Gabriele-de Vries Syndrome

Mendelian MONDO:0044738 Pathograph 38 Show in embeddings browser syndromic intellectual disability multiple congenital anomalies/dysmorphic syndrome-intellectual disability

Gabriele-de Vries syndrome (GADEVS) is an autosomal dominant neurodevelopmental and multiple-congenital-anomaly syndrome caused by heterozygous pathogenic variants in YY1, or by deletions of 14q32.2 that include YY1, which in all tested families have arisen de novo. YY1 is a zinc-finger transcription factor that acts as both activator and repressor and regulates enhancer activity. Truncating alleles, whole-gene deletions and missense variants in the C-terminal zinc-finger DNA-binding domain converge on haploinsufficiency: in patient-derived cells YY1 chromatin occupancy is globally reduced, H3K27 acetylation is lost at YY1-bound enhancers, and in patient iPSC-derived cortical organoids and neurons cell-type-specific transcriptional networks of neural progenitors and excitatory neurons are disrupted. Clinically, mild-to-profound developmental delay or intellectual disability is present in all affected individuals, accompanied by speech and motor delay, intrauterine growth restriction or low birth weight, feeding difficulties, hypotonia and gait abnormalities, behavioral features (ADHD, anxiety, autistic behavior), facial dysmorphism, and variable congenital anomalies of the brain, eye, heart, kidney, genitalia and skeleton. A subset develop a juvenile- or adult-onset movement disorder dominated by dystonia. A peripheral-blood DNA methylation episignature supports variant classification. Management is supportive.

Ask OpenScientist

Ask a research question about Gabriele-de Vries Syndrome. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).

Submitting...

Do not include personal health information in your question. Questions and results are cached in your browser's local storage.

1
Inheritance
8
Pathophys.
31
Phenotypes
38
Pathograph
1
Genes
5
Variants
3
Medical Actions
1
Datasets
2
Models
1
References
1
Deep Research
👪

Inheritance

1
Autosomal dominant inheritance HP:0000006
Autosomal dominant. Every proband whose parents have been tested carries a de novo YY1 variant or deletion; sib recurrence risk is estimated at about 1% because parental germline mosaicism cannot be excluded.
Autosomal dominant inheritance Penetrance: UNKNOWN Expressivity: VARIABLE
Show evidence (2 references)
PMID:31145572 SUPPORT Human Clinical
"Gabriele-de Vries syndrome is inherited in an autosomal dominant manner. All probands reported to date with Gabriele-de Vries syndrome whose parents have undergone molecular genetic testing have the disorder as a result of a de novo YY1 pathogenic variant or deletion."
GeneReviews states dominant inheritance and that all tested probands carry a de novo YY1 variant or deletion.
PMID:28575647 SUPPORT Human Clinical
"We have identified 23 individuals with de novo mutations or deletions of YY1"
The founding 23-person series consisted entirely of de novo YY1 variants or deletions.
⚙

Pathophysiology

8
YY1 Haploinsufficiency
Mechanism confidence: Established
Heterozygous, de novo YY1 alleles (frameshift and nonsense variants, whole-gene or 14q32.2 deletions, and missense variants in the zinc-finger DNA-binding domain) reduce the dose of functional YY1. Patient clinical and molecular data define the syndrome as a haploinsufficiency disorder.
YY1 hgnc:12856 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves YY1 (hgnc:12856). hgnc:12856 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context YY1 hgnc:12856 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns YY1 (hgnc:12856). hgnc:12856 is a gene from the HUGO Gene Nomenclature Committee. variant_origin: DE_NOVO zygosity: HETEROZYGOUS functional_impact_category: LOSS_OF_FUNCTION
De novo heterozygous truncating variants, deletions and zinc-finger missense variants, interpreted as loss of function causing haploinsufficiency.
Downstream
Reduced YY1 Chromatin Occupancy
Intrauterine Growth Restriction
Feeding Difficulties
Attention Deficit Hyperactivity Disorder
Anxiety
Autistic Behavior
Congenital Heart Defect
Cleft Palate
Pierre-Robin Sequence
Craniosynostosis
Renal Anomaly
Cryptorchidism
Skeletal Anomaly
Facial Dysmorphism
Dystonia
Show evidence (2 references)
PMID:28575647 SUPPORT Human Clinical
"Our combined clinical and molecular data define "YY1 syndrome" as a haploinsufficiency syndrome."
The founding series concludes that the syndrome is caused by YY1 haploinsufficiency.
PMID:39987231 SUPPORT In Vitro
"Germline mutations of YY1 cause Gabriele-de Vries syndrome (GADEVS)"
Independent patient iPSC study restating germline YY1 mutation as the cause of GADEVS.
Impaired YY1 Zinc-Finger DNA Binding
Mechanism confidence: Provisional
Disease-associated missense variants cluster in the four C-terminal zinc fingers that form the YY1 DNA-binding domain. The recurrent p.Asp380Tyr substitution alters YY1 structure only modestly but impairs the specificity of DNA binding, so missense alleles can reduce effective YY1 function without reducing protein amount.
YY1 hgnc:12856 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves YY1 (hgnc:12856). hgnc:12856 is a gene from the HUGO Gene Nomenclature Committee.
YY1 sequence-specific DNA binding GO:0000978 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased YY1 sequence-specific DNA binding, annotated with RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978). GO:0000978 is a molecular function from the Gene Ontology.
Downstream
Reduced YY1 Chromatin Occupancy
Show evidence (1 reference)
PMID:32077676 SUPPORT In Vitro
"Recently, various alterations in the Yin Yang 1's DNA binding domain were linked with an unexplained intellectual disability named Gabriele-de Vries syndrome."
Places the disease-associated missense variants in the DNA-binding domain.
Reduced YY1 Chromatin Occupancy
Mechanism confidence: Established
In patient-derived lymphoblastoid cells, YY1 binding is lost genome-wide, with relative retention at the highest-occupancy sites, for both deletion and missense alleles.
YY1 hgnc:12856 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves YY1 (hgnc:12856). hgnc:12856 is a gene from the HUGO Gene Nomenclature Committee.
Experimental models
Patient lymphoblastoid cell lines CELL LINE
Downstream
Loss of H3K27 Acetylation at YY1-Bound Enhancers
Show evidence (1 reference)
PMID:28575647 SUPPORT In Vitro
"Through immunoprecipitation of YY1-bound chromatin from affected individuals' cells with antibodies recognizing both ends of the protein, we show that YY1 deletions and missense mutations lead to a global loss of YY1 binding with a preferential retention at high-occupancy sites."
Direct ChIP measurement of reduced YY1 occupancy in patient cells.
Loss of H3K27 Acetylation at YY1-Bound Enhancers
Mechanism confidence: Established
Reduced YY1 occupancy is accompanied by widespread loss of the active enhancer mark H3K27ac, most pronounced at YY1-bound enhancers. GO's histone-acetylation process terms are obsolete, so the node is described in prose rather than bound to a process term.
Experimental models
Patient lymphoblastoid cell lines CELL LINE
Downstream
Dysregulated Cell-Type-Specific Transcriptional Networks
Show evidence (1 reference)
PMID:28575647 SUPPORT In Vitro
"we uncover a widespread loss of H3K27 acetylation in particular on the YY1-bound enhancers, underscoring a crucial role for YY1 in enhancer regulation"
Patient lymphoblastoid cells show enhancer H3K27ac loss.
Dysregulated Cell-Type-Specific Transcriptional Networks
Mechanism confidence: Provisional
In patient iPSC-derived cortical organoids and NGN2-induced neurons, YY1 haploinsufficiency alters cell-type-specific gene regulatory networks in radial glia, intermediate progenitors and excitatory neurons, including an aberrantly rewired YY1-NEUROG2-ETV5 regulatory interplay.
radial glial cell CL:0000681 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves radial glial cell (CL:0000681). CL:0000681 is a cell type from the Cell Ontology. neural progenitor cell CL:0011020 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neural progenitor cell (CL:0011020). CL:0011020 is a cell type from the Cell Ontology. excitatory (glutamatergic) neuron CL:0000679 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves excitatory (glutamatergic) neuron, annotated with glutamatergic neuron (CL:0000679). CL:0000679 is a cell type from the Cell Ontology.
regulation of transcription by RNA polymerase II GO:0006357 ↕ DYSREGULATED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated regulation of transcription by RNA polymerase II (GO:0006357). GO:0006357 is a biological process from the Gene Ontology.
Downstream
Disrupted Corticogenesis
Impaired Synapse Formation
Non-Cell-Autonomous Astrocyte Pro-Inflammatory Activation
Show evidence (1 reference)
PMID:39987231 SUPPORT In Vitro
"Mechanistically, cell type resolved reconstruction of gene regulatory networks uncovered the regulatory interplay between YY1, NEUROG2 and ETV5 and its aberrant rewiring in GADEVS."
Single-cell multiomic network reconstruction in patient-derived neural lineages identifies the rewired YY1-NEUROG2-ETV5 axis.
Disrupted Corticogenesis
Mechanism confidence: Provisional
Patient-derived cortical organoids show disrupted corticogenesis at the level of neural progenitors and differentiated neurons, with cytoarchitectural defects (irregular ventricle-like structures) that the authors relate to GADEVS clinical features.
cerebral cortex development GO:0021987 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal cerebral cortex development (GO:0021987). GO:0021987 is a biological process from the Gene Ontology.
Experimental models
Patient iPSC-derived cortical organoids and NGN2 neurons ORGANOID
Downstream
Intellectual Disability
Global Developmental Delay
Delayed Speech and Language Development
Motor Delay
Abnormal Brain Morphology
Show evidence (1 reference)
PMID:39987231 SUPPORT In Vitro
"disrupting corticogenesis at the level of neural progenitors and terminally differentiated neurons, including cytoarchitectural defects reminiscent of GADEVS clinical features"
Organoid-level evidence of abnormal cortical development.
Impaired Synapse Formation
Mechanism confidence: Provisional
Patient iPSC-derived excitatory neurons show disturbed synaptic transcriptional programs; synaptic formation is one of the domains most vulnerable to reduced YY1 dosage.
excitatory (glutamatergic) neuron CL:0000679 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves excitatory (glutamatergic) neuron, annotated with glutamatergic neuron (CL:0000679). CL:0000679 is a cell type from the Cell Ontology.
synapse organization GO:0050808 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal synapse organization (GO:0050808). GO:0050808 is a biological process from the Gene Ontology.
Downstream
Intellectual Disability
Show evidence (1 reference)
PMID:39987231 SUPPORT In Vitro
"Together, neurodevelopmental trajectories, synaptic formation and neuronal-astrocyte cross talk emerged as salient domains of YY1 dosage-dependent vulnerability."
Identifies synaptic formation as a YY1 dosage-sensitive process.
Non-Cell-Autonomous Astrocyte Pro-Inflammatory Activation
Mechanism confidence: Hypothetical
Astrocytes co-cultured with GADEVS patient-derived neurons adopt a pro-inflammatory activated transcriptional state, a non-cell-autonomous effect of neuronal YY1 haploinsufficiency. Its contribution to the clinical phenotype in patients is untested.
astrocyte CL:0000127 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves astrocyte (CL:0000127). CL:0000127 is a cell type from the Cell Ontology.
astrocyte activation GO:0048143 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased astrocyte activation (GO:0048143). GO:0048143 is a biological process from the Gene Ontology.
Experimental models
Patient iPSC-derived cortical organoids and NGN2 neurons ORGANOID
Show evidence (1 reference)
PMID:39987231 SUPPORT In Vitro
"Transcriptional alterations in neurons propagated to neighboring astrocytes through a major non-cell autonomous pro-inflammatory effect that grounds the rationale for modulatory interventions."
Neuron-astrocyte co-culture evidence for astrocyte activation.
⬡

