufficiency are associated with cleft palate (CP), facial
      dysmorphism and intellectual disability (ID).
    explanation: >-
      Directly links SATB2 haploinsufficiency from 2q33.1 deletions to cleft
      palate and facial dysmorphism.
  - reference: PMID:27774744
    reference_title: "SATB2-associated syndrome: Mechanisms, phenotype, and practical recommendations."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      At birth, mice lacking Satb2 have severely reduced jaw length and die from
      cleft palate
    explanation: >-
      Mouse knockout data establish the dosage-sensitive role of SATB2 in jaw
      growth and palate closure underlying the human craniofacial phenotype.
  downstream:
  - target: Cleft palate
    description: >-
      Failure of palatal shelf fusion produces cleft palate.
  - target: High palate
    description: >-
      Disrupted palatal morphogenesis produces a high-arched palate when overt
      clefting is absent.
  - target: Abnormal facial shape
    description: >-
      Disturbed craniofacial patterning produces the characteristic facial
      dysmorphism.
  - target: Micrognathia
    causal_link_type: DIRECT
    description: >-
      Impaired SATB2-dependent jaw growth and distal mandibular patterning
      produces micrognathia.
  - target: Abnormality of the dentition
    causal_link_type: DIRECT
    description: >-
      Disrupted craniofacial/odontogenic development produces dental crowding and
      abnormally shaped teeth.
- name: Cortical neuron specification defect
  description: >-
    SATB2 specifies upper-layer cortico-cortical projection neurons and the
    formation of callosal axonal projections. Its loss misroutes these neurons,
    providing a mechanism for the severe intellectual disability and the profound
    speech/language impairment.
  conforms_to: "projection_neuron_subtype_specification#Altered Laminar and Projection-Subtype Identity"
  cell_types:
  - preferred_term: cortical upper-layer projection neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: cerebral cortex neuron differentiation
    modifier: DECREASED
    term:
      id: GO:0021895
      label: cerebral cortex neuron differentiation
  evidence:
  - reference: PMID:27774744
    reference_title: "SATB2-associated syndrome: Mechanisms, phenotype, and practical recommendations."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      In mice, studies have found a critical role for Satb2 in brain
      development, particularly in the specification of cortical upper layer
      neurons
    explanation: >-
      Mouse data establish SATB2's role in specifying upper-layer cortical
      neurons, the developmental basis for the cognitive phenotype.
  - reference: PMID:24301056
    reference_title: Further delineation of the SATB2 phenotype.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Vertebrate animal models have shown that Satb2 has a crucial role in
      craniofacial patterning and osteoblast differentiation, as well as in
      determining the fates of neuronal projections in the developing neocortex.
    explanation: >-
      Confirms the conserved role of SATB2 in determining cortical neuronal
      projection fates relevant to the neurodevelopmental phenotype.
  downstream:
  - target: Intellectual disability
    description: >-
      Defective cortical neuron specification produces intellectual disability.
  - target: Global developmental delay
    description: >-
      Disrupted neurodevelopment presents as global developmental delay.
  - target: Delayed speech and language development
    description: >-
      Cortical/speech-network involvement produces severely impaired speech and
      language development.
  - target: Absent speech
    description: >-
      The most severe end of the speech phenotype is absent speech.
- name: Osteoblast differentiation defect and bone fragility
  description: >-
    SATB2 promotes osteoblast differentiation and bone mineralization (in part by
    regulating osteogenic transcription). Its haploinsufficiency reduces bone
    mineral density and, particularly with alleles that escape nonsense-mediated
    decay, produces increased bone turnover, fractures, tibial bowing, and
    scoliosis.
  cell_types:
  - preferred_term: osteoblast
    term:
      id: CL:0000062
      label: osteoblast
  biological_processes:
  - preferred_term: osteoblast differentiation
    modifier: DECREASED
    term:
      id: GO:0001649
      label: osteoblast differentiation
  evidence:
  - reference: PMID:35241104
    reference_title: "SATB2-associated syndrome: characterization of skeletal features and of bone fragility in a prospective cohort of 19 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We conclude that SATB2 pathogenic variants are responsible for skeletal
      demineralization and osteoporosis. We found increased levels of bone
      formation markers, supporting the key role of SATB2 in osteoblast
      differentiation.
    explanation: >-
      A prospective cohort links SATB2 loss to skeletal demineralization and
      osteoporosis via osteoblast dysfunction.
  - reference: PMID:27774744
    reference_title: "SATB2-associated syndrome: Mechanisms, phenotype, and practical recommendations."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      loss of Satb2 leads to reduced levels of bone mineralization, resulting in
      short and brittle limb bones
    explanation: >-
      Mouse data establish the osteogenic role of SATB2 underlying the human bone
      fragility phenotype.
  downstream:
  - target: Reduced bone mineral density
    description: >-
      Impaired osteoblast function reduces bone mineral density.
  - target: Increased susceptibility to fractures
    description: >-
      Low bone mass and increased bone turnover predispose to fractures.