Pathograph

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

Phenotypes

31
Cardiovascular 1
Congenital Heart Defect Abnormal heart morphology HP:0001627 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Congenital heart defect, annotated with Abnormal heart morphology (HP:0001627). HP:0001627 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31145572 SUPPORT Human Clinical
"strabismus, refractive error, congenital heart defects, renal anomalies, cryptorchidism, and skeletal anomalies are treated per standard practice"
GeneReviews lists congenital heart defects.
Digestive 3
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:31145572 SUPPORT Human Clinical
"Intrauterine growth restriction or low birth weight and feeding difficulties are common."
GeneReviews describes feeding difficulties as common.
Gastroesophageal Reflux HP:0002020 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Gastroesophageal reflux (HP:0002020). HP:0002020 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31145572 SUPPORT Human Clinical
"feeding difficulties, gastroesophageal reflux, constipation, seizures, behavioral manifestations"
Listed among GeneReviews manifestations requiring treatment.
Constipation HP:0002019 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Constipation (HP:0002019). HP:0002019 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31145572 SUPPORT Human Clinical
"feeding difficulties, gastroesophageal reflux, constipation, seizures, behavioral manifestations"
Listed among GeneReviews manifestations requiring treatment.
Ear 1
Hearing Impairment HP:0000365 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hearing impairment (HP:0000365). HP:0000365 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35829845 SUPPORT Human Clinical
"Undescribed or uncommon clinical features in this patient included non-febrile seizures, severe scoliosis, hearing impairment, and chorioretinitis."
Single case; described by the authors as uncommon.
Endocrine 1
Hypothyroidism OCCASIONAL HP:0000821 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypothyroidism (HP:0000821). HP:0000821 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40655401 SUPPORT Human Clinical
"Hypothyroidism has been reported in four previous cases (12%) of GADEVS, but autoimmune thyroiditis has not been documented."
Literature-derived proportion (4 cases, 12%), mapped to OCCASIONAL; the denominator is published cases, not a systematic cohort.
Eye 2
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 (2 references)
PMID:31145572 SUPPORT Human Clinical
"strabismus, refractive error, congenital heart defects, renal anomalies, cryptorchidism, and skeletal anomalies are treated per standard practice"
GeneReviews lists strabismus among manifestations requiring treatment.
PMID:40655401 SUPPORT Human Clinical
"Physical examination revealed mild facial dysmorphism, strabismus, an enlarged thyroid gland, and elongated fingers."
Single case with strabismus.
Refractive Error Abnormality of refraction HP:0000539 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Refractive error, annotated with Abnormality of refraction (HP:0000539). HP:0000539 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31145572 SUPPORT Human Clinical
"strabismus, refractive error, congenital heart defects, renal anomalies, cryptorchidism, and skeletal anomalies are treated per standard practice"
GeneReviews lists refractive error among manifestations requiring treatment.
Genitourinary 2
Renal Anomaly Abnormal renal morphology HP:0012210 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Congenital renal anomaly, annotated with Abnormal renal morphology (HP:0012210). HP:0012210 is a phenotype from the Human Phenotype Ontology.
Coarse binding: source unspecified
Show evidence (1 reference)
PMID:31145572 SUPPORT Human Clinical
"strabismus, refractive error, congenital heart defects, renal anomalies, cryptorchidism, and skeletal anomalies are treated per standard practice"
GeneReviews names renal anomalies without specifying them in the abstract, so a coarse term is bound.
Cryptorchidism HP:0000028 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cryptorchidism (HP:0000028). HP:0000028 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:35027293 SUPPORT Human Clinical
"We expanded the clinical profile of GADEVS to include thin/sparse hair and cryptorchidism."
The 13-person cohort added cryptorchidism to the phenotype.
PMID:31145572 SUPPORT Human Clinical
"strabismus, refractive error, congenital heart defects, renal anomalies, cryptorchidism, and skeletal anomalies are treated per standard practice"
GeneReviews lists cryptorchidism among manifestations requiring treatment.
Head and Neck 4
Facial Dysmorphism Abnormal facial shape HP:0001999 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Distinctive facial dysmorphism, annotated with Abnormal facial shape (HP:0001999). HP:0001999 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:37658636 SUPPORT Human Clinical
"Gabriele-de Vries syndrome is a rare autosomal dominant genetic disease characterized by global development delay/intellectual disability, delayed language development, feeding difficulties, and distinctive facial dysmorphism."
Facial dysmorphism is a characteristic feature.
PMID:35027293 SUPPORT Human Clinical
"Gabriele-de Vries syndrome (GADEVS) is a rare genetic disorder characterized by developmental delay and/or intellectual disability, hypotonia, feeding difficulties, and distinct facial features."
Distinct facial features are characteristic.
Cleft Palate 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:31145572 SUPPORT Human Clinical
"craniofacial anomalies (Pierre Robin sequence, cleft palate, craniosynostosis, abnormalities of the lacrimal duct)"
GeneReviews lists cleft palate among craniofacial anomalies to be treated.
Pierre-Robin Sequence HP:0000201 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pierre Robin sequence, annotated with Pierre-Robin sequence (HP:0000201). HP:0000201 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31145572 SUPPORT Human Clinical
"craniofacial anomalies (Pierre Robin sequence, cleft palate, craniosynostosis, abnormalities of the lacrimal duct)"
GeneReviews lists Pierre Robin sequence among craniofacial anomalies.
Craniosynostosis HP:0001363 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Craniosynostosis (HP:0001363). HP:0001363 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31145572 SUPPORT Human Clinical
"craniofacial anomalies (Pierre Robin sequence, cleft palate, craniosynostosis, abnormalities of the lacrimal duct)"
GeneReviews lists craniosynostosis among craniofacial anomalies.
Integument 1
Sparse Hair HP:0008070 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Thin or sparse hair, annotated with Sparse hair (HP:0008070). HP:0008070 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35027293 SUPPORT Human Clinical
"We expanded the clinical profile of GADEVS to include thin/sparse hair and cryptorchidism."
The 13-person cohort added thin/sparse hair to the phenotype.
Musculoskeletal 2
Hypotonia HP:0001252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypotonia (HP:0001252). HP:0001252 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:31145572 SUPPORT Human Clinical
"About half of affected individuals have neurologic manifestations, including hypotonia and gait abnormalities."
GeneReviews lists hypotonia among neurologic manifestations.
PMID:35027293 SUPPORT Human Clinical
"Gabriele-de Vries syndrome (GADEVS) is a rare genetic disorder characterized by developmental delay and/or intellectual disability, hypotonia, feeding difficulties, and distinct facial features."
Hypotonia is listed among the characteristic features.
Skeletal Anomaly Abnormality of the skeletal system HP:0000924 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Congenital skeletal anomaly, annotated with Abnormality of the skeletal system (HP:0000924). HP:0000924 is a phenotype from the Human Phenotype Ontology.
Coarse binding: source unspecified
Show evidence (1 reference)
PMID:31145572 SUPPORT Human Clinical
"strabismus, refractive error, congenital heart defects, renal anomalies, cryptorchidism, and skeletal anomalies are treated per standard practice"
GeneReviews names skeletal anomalies without specifying them in the abstract, so a coarse term is bound.
Nervous System 13
Intellectual Disability OBLIGATE 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 (2 references)
PMID:31145572 SUPPORT Human Clinical
"Gabriele-de Vries syndrome is characterized by mild-to-profound developmental delay / intellectual disability (DD/ID) in all affected individuals"
GeneReviews reports DD/ID in all affected individuals.
PMID:28575647 SUPPORT Human Clinical
"phenotypic features that define a syndrome of cognitive impairment, behavioral alterations, intrauterine growth restriction, feeding problems, and various congenital malformations"
Cognitive impairment is a defining feature of the founding series. The GeneReviews chapter draws on these same patients, so the two items are not independent replication.
Global Developmental Delay OBLIGATE 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:31145572 SUPPORT Human Clinical
"Gabriele-de Vries syndrome is characterized by mild-to-profound developmental delay / intellectual disability (DD/ID) in all affected individuals"
GeneReviews reports DD/ID in all affected individuals.
Delayed Speech and Language Development 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 (2 references)
PMID:37658636 SUPPORT Human Clinical
"Gabriele-de Vries syndrome is a rare autosomal dominant genetic disease characterized by global development delay/intellectual disability, delayed language development, feeding difficulties, and distinctive facial dysmorphism."
Delayed language development is listed among the characteristic features.
PMID:34729769 SUPPORT Human Clinical
"The proband presented with delayed motor and speech development"
Single-case report of speech delay.
Motor Delay HP:0001270 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Motor delay (HP:0001270). HP:0001270 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:34729769 SUPPORT Human Clinical
"The proband presented with delayed motor and speech development"
Single-case report of motor delay.
PMID:37658636 SUPPORT Human Clinical
"The current report describes a female patient with motor delay and a facial dysmorphism phenotype."
A second, unrelated case report with motor delay.
Gait Disturbance HP:0001288 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Gait abnormality, annotated with Gait disturbance (HP:0001288). HP:0001288 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31145572 SUPPORT Human Clinical
"About half of affected individuals have neurologic manifestations, including hypotonia and gait abnormalities."
GeneReviews lists gait abnormalities among neurologic manifestations.
Ataxia HP:0001251 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ataxia (HP:0001251). HP:0001251 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:34729769 SUPPORT Human Clinical
"The proband presented with delayed motor and speech development, ataxia, abnormal gait, autistic behavior, brain atrophy, and severe learning disability."
Single-case report of ataxia.
PMID:32627382 SUPPORT Human Clinical
"a complex movement disorder including an action tremor, cerebellar ataxia, dystonia, and partial ocular apraxia"
A second unrelated case with cerebellar ataxia.
Dystonia HP:0001332 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dystonia (HP:0001332). HP:0001332 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:41554999 SUPPORT Human Clinical
"About half of affected individuals develop movement disorders, including dystonia."
Background statement in a case report; the half refers to movement disorders as a class, so no dystonia-specific frequency is recorded.
PMID:32627382 SUPPORT Human Clinical
"Movement disorders were reported in 5/10 cases of the original series, but no detailed description was provided."
Restates the movement-disorder count from the founding series; this is the same cohort as PMID:28575647, not new patients.
PMID:35172867 SUPPORT Human Clinical
"All these patients had an early developmental delay and displayed a movement disorder (dystonia/ataxia/tremor) which manifested for the first time, or worsened, in the adulthood"
Adult-onset or worsening movement disorder in a series that includes a YY1 patient; the sentence covers four different genetic disorders.
Tremor HP:0001337 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Action tremor, annotated with Tremor (HP:0001337). HP:0001337 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32627382 SUPPORT Human Clinical
"a complex movement disorder including an action tremor, cerebellar ataxia, dystonia, and partial ocular apraxia"
Single-case report of action tremor.
Seizure HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:31145572 SUPPORT Human Clinical
"feeding difficulties, gastroesophageal reflux, constipation, seizures, behavioral manifestations"
Seizures are listed among GeneReviews manifestations requiring treatment.
PMID:35829845 SUPPORT Human Clinical
"Undescribed or uncommon clinical features in this patient included non-febrile seizures, severe scoliosis, hearing impairment, and chorioretinitis."
Single case with non-febrile seizures, described as uncommon.
Attention Deficit Hyperactivity Disorder HP:0007018 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Attention deficit hyperactivity disorder (HP:0007018). HP:0007018 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31145572 SUPPORT Human Clinical
"Behavioral issues can include attention-deficit/hyperactivity disorder, anxiety, autism or autistic behavior, and schizoaffective disorder."
GeneReviews lists ADHD among behavioral issues.
Anxiety HP:0000739 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Anxiety (HP:0000739). HP:0000739 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31145572 SUPPORT Human Clinical
"Behavioral issues can include attention-deficit/hyperactivity disorder, anxiety, autism or autistic behavior, and schizoaffective disorder."
GeneReviews lists anxiety among behavioral issues.
Autistic Behavior HP:0000729 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Autism or autistic behavior, annotated with Autistic behavior (HP:0000729). HP:0000729 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:31145572 SUPPORT Human Clinical
"Behavioral issues can include attention-deficit/hyperactivity disorder, anxiety, autism or autistic behavior, and schizoaffective disorder."
GeneReviews lists autism or autistic behavior among behavioral issues.
PMID:34729769 SUPPORT Human Clinical
"The proband presented with delayed motor and speech development, ataxia, abnormal gait, autistic behavior, brain atrophy, and severe learning disability."
Single case with autistic behavior.
Abnormal Brain Morphology HP:0012443 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Congenital brain anomaly, annotated with Abnormal brain morphology (HP:0012443). HP:0012443 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31145572 SUPPORT Human Clinical
"Congenital brain, eye, heart, kidney, genital, and/or skeletal system anomalies have also been reported."
GeneReviews reports congenital brain anomalies.
Growth 1
Intrauterine Growth Restriction FREQUENT Intrauterine growth retardation HP:0001511 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intrauterine growth restriction or low birth weight, annotated with Intrauterine growth retardation (HP:0001511). HP:0001511 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31145572 SUPPORT Human Clinical
"Intrauterine growth restriction or low birth weight and feeding difficulties are common."
GeneReviews describes IUGR or low birth weight as common, mapped to the FREQUENT band.
🧬

Genetic Associations

1
YY1 (Causative)
Gene: YY1 hgnc:12856 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is YY1 (hgnc:12856). hgnc:12856 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: DE_NOVO
Show evidence (1 reference)
PMID:31145572 SUPPORT Human Clinical
"The diagnosis of Gabriele-de Vries syndrome is established in a proband by the identification of a heterozygous pathogenic variant involving YY1 or a heterozygous deletion of 14q32.2 involving only YY1."
GeneReviews defines the causal genotype.
Variants (5)
p.Glu231Ilefs*25 Pathogenic
deletion
De novo frameshift NM_003403:c.690delA reported in an Iranian boy with motor and speech delay, ataxia and autistic behavior.
Show evidence (1 reference)
PMID:34729769 SUPPORT Human Clinical
"The novel de novo pathogenic variant detected in this study (NM_003403:c.690delA, p.Glu231Ilefs*25) was identified by whole-exome sequencing and confirmed by Sanger sequencing."
Reports the variant as de novo and pathogenic.
p.Val153fs*97
deletion
Novel heterozygous frameshift NM_003403.5:c.458_476del.
Show evidence (1 reference)
PMID:37658636 SUPPORT Human Clinical
"A novel heterozygous frameshift mutation NM_003403.5:c.458_476del (p. V153fs*97) in the YY1 gene was detected in the proband."
Reports the variant in a GADEVS proband.
p.Cys303Arg Pathogenic
single nucleotide variant
De novo missense NM_003403.4:c.907T>C in a woman with mild intellectual disability and a complex movement disorder (action tremor, cerebellar ataxia, dystonia).
Show evidence (1 reference)
PMID:32627382 SUPPORT Human Clinical
"Whole-exome sequencing revealed a novel heterozygous de novo mutation in YY1"
Reports the de novo variant, which the abstract identifies in a bracketed span (omitted from the snippet because bracketed text is stripped before matching) as c.907T>C p.(Cys303Arg) and classifies as ACMG pathogenic.
p.Asn369Ser Pathogenic
single nucleotide variant
De novo missense NM_003403.5:c.1106A>G reported with phenotype expansion and skewed X inactivation.
Show evidence (1 reference)
PMID:35829845 SUPPORT Human Clinical
"we describe clinical and molecular findings from a Brazilian female harbouring a de novo missense pathogenic variant in YY1 gene (NM_003403.5:c.1106A > G; p.Asn369Ser)"
Reports the variant as de novo and pathogenic.
p.Asp380Tyr
single nucleotide variant
Recurrent zinc-finger missense substitution that impairs DNA-binding specificity in vitro.
Show evidence (1 reference)
PMID:32077676 SUPPORT In Vitro
"a repetitively occurring substitution of aspartate-380 for tyrosine was analyzed to assess its impact on Yin Yang 1's structure and DNA binding"
Describes the variant as recurrent and characterizes it functionally.
💊

Medical Actions

3
Symptom-Directed Supportive Care
Category: Therapeutic 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
Platform: Other
No disease-modifying therapy exists. Developmental delay, craniofacial anomalies, feeding difficulties, reflux, constipation, seizures, behavioral manifestations, eye findings, congenital heart and renal anomalies, cryptorchidism and skeletal anomalies are each treated per standard practice.
Show evidence (1 reference)
PMID:31145572 SUPPORT Human Clinical
"Treatment of manifestations: Developmental delay / intellectual disability, craniofacial anomalies (Pierre Robin sequence, cleft palate, craniosynostosis, abnormalities of the lacrimal duct), feeding difficulties, gastroesophageal reflux, constipation, seizures, behavioral manifestations,..."
GeneReviews management is symptom-directed standard care.
Pallidal Deep Brain Stimulation for Dystonia
Category: Therapeutic Action: bilateral GPi deep brain stimulationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is bilateral GPi deep brain stimulation, annotated with Deep Brain Stimulation (NCIT:C21024). NCIT:C21024 is a clinical intervention from the NCI Thesaurus. Ontology label: Deep Brain Stimulation NCIT:C21024
Platform: Device
Bilateral globus pallidus internus deep brain stimulation has been used for medication-refractory generalized dystonia; evidence is limited to case reports.
Target Phenotypes: Dystonia HP:0001332 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Dystonia (HP:0001332). HP:0001332 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41554999 SUPPORT Human Clinical
"The Burke-Fahn-Marsden motor score decreased from 100 to 50, and the disability score decreased from 20 to 14 at six months."
Single-patient report of improvement after GPi-DBS; it notes only one similar case had been reported.
Levothyroxine for Hypothyroidism
Category: Therapeutic Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: levothyroxine NCIT:C62080 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses levothyroxine (NCIT:C62080). NCIT:C62080 is a therapeutic agent from the NCI Thesaurus.
Platform: Small molecule
Hypothyroidism, including autoimmune thyroiditis, is treated with standard levothyroxine replacement.
Target Phenotypes: Hypothyroidism HP:0000821 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Hypothyroidism (HP:0000821). HP:0000821 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40655401 SUPPORT Human Clinical
"Levothyroxine replacement therapy successfully corrected the hypothyroidism."
Single-case report of treated hypothyroidism.
🔬

Diagnosis

2
YY1 Molecular Genetic Testing
Diagnosis requires a heterozygous pathogenic YY1 variant or a 14q32.2 deletion involving YY1, because the clinical features are variable and nonspecific. Exome sequencing with Sanger confirmation identified the variants in several case reports.
molecular genetic testing for YY1 NCIT:C15709 NCI Thesaurus (NCIT)
Results: A heterozygous pathogenic YY1 sequence variant or a deletion including YY1.
Show evidence (2 references)
PMID:31145572 SUPPORT Human Clinical
"The diagnosis of Gabriele-de Vries syndrome is established in a proband by the identification of a heterozygous pathogenic variant involving YY1 or a heterozygous deletion of 14q32.2 involving only YY1."
GeneReviews diagnostic criterion.
PMID:34729769 SUPPORT Human Clinical
"The investigations for a suspected case of Gabriele-de Vries Syndrome must involve molecular diagnosis of the disease and its underlying genetic defect because the clinical investigations are generally variable and nonspecific."
Clinical features alone are insufficient for diagnosis.
Peripheral Blood DNA Methylation Episignature
A GADEVS-specific peripheral-blood DNA methylation episignature, derived from 13 individuals, supports classification of YY1 variants of uncertain significance. It is a diagnostic biomarker, not a demonstrated step in the causal chain.
DNA methylation episignature analysis NCIT:C63328 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:35027293 SUPPORT Human Clinical
"We also highlighted the utility of DNA methylation episignature analysis for classification of variants of unknown clinical significance."
Establishes the episignature as a variant-classification aid.
📊

Prevalence

1
Worldwide (published case reports and series)
Cases In Literature Ultra Rare
A 2023 literature review counted 28 genetically characterized patients reported to that date. Population prevalence and incidence are unknown.
Show evidence (1 reference)
PMID:37658636 SUPPORT Human Clinical
"A total of 28 patients with genetic abnormalities and clinical phenotypes have been reported in the literature thus far."
Literature count of published, genetically characterized GADEVS patients at the time of the review.
📊

Related Datasets

1
YY1 haploinsufficiency causes an intellectual disability syndrome featuring transcriptional and chromatin dysfunction. geo:GSE98478
GEO SuperSeries for the founding study: YY1 and histone ChIP-seq and RNA-seq in lymphoblastoid cells from affected individuals and controls.
human CHIP SEQ
PMID:28575647
🧫

Experimental Models

2
Patient iPSC-derived cortical organoids and NGN2 neurons ORGANOID
2D and 3D patient-derived neural lineages (cortical organoids, NGN2-induced excitatory neurons, and neuron-astrocyte co-culture) analyzed by imaging, single-cell multiomics and gene regulatory network reconstruction.
Publication
PMID:39987231
Pathograph links
Disrupted Corticogenesis recapitulates fidelity: moderate observes: tissue
Limitations: In vitro organoids lack vasculature and whole-brain context; the link from organoid cytoarchitecture to patient brain findings is by analogy.
Show evidence (1 reference)
PMID:39987231 SUPPORT In Vitro
"we combined large-scale imaging, single-cell multiomics and gene regulatory network reconstruction in 2D and 3D patient-derived physiopathologically relevant cell lineages"
Describes the patient-derived model systems.
Non-Cell-Autonomous Astrocyte Pro-Inflammatory Activation recapitulates fidelity: unknown observes: cellular
Limitations: Co-culture system; whether astrocyte activation occurs in patient brain is untested.
Show evidence (1 reference)
PMID:39987231 SUPPORT In Vitro
"Transcriptional alterations in neurons propagated to neighboring astrocytes through a major non-cell autonomous pro-inflammatory effect"
Co-culture readout of astrocyte activation.
Patient lymphoblastoid cell lines CELL_LINE
Lymphoblastoid cells from affected individuals carrying YY1 deletions or missense variants, used for YY1 and histone ChIP-seq and RNA-seq.
Publication
PMID:28575647
Pathograph links
Reduced YY1 Chromatin Occupancy recapitulates fidelity: moderate observes: molecular
Limitations: Transformed blood-derived cells; chromatin findings may not transfer to developing neural cells.
Show evidence (1 reference)
PMID:28575647 SUPPORT In Vitro
"Through immunoprecipitation of YY1-bound chromatin from affected individuals' cells with antibodies recognizing both ends of the protein"
ChIP in patient-derived cells.
Loss of H3K27 Acetylation at YY1-Bound Enhancers recapitulates fidelity: moderate observes: molecular
Limitations: Transformed blood-derived cells; enhancer landscapes differ from those of neural progenitors.
Show evidence (1 reference)
PMID:28575647 SUPPORT In Vitro
"we uncover a widespread loss of H3K27 acetylation in particular on the YY1-bound enhancers"
Histone ChIP in patient-derived cells.
{ }