  - target: Tibial bowing
    causal_link_type: DIRECT
    description: >-
      Mechanically weakened bone produces progressive tibial bowing.
  - target: Scoliosis
    causal_link_type: DIRECT
    description: >-
      Skeletal fragility and vertebral involvement contribute to scoliosis.
- name: Additional contiguous-gene contribution to the behavioural and ectodermal phenotype
  description: >-
    Beyond SATB2, loss of neighbouring genes is thought to shape the more complex
    behavioural phenotype (with the glutaminase gene GLS and MYO1B/TMEFF2 proposed
    as candidates), while thin skin and sparse hair in patients with larger
    deletions are attributed to loss of additional, as-yet-undefined ectodermal
    genes.
  genes:
  - preferred_term: GLS
    term:
      id: hgnc:4331
      label: GLS
  - preferred_term: MYO1B
    term:
      id: hgnc:7596
      label: MYO1B
  - preferred_term: TMEFF2
    term:
      id: hgnc:11867
      label: TMEFF2
  evidence:
  - reference: PMID:26811410
    reference_title: Specific behavioural phenotype and secondary cognitive decline as a result of an 8.6 Mb deletion of 2q32.2q33.1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      it is our opinion that the SATB2 gene is also crucial to the behavioural
      problems noted in this current proband and that deletion of the GLS,
      MYO1B, and TMEFF2 genes presumably contributes to the more complex
      behavioural characteristics observed
    explanation: >-
      Supports a contiguous-gene contribution beyond SATB2 to the complex
      behavioural phenotype.
  - reference: PMID:19668335
    reference_title: Small deletions of SATB2 cause some of the clinical features of the 2q33.1 microdeletion syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Only one of the subjects presented here had a cleft palate, suggesting
      reduced penetrance for this feature.
    explanation: >-
      Intragenic SATB2 deletions show reduced penetrance of cleft palate,
      consistent with variable expressivity and contributions of additional loci
      to the full deletion phenotype.
  downstream:
  - target: Autistic behavior
    description: >-
      Combined gene loss contributes to autistic features within the behavioural
      spectrum.
  - target: Aggressive behavior
    description: >-
      The recurrent behavioural pattern includes aggression and self-injury.
  - target: Sleep disturbance
    description: >-
      Sleeping problems are part of the recurrent behavioural phenotype.
  - target: Sparse hair
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - loss of additional ectodermal genes in larger deletions
    description: >-
      Thin, sparse hair is an ectodermal feature attributed to broader 2q32-q33
      deletion beyond SATB2.
phenotypes:
- name: Intellectual disability
  frequency: VERY_FREQUENT
  description: >-
    Developmental delay / intellectual disability is present in essentially all
    affected individuals and is frequently in the moderate-to-severe range.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:29023086
    reference_title: SATB2-Associated Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      SATB2-associated syndrome (SAS) is a multisystem disorder in which all
      affected individuals have developmental delay / intellectual disability
      that can range from mild to profound but is most commonly moderate to
      profound.
    explanation: >-
      GeneReviews documents intellectual disability in all affected individuals.
- name: Global developmental delay
  frequency: VERY_FREQUENT
  description: >-
    Global developmental delay is a universal early manifestation.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:29023086
    reference_title: SATB2-Associated Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      SATB2-associated syndrome (SAS) is a multisystem disorder in which all
      affected individuals have developmental delay / intellectual disability
      that can range from mild to profound but is most commonly moderate to
      profound.
    explanation: >-
      GeneReviews documents developmental delay in all affected individuals.
- name: Delayed speech and language development
  frequency: VERY_FREQUENT
  description: >-
    Severe speech and language impairment is one of the most consistent and
    distinctive features.
  phenotype_term:
    preferred_term: Delayed speech and language development
    term:
      id: HP:0000750
      label: Delayed speech and language development
  evidence:
  - reference: PMID:40474278
    reference_title: "Oral phenotype in SATB2-associated syndrome: cross-sectional study of the French cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A major language delay was described in all patients; 65% had a vocabulary
      of 10 words or less.
    explanation: >-
      Cohort data document major language delay in all patients.
- name: Absent speech
  frequency: VERY_FREQUENT
  description: >-
    Many affected individuals never develop functional speech.
  phenotype_term:
    preferred_term: Absent speech
    term:
      id: HP:0001344
      label: Absent speech
  evidence:
  - reference: PMID:28151491
    reference_title: Clinical and molecular consequences of disease-associated de novo mutations in SATB2.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Recurrent clinical features included neurodevelopmental impairment
      (19/19), absent/near absent speech (16/19), normal somatic growth (17/19),
      cleft palate (9/19), drooling (12/19), and dental anomalies (8/19).
    explanation: >-
      Absent or near-absent speech in 16/19 supports a very frequent severe
      speech phenotype.