Source YAML

click to show 
name: Gabriele-de Vries Syndrome
creation_date: "2026-10-18T00:00:00Z"
synonyms:
- Gabriele de Vries syndrome
- GADEVS
- YY1 syndrome
- YY1 haploinsufficiency syndrome
description: >-
  Gabriele-de Vries syndrome (GADEVS) is an autosomal dominant
  neurodevelopmental and multiple-congenital-anomaly syndrome caused by
  heterozygous pathogenic variants in YY1, or by deletions of 14q32.2 that
  include YY1, which in all tested families have arisen de novo. YY1 is a
  zinc-finger transcription factor that acts as both activator and repressor
  and regulates enhancer activity. Truncating alleles, whole-gene deletions
  and missense variants in the C-terminal zinc-finger DNA-binding domain
  converge on haploinsufficiency: in patient-derived cells YY1 chromatin
  occupancy is globally reduced, H3K27 acetylation is lost at YY1-bound
  enhancers, and in patient iPSC-derived cortical organoids and neurons
  cell-type-specific transcriptional networks of neural progenitors and
  excitatory neurons are disrupted. Clinically, mild-to-profound
  developmental delay or intellectual disability is present in all affected
  individuals, accompanied by speech and motor delay, intrauterine growth
  restriction or low birth weight, feeding difficulties, hypotonia and gait
  abnormalities, behavioral features (ADHD, anxiety, autistic behavior),
  facial dysmorphism, and variable congenital anomalies of the brain, eye,
  heart, kidney, genitalia and skeleton. A subset develop a juvenile- or
  adult-onset movement disorder dominated by dystonia. A peripheral-blood DNA
  methylation episignature supports variant classification. Management is
  supportive.
category: Mendelian
disease_term:
  preferred_term: Gabriele-de Vries syndrome
  term:
    id: MONDO:0044738
    label: Gabriele de Vries syndrome
parents:
- syndromic intellectual disability
- multiple congenital anomalies/dysmorphic syndrome-intellectual disability
inheritance:
- name: Autosomal dominant inheritance
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    Autosomal dominant. Every proband whose parents have been tested carries a
    de novo YY1 variant or deletion; sib recurrence risk is estimated at about
    1% because parental germline mosaicism cannot be excluded.
  penetrance: UNKNOWN
  expressivity: VARIABLE
  evidence:
  - reference: PMID:31145572
    reference_title: "Gabriele-de Vries Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Gabriele-de Vries syndrome is inherited in an autosomal dominant manner.
      All probands reported to date with Gabriele-de Vries syndrome whose
      parents have undergone molecular genetic testing have the disorder as a
      result of a de novo YY1 pathogenic variant or deletion.
    explanation: >-
      GeneReviews states dominant inheritance and that all tested probands
      carry a de novo YY1 variant or deletion.
  - reference: PMID:28575647
    reference_title: "YY1 Haploinsufficiency Causes an Intellectual Disability Syndrome Featuring Transcriptional and Chromatin Dysfunction."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We have identified 23 individuals with de novo mutations or deletions of
      YY1
    explanation: >-
      The founding 23-person series consisted entirely of de novo YY1 variants
      or deletions.
prevalence:
- population: Worldwide (published case reports and series)
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    A 2023 literature review counted 28 genetically characterized patients
    reported to that date. Population prevalence and incidence are unknown.
  evidence:
  - reference: PMID:37658636
    reference_title: "Clinical analysis of Gabriele-de Vries caused by YY1 mutations and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A total of 28 patients with genetic abnormalities and clinical
      phenotypes have been reported in the literature thus far.
    explanation: >-
      Literature count of published, genetically characterized GADEVS
      patients at the time of the review.
pathophysiology:
- name: YY1 Haploinsufficiency
  description: >-
    Heterozygous, de novo YY1 alleles (frameshift and nonsense variants,
    whole-gene or 14q32.2 deletions, and missense variants in the zinc-finger
    DNA-binding domain) reduce the dose of functional YY1. Patient clinical and
    molecular data define the syndrome as a haploinsufficiency disorder.
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  genes:
  - preferred_term: YY1
    term:
      id: hgnc:12856
      label: YY1
  genetic_context:
    gene:
      preferred_term: YY1
      term:
        id: hgnc:12856
        label: YY1
    variant_origin: DE_NOVO
    zygosity: HETEROZYGOUS
    functional_impact_category: LOSS_OF_FUNCTION
    description: >-
      De novo heterozygous truncating variants, deletions and zinc-finger
      missense variants, interpreted as loss of function causing
      haploinsufficiency.
  evidence:
  - reference: PMID:28575647
    reference_title: "YY1 Haploinsufficiency Causes an Intellectual Disability Syndrome Featuring Transcriptional and Chromatin Dysfunction."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our combined clinical and molecular data define "YY1 syndrome" as a
      haploinsufficiency syndrome.
    explanation: >-
      The founding series concludes that the syndrome is caused by YY1
      haploinsufficiency.
  - reference: PMID:39987231
    reference_title: "YY1 mutations disrupt corticogenesis through a cell type specific rewiring of cell-autonomous and non-cell-autonomous transcriptional programs."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Germline mutations of YY1 cause Gabriele-de Vries syndrome (GADEVS)"
    explanation: >-
      Independent patient iPSC study restating germline YY1 mutation as the
      cause of GADEVS.
  downstream:
  - target: Reduced YY1 Chromatin Occupancy
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:28575647
      reference_title: "YY1 Haploinsufficiency Causes an Intellectual Disability Syndrome Featuring Transcriptional and Chromatin Dysfunction."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        we show that YY1 deletions and missense mutations lead to a global
        loss of YY1 binding with a preferential retention at high-occupancy
        sites
      explanation: >-
        ChIP of YY1-bound chromatin in affected individuals' cells shows that
        both deletions and missense variants reduce YY1 genome-wide binding.
  - target: Intrauterine Growth Restriction
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence: &founding_syndrome_def
    - reference: PMID:28575647
      reference_title: "YY1 Haploinsufficiency Causes an Intellectual Disability Syndrome Featuring Transcriptional and Chromatin Dysfunction."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We have identified 23 individuals with de novo mutations or deletions
        of YY1 and phenotypic features that define a syndrome of cognitive
        impairment, behavioral alterations, intrauterine growth restriction,
        feeding problems, and various congenital malformations.
      explanation: >-
        The founding series ties YY1 loss to this feature; no intermediate
        mechanism has been studied.
  - target: Feeding Difficulties
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence: *founding_syndrome_def
  - target: Attention Deficit Hyperactivity Disorder
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence: *founding_syndrome_def
  - target: Anxiety
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence: *founding_syndrome_def
  - target: Autistic Behavior
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence: *founding_syndrome_def
  - target: Congenital Heart Defect
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence: *founding_syndrome_def
  - target: Cleft Palate
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence: *founding_syndrome_def
  - target: Pierre-Robin Sequence
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence: *founding_syndrome_def
  - target: Craniosynostosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence: *founding_syndrome_def
  - target: Renal Anomaly
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence: *founding_syndrome_def
  - target: Cryptorchidism
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence: *founding_syndrome_def
  - target: Skeletal Anomaly
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence: *founding_syndrome_def
  - target: Facial Dysmorphism
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:37658636
      reference_title: "Clinical analysis of Gabriele-de Vries caused by YY1 mutations and literature review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        distinctive facial dysmorphism. It is caused by pathogenic variants in
        YY1.
      explanation: >-
        Facial dysmorphism is attributed to pathogenic YY1 variants; the
        developmental route (for example via neural crest) is not studied in
        patients.
  - target: Dystonia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:41554999
      reference_title: "Long-term benefit of GPi-DBS in YY1-related dystonia: a case report."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Gabriele-de Vries syndrome (GADEVS) is a rare genetic disorder caused
        by mutations in the YY1 gene.
      explanation: >-
        Case report of de novo YY1 nonsense variant with progressive
        generalized dystonia; how YY1 loss produces dystonia is unknown.
- name: Impaired YY1 Zinc-Finger DNA Binding
  description: >-
    Disease-associated missense variants cluster in the four C-terminal zinc
    fingers that form the YY1 DNA-binding domain. The recurrent p.Asp380Tyr
    substitution alters YY1 structure only modestly but impairs the
    specificity of DNA binding, so missense alleles can reduce effective YY1
    function without reducing protein amount.
  biological_scale: MOLECULAR
  mechanism_confidence: PROVISIONAL
  genes:
  - preferred_term: YY1
    term:
      id: hgnc:12856
      label: YY1
  molecular_functions:
  - preferred_term: YY1 sequence-specific DNA binding
    modifier: DECREASED
    term:
      id: GO:0000978
      label: RNA polymerase II cis-regulatory region sequence-specific DNA binding
  evidence:
  - reference: PMID:32077676
    reference_title: "The effect of D380Y pathogenic mutation in human Yin Yang 1 on the protein's structure and function."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Recently, various alterations in the Yin Yang 1's DNA binding domain
      were linked with an unexplained intellectual disability named
      Gabriele-de Vries syndrome.
    explanation: >-
      Places the disease-associated missense variants in the DNA-binding
      domain.
  downstream:
  - target: Reduced YY1 Chromatin Occupancy
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:32077676
      reference_title: "The effect of D380Y pathogenic mutation in human Yin Yang 1 on the protein's structure and function."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        The substitution was found to affect Yin Yang 1's secondary and
        tertiary structure to a limited extent and to impair the specificity
        of its interaction with DNA.
      explanation: >-
        Biophysical study of recombinant p.Asp380Tyr YY1 shows impaired DNA
        binding specificity, a route to reduced productive occupancy for a
        missense allele.
- name: Reduced YY1 Chromatin Occupancy
  description: >-
    In patient-derived lymphoblastoid cells, YY1 binding is lost genome-wide,
    with relative retention at the highest-occupancy sites, for both deletion
    and missense alleles.
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  genes:
  - preferred_term: YY1
    term:
      id: hgnc:12856
      label: YY1
  evidence:
  - reference: PMID:28575647
    reference_title: "YY1 Haploinsufficiency Causes an Intellectual Disability Syndrome Featuring Transcriptional and Chromatin Dysfunction."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Through immunoprecipitation of YY1-bound chromatin from affected
      individuals' cells with antibodies recognizing both ends of the protein,
      we show that YY1 deletions and missense mutations lead to a global loss
      of YY1 binding with a preferential retention at high-occupancy sites.
    explanation: >-
      Direct ChIP measurement of reduced YY1 occupancy in patient cells.
  downstream:
  - target: Loss of H3K27 Acetylation at YY1-Bound Enhancers
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:28575647
      reference_title: "YY1 Haploinsufficiency Causes an Intellectual Disability Syndrome Featuring Transcriptional and Chromatin Dysfunction."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        we uncover a widespread loss of H3K27 acetylation in particular on the
        YY1-bound enhancers, underscoring a crucial role for YY1 in enhancer
        regulation
      explanation: >-
        The same patient cells show H3K27ac loss concentrated at YY1-bound
        enhancers, linking reduced occupancy to enhancer inactivation.
- name: Loss of H3K27 Acetylation at YY1-Bound Enhancers
  description: >-
    Reduced YY1 occupancy is accompanied by widespread loss of the active
    enhancer mark H3K27ac, most pronounced at YY1-bound enhancers. GO's
    histone-acetylation process terms are obsolete, so the node is described
    in prose rather than bound to a process term.
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  evidence:
  - reference: PMID:28575647
    reference_title: "YY1 Haploinsufficiency Causes an Intellectual Disability Syndrome Featuring Transcriptional and Chromatin Dysfunction."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      we uncover a widespread loss of H3K27 acetylation in particular on the
      YY1-bound enhancers, underscoring a crucial role for YY1 in enhancer
      regulation
    explanation: >-
      Patient lymphoblastoid cells show enhancer H3K27ac loss.
  downstream:
  - target: Dysregulated Cell-Type-Specific Transcriptional Networks
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:28575647
      reference_title: "YY1 Haploinsufficiency Causes an Intellectual Disability Syndrome Featuring Transcriptional and Chromatin Dysfunction."
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: INDIRECT
      snippet: >-
        Collectively, these results define a clinical syndrome caused by
        haploinsufficiency of YY1 through dysregulation of key transcriptional
        regulators.
      explanation: >-
        The authors connect the chromatin findings to transcriptional
        dysregulation; the enhancer-to-network step in neural cells is
        inferred from lymphoblastoid data rather than measured in brain cells.
- name: Dysregulated Cell-Type-Specific Transcriptional Networks
  description: >-
    In patient iPSC-derived cortical organoids and NGN2-induced neurons, YY1
    haploinsufficiency alters cell-type-specific gene regulatory networks in
    radial glia, intermediate progenitors and excitatory neurons, including an
    aberrantly rewired YY1-NEUROG2-ETV5 regulatory interplay.
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  cell_types:
  - preferred_term: radial glial cell
    term:
      id: CL:0000681
      label: radial glial cell
  - preferred_term: neural progenitor cell
    term:
      id: CL:0011020
      label: neural progenitor cell
  - preferred_term: excitatory (glutamatergic) neuron
    term:
      id: CL:0000679
      label: glutamatergic neuron
  biological_processes:
  - preferred_term: regulation of transcription by RNA polymerase II
    modifier: DYSREGULATED
    term:
      id: GO:0006357
      label: regulation of transcription by RNA polymerase II
  evidence:
  - reference: PMID:39987231
    reference_title: "YY1 mutations disrupt corticogenesis through a cell type specific rewiring of cell-autonomous and non-cell-autonomous transcriptional programs."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Mechanistically, cell type resolved reconstruction of gene regulatory
      networks uncovered the regulatory interplay between YY1, NEUROG2 and
      ETV5 and its aberrant rewiring in GADEVS.
    explanation: >-
      Single-cell multiomic network reconstruction in patient-derived neural
      lineages identifies the rewired YY1-NEUROG2-ETV5 axis.
  downstream:
  - target: Disrupted Corticogenesis
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:39987231
      reference_title: "YY1 mutations disrupt corticogenesis through a cell type specific rewiring of cell-autonomous and non-cell-autonomous transcriptional programs."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        YY1 haploinsufficiency causes a pervasive alteration of cell type
        specific transcriptional networks, disrupting corticogenesis at the
        level of neural progenitors and terminally differentiated neurons
      explanation: >-
        Organoid data tie the transcriptional network alteration to disrupted
        cortical development.
  - target: Impaired Synapse Formation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:39987231
      reference_title: "YY1 mutations disrupt corticogenesis through a cell type specific rewiring of cell-autonomous and non-cell-autonomous transcriptional programs."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Together, neurodevelopmental trajectories, synaptic formation and
        neuronal-astrocyte cross talk emerged as salient domains of YY1
        dosage-dependent vulnerability.
      explanation: >-
        Synaptic formation is identified as a YY1 dosage-sensitive domain in
        patient-derived neurons.
  - target: Non-Cell-Autonomous Astrocyte Pro-Inflammatory Activation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:39987231
      reference_title: "YY1 mutations disrupt corticogenesis through a cell type specific rewiring of cell-autonomous and non-cell-autonomous transcriptional programs."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Transcriptional alterations in neurons propagated to neighboring
        astrocytes through a major non-cell autonomous pro-inflammatory effect
      explanation: >-
        Neuron-astrocyte co-culture shows mutant-neuron transcriptional changes
        propagating to astrocytes.
- name: Disrupted Corticogenesis
  description: >-
    Patient-derived cortical organoids show disrupted corticogenesis at the
    level of neural progenitors and differentiated neurons, with
    cytoarchitectural defects (irregular ventricle-like structures) that the
    authors relate to GADEVS clinical features.
  biological_scale: TISSUE
  mechanism_confidence: PROVISIONAL
  biological_processes:
  - preferred_term: cerebral cortex development
    modifier: ABNORMAL
    term:
      id: GO:0021987
      label: cerebral cortex development
  evidence:
  - reference: PMID:39987231
    reference_title: "YY1 mutations disrupt corticogenesis through a cell type specific rewiring of cell-autonomous and non-cell-autonomous transcriptional programs."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      disrupting corticogenesis at the level of neural progenitors and
      terminally differentiated neurons, including cytoarchitectural defects
      reminiscent of GADEVS clinical features
    explanation: >-
      Organoid-level evidence of abnormal cortical development.
  downstream:
  - target: Intellectual Disability
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:39987231
      reference_title: "YY1 mutations disrupt corticogenesis through a cell type specific rewiring of cell-autonomous and non-cell-autonomous transcriptional programs."
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: INDIRECT
      snippet: >-
        Our findings underscore the reach of advanced in vitro models in
        capturing developmental antecedents of clinical features and exposing
        their underlying mechanisms
      explanation: >-
        The organoid findings are presented as developmental antecedents of
        the clinical neurodevelopmental phenotype; the bridge to intellectual
        disability is inferred, not measured.
  - target: Global Developmental Delay
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:39987231
      reference_title: "YY1 mutations disrupt corticogenesis through a cell type specific rewiring of cell-autonomous and non-cell-autonomous transcriptional programs."
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: INDIRECT
      snippet: >-
        Germline mutations of YY1 cause Gabriele-de Vries syndrome (GADEVS), a
        neurodevelopmental disorder featuring intellectual disability and a
        wide range of systemic manifestations.
      explanation: >-
        Frames the corticogenesis defect within the neurodevelopmental
        disorder; the link to developmental delay is inferred.
  - target: Delayed Speech and Language Development
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:39987231
      reference_title: "YY1 mutations disrupt corticogenesis through a cell type specific rewiring of cell-autonomous and non-cell-autonomous transcriptional programs."
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: INDIRECT
      snippet: >-
        Our findings underscore the reach of advanced in vitro models in
        capturing developmental antecedents of clinical features and exposing
        their underlying mechanisms
      explanation: >-
        The organoid corticogenesis defect is offered as a developmental
        antecedent of the neurodevelopmental phenotype; the link to this
        specific delay is inferred, not measured.
  - target: Motor Delay
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:39987231
      reference_title: "YY1 mutations disrupt corticogenesis through a cell type specific rewiring of cell-autonomous and non-cell-autonomous transcriptional programs."
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: INDIRECT
      snippet: >-
        Our findings underscore the reach of advanced in vitro models in
        capturing developmental antecedents of clinical features and exposing
        their underlying mechanisms
      explanation: >-
        The organoid corticogenesis defect is offered as a developmental
        antecedent of the neurodevelopmental phenotype; the link to this
        specific delay is inferred, not measured.
  - target: Abnormal Brain Morphology
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:39987231
      reference_title: "YY1 mutations disrupt corticogenesis through a cell type specific rewiring of cell-autonomous and non-cell-autonomous transcriptional programs."
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: INDIRECT
      snippet: >-
        including cytoarchitectural defects reminiscent of GADEVS clinical
        features
      explanation: >-
        Organoid cytoarchitectural defects are proposed to parallel the
        structural brain findings of patients.
- name: Impaired Synapse Formation
  description: >-
    Patient iPSC-derived excitatory neurons show disturbed synaptic
    transcriptional programs; synaptic formation is one of the domains most
    vulnerable to reduced YY1 dosage.
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  cell_types:
  - preferred_term: excitatory (glutamatergic) neuron
    term:
      id: CL:0000679
      label: glutamatergic neuron
  biological_processes:
  - preferred_term: synapse organization
    modifier: ABNORMAL
    term:
      id: GO:0050808
      label: synapse organization
  evidence:
  - reference: PMID:39987231
    reference_title: "YY1 mutations disrupt corticogenesis through a cell type specific rewiring of cell-autonomous and non-cell-autonomous transcriptional programs."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Together, neurodevelopmental trajectories, synaptic formation and
      neuronal-astrocyte cross talk emerged as salient domains of YY1
      dosage-dependent vulnerability.
    explanation: >-
      Identifies synaptic formation as a YY1 dosage-sensitive process.
  downstream:
  - target: Intellectual Disability
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:39987231
      reference_title: "YY1 mutations disrupt corticogenesis through a cell type specific rewiring of cell-autonomous and non-cell-autonomous transcriptional programs."
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: INDIRECT
      snippet: >-
        Our findings underscore the reach of advanced in vitro models in
        capturing developmental antecedents of clinical features and exposing
        their underlying mechanisms
      explanation: >-
        Synaptic defects in vitro are offered as antecedents of the clinical
        cognitive phenotype; the link is inferential.
- name: Non-Cell-Autonomous Astrocyte Pro-Inflammatory Activation
  description: >-
    Astrocytes co-cultured with GADEVS patient-derived neurons adopt a
    pro-inflammatory activated transcriptional state, a non-cell-autonomous
    effect of neuronal YY1 haploinsufficiency. Its contribution to the
    clinical phenotype in patients is untested.
  biological_scale: CELLULAR
  mechanism_confidence: HYPOTHETICAL
  cell_types:
  - preferred_term: astrocyte
    term:
      id: CL:0000127
      label: astrocyte
  biological_processes:
  - preferred_term: astrocyte activation
    modifier: INCREASED
    term:
      id: GO:0048143
      label: astrocyte activation
  evidence:
  - reference: PMID:39987231
    reference_title: "YY1 mutations disrupt corticogenesis through a cell type specific rewiring of cell-autonomous and non-cell-autonomous transcriptional programs."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Transcriptional alterations in neurons propagated to neighboring
      astrocytes through a major non-cell autonomous pro-inflammatory effect
      that grounds the rationale for modulatory interventions.
    explanation: >-
      Neuron-astrocyte co-culture evidence for astrocyte activation.
phenotypes:
- category: Neurodevelopmental
  name: Intellectual Disability
  description: >-
    Mild-to-profound intellectual disability is present in all affected
    individuals.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  frequency: OBLIGATE
  evidence:
  - reference: PMID:31145572
    reference_title: "Gabriele-de Vries Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Gabriele-de Vries syndrome is characterized by mild-to-profound
      developmental delay / intellectual disability (DD/ID) in all affected
      individuals
    explanation: GeneReviews reports DD/ID in all affected individuals.
  - reference: PMID:28575647
    reference_title: "YY1 Haploinsufficiency Causes an Intellectual Disability Syndrome Featuring Transcriptional and Chromatin Dysfunction."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      phenotypic features that define a syndrome of cognitive impairment,
      behavioral alterations, intrauterine growth restriction, feeding
      problems, and various congenital malformations
    explanation: >-
      Cognitive impairment is a defining feature of the founding series. The
      GeneReviews chapter draws on these same patients, so the two items are
      not independent replication.
- category: Neurodevelopmental
  name: Global Developmental Delay
  description: Developmental delay is present from early childhood in all affected individuals.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  frequency: OBLIGATE
  evidence:
  - reference: PMID:31145572
    reference_title: "Gabriele-de Vries Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Gabriele-de Vries syndrome is characterized by mild-to-profound
      developmental delay / intellectual disability (DD/ID) in all affected
      individuals
    explanation: GeneReviews reports DD/ID in all affected individuals.
- category: Neurodevelopmental
  name: Delayed Speech and Language Development
  phenotype_term:
    preferred_term: Delayed speech and language development
    term:
      id: HP:0000750
      label: Delayed speech and language development
  evidence:
  - reference: PMID:37658636
    reference_title: "Clinical analysis of Gabriele-de Vries caused by YY1 mutations and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Gabriele-de Vries syndrome is a rare autosomal dominant genetic disease
      characterized by global development delay/intellectual disability,
      delayed language development, feeding difficulties, and distinctive
      facial dysmorphism.
    explanation: Delayed language development is listed among the characteristic features.
  - reference: PMID:34729769
    reference_title: "Clinical features of patients with Yin Yang 1 deficiency causing Gabriele-de Vries syndrome: A new case and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The proband presented with delayed motor and speech development
    explanation: Single-case report of speech delay.
- category: Neurodevelopmental
  name: Motor Delay
  phenotype_term:
    preferred_term: Motor delay
    term:
      id: HP:0001270
      label: Motor delay
  evidence:
  - reference: PMID:34729769
    reference_title: "Clinical features of patients with Yin Yang 1 deficiency causing Gabriele-de Vries syndrome: A new case and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The proband presented with delayed motor and speech development
    explanation: Single-case report of motor delay.
  - reference: PMID:37658636
    reference_title: "Clinical analysis of Gabriele-de Vries caused by YY1 mutations and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The current report describes a female patient with motor delay and a facial dysmorphism phenotype.
    explanation: A second, unrelated case report with motor delay.
- category: Growth
  name: Intrauterine Growth Restriction
  description: >-
    Intrauterine growth restriction or low birth weight is common.
  phenotype_term:
    preferred_term: Intrauterine growth restriction or low birth weight
    term:
      id: HP:0001511
      label: Intrauterine growth retardation
  frequency: FREQUENT
  evidence:
  - reference: PMID:31145572
    reference_title: "Gabriele-de Vries Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Intrauterine growth restriction or low birth weight and feeding difficulties are common.
    explanation: >-
      GeneReviews describes IUGR or low birth weight as common, mapped to the
      FREQUENT band.
- category: Gastrointestinal
  name: Feeding Difficulties
  phenotype_term:
    preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
  frequency: FREQUENT
  evidence:
  - reference: PMID:31145572
    reference_title: "Gabriele-de Vries Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Intrauterine growth restriction or low birth weight and feeding difficulties are common.
    explanation: GeneReviews describes feeding difficulties as common.
- category: Gastrointestinal
  name: Gastroesophageal Reflux
  phenotype_term:
    preferred_term: Gastroesophageal reflux
    term:
      id: HP:0002020
      label: Gastroesophageal reflux
  evidence:
  - reference: PMID:31145572
    reference_title: "Gabriele-de Vries Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: feeding difficulties, gastroesophageal reflux, constipation, seizures, behavioral manifestations
    explanation: Listed among GeneReviews manifestations requiring treatment.