- name: Drooling
  frequency: VERY_FREQUENT
  description: >-
    Drooling is a recurrent oral-motor manifestation reflecting impaired oral
    motor coordination, alongside the severe speech and feeding involvement.
  phenotype_term:
    preferred_term: Drooling
    term:
      id: HP:0002307
      label: Drooling
  evidence:
  - reference: PMID:28151491
    reference_title: Clinical and molecular consequences of disease-associated de novo mutations in SATB2.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Recurrent clinical features included neurodevelopmental impairment
      (19/19), absent/near absent speech (16/19), normal somatic growth (17/19),
      cleft palate (9/19), drooling (12/19), and dental anomalies (8/19).
    explanation: >-
      Drooling in 12/19 (63%) supports a very frequent oral-motor phenotype.
- name: Cleft palate
  frequency: FREQUENT
  description: >-
    Cleft palate is a characteristic craniofacial feature, although penetrance is
    incomplete and a high-arched palate may occur instead.
  phenotype_term:
    preferred_term: Cleft palate
    term:
      id: HP:0000175
      label: Cleft palate
  evidence:
  - reference: PMID:28151491
    reference_title: Clinical and molecular consequences of disease-associated de novo mutations in SATB2.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Recurrent clinical features included neurodevelopmental impairment
      (19/19), absent/near absent speech (16/19), normal somatic growth (17/19),
      cleft palate (9/19), drooling (12/19), and dental anomalies (8/19).
    explanation: >-
      Cleft palate in 9/19 (47%) supports a frequent palatal phenotype.
- name: High palate
  description: >-
    A high-arched palate is part of the palatal anomaly spectrum and may occur in
    the absence of overt clefting.
  phenotype_term:
    preferred_term: High palate
    term:
      id: HP:0000218
      label: High palate
  evidence:
  - reference: PMID:19668335
    reference_title: Small deletions of SATB2 cause some of the clinical features of the 2q33.1 microdeletion syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical features of this syndrome include severe mental retardation,
      growth retardation, dysmorphic features, thin and sparse hair, feeding
      difficulties and cleft or high palate.
    explanation: >-
      The defining clinical description includes cleft or high palate.
- name: Feeding difficulties
  frequency: FREQUENT
  description: >-
    Early and often persistent feeding difficulties are common and relate to the
    palatal and oromotor involvement.
  phenotype_term:
    preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
  evidence:
  - reference: PMID:40474278
    reference_title: "Oral phenotype in SATB2-associated syndrome: cross-sectional study of the French cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Early and persistent feeding difficulties were found in 55% of the
      children.
    explanation: >-
      Cohort data document feeding difficulties in a majority of children.
- name: Growth delay
  frequency: FREQUENT
  description: >-
    Pre- and postnatal growth retardation is common in patients with the
    contiguous deletion.
  phenotype_term:
    preferred_term: Growth delay
    term:
      id: HP:0001510
      label: Growth delay
  evidence:
  - reference: PMID:27774744
    reference_title: "SATB2-associated syndrome: Mechanisms, phenotype, and practical recommendations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      feeding difficulties (76%), pre‐ or postnatal growth retardation (71%),
      hypotonia (53%), thin skin or reduced subcutaneous fat (53%), cleft palate
      (47%), brain MRI abnormalities (45%), and dental crowding (44%)
    explanation: >-
      The review's tabulation of large-deletion features documents pre- or
      postnatal growth retardation in 71% of patients, supporting a frequent
      growth-delay phenotype.
- name: Hypotonia
  frequency: FREQUENT
  description: >-
    Hypotonia is present in most affected individuals.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:27774744
    reference_title: "SATB2-associated syndrome: Mechanisms, phenotype, and practical recommendations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      hypotonia (53%), thin skin or reduced subcutaneous fat (53%), cleft palate
      (47%), brain MRI abnormalities (45%), and dental crowding (44%)
    explanation: >-
      Hypotonia is documented in 53% of patients with large deletions.
- name: Abnormality of the dentition
  frequency: VERY_FREQUENT
  description: >-
    Dental anomalies (crowding, abnormally shaped teeth, hypodontia, delayed
    eruption) are very common.
  phenotype_term:
    preferred_term: Abnormality of the dentition
    term:
      id: HP:0000164
      label: Abnormality of the dentition
  evidence:
  - reference: PMID:40474278
    reference_title: "Oral phenotype in SATB2-associated syndrome: cross-sectional study of the French cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      An anomaly of RS spectrum was found in half the cases, and dental
      malformations were described in 90%.
    explanation: >-
      Dental malformations in 90% support a very frequent dental phenotype.
- name: Abnormal facial shape
  description: >-
    Characteristic but nonspecific facial dysmorphism aids recognition of the
    syndrome.
  phenotype_term:
    preferred_term: Abnormal facial shape
    term:
      id: HP:0001999
      label: Abnormal facial shape
  evidence:
  - reference: PMID:24301056
    reference_title: Further delineation of the SATB2 phenotype.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In humans, chromosomal translocations and deletions of 2q33.1 leading to
      SATB2 haploinsufficiency are associated with cleft palate (CP), facial
      dysmorphism and intellectual disability (ID).
    explanation: >-
      Facial dysmorphism is a recognized feature of SATB2 haploinsufficiency from
      2q33.1 deletions.
- name: Micrognathia
  description: >-
    Micrognathia (small/underdeveloped mandible) is a recurrent craniofacial
    feature reflecting the SATB2-dependent program for jaw growth and patterning.
  phenotype_term:
    preferred_term: Micrognathia
    term:
      id: HP:0000347
      label: Micrognathia
  evidence:
  - reference: PMID:27774744
    reference_title: "SATB2-associated syndrome: Mechanisms, phenotype, and practical recommendations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Behavioral abnormalities, facial dysmorphism, cleft palate, micrognathia,
      dental anomalies, and musculoskeletal changes have also been reported
      consistently in all etiological subgroups
    explanation: >-
      Micrognathia is reported consistently across all etiological subgroups of
      SATB2-associated syndrome, including the deletion form.
  - reference: PMID:27774744
    reference_title: "SATB2-associated syndrome: Mechanisms, phenotype, and practical recommendations."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      The SAS phenotype also includes craniofacial anomalies that include
      micrognathia and cleft palate. Similarly, Satb2 knock‐out mice display
      hypoplasia of the distal jaw skeleton.
    explanation: >-
      Satb2 knockout mice recapitulate distal jaw hypoplasia, the developmental
      basis for the human micrognathia phenotype.
- name: Sparse hair
  description: >-
    Thin and sparse hair, often with thin skin and reduced subcutaneous fat, is an
    ectodermal feature seen particularly with larger deletions.
  phenotype_term:
    preferred_term: Sparse hair
    term:
      id: HP:0008070
      label: Sparse hair
  evidence:
  - reference: PMID:26811410
    reference_title: Specific behavioural phenotype and secondary cognitive decline as a result of an 8.6 Mb deletion of 2q32.2q33.1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Individuals with deletions of 2q32q33 and who present with learning
      difficulties, growth retardation, dysmorphic features, thin and sparse
      hair, feeding difficulties, and high or cleft palate have been classified
      as having a new microdeletion syndrome.
    explanation: >-
      Thin and sparse hair is part of the defining phenotype of the 2q32q33
      deletion syndrome.
- name: Autistic behavior
  description: >-
    Autistic features are part of the recurrent behavioural phenotype, alongside a
    frequently jovial/friendly personality.
  phenotype_term:
    preferred_term: Autistic behavior
    term:
      id: HP:0000729
      label: Autistic behavior
  evidence:
  - reference: PMID:28151491
    reference_title: Clinical and molecular consequences of disease-associated de novo mutations in SATB2.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The behavioral phenotype appeared to show the most marked discrepancy
      within the cohort, with both severe autistic features and friendly/happy
      personalities being recurrently reported.
    explanation: >-
      Severe autistic features are recurrently reported within the behavioural
      phenotype.
- name: Aggressive behavior
  description: >-
    A specific behavioural pattern with aggression, self-injury, and motor
    restlessness has been described.
  phenotype_term:
    preferred_term: Aggressive behavior
    term:
      id: HP:0000718
      label: Aggressive behavior
  evidence:
  - reference: PMID:26811410
    reference_title: Specific behavioural phenotype and secondary cognitive decline as a result of an 8.6 Mb deletion of 2q32.2q33.1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A specific behavioural pattern, with hyperactivity and motor restlessness,
      chaotic behaviour, a happy personality but with periods of aggression and
      anxiety, sleeping problems and self-mutilation, has also been reported in
      some of these patients.
    explanation: >-
      Aggression and self-injury are described within the recurrent behavioural
      pattern.
- name: Sleep disturbance
  description: >-
    Sleeping problems recur within the behavioural phenotype.
  phenotype_term:
    preferred_term: Sleep disturbance
    term:
      id: HP:0002360
      label: Sleep disturbance
  evidence:
  - reference: PMID:26811410
    reference_title: Specific behavioural phenotype and secondary cognitive decline as a result of an 8.6 Mb deletion of 2q32.2q33.1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A specific behavioural pattern, with hyperactivity and motor restlessness,
      chaotic behaviour, a happy personality but with periods of aggression and
      anxiety, sleeping problems and self-mutilation, has also been reported in
      some of these patients.
    explanation: >-
      Sleeping problems are part of the recurrent behavioural phenotype.
- name: Seizure
  frequency: OCCASIONAL
  description: >-
    Clinical seizures occur in a minority of patients, while subclinical EEG
    abnormalities are more frequent.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:29023086
    reference_title: SATB2-Associated Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      While only about 20% of affected individuals have clinical seizures, a
      subset of affected individuals have electrical status epilepticus in sleep.
    explanation: >-
      GeneReviews documents clinical seizures in about 20% of patients.