- category: Gastrointestinal
  name: Constipation
  phenotype_term:
    preferred_term: Constipation
    term:
      id: HP:0002019
      label: Constipation
  evidence:
  - reference: PMID:31145572
    reference_title: "Gabriele-de Vries Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: feeding difficulties, gastroesophageal reflux, constipation, seizures, behavioral manifestations
    explanation: Listed among GeneReviews manifestations requiring treatment.
- category: Neurologic
  name: Hypotonia
  description: >-
    About half of affected individuals have neurologic manifestations,
    including hypotonia; the fraction with hypotonia specifically is not
    stated.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:31145572
    reference_title: "Gabriele-de Vries Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: About half of affected individuals have neurologic manifestations, including hypotonia and gait abnormalities.
    explanation: GeneReviews lists hypotonia among neurologic manifestations.
  - reference: PMID:35027293
    reference_title: "DNA methylation episignature in Gabriele-de Vries syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Gabriele-de Vries syndrome (GADEVS) is a rare genetic disorder
      characterized by developmental delay and/or intellectual disability,
      hypotonia, feeding difficulties, and distinct facial features.
    explanation: Hypotonia is listed among the characteristic features.
- category: Neurologic
  name: Gait Disturbance
  phenotype_term:
    preferred_term: Gait abnormality
    term:
      id: HP:0001288
      label: Gait disturbance
  evidence:
  - reference: PMID:31145572
    reference_title: "Gabriele-de Vries Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: About half of affected individuals have neurologic manifestations, including hypotonia and gait abnormalities.
    explanation: GeneReviews lists gait abnormalities among neurologic manifestations.
- category: Neurologic
  name: Ataxia
  phenotype_term:
    preferred_term: Ataxia
    term:
      id: HP:0001251
      label: Ataxia
  evidence:
  - reference: PMID:34729769
    reference_title: "Clinical features of patients with Yin Yang 1 deficiency causing Gabriele-de Vries syndrome: A new case and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The proband presented with delayed motor and speech development, ataxia,
      abnormal gait, autistic behavior, brain atrophy, and severe learning
      disability.
    explanation: Single-case report of ataxia.
  - reference: PMID:32627382
    reference_title: "Complex movement disorder in a patient with heterozygous YY1 mutation (Gabriele-de Vries syndrome)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: a complex movement disorder including an action tremor, cerebellar ataxia, dystonia, and partial ocular apraxia
    explanation: A second unrelated case with cerebellar ataxia.
- category: Neurologic
  name: Dystonia
  description: >-
    Movement disorders, chiefly dystonia, occur in a subset and can begin in
    adolescence or adulthood and progress; generalized dystonia refractory to
    medication has been treated with pallidal deep brain stimulation.
  phenotype_term:
    preferred_term: Dystonia
    term:
      id: HP:0001332
      label: Dystonia
  evidence:
  - reference: PMID:41554999
    reference_title: "Long-term benefit of GPi-DBS in YY1-related dystonia: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: About half of affected individuals develop movement disorders, including dystonia.
    explanation: >-
      Background statement in a case report; the half refers to movement
      disorders as a class, so no dystonia-specific frequency is recorded.
  - reference: PMID:32627382
    reference_title: "Complex movement disorder in a patient with heterozygous YY1 mutation (Gabriele-de Vries syndrome)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Movement disorders were reported in 5/10 cases of the original series, but no detailed description was provided.
    explanation: >-
      Restates the movement-disorder count from the founding series; this is
      the same cohort as PMID:28575647, not new patients.
  - reference: PMID:35172867
    reference_title: "Untangling neurodevelopmental disorders in the adulthood: a movement disorder is the clue."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: All these patients had an early developmental delay and displayed a movement disorder (dystonia/ataxia/tremor) which manifested for the first time, or worsened, in the adulthood
    explanation: >-
      Adult-onset or worsening movement disorder in a series that includes a
      YY1 patient; the sentence covers four different genetic disorders.
- category: Neurologic
  name: Tremor
  phenotype_term:
    preferred_term: Action tremor
    term:
      id: HP:0001337
      label: Tremor
  evidence:
  - reference: PMID:32627382
    reference_title: "Complex movement disorder in a patient with heterozygous YY1 mutation (Gabriele-de Vries syndrome)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: a complex movement disorder including an action tremor, cerebellar ataxia, dystonia, and partial ocular apraxia
    explanation: Single-case report of action tremor.
- category: Neurologic
  name: Seizure
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:31145572
    reference_title: "Gabriele-de Vries Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: feeding difficulties, gastroesophageal reflux, constipation, seizures, behavioral manifestations
    explanation: Seizures are listed among GeneReviews manifestations requiring treatment.
  - reference: PMID:35829845
    reference_title: "A de novo YY1 missense variant expanding the Gabriele-de Vries syndrome phenotype and affecting X-chromosome inactivation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Undescribed or uncommon clinical features in this patient included
      non-febrile seizures, severe scoliosis, hearing impairment, and
      chorioretinitis.
    explanation: Single case with non-febrile seizures, described as uncommon.
- category: Behavioral
  name: Attention Deficit Hyperactivity Disorder
  phenotype_term:
    preferred_term: Attention deficit hyperactivity disorder
    term:
      id: HP:0007018
      label: Attention deficit hyperactivity disorder
  evidence:
  - reference: PMID:31145572
    reference_title: "Gabriele-de Vries Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Behavioral issues can include attention-deficit/hyperactivity disorder, anxiety, autism or autistic behavior, and schizoaffective disorder.
    explanation: GeneReviews lists ADHD among behavioral issues.
- category: Behavioral
  name: Anxiety
  phenotype_term:
    preferred_term: Anxiety
    term:
      id: HP:0000739
      label: Anxiety
  evidence:
  - reference: PMID:31145572
    reference_title: "Gabriele-de Vries Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Behavioral issues can include attention-deficit/hyperactivity disorder, anxiety, autism or autistic behavior, and schizoaffective disorder.
    explanation: GeneReviews lists anxiety among behavioral issues.
- category: Behavioral
  name: Autistic Behavior
  phenotype_term:
    preferred_term: Autism or autistic behavior
    term:
      id: HP:0000729
      label: Autistic behavior
  evidence:
  - reference: PMID:31145572
    reference_title: "Gabriele-de Vries Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Behavioral issues can include attention-deficit/hyperactivity disorder, anxiety, autism or autistic behavior, and schizoaffective disorder.
    explanation: GeneReviews lists autism or autistic behavior among behavioral issues.
  - reference: PMID:34729769
    reference_title: "Clinical features of patients with Yin Yang 1 deficiency causing Gabriele-de Vries syndrome: A new case and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The proband presented with delayed motor and speech development, ataxia,
      abnormal gait, autistic behavior, brain atrophy, and severe learning
      disability.
    explanation: Single case with autistic behavior.
- category: Craniofacial
  name: Facial Dysmorphism
  description: >-
    Distinctive but variable facial features. The cited abstracts do not
    itemize the individual features, so a broad facial-shape term is bound.
  phenotype_term:
    preferred_term: Distinctive facial dysmorphism
    term:
      id: HP:0001999
      label: Abnormal facial shape
  evidence:
  - reference: PMID:37658636
    reference_title: "Clinical analysis of Gabriele-de Vries caused by YY1 mutations and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Gabriele-de Vries syndrome is a rare autosomal dominant genetic disease
      characterized by global development delay/intellectual disability,
      delayed language development, feeding difficulties, and distinctive
      facial dysmorphism.
    explanation: Facial dysmorphism is a characteristic feature.
  - reference: PMID:35027293
    reference_title: "DNA methylation episignature in Gabriele-de Vries syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Gabriele-de Vries syndrome (GADEVS) is a rare genetic disorder
      characterized by developmental delay and/or intellectual disability,
      hypotonia, feeding difficulties, and distinct facial features.
    explanation: Distinct facial features are characteristic.
- category: Craniofacial
  name: Cleft Palate
  phenotype_term:
    preferred_term: Cleft palate
    term:
      id: HP:0000175
      label: Cleft palate
  evidence:
  - reference: PMID:31145572
    reference_title: "Gabriele-de Vries Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: craniofacial anomalies (Pierre Robin sequence, cleft palate, craniosynostosis, abnormalities of the lacrimal duct)
    explanation: GeneReviews lists cleft palate among craniofacial anomalies to be treated.
- category: Craniofacial
  name: Pierre-Robin Sequence
  phenotype_term:
    preferred_term: Pierre Robin sequence
    term:
      id: HP:0000201
      label: Pierre-Robin sequence
  evidence:
  - reference: PMID:31145572
    reference_title: "Gabriele-de Vries Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: craniofacial anomalies (Pierre Robin sequence, cleft palate, craniosynostosis, abnormalities of the lacrimal duct)
    explanation: GeneReviews lists Pierre Robin sequence among craniofacial anomalies.
- category: Craniofacial
  name: Craniosynostosis
  phenotype_term:
    preferred_term: Craniosynostosis
    term:
      id: HP:0001363
      label: Craniosynostosis
  evidence:
  - reference: PMID:31145572
    reference_title: "Gabriele-de Vries Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: craniofacial anomalies (Pierre Robin sequence, cleft palate, craniosynostosis, abnormalities of the lacrimal duct)
    explanation: GeneReviews lists craniosynostosis among craniofacial anomalies.
- category: Neurologic
  name: Abnormal Brain Morphology
  description: >-
    Congenital brain anomalies have been reported; findings are heterogeneous
    and some individuals have normal imaging.
  phenotype_term:
    preferred_term: Congenital brain anomaly
    term:
      id: HP:0012443
      label: Abnormal brain morphology
  evidence:
  - reference: PMID:31145572
    reference_title: "Gabriele-de Vries Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Congenital brain, eye, heart, kidney, genital, and/or skeletal system anomalies have also been reported.
    explanation: GeneReviews reports congenital brain anomalies.
- category: Ophthalmologic
  name: Strabismus
  phenotype_term:
    preferred_term: Strabismus
    term:
      id: HP:0000486
      label: Strabismus
  evidence:
  - reference: PMID:31145572
    reference_title: "Gabriele-de Vries Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: strabismus, refractive error, congenital heart defects, renal anomalies, cryptorchidism, and skeletal anomalies are treated per standard practice
    explanation: GeneReviews lists strabismus among manifestations requiring treatment.
  - reference: PMID:40655401
    reference_title: "Hashimoto's thyroiditis and nanophthalmos in Gabriele-de Vries syndrome: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Physical examination revealed mild facial dysmorphism, strabismus, an enlarged thyroid gland, and elongated fingers.
    explanation: Single case with strabismus.
- category: Ophthalmologic
  name: Refractive Error
  phenotype_term:
    preferred_term: Refractive error
    term:
      id: HP:0000539
      label: Abnormality of refraction
  evidence:
  - reference: PMID:31145572
    reference_title: "Gabriele-de Vries Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: strabismus, refractive error, congenital heart defects, renal anomalies, cryptorchidism, and skeletal anomalies are treated per standard practice
    explanation: GeneReviews lists refractive error among manifestations requiring treatment.
- category: Cardiovascular
  name: Congenital Heart Defect
  phenotype_term:
    preferred_term: Congenital heart defect
    term:
      id: HP:0001627
      label: Abnormal heart morphology
  evidence:
  - reference: PMID:31145572
    reference_title: "Gabriele-de Vries Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: strabismus, refractive error, congenital heart defects, renal anomalies, cryptorchidism, and skeletal anomalies are treated per standard practice
    explanation: GeneReviews lists congenital heart defects.
- category: Renal
  name: Renal Anomaly
  phenotype_term:
    preferred_term: Congenital renal anomaly
    term:
      id: HP:0012210
      label: Abnormal renal morphology
    coarse_binding_basis: SOURCE_UNSPECIFIED
  evidence:
  - reference: PMID:31145572
    reference_title: "Gabriele-de Vries Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: strabismus, refractive error, congenital heart defects, renal anomalies, cryptorchidism, and skeletal anomalies are treated per standard practice
    explanation: >-
      GeneReviews names renal anomalies without specifying them in the
      abstract, so a coarse term is bound.
- category: Genitourinary
  name: Cryptorchidism
  phenotype_term:
    preferred_term: Cryptorchidism
    term:
      id: HP:0000028
      label: Cryptorchidism
  evidence:
  - reference: PMID:35027293
    reference_title: "DNA methylation episignature in Gabriele-de Vries syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We expanded the clinical profile of GADEVS to include thin/sparse hair and cryptorchidism.
    explanation: The 13-person cohort added cryptorchidism to the phenotype.
  - reference: PMID:31145572
    reference_title: "Gabriele-de Vries Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: strabismus, refractive error, congenital heart defects, renal anomalies, cryptorchidism, and skeletal anomalies are treated per standard practice
    explanation: GeneReviews lists cryptorchidism among manifestations requiring treatment.
- category: Skeletal
  name: Skeletal Anomaly
  phenotype_term:
    preferred_term: Congenital skeletal anomaly
    term:
      id: HP:0000924
      label: Abnormality of the skeletal system
    coarse_binding_basis: SOURCE_UNSPECIFIED
  evidence:
  - reference: PMID:31145572
    reference_title: "Gabriele-de Vries Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: strabismus, refractive error, congenital heart defects, renal anomalies, cryptorchidism, and skeletal anomalies are treated per standard practice
    explanation: >-
      GeneReviews names skeletal anomalies without specifying them in the
      abstract, so a coarse term is bound.
- category: Dermatologic
  name: Sparse Hair
  phenotype_term:
    preferred_term: Thin or sparse hair
    term:
      id: HP:0008070
      label: Sparse hair
  evidence:
  - reference: PMID:35027293
    reference_title: "DNA methylation episignature in Gabriele-de Vries syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We expanded the clinical profile of GADEVS to include thin/sparse hair and cryptorchidism.
    explanation: The 13-person cohort added thin/sparse hair to the phenotype.
- category: Endocrine
  name: Hypothyroidism
  description: >-
    Hypothyroidism had been reported in four of the published cases (12%); one
    girl had autoimmune (Hashimoto) thyroiditis.
  phenotype_term:
    preferred_term: Hypothyroidism
    term:
      id: HP:0000821
      label: Hypothyroidism
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:40655401
    reference_title: "Hashimoto's thyroiditis and nanophthalmos in Gabriele-de Vries syndrome: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Hypothyroidism has been reported in four previous cases (12%) of GADEVS, but autoimmune thyroiditis has not been documented.
    explanation: >-
      Literature-derived proportion (4 cases, 12%), mapped to OCCASIONAL; the
      denominator is published cases, not a systematic cohort.
- category: Otologic
  name: Hearing Impairment
  phenotype_term:
    preferred_term: Hearing impairment
    term:
      id: HP:0000365
      label: Hearing impairment
  evidence:
  - reference: PMID:35829845
    reference_title: "A de novo YY1 missense variant expanding the Gabriele-de Vries syndrome phenotype and affecting X-chromosome inactivation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Undescribed or uncommon clinical features in this patient included
      non-febrile seizures, severe scoliosis, hearing impairment, and
      chorioretinitis.
    explanation: Single case; described by the authors as uncommon.
genetic:
- name: YY1
  gene_term:
    preferred_term: YY1
    term:
      id: hgnc:12856
      label: YY1
  association: Causative
  presence: Positive
  relationship_type: CAUSATIVE
  variant_origin: DE_NOVO
  notes: >-
    Heterozygous intragenic YY1 variants (frameshift, nonsense, splice and
    zinc-finger missense) or 14q32.2 deletions including YY1. Larger
    deletions also remove neighboring genes. ClinGen's Definitive AD
    classification for YY1 is recorded against "complex neurodevelopmental
    disorder" (MONDO:0100038), a broader disease, so it is not copied here as
    a gene-disease validity assertion for this entry.
  evidence:
  - reference: PMID:31145572
    reference_title: "Gabriele-de Vries Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The diagnosis of Gabriele-de Vries syndrome is established in a proband
      by the identification of a heterozygous pathogenic variant involving YY1
      or a heterozygous deletion of 14q32.2 involving only YY1.
    explanation: GeneReviews defines the causal genotype.
  variants:
  - name: p.Glu231Ilefs*25
    description: >-
      De novo frameshift NM_003403:c.690delA reported in an Iranian boy with
      motor and speech delay, ataxia and autistic behavior.
    variant_type: deletion
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:34729769
      reference_title: "Clinical features of patients with Yin Yang 1 deficiency causing Gabriele-de Vries syndrome: A new case and review of the literature."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The novel de novo pathogenic variant detected in this study
        (NM_003403:c.690delA, p.Glu231Ilefs*25) was identified by whole-exome
        sequencing and confirmed by Sanger sequencing.
      explanation: Reports the variant as de novo and pathogenic.
  - name: p.Val153fs*97
    description: Novel heterozygous frameshift NM_003403.5:c.458_476del.
    variant_type: deletion
    evidence:
    - reference: PMID:37658636
      reference_title: "Clinical analysis of Gabriele-de Vries caused by YY1 mutations and literature review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: A novel heterozygous frameshift mutation NM_003403.5:c.458_476del (p. V153fs*97) in the YY1 gene was detected in the proband.
      explanation: Reports the variant in a GADEVS proband.
  - name: p.Cys303Arg
    description: >-
      De novo missense NM_003403.4:c.907T>C in a woman with mild intellectual
      disability and a complex movement disorder (action tremor, cerebellar
      ataxia, dystonia).
    variant_type: single nucleotide variant
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:32627382
      reference_title: "Complex movement disorder in a patient with heterozygous YY1 mutation (Gabriele-de Vries syndrome)."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Whole-exome sequencing revealed a novel heterozygous de novo mutation
        in YY1
      explanation: >-
        Reports the de novo variant, which the abstract identifies in a
        bracketed span (omitted from the snippet because bracketed text is
        stripped before matching) as c.907T>C p.(Cys303Arg) and classifies as
        ACMG pathogenic.
  - name: p.Asn369Ser
    description: De novo missense NM_003403.5:c.1106A>G reported with phenotype expansion and skewed X inactivation.
    variant_type: single nucleotide variant
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:35829845
      reference_title: "A de novo YY1 missense variant expanding the Gabriele-de Vries syndrome phenotype and affecting X-chromosome inactivation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        we describe clinical and molecular findings from a Brazilian female
        harbouring a de novo missense pathogenic variant in YY1 gene
        (NM_003403.5:c.1106A > G; p.Asn369Ser)
      explanation: Reports the variant as de novo and pathogenic.
  - name: p.Asp380Tyr
    description: >-
      Recurrent zinc-finger missense substitution that impairs DNA-binding
      specificity in vitro.
    variant_type: single nucleotide variant
    evidence:
    - reference: PMID:32077676
      reference_title: "The effect of D380Y pathogenic mutation in human Yin Yang 1 on the protein's structure and function."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        a repetitively occurring substitution of aspartate-380 for tyrosine was
        analyzed to assess its impact on Yin Yang 1's structure and DNA binding
      explanation: Describes the variant as recurrent and characterizes it functionally.
diagnosis:
- name: YY1 Molecular Genetic Testing
  description: >-
    Diagnosis requires a heterozygous pathogenic YY1 variant or a 14q32.2
    deletion involving YY1, because the clinical features are variable and
    nonspecific. Exome sequencing with Sanger confirmation identified the
    variants in several case reports.
  diagnosis_term:
    preferred_term: molecular genetic testing for YY1
    term:
      id: NCIT:C15709
      label: Genetic Testing
  results: >-
    A heterozygous pathogenic YY1 sequence variant or a deletion including
    YY1.
  evidence:
  - reference: PMID:31145572
    reference_title: "Gabriele-de Vries Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The diagnosis of Gabriele-de Vries syndrome is established in a proband
      by the identification of a heterozygous pathogenic variant involving YY1
      or a heterozygous deletion of 14q32.2 involving only YY1.
    explanation: GeneReviews diagnostic criterion.
  - reference: PMID:34729769
    reference_title: "Clinical features of patients with Yin Yang 1 deficiency causing Gabriele-de Vries syndrome: A new case and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The investigations for a suspected case of Gabriele-de Vries Syndrome
      must involve molecular diagnosis of the disease and its underlying
      genetic defect because the clinical investigations are generally
      variable and nonspecific.
    explanation: Clinical features alone are insufficient for diagnosis.
- name: Peripheral Blood DNA Methylation Episignature
  description: >-
    A GADEVS-specific peripheral-blood DNA methylation episignature,
    derived from 13 individuals, supports classification of YY1 variants of
    uncertain significance. It is a diagnostic biomarker, not a demonstrated
    step in the causal chain.
  diagnosis_term:
    preferred_term: DNA methylation episignature analysis
    term:
      id: NCIT:C63328
      label: DNA Methylation Analysis
  evidence:
  - reference: PMID:35027293
    reference_title: "DNA methylation episignature in Gabriele-de Vries syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We also highlighted the utility of DNA methylation episignature analysis
      for classification of variants of unknown clinical significance.
    explanation: Establishes the episignature as a variant-classification aid.
treatments:
- name: Symptom-Directed Supportive Care
  description: >-
    No disease-modifying therapy exists. Developmental delay, craniofacial
    anomalies, feeding difficulties, reflux, constipation, seizures,
    behavioral manifestations, eye findings, congenital heart and renal
    anomalies, cryptorchidism and skeletal anomalies are each treated per
    standard practice.
  action_category: THERAPEUTIC
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:31145572
    reference_title: "Gabriele-de Vries Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Treatment of manifestations: Developmental delay / intellectual
      disability, craniofacial anomalies (Pierre Robin sequence, cleft palate,
      craniosynostosis, abnormalities of the lacrimal duct), feeding
      difficulties, gastroesophageal reflux, constipation, seizures,
      behavioral manifestations, strabismus, refractive error, congenital
      heart defects, renal anomalies, cryptorchidism, and skeletal anomalies
      are treated per standard practice.
    explanation: GeneReviews management is symptom-directed standard care.
- name: Pallidal Deep Brain Stimulation for Dystonia
  description: >-
    Bilateral globus pallidus internus deep brain stimulation has been used
    for medication-refractory generalized dystonia; evidence is limited to
    case reports.
  action_category: THERAPEUTIC
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: bilateral GPi deep brain stimulation
    term:
      id: NCIT:C21024
      label: Deep Brain Stimulation
  target_phenotypes:
  - preferred_term: Dystonia
    term:
      id: HP:0001332
      label: Dystonia
  evidence:
  - reference: PMID:41554999
    reference_title: "Long-term benefit of GPi-DBS in YY1-related dystonia: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The Burke-Fahn-Marsden motor score decreased from 100 to 50, and the
      disability score decreased from 20 to 14 at six months.
    explanation: >-
      Single-patient report of improvement after GPi-DBS; it notes only one
      similar case had been reported.
- name: Levothyroxine for Hypothyroidism
  description: >-
    Hypothyroidism, including autoimmune thyroiditis, is treated with
    standard levothyroxine replacement.
  action_category: THERAPEUTIC
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: levothyroxine
      term:
        id: NCIT:C62080
        label: Levothyroxine
  target_phenotypes:
  - preferred_term: Hypothyroidism
    term:
      id: HP:0000821
      label: Hypothyroidism
  evidence:
  - reference: PMID:40655401
    reference_title: "Hashimoto's thyroiditis and nanophthalmos in Gabriele-de Vries syndrome: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Levothyroxine replacement therapy successfully corrected the hypothyroidism.
    explanation: Single-case report of treated hypothyroidism.
experimental_models:
- name: Patient iPSC-derived cortical organoids and NGN2 neurons
  description: >-
    2D and 3D patient-derived neural lineages (cortical organoids,
    NGN2-induced excitatory neurons, and neuron-astrocyte co-culture)
    analyzed by imaging, single-cell multiomics and gene regulatory network
    reconstruction.
  experimental_model_type: ORGANOID
  publication: PMID:39987231
  modeled_mechanisms:
  - target: Disrupted Corticogenesis
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    limitations: >-
      In vitro organoids lack vasculature and whole-brain context; the link
      from organoid cytoarchitecture to patient brain findings is by analogy.
    evidence:
    - reference: PMID:39987231
      reference_title: "YY1 mutations disrupt corticogenesis through a cell type specific rewiring of cell-autonomous and non-cell-autonomous transcriptional programs."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        we combined large-scale imaging, single-cell multiomics and gene
        regulatory network reconstruction in 2D and 3D patient-derived
        physiopathologically relevant cell lineages
      explanation: Describes the patient-derived model systems.
  - target: Non-Cell-Autonomous Astrocyte Pro-Inflammatory Activation
    relationship: RECAPITULATES
    fidelity: UNKNOWN
    model_scale: CELLULAR
    limitations: >-
      Co-culture system; whether astrocyte activation occurs in patient brain
      is untested.
    evidence:
    - reference: PMID:39987231
      reference_title: "YY1 mutations disrupt corticogenesis through a cell type specific rewiring of cell-autonomous and non-cell-autonomous transcriptional programs."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Transcriptional alterations in neurons propagated to neighboring
        astrocytes through a major non-cell autonomous pro-inflammatory effect
      explanation: Co-culture readout of astrocyte activation.
- name: Patient lymphoblastoid cell lines
  description: >-
    Lymphoblastoid cells from affected individuals carrying YY1 deletions or
    missense variants, used for YY1 and histone ChIP-seq and RNA-seq.
  experimental_model_type: CELL_LINE
  publication: PMID:28575647
  modeled_mechanisms:
  - target: Reduced YY1 Chromatin Occupancy
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: MOLECULAR
    limitations: >-
      Transformed blood-derived cells; chromatin findings may not transfer to
      developing neural cells.
    evidence:
    - reference: PMID:28575647
      reference_title: "YY1 Haploinsufficiency Causes an Intellectual Disability Syndrome Featuring Transcriptional and Chromatin Dysfunction."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Through immunoprecipitation of YY1-bound chromatin from affected
        individuals' cells with antibodies recognizing both ends of the protein
      explanation: ChIP in patient-derived cells.
  - target: Loss of H3K27 Acetylation at YY1-Bound Enhancers
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: MOLECULAR
    limitations: >-
      Transformed blood-derived cells; enhancer landscapes differ from those
      of neural progenitors.
    evidence:
    - reference: PMID:28575647
      reference_title: "YY1 Haploinsufficiency Causes an Intellectual Disability Syndrome Featuring Transcriptional and Chromatin Dysfunction."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        we uncover a widespread loss of H3K27 acetylation in particular on the
        YY1-bound enhancers
      explanation: Histone ChIP in patient-derived cells.
datasets:
- accession: geo:GSE98478
  title: YY1 haploinsufficiency causes an intellectual disability syndrome featuring transcriptional and chromatin dysfunction.
  description: >-
    GEO SuperSeries for the founding study: YY1 and histone ChIP-seq and
    RNA-seq in lymphoblastoid cells from affected individuals and controls.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: CHIP_SEQ
  publication: PMID:28575647
references:
- reference: PMID:31145572
  title: "Gabriele-de Vries Syndrome."
  tags:
  - GeneReviews
📚

References & Deep Research

References

1
PMID:31145572
Gabriele-de Vries Syndrome.
No top-level findings curated for this source.

Deep Research

1

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

Evaluations and curation notes (1)

Create: Gabriele-de Vries Syndrome · 2026-10-18T05:50:29Z · View source

Created the Gabriele-de Vries syndrome (MONDO:0044738, YY1) entry from the Perplexity sonar-deep-research report, run with --param reasoning_effort=low because default-effort requests were dropped by the network after about five minutes. Report validation: 25/25 references resolved, 0 off topic, no quotes checked; term validation 99 checked, 0 unresolved, 3 obsolete GO/CL terms (GO:0016573, GO:0044237, CL:0002609) not used; needs_review true. just preflight-dr PASS (YY1 mentioned 65 times, OMIM 617557 matches MONDO). GeneReviews chapter PMID:31145572 (NBK541730) tagged and used as the phenotype baseline; its abstract-listed features are all represented except schizoaffective disorder and lacrimal duct abnormalities, each named once in the abstract and not curated as phenotypes in this pass. Every PMID was found by PubMed esearch in the same step, not recalled. The organoid study is cited as the peer-reviewed Mol Psychiatry version PMID:39987231 rather than the bioRxiv preprint PMID:38405909. Not used: PMID:33638881 and PMID:37690905 (cached with empty bodies), PMID:37189872 (spinal dysraphism single case whose abstract attributes the variant to GNAS). ClinGen Definitive AD for YY1 is against complex neurodevelopmental disorder (MONDO:0100038), so no gene_disease_validity was recorded. Not conformed to epigenetic_machinery_neurodevelopmental_dysregulation: that module excludes sequence-specific transcription factors whose loss dysregulates target genes, and YY1 is one, although the H3K27ac loss at YY1-bound enhancers makes the case arguable. Histone-acetylation GO process terms are obsolete, so the H3K27ac node has no process binding. Phenotype-to-mechanism edges from the YY1 root use the founding-series syndrome definition with INDIRECT_UNKNOWN_INTERMEDIATES; organoid-to-clinical edges are marked directness INDIRECT. Validated with just validate, validate-terms, count-verified-snippets, the offline gates, and validate-disorders.

Perplexity ▸
Gabriele-de Vries syndrome: disease-characteristics research report
sonar-deep-research 58 citations 2026-10-18T05:33:08.490994

Gabriele-de Vries syndrome: disease-characteristics research report

Disease: Gabriele-de Vries syndrome
Preferred abbreviation: GADEVS
Molecular basis: Heterozygous loss of function of YY1
Inheritance: Autosomal dominant, usually de novo
MONDO: MONDO:0044738
Evidence cut-off: October 18, 2026

Evidence caveat: GADEVS is exceptionally rare. Most clinical frequencies derive from cohorts of approximately 10–37 molecularly diagnosed individuals, sometimes mixing intragenic variants with larger 14q32 deletions. Percentages should therefore be treated as provisional, ascertainment-sensitive estimates rather than population parameters.