- name: Reduced bone mineral density
  frequency: FREQUENT
  description: >-
    Reduced bone mineral density / osteoporosis is part of the skeletal phenotype
    and warrants surveillance. Reported frequency is strongly
    ascertainment-dependent: a dedicated skeletal-imaging cohort found
    skeletal demineralization
    in 94% (Mouillé et al., PMID:35241104), whereas GeneReviews estimates
    documented low bone mineral density in only about one quarter of affected
    individuals (PMID:29023086), reflecting the difference between systematic
    skeletal phenotyping and routine clinical ascertainment.
  phenotype_term:
    preferred_term: Reduced bone mineral density
    term:
      id: HP:0004349
      label: Reduced bone mineral density
  evidence:
  - reference: PMID:35241104
    reference_title: "SATB2-associated syndrome: characterization of skeletal features and of bone fragility in a prospective cohort of 19 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Skeletal demineralization (16/17, 94%) and cortical thinning of vertebrae
      (15/17) were the most frequent radiological features at the spine.
    explanation: >-
      Skeletal demineralization in 94% supports a frequent low-bone-mass
      phenotype.
- name: Increased susceptibility to fractures
  frequency: FREQUENT
  description: >-
    Fractures, including vertebral compression fractures, occur as a consequence
    of bone fragility.
  phenotype_term:
    preferred_term: Increased susceptibility to fractures
    term:
      id: HP:0002659
      label: Increased susceptibility to fractures
  evidence:
  - reference: PMID:35241104
    reference_title: "SATB2-associated syndrome: characterization of skeletal features and of bone fragility in a prospective cohort of 19 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Vertebral compression fractures affected 6/17 patients (35%).
    explanation: >-
      Vertebral compression fractures in 35% support a frequent fracture
      susceptibility.
- name: Tibial bowing
  description: >-
    Progressive tibial bowing is reported, particularly with SATB2 alleles
    associated with more severe bone disease.
  phenotype_term:
    preferred_term: Tibial bowing
    term:
      id: HP:0002982
      label: Tibial bowing
  evidence:
  - reference: PMID:27409069
    reference_title: "Increased bone turnover, osteoporosis, progressive tibial bowing, fractures, and scoliosis in a patient with a final-exon SATB2 frameshift mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report a SATB2 mutation (c.2018dupA; p.(H673fs)) in a 15-year-old
      patient whose SATB2-associated syndrome phenotype is accompanied by
      osteoporosis, fractures, progressive tibial bowing, and scoliosis.
    explanation: >-
      Documents progressive tibial bowing within the bone phenotype.
- name: Scoliosis
  description: >-
    Scoliosis is part of the skeletal phenotype.
  phenotype_term:
    preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  evidence:
  - reference: PMID:29023086
    reference_title: SATB2-Associated Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Skeletal anomalies can include scoliosis, tibial bowing, and joint
      contractures.
    explanation: >-
      GeneReviews lists scoliosis among the skeletal anomalies.
- name: Strabismus
  description: >-
    Eye anomalies, including strabismus and refractive error, are reported.
  phenotype_term:
    preferred_term: Strabismus
    term:
      id: HP:0000486
      label: Strabismus
  evidence:
  - reference: PMID:29023086
    reference_title: SATB2-Associated Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Other finding can include pre- and postnatal growth restriction, feeding
      issues, and eye anomalies (strabismus, refractive error).
    explanation: >-
      GeneReviews lists strabismus among the eye anomalies.
- name: Abnormal heart morphology
  frequency: OCCASIONAL
  description: >-
    Congenital cardiovascular defects are reported mainly in patients with larger
    deletions involving SATB2 and adjacent genes.
  phenotype_term:
    preferred_term: Abnormal heart morphology
    term:
      id: HP:0001627
      label: Abnormal heart morphology
  evidence:
  - reference: PMID:29023086
    reference_title: SATB2-Associated Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In those with a larger deletion involving SATB2 and adjacent genes,
      cardiovascular, genitourinary, and ectodermal findings may also be present.
    explanation: >-
      GeneReviews attributes cardiovascular findings to larger contiguous
      deletions.
biochemical:
- name: Osteocalcin
  presence: INCREASED
  context: >-
    Bone-formation marker; elevated in SATB2-associated syndrome, consistent
    with the SATB2-dependent role in osteoblast differentiation and increased
    bone turnover.
  biomarker_term:
    preferred_term: osteocalcin
    term:
      id: NCIT:C104592
      label: Osteocalcin
  readouts:
  - target: Osteoblast differentiation defect and bone fragility
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Elevated osteocalcin reports increased bone turnover/formation arising from
      the SATB2-dependent osteoblast program.
  evidence:
  - reference: PMID:35241104
    reference_title: "SATB2-associated syndrome: characterization of skeletal features and of bone fragility in a prospective cohort of 19 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      osteocalcin and serum procollagen type 1 amino-terminal propeptide
      (P1NP) were both increased. Vitamin D insufficiency was frequent (66.7%).
    explanation: >-
      The prospective skeletal cohort documents increased osteocalcin as a
      bone-formation marker.
  - reference: PMID:27409069
    reference_title: "Increased bone turnover, osteoporosis, progressive tibial bowing, fractures, and scoliosis in a patient with a final-exon SATB2 frameshift mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Elevations in alkaline phosphatase, urinary N-telopeptide/creatinine
      ratio, and osteocalcin in the patient indicate increased bone turnover.
    explanation: >-
      A dominant-negative-allele patient shows elevated osteocalcin indicating
      increased bone turnover.
- name: Procollagen type 1 amino-terminal propeptide (P1NP)
  presence: INCREASED
  context: >-
    Bone-formation marker; elevated in the SATB2-associated skeletal phenotype.
  biomarker_term:
    preferred_term: procollagen type I N-terminal peptide (P1NP)
    term:
      id: NCIT:C116963
      label: Procollagen Type I N-Terminal Peptide
  readouts:
  - target: Osteoblast differentiation defect and bone fragility
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Elevated P1NP reports increased osteoblastic bone-formation activity.
  evidence:
  - reference: PMID:35241104
    reference_title: "SATB2-associated syndrome: characterization of skeletal features and of bone fragility in a prospective cohort of 19 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      osteocalcin and serum procollagen type 1 amino-terminal propeptide
      (P1NP) were both increased. Vitamin D insufficiency was frequent (66.7%).
    explanation: >-
      The prospective skeletal cohort documents increased P1NP as a
      bone-formation marker.
- name: Alkaline phosphatase
  presence: INCREASED
  context: >-
    Bone-turnover marker reported as elevated in a SATB2-associated syndrome
    patient with a dominant-negative allele; in a separate skeletal cohort ALP
    was in the upper-normal range, reflecting variable expression.
  biomarker_term:
    preferred_term: alkaline phosphatase
    term:
      id: NCIT:C16276
      label: Alkaline Phosphatase
  readouts:
  - target: Osteoblast differentiation defect and bone fragility
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Elevated alkaline phosphatase reports increased bone turnover.
  evidence:
  - reference: PMID:27409069
    reference_title: "Increased bone turnover, osteoporosis, progressive tibial bowing, fractures, and scoliosis in a patient with a final-exon SATB2 frameshift mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Elevations in alkaline phosphatase, urinary N-telopeptide/creatinine
      ratio, and osteocalcin in the patient indicate increased bone turnover.
    explanation: >-
      A dominant-negative-allele patient shows elevated alkaline phosphatase
      indicating increased bone turnover.
- name: Urinary N-telopeptide/creatinine ratio
  presence: INCREASED
  context: >-
    Bone-resorption marker; elevated urinary N-telopeptide/creatinine ratio
    reflects increased bone turnover in the skeletal phenotype.
  biomarker_term:
    preferred_term: N-telopeptide
    term:
      id: NCIT:C68563
      label: N-Telopeptide
  readouts:
  - target: Osteoblast differentiation defect and bone fragility
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Elevated urinary N-telopeptide reports increased bone resorption / turnover.
  evidence:
  - reference: PMID:27409069
    reference_title: "Increased bone turnover, osteoporosis, progressive tibial bowing, fractures, and scoliosis in a patient with a final-exon SATB2 frameshift mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Elevations in alkaline phosphatase, urinary N-telopeptide/creatinine
      ratio, and osteocalcin in the patient indicate increased bone turnover.
    explanation: >-
      The urinary N-telopeptide/creatinine ratio is elevated, indicating
      increased bone resorption.
genetic:
- name: 2q32-q33 contiguous-gene deletion
  association: Causal chromosomal deletion
  notes: >-
    Interstitial deletion of 2q32-q33 encompassing SATB2 and adjacent genes;
    SATB2 haploinsufficiency is the best-established gene-level driver of the
    cognitive and palatal phenotype.
  evidence:
  - reference: PMID:26811410
    reference_title: Specific behavioural phenotype and secondary cognitive decline as a result of an 8.6 Mb deletion of 2q32.2q33.1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Chromosomal abnormalities involving 2q32q33 deletions are very rare and
      present with a specific phenotype.
    explanation: >-
      Establishes the causal 2q32q33 deletion and its recognizable phenotype.
  - reference: PMID:19668335
    reference_title: Small deletions of SATB2 cause some of the clinical features of the 2q33.1 microdeletion syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our results suggest that deletion of SATB2 is responsible for several of
      the clinical features associated with 2q32q33 microdeletion syndrome.
    explanation: >-
      Pinpoints SATB2 within the deletion as responsible for several core
      features.
- name: SATB2 haploinsufficiency
  gene_term:
    preferred_term: SATB2
    term:
      id: hgnc:21637
      label: SATB2
  association: Major dosage-sensitive driver gene
  notes: >-
    SATB2 is the major dosage-sensitive driver gene; its loss by deletion (or by
    point mutation in the broader SATB2-associated syndrome) produces a convergent
    phenotype.
  evidence:
  - reference: PMID:27409069
    reference_title: "Increased bone turnover, osteoporosis, progressive tibial bowing, fractures, and scoliosis in a patient with a final-exon SATB2 frameshift mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Haploinsufficiency of SATB2 causes cleft palate, intellectual disability
      with deficient speech, facial and dental abnormalities, and other variable
      features known collectively as SATB2-associated syndrome.
    explanation: >-
      Summarizes SATB2 haploinsufficiency as the driver of the recognizable
      phenotype.
environmental: []
treatments:
- name: Supportive and multidisciplinary care
  description: >-
    Management is supportive and multidisciplinary, with standard treatment of
    developmental delay/intellectual disability, neurobehavioural issues, palatal,
    dental, skeletal, and ophthalmologic manifestations.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:27774744
    reference_title: "SATB2-associated syndrome: Mechanisms, phenotype, and practical recommendations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The multisystemic nature of this syndrome demands a multisystemic approach
      and we propose evaluation and management guidelines.
    explanation: >-
      The review frames a multisystem, supportive management approach.