1. Disease information

Definition and overview

Gabriele-de Vries syndrome is a congenital, multisystem neurodevelopmental disorder caused by heterozygous pathogenic variants in, or deletions involving, YY1, a zinc-finger transcription factor and chromatin regulator at 14q32.2. The defining manifestations are developmental delay/intellectual disability, delayed speech, feeding difficulty, characteristic but variable facial dysmorphism, prenatal or postnatal growth disturbance, behavioral abnormalities, hypotonia or movement/gait disorders, and variably penetrant congenital anomalies of the brain, eyes, heart, kidneys, genitalia, skeleton, and craniofacial structures. [31][32]

The foundational 2017 study identified 23 affected individuals—10 with de novo intragenic variants and 13 with deletions encompassing YY1—and concluded:

“Our combined clinical and molecular data define ‘YY1 syndrome’ as a haploinsufficiency syndrome.”
—Gabriele et al., 2017, PMID: 28575647 [20]

GADEVS is therefore best classified as a Mendelian autosomal-dominant chromatin/transcriptional-regulation disorder, sometimes described mechanistically as an enhanceropathy.

Identifiers and terminology

Resource Identifier/name
MONDO MONDO:0044738
OMIM disease 617557, Gabriele-de Vries syndrome
OMIM gene 600013, YY1
Orphanet ORPHA:506358
MedGen C4479652, UID 1375401
SNOMED CT 1186730002, Gabriele-de Vries syndrome / YY1 haploinsufficiency syndrome
ICD-10 Q87.8, other specified congenital malformation syndromes, not elsewhere classified; no dedicated GADEVS code [210]
ICD-11 No clearly established disease-specific code; code according to the dominant congenital-malformation or neurodevelopmental presentation
MeSH No dedicated GADEVS heading identified; literature is indexed under terms such as Intellectual Disability, Developmental Disabilities, and YY1 Transcription Factor
UMLS/MedGen concept C4479652
Category Mendelian; genetic neurodevelopmental/multiple-congenital-anomaly syndrome

Identifiers, synonyms, and the associated locus are consolidated by MedGen, which links MONDO:0044738, OMIM 617557, ORPHA:506358, SNOMED CT 1186730002, and YY1 at 14q32.2. [31]

Synonyms

  • Gabriele-de Vries syndrome
  • Gabriele de Vries syndrome
  • GADEVS
  • YY1 haploinsufficiency syndrome
  • YY1 syndrome
  • YY1-related syndrome

Evidence granularity

The information in this report is predominantly aggregated disease-level evidence derived from published case series, GeneReviews, Orphanet, ClinVar, and mechanistic studies. Original reports use individual clinical records, parental testing, imaging, and molecular laboratory data, but this is not a report generated from a single patient’s EHR.

2. Etiology

Causal factors

The primary cause is a heterozygous germline pathogenic variant in YY1 or a deletion of 14q32.2 that disrupts YY1. Established classes include:

  • Nonsense and frameshift variants causing nonsense-mediated decay or truncated protein
  • Missense substitutions concentrated in the C-terminal zinc-finger DNA-binding domains
  • In-frame deletions affecting zinc-finger structure
  • Canonical splice variants
  • Partial or whole-gene deletions
  • Larger 14q32 deletions that include YY1 and additional genes

The founding study found no disease variants in then-available control databases and experimentally demonstrated reduced YY1 chromatin occupancy for both truncating and zinc-finger missense variants. [34]

Risk factors

Factor Evidence and interpretation
Pathogenic YY1 variant Necessary molecular risk factor in confirmed monogenic GADEVS
Parental carrier status No conventionally inherited familial series is established; parental testing is still essential
Parental germline mosaicism Theoretical recurrence mechanism; no confirmed cases in the older GeneReviews dataset
Advanced parental age No GADEVS-specific association demonstrated
Sex Both sexes are affected; no reliable sex bias established
Ethnicity/geography Cases occur across multiple ancestries; no population enrichment or founder variant established
Consanguinity Not causative for this dominant, typically de novo disorder
Family history Usually negative because most variants are de novo
Environment/lifestyle No environmental, dietary, infectious, toxic, or occupational cause has been demonstrated

All tested parents in the early cohorts were negative for the proband’s variant in blood, supporting predominantly de novo occurrence. The estimated sibling recurrence risk after negative parental blood testing is approximately 1%, reflecting possible germline mosaicism. [46]

Protective factors

No genetic protective allele, diet, medication, lifestyle, vaccination, or environmental exposure has been shown to prevent GADEVS. The incomplete phenotype of some Yy1-heterozygous mice suggests genetic-background modifiers probably exist, but no human modifier gene has been validated. In C57BL/6-backcrossed mice, only 7/29 heterozygotes—about 24%—showed developmental retardation or neurulation defects, illustrating background-dependent penetrance in that model. [171]

Gene–environment interaction

No specific human YY1-by-environment interaction is established. Environmental conditions can influence general developmental outcome—nutrition, access to therapy, educational support, seizure control—but do not appear to initiate the syndrome. The relevant “environment” at the mechanistic level is primarily the developmental cellular environment: mutant neurons can alter neighboring astrocyte inflammatory transcription even when the astrocytes themselves are genetically normal. [1]

3. Phenotypes

Core phenotype catalogue

Frequencies below preferentially use intragenic-variant cohorts because large deletions may create contiguous-gene effects. “Rare” usually means one or a few published individuals.

Phenotype/type Onset, severity, course, frequency Functional/QOL impact Suggested HPO term
Developmental delay Infancy/early childhood; mild to profound; essentially universal in established cases Dependence in education, communication and activities of daily living Global developmental delay HP:0001263
Intellectual disability Childhood recognition; usually mild–moderate, occasionally severe/profound; lifelong Educational, vocational and independent-living limitations Intellectual disability HP:0001249
Motor delay Infancy; 8/10 in the original intragenic cohort; walking 15 months–6.5 years, median approximately 2 years Reduced mobility; need for PT or assistive devices Delayed gross motor development HP:0002194
Speech/language delay Childhood; at least 5/10 early cases, ranging from mild delay to absent speech Major effect on education and social participation; AAC may be required Delayed speech and language development HP:0000750
Feeding difficulty/dysphagia Usually neonatal or infancy; common; variable persistence Poor growth, aspiration risk, caregiver burden; some require gastrostomy Feeding difficulties HP:0011968; dysphagia HP:0002015
IUGR/low birth weight Antenatal/neonatal; low birth weight 5/9 in an early cohort Neonatal feeding/growth surveillance IUGR HP:0001511; low birth weight HP:0001518
Short stature/poor growth Childhood; minority; weight may catch up Endocrine assessment and nutritional support Short stature HP:0004322
Hypotonia Congenital/childhood; approximately half when neurologic manifestations are combined Delayed motor milestones, feeding and gait difficulty Muscular hypotonia HP:0001252
Abnormal gait Childhood; toe walking, waddling, ataxic or dystonic gait; variable Falls, mobility restriction, assistive-device need Gait disturbance HP:0001288
Dystonia/tremor/myoclonus Childhood to juvenile onset; uncommon but potentially progressive and severe Pain, impaired walking, hand use, speech and self-care Dystonia HP:0001332; tremor HP:0001337; myoclonus HP:0001336
Seizures Rare; febrile and non-febrile cases reported Injury risk and medication burden Seizure HP:0001250
Behavioral/psychiatric features Childhood onward; 5/9 in the early series School, family and social-function impact Abnormal behavior HP:0000708
Autism/autistic behavior Childhood; variable Social-communication and adaptive-function effects Autism HP:0000717
ADHD/hyperactivity Childhood; variable Attention and educational impairment ADHD HP:0007018
Anxiety Childhood/adolescence/adulthood Emotional distress and reduced participation Anxiety HP:0000739
Sleep disturbance Childhood onward; 2/9 in early data Family sleep and daytime functioning Sleep abnormality HP:0002360
Facial asymmetry Congenital; common in original descriptions; generally stable Usually cosmetic, occasionally linked to craniofacial evaluation Facial asymmetry HP:0000324
Broad forehead Congenital; 10/10 in the original intragenic cohort Diagnostic clue, little direct functional impact Broad forehead HP:0000337
Posteriorly rotated/simple ears Congenital; common Usually minimal functional effect Posteriorly rotated ears HP:0000358
Full upper eyelids/periorbital fullness Congenital/childhood; common Primarily morphologic Periorbital fullness HP:0000629
Downslanted palpebral fissures Congenital; variable Primarily morphologic Downslanting palpebral fissures HP:0000494
Bulbous/full nasal tip Congenital; common Primarily morphologic Bulbous nose HP:0000414
Thick lower-lip vermilion Congenital; common Primarily morphologic Thick lower lip vermilion HP:0000179
Micrognathia/Pierre Robin/cleft palate Congenital; rare Airway, feeding, speech and surgical burden Micrognathia HP:0000347; cleft palate HP:0000175
Craniosynostosis Congenital; uncommon, more frequent in large deletions Abnormal skull growth; possible neurosurgery Craniosynostosis HP:0001363
Strabismus/refractive error Childhood; eye findings in more than half in early summaries Visual development and school functioning Strabismus HP:0000486; hypermetropia HP:0000540
Brain MRI abnormalities Congenital/childhood; inconsistent Variable neurologic significance Abnormal brain MRI HP:0410263
Cardiac anomaly Congenital; rare: PFO, Ebstein anomaly, septal or arch lesions Cardiology follow-up or intervention Congenital heart defect HP:0001627
Hydronephrosis/UPJ stenosis Congenital; hydronephrosis 2/7 and UPJ stenosis 1/7 in early data UTI/renal-function surveillance Hydronephrosis HP:0000126
Cryptorchidism Congenital; expanded phenotype in the 2022 cohort Fertility/malignancy risk and surgery Cryptorchidism HP:0000028
Joint laxity, patellar luxation, arthrogryposis Congenital/childhood; individually rare Mobility and orthopedic burden Joint hypermobility HP:0001382; distal arthrogryposis HP:0005684
Hypothyroidism/GH deficiency Childhood; uncommon Growth, energy and neurodevelopment; treatable Hypothyroidism HP:0000821; GH deficiency HP:0000824
Thin/sparse hair Congenital/childhood; newly emphasized in 2022 Mostly cosmetic Sparse hair HP:0008070
Hearing impairment Uncommon but reported Communication and education Hearing impairment HP:0000365
Recurrent infections Approximately 1/5 in one patient-oriented summary, but poorly characterized Illness and health-care burden Recurrent infections HP:0002719

The original ten-person intragenic cohort documented walking as late as 6.5 years, moderate–severe ID in some individuals, gastrostomy use in three, and heterogeneous MRI abnormalities. [20] The later methylation cohort added thin/sparse hair and cryptorchidism to the recognized spectrum. [76] A 2024 clinical review stated that about 90% of compiled patients had motor delay or intellectual disability, although denominator definitions varied. [68]

Neuroimaging

Reported findings include delayed myelination, cortical dysplasia, frontal gliosis, enlarged subarachnoid spaces or ventricles, white-matter loss or foci, encephalomalacia, and corpus-callosum hypoplasia/agenesis. These findings are neither obligatory nor specific. Some affected individuals have a normal MRI. [46]

Rare expansion phenotypes

A 2023 newborn report described lumbosacral meningomyelocele, hydrocephalus, Chiari II malformation, syringomyelia, spinal cysts, and tethered cord, but this is a single association and not yet an established recurrent YY1 phenotype. The authors called it the first GADEVS case with spinal dysraphism. PMID: 37189872, published March 26, 2023. [238][243]

Quality-of-life evidence

No GADEVS-specific EQ-5D, SF-36, PROMIS, or validated natural-history/QOL study was identified. Expected burden derives from intellectual disability, limited speech, feeding support, movement disorder, behavioral symptoms, congenital surgery, and need for lifelong educational and rehabilitative services.

4. Genetic and molecular information

Gene and protein

Attribute Value
Gene YY1, YY1 transcription factor
HGNC HGNC:12856
NCBI Gene 7528
Ensembl ENSG00000100811
OMIM gene 600013
UniProt P25490
Cytogenetic locus 14q32.2
GRCh38 coordinates chr14:100,239,144–100,282,788
MANE transcript NM_003403.5
Protein NP_003394.1, 414 amino acids
Functional class Ubiquitous GLI/Krüppel-class zinc-finger transcription factor; transcriptional activator/repressor and chromatin-loop regulator

These identifiers and the current MANE transcript are provided by NCBI/ENCODE. [92][93]

Representative disease-associated variants

Variant, NM_003403.5 Class Reported interpretation/effect
c.385del, p.Asp129Ilefs*127 Frameshift Pathogenic; loss of function
c.458_476del, p.Val153fs*97 Frameshift De novo, pathogenic by PVS1_Strong+PS2+PM2; absent from HGMD, dbSNP, ExAC, gnomAD and ClinVar when reported [123]
c.535A>T, p.Lys179Ter Nonsense NMD; approximately 50% protein in patient cells
c.690del, p.Glu231Ilefs*25 Frameshift De novo, pathogenic; PMID 34729769 [105]
c.958C>T, p.His320Tyr Missense, zinc finger 1 Pathogenic; impaired zinc coordination/DNA binding
c.1015A>C, p.Lys339Gln Missense, zinc finger 2 Pathogenic; impaired DNA interaction
c.1030C>T, p.Gln344Ter Nonsense Loss of zinc fingers 3–4
c.1096C>G, p.Leu366Val Missense, zinc finger 3 Pathogenic
c.1097T>C, p.Leu366Pro Missense, zinc finger 3 Pathogenic
c.1138G>T, p.Asp380Tyr Missense, zinc finger 4 Pathogenic; predicted destabilization
c.1173del, p.Asn391Lysfs*10 Frameshift Disrupts zinc finger 4
c.1174_1176del, p.Lys393del In-frame deletion Disrupts zinc finger 4
c.1062+1G>A Canonical splice ClinVar pathogenic
Whole/partial YY1 deletion Copy-number loss Haploinsufficiency
Larger 14q32.2 deletion Structural variant GADEVS plus possible contiguous-gene effects

ClinVar-linked summaries listed at least 36 disease-associated submissions by 2025, although submission count is not equivalent to independent affected individuals or expert-panel curation. [121]

Variant origin and frequency

  • Established variants are germline heterozygous.
  • Most confirmed cases are de novo.
  • Pathogenic truncating and critical zinc-finger variants are generally absent or exceptionally rare in population databases.
  • The gene is strongly loss-of-function constrained; one case report cited pLI 0.99 and observed/expected loss-of-function ratio approximately 0.10. [130]
  • Somatic YY1 variants occur in some tumors, notably insulinoma, but do not imply constitutional GADEVS or hereditary tumor predisposition.

Functional consequence

The dominant established mechanism is haploinsufficiency. Truncating alleles reduce dosage; zinc-finger missense alleles can preserve protein quantity while eliminating effective chromatin binding. The 2024/2025 organoid study suggested that at least one variant, p.Cys303Arg, could exert a dominant-negative effect, but that interpretation was inferred from elevated mutant protein and reduced binding and is not yet a general mechanism for all YY1 missense variants. [18]

Modifier genes and genotype–phenotype relationships

No validated human modifier gene or robust genotype–phenotype correlation exists. Larger deletions may be more severe because of neighboring genes or disruption of the chromosome-14 imprinted region. Missense variants outside the usual zinc-finger region warrant caution and may benefit from episignature or functional testing.