- name: Genetic counseling
  description: >-
    Genetic counseling addresses the de novo nature of most cases and the small
    recurrence risk from parental mosaicism.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:29023086
    reference_title: SATB2-Associated Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      SAS is an autosomal dominant disorder. Almost all probands with SAS
      reported to date have the disorder as the result of a de novo genetic
      event.
    explanation: >-
      The inheritance pattern and de novo nature underpin genetic counseling.
- name: Speech therapy and augmentative communication
  description: >-
    Early speech therapy and augmentative/alternative communication are central
    given the near-universal severe speech impairment.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: speech therapy
    term:
      id: NCIT:C159273
      label: Speech Language Therapy
  evidence:
  - reference: PMID:40474278
    reference_title: "Oral phenotype in SATB2-associated syndrome: cross-sectional study of the French cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A major language delay was described in all patients; 65% had a vocabulary
      of 10 words or less.
    explanation: >-
      The universal severe language phenotype supports early speech-language
      intervention.
- name: Feeding and nutritional therapy
  description: >-
    Feeding therapy, swallowing evaluation, and nutritional support address the
    common early feeding difficulties; gastrostomy may be required when feeding
    issues persist.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: dietary intervention
    term:
      id: NCIT:C15447
      label: Dietary Intervention
  evidence:
  - reference: PMID:40474278
    reference_title: "Oral phenotype in SATB2-associated syndrome: cross-sectional study of the French cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Early and persistent feeding difficulties were found in 55% of the
      children.
    explanation: >-
      Frequent feeding difficulties support feeding/nutritional intervention.
- name: Physical therapy
  description: >-
    Physical therapy addresses hypotonia and motor delay.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: physical therapy
    term:
      id: NCIT:C15302
      label: Physical Therapy
  evidence:
  - reference: PMID:27774744
    reference_title: "SATB2-associated syndrome: Mechanisms, phenotype, and practical recommendations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Physical and occupational therapies assessment is equally indicated, with
      therapy provided as necessary.
    explanation: >-
      The review recommends physical therapy as part of management.
- name: Occupational therapy
  description: >-
    Occupational therapy supports adaptive and fine-motor skills.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: occupational therapy
    term:
      id: NCIT:C121351
      label: Occupational Therapy
  evidence:
  - reference: PMID:27774744
    reference_title: "SATB2-associated syndrome: Mechanisms, phenotype, and practical recommendations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Physical and occupational therapies assessment is equally indicated, with
      therapy provided as necessary.
    explanation: >-
      The review recommends occupational therapy as part of management.
- name: Early intervention and educational support
  description: >-
    Early-intervention programs and individualized education plans support
    development given the universal cognitive and speech involvement.
  treatment_term:
    preferred_term: early intervention services
    term:
      id: NCIT:C159524
      label: Early Intervention
  evidence:
  - reference: PMID:29023086
    reference_title: SATB2-Associated Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Standard treatment for developmental delay / intellectual disability,
      neurobehavioral issues, cleft palate, micrognathia, dental anomalies,
      scoliosis, tibial bowing, joint contractures, spasticity, epilepsy,
      undescended testes, inguinal hernia, hypospadias, refractive error,
      strabismus, and congenital heart defects.
    explanation: >-
      GeneReviews recommends standard developmental treatment for the cognitive
      phenotype.
- name: Behavioral and mental-health support
  description: >-
    Behavioural interventions and mental-health support address the recurrent
    behavioural phenotype (aggression, self-injury, hyperactivity, sleep
    problems).
  treatment_term:
    preferred_term: cognitive and behavioral intervention
    term:
      id: NCIT:C15184
      label: Behavioral Intervention
  evidence:
  - reference: PMID:27774744
    reference_title: "SATB2-associated syndrome: Mechanisms, phenotype, and practical recommendations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      From the neurodevelopmental perspective, medical management of behavioral
      issues could be required with further psychological mental health support.
    explanation: >-
      The review recommends behavioural and mental-health management.
- name: Antiepileptic drug therapy
  description: >-
    Anticonvulsant therapy is indicated when clinical seizures occur (about 20%
    of patients).
  treatment_term:
    preferred_term: anticonvulsant agent therapy
    term:
      id: NCIT:C64172
      label: Anticonvulsant Therapy
  evidence:
  - reference: PMID:29023086
    reference_title: SATB2-Associated Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      While only about 20% of affected individuals have clinical seizures, a
      subset of affected individuals have electrical status epilepticus in sleep.
    explanation: >-
      Clinical seizures in a subset support antiepileptic management when present.
- name: Bone-directed therapy and bisphosphonates
  description: >-
    Bone health management includes optimizing physical activity and calcium /
    vitamin D, with bisphosphonates or denosumab and bone-turnover surveillance to
    prevent fractures and progressive deformity.
  treatment_term:
    preferred_term: bisphosphonate agent therapy
    term:
      id: NCIT:C198585
      label: Bisphosphonate Therapy
  evidence:
  - reference: PMID:27409069
    reference_title: "Increased bone turnover, osteoporosis, progressive tibial bowing, fractures, and scoliosis in a patient with a final-exon SATB2 frameshift mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We propose surveillance and treatment with osteoclast inhibitors to
      prevent fractures and to slow progressive bone deformities.
    explanation: >-
      Osteoclast-inhibitor therapy (bisphosphonates) is proposed for the bone
      phenotype.
diagnosis:
- name: Chromosomal microarray
  description: >-
    Chromosomal microarray defines the 2q32-q33 deletion and its gene content and
    is the principal diagnostic test for the contiguous-gene deletion.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:29023086
    reference_title: SATB2-Associated Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a heterozygous non-recurrent deletion at 2q33.1 that includes SATB2
    explanation: >-
      GeneReviews lists a 2q33.1 deletion including SATB2 as a diagnostic
      molecular finding, identified by chromosomal microarray.
- name: Molecular genetic testing
  description: >-
    Sequencing and deletion/duplication analysis of SATB2 (or a multigene panel /
    exome) confirms the diagnosis across the spectrum of SATB2 alterations.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: NCIT:C19770
      label: Molecular Analysis
  evidence:
  - reference: PMID:24301056
    reference_title: Further delineation of the SATB2 phenotype.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Exome sequencing revealed a de novo nonsense mutation in the SATB2 gene
      (c.715C>T; p.R239*).
    explanation: >-
      Molecular sequencing identifies SATB2 alterations in patients without a
      visible deletion.
differential_diagnoses:
- name: 2q37 deletion syndrome
  description: >-
    2q37 deletion syndrome is another chromosome 2q contiguous-gene deletion with
    developmental delay, but differs in gene content (HDAC4) and skeletal
    phenotype (brachydactyly type E).
  disease_term:
    preferred_term: 2q37 microdeletion syndrome
    term:
      id: MONDO:0010886
      label: 2q37 microdeletion syndrome
datasets: []
references:
- reference: PMID:29023086
  title: "SATB2-Associated Syndrome."
  tags:
  - GeneReviews
  findings: []
- reference: PMID:19668335
  title: "Small deletions of SATB2 cause some of the clinical features of the 2q33.1 microdeletion syndrome."
  findings: []
- reference: PMID:27774744
  title: "SATB2-associated syndrome: Mechanisms, phenotype, and practical recommendations."
  findings: []
- reference: PMID:24301056
  title: "Further delineation of the SATB2 phenotype."
  findings: []
- reference: PMID:28151491
  title: "Clinical and molecular consequences of disease-associated de novo mutations in SATB2."
  findings: []
- reference: PMID:26811410
  title: "Specific behavioural phenotype and secondary cognitive decline as a result of an 8.6 Mb deletion of 2q32.2q33.1."
  findings: []
- reference: PMID:27409069
  title: "Increased bone turnover, osteoporosis, progressive tibial bowing, fractures, and scoliosis in a patient with a final-exon SATB2 frameshift mutation."
  findings: []
- reference: PMID:35241104
  title: "SATB2-associated syndrome: characterization of skeletal features and of bone fragility in a prospective cohort of 19 patients."
  findings: []
- reference: PMID:40474278
  title: "Oral phenotype in SATB2-associated syndrome: cross-sectional study of the French cohort."
  findings: []
📚

References & Deep Research

References

9
PMID:29023086
SATB2-Associated Syndrome.
No top-level findings curated for this source.
PMID:19668335
Small deletions of SATB2 cause some of the clinical features of the 2q33.1 microdeletion syndrome.
No top-level findings curated for this source.
PMID:27774744
SATB2-associated syndrome: Mechanisms, phenotype, and practical recommendations.
No top-level findings curated for this source.
PMID:24301056
Further delineation of the SATB2 phenotype.
No top-level findings curated for this source.
PMID:28151491
Clinical and molecular consequences of disease-associated de novo mutations in SATB2.
No top-level findings curated for this source.
PMID:26811410
Specific behavioural phenotype and secondary cognitive decline as a result of an 8.6 Mb deletion of 2q32.2q33.1.
No top-level findings curated for this source.
PMID:27409069
Increased bone turnover, osteoporosis, progressive tibial bowing, fractures, and scoliosis in a patient with a final-exon SATB2 frameshift mutation.
No top-level findings curated for this source.
PMID:35241104
SATB2-associated syndrome: characterization of skeletal features and of bone fragility in a prospective cohort of 19 patients.
No top-level findings curated for this source.
PMID:40474278
Oral phenotype in SATB2-associated syndrome: cross-sectional study of the French cohort.
No top-level findings curated for this source.