Epigenetics

A distinctive peripheral-blood DNA-methylation episignature was identified from 13 available DNA samples, supporting functional confirmation and possible reclassification of uncertain variants. PMID: 35027293, published January 10, 2022 online / April 2022 print. [76]

At the chromatin level, affected lymphoblastoid cells showed reduced YY1 binding, loss of H3K27 acetylation particularly at YY1-bound enhancers, and a relative shift toward repressive H3K27 methylation at some loci. [11]

5. Environmental information

Domain Conclusion
Toxins, radiation, pollution No demonstrated etiologic role
Smoking, alcohol, diet, exercise No evidence that these cause or prevent GADEVS
Occupational exposure Not applicable to congenital causation
Infectious agents No pathogen causes or triggers the syndrome
Maternal environment No specific association established
Environmental modification of outcome General developmental supports, nutrition, safe feeding, treatment of hearing/vision problems and early education can modify functional outcome, not genotype

No CHEBI disease-causing chemical should currently be assigned.

6. Mechanism and pathophysiology

Ordered causal chain

  1. A heterozygous truncating/deletion allele or critical zinc-finger missense variant in YY1 leads to reduced effective YY1 dosage or DNA-binding capacity.
  2. Reduced functional YY1 leads to a global loss of YY1 chromatin occupancy, with preferential retention at high-affinity/high-occupancy sites.
  3. Loss of occupancy at promoters and especially enhancers results in reduced H3K27 acetylation and altered enhancer–promoter regulation; increased H3K27me3 at some affected sites is consistent with transcriptional repression.
  4. Dysregulated chromatin architecture leads to cell-type-specific changes in transcriptional networks governing organogenesis, metabolism, protein synthesis, neural-progenitor survival, differentiation and synapse formation.
  5. Neurodevelopmental branch: altered YY1–NEUROG2–ETV5 regulation in radial glia and intermediate progenitors leads to disturbed corticogenesis and abnormal ventricle-like cytoarchitecture.
  6. Impaired neural-progenitor biosynthesis/cell-cycle control results in G1/S arrest and p53-dependent apoptosis in mouse conditional knockouts; contribution of the same pathway to human heterozygous disease is strongly plausible but partly inferred.
  7. Altered excitatory-neuron transcription and synaptic organization lead to abnormal neuronal maturation, connectivity and signaling, providing a mechanistic bridge to DD/ID, speech delay, seizures and movement/behavioral phenotypes.
  8. Glial branch: altered signals from mutant neurons lead to non-cell-autonomous activation of adjacent astrocytes and an inflammatory/astrogliosis-like transcriptional response; its importance in living patients remains inferred from co-culture.
  9. Dysregulation in neural crest and non-neural embryonic lineages leads to variably penetrant craniofacial, ocular, cardiac, renal, genital and skeletal malformations.
  10. The combined developmental and network-level abnormalities result in the multisystem GADEVS phenotype.

Direct human cellular evidence

In lymphoblastoid cells from four affected individuals:

  • YY1 peaks were markedly reduced.
  • Quantitative analysis estimated a 43%–87% global decrease in occupancy, depending on normalization.
  • 416 consistently lost peaks were identified.
  • There were 152 differentially expressed genes, including enrichment for chromatin-silencing functions.
  • About 82% of YY1-bound enhancers showed significantly reduced H3K27ac under one normalization scheme.
  • Distally regulated YY1 genes were disproportionately likely to be differentially expressed.
  • Data are deposited as GEO GSE98478. [11]

The authors’ abstract directly stated:

“YY1 deletions and missense mutations lead to a global loss of YY1 binding with a preferential retention at high-occupancy sites.” [20]

2024 single-cell and organoid research

Pereira et al. combined patient-derived iPSCs, cortical organoids, NGN2-induced neurons, neuron–astrocyte co-culture, single-cell RNA/ATAC multiomics, imaging, and regulatory-network reconstruction. PMID: 38405909, online publication February 17, 2024. [18][260]

Key findings included:

  • Three patient lines: p.Lys179Ter, p.Asp129Ilefs*127, and p.Cys303Arg.
  • Reduced YY1 binding in all affected lines.
  • 764 iPSC DEGs at the reported threshold, 585 downregulated.
  • Day-30 organoids: 31,214 cells; strong disruption in radial glia, intermediate progenitors and maturing excitatory neurons.
  • Day-90 organoids: 32,677 cells; broad dysregulation and an increased upper-layer-neuron cluster.
  • GADEVS organoids developed irregular PAX6-positive ventricle-like structures.
  • NGN2 cultures contained 14,828 cells; glutamatergic neurons were the most dysregulated.
  • Astrocytes exposed to GADEVS neurons had 291 DEGs—248 upregulated and 43 downregulated—with immune/cell-activation enrichment.
  • Regulatory reconstruction implicated YY1, NEUROG2, ETV5, MYC, MXI1, EBF3 and related networks.

The abstract concluded:

“YY1 haploinsufficiency causes a pervasive alteration of cell type specific transcriptional networks, disrupting corticogenesis at the level of neural progenitors and terminally differentiated neurons.” [18]

Molecular pathways and processes

Mechanism Evidence status Suggested GO terms
DNA-dependent transcriptional activation/repression Directly established DNA-templated transcription GO:0006351; regulation of transcription GO:0006355
Enhancer–promoter looping/chromatin organization Established YY1 biology; disease-linked occupancy effects demonstrated Chromatin organization GO:0006325; chromosome organization GO:0051276
Histone H3K27 acetylation loss Directly demonstrated in patient cells Histone acetylation GO:0016573
Neural-progenitor proliferation/survival Strong mouse-model evidence; supported by organoid transcription Neural precursor cell proliferation GO:0061351; regulation of cell cycle GO:0051726
p53-dependent apoptosis Direct in conditional mouse knockout; inferred contribution to GADEVS Intrinsic apoptotic signaling by p53 GO:0072332
Corticogenesis/neurogenesis Directly disrupted in patient-derived organoids Neurogenesis GO:0022008; cerebral cortex development GO:0021987
Synapse assembly/signaling Transcriptomic and imaging evidence Synapse organization GO:0050808; trans-synaptic signaling GO:0099537
MAPK/EGFR signaling Enriched in late radial-glial communication analyses; subtle and computationally inferred MAPK cascade GO:0000165; EGFR signaling GO:0007173
Astrocyte activation/inflammation Direct co-culture transcriptomics, but in-vitro significance Astrocyte activation GO:0048143; inflammatory response GO:0006954
Protein synthesis/metabolism Mouse cortical knockout evidence Translation GO:0006412; cellular metabolic process GO:0044237
Oligodendrocyte differentiation/myelination Established YY1 biology; possible relevance to delayed myelination Oligodendrocyte differentiation GO:0048709; myelination GO:0042552

Relevant cell types

Cell type Role Suggested CL term
Neural stem/progenitor cell Proliferation and survival are dosage-sensitive Neural stem cell CL:0000047
Radial glial cell Disrupted developmental transcription and intercellular signaling Radial glial cell CL:0000681
Intermediate neuronal progenitor Altered indirect neurogenesis Neural progenitor cell CL:0011020
Excitatory/glutamatergic neuron Strong synaptic and transcriptional disturbance Glutamatergic neuron CL:0000679
Cortical neuron Principal affected differentiated lineage Cerebral cortex neuron CL:0002609
Astrocyte Non-cell-autonomous inflammatory activation Astrocyte CL:0000127
Neural crest cell Plausible source of craniofacial and peripheral anomalies Neural crest cell CL:0000333
Oligodendrocyte progenitor YY1-dependent differentiation/myelination Oligodendrocyte precursor cell CL:0002453
Lymphoblastoid cell Experimental chromatin/transcriptomic model, not principal diseased tissue B lymphoblast CL:0000905

Omics and advanced technologies

  • Bulk RNA-seq/ChIP-seq: Patient lymphoblastoid cells and iPSCs.
  • Single-cell multiome: Simultaneous RNA expression and chromatin accessibility in cortical organoids.
  • 3D models: Patient-derived cortical organoids.
  • Cell–cell communication analysis: LIANA/tensor-cell2cell and neuron–astrocyte transwell co-culture.
  • Regulatory-network inference: CellOracle, Cicero, PROGENy, VIPER and DoRothEA.
  • Proteomics/metabolomics/lipidomics: No replicated GADEVS-specific clinical signature identified.
  • Spatial transcriptomics: No published disease-specific study identified.
  • CRISPR screens: No GADEVS-focused therapeutic screen identified.

7. Anatomical structures affected

Level/system Structures and manifestations Suggested ontology
Central nervous system Cerebral cortex, white matter, corpus callosum, ventricles; occasionally spinal cord Brain UBERON:0000955; cerebral cortex UBERON:0000956; white matter UBERON:0002316
Craniofacial Forehead, jaws, palate, cranial sutures, ears, lips Face UBERON:0001456; palate UBERON:0007375
Eyes/visual system Ocular alignment and refraction; rare micro/nanophthalmos Eye UBERON:0000970
Cardiovascular Atrial septum, tricuspid valve, aortic arch/collaterals Heart UBERON:0000948
Renal/urinary Kidneys, renal pelvis and ureteropelvic junction Kidney UBERON:0002113
Genital Testes/scrotum/penis; cryptorchidism or micropenis Testis UBERON:0000473
Skeletal/joints Skull, hands/feet, patellae and limb joints Skeleton UBERON:0001434
Gastrointestinal/oropharyngeal Oral–pharyngeal swallowing apparatus, esophagus; reflux/constipation Esophagus UBERON:0001043
Endocrine Thyroid and pituitary growth axis Thyroid gland UBERON:0002046
Subcellular Nucleus and chromatin; enhancer/promoter complexes Nucleus GO:0005634; chromatin GO:0000785
Protein compartment Nuclear transcriptional/chromatin-regulatory complexes Transcription regulator complex GO:0005667

Facial asymmetry can be lateralized, but no consistent right/left predilection is known. Most neurologic and systemic involvement is bilateral or diffuse.

8. Temporal development

  • Biologic onset: Prenatal, because YY1 dosage affects embryogenesis, growth and organogenesis.
  • Clinical onset: Antenatal IUGR or congenital anomaly; neonatal feeding/hypotonia; developmental and speech delays become apparent during infancy or early childhood. Orphanet classifies onset as antenatal/neonatal. [32]
  • Pattern: Chronic and lifelong, not episodic or relapsing.
  • Development: Children generally acquire skills, but at a delayed rate. Developmental disability itself is usually stable rather than neurodegenerative.
  • Potentially progressive components: Dystonia and related gait/movement disorders can progress substantially in a minority.
  • No formal stages: There is no accepted early/intermediate/advanced staging system.
  • Remission: No spontaneous molecular remission; individual feeding or growth problems may improve, while therapies can improve function.
  • Critical period: Prenatal corticogenesis is the primary biological vulnerability; infancy and preschool years are the practical window for early PT/OT/speech/feeding and communication intervention.

Adult natural-history data remain sparse. Newer adult analyses suggest that thyroid abnormalities, motor impairment, hearing loss and anxiety may be especially relevant in adulthood, but denominators are very small. [227]

9. Inheritance and population

Genetic inheritance

Characteristic Current conclusion
Mode Autosomal dominant
Typical origin De novo
Penetrance Not formally quantified; DD/ID appears highly penetrant among clinically ascertained pathogenic-variant carriers
Expressivity Markedly variable
Anticipation Not reported; no repeat-expansion mechanism
Germline mosaicism Theoretical; not conclusively documented in early reports
Sibling recurrence Approximately 1% after negative parental blood testing
Offspring risk Theoretical 50% for a heterozygous affected individual, although reproduction has been rarely documented
Founder effect None known
Carrier frequency Not meaningful for a usually de novo dominant disorder
Consanguinity No causal role

Epidemiology

True prevalence and incidence are unknown. GeneReviews cited detection of de novo pathogenic YY1 variants in approximately 0.03%–1% of selected cohorts with unexplained intellectual disability, not in the general population. [66]

The 2017 discovery cohort found ten intragenic variants among 14,969 individuals with intellectual disability—approximately 0.067%—but the constituent cohorts used different ascertainment and sequencing approaches. [20]

By 2024, a patient-community summary stated that at least 37 molecularly recognized individuals had been identified clinically. [23] This is not a prevalence estimate and likely undercounts unpublished diagnoses.

No credible annual incidence, male:female ratio, ethnicity-specific prevalence, endemic region, geographic gradient, or founder variant has been established.

10. Diagnostics

Diagnostic standard

There are no sufficient clinical criteria. Diagnosis requires:

  1. A heterozygous pathogenic or likely pathogenic YY1 sequence variant; or
  2. A heterozygous deletion disrupting YY1, interpreted in the context of whether neighboring genes are also deleted.

GeneReviews specifically notes that the phenotype is not sufficiently specific for diagnosis without molecular confirmation. [46]

Recommended testing strategy

Test Utility
Chromosomal microarray Detects whole-gene/larger 14q32 copy-number losses; should define neighboring genes and the imprinted region
Neurodevelopmental multigene panel Appropriate if it includes YY1 and sequence plus deletion/duplication analysis
Trio whole-exome sequencing High utility because the phenotype is nonspecific and most variants are de novo
Trio whole-genome sequencing Useful for coding variants, splice/regulatory variants and better structural-variant breakpoint resolution
YY1 single-gene sequencing Reasonable only when phenotype/known family variant is strongly suggestive; not usually first-line
Sanger sequencing Confirmation and parental segregation testing
Gene-targeted del/dup testing Can detect exon-level events but is less informative than genome-wide CNV testing for larger deletions
DNA methylation episignature Functional adjunct for VUS or atypical variants; not a replacement for sequence/CNV testing
RNA sequencing Research/selected splice-VUS clarification; not routine
Karyotype/FISH Low yield for intragenic variants; may characterize large cytogenetic rearrangements
mtDNA/repeat-expansion testing Not indicated specifically for GADEVS
Liquid biopsy Not applicable

The 2024 case report used WES followed by Sanger confirmation to identify c.458_476del, p.Val153fs*97. [16] GTR listed four available clinical testing entries in the retrieved version, although laboratory availability changes over time. [55]

Baseline evaluation after molecular diagnosis

  • Growth parameters, nutrition and feeding/swallow safety
  • Comprehensive developmental, speech/language and adaptive assessment
  • Neurologic examination; EEG only for suspected seizures
  • Brain MRI for abnormal head growth, seizures, regression, focal signs or substantial movement disorder
  • Behavioral/autism/ADHD/anxiety and sleep screening
  • Ophthalmology and hearing assessment
  • Echocardiography
  • Renal ultrasound
  • Examination for cryptorchidism and other genital anomalies
  • Craniofacial assessment for cleft palate, micrognathia, craniosynostosis or abnormal skull shape
  • Musculoskeletal examination
  • Thyroid function and growth/endocrine evaluation where indicated

These recommendations closely follow the GeneReviews multidisciplinary evaluation table. [46]

Laboratory biomarkers

No routine serum enzyme, metabolite, protein, immune or endocrine biomarker diagnoses GADEVS. Thyroid studies, growth-axis testing and nutritional laboratories are problem-directed. The only disease-linked molecular biomarkers are:

  • Pathogenic/likely pathogenic YY1 genotype
  • 14q32 deletion
  • Peripheral-blood DNA-methylation episignature

Differential diagnosis

The differential is broad because GADEVS lacks a pathognomonic clinical sign:

  • Other chromatinopathies/enhanceropathies
  • KANSL1-related Koolen-de Vries syndrome
  • Wiedemann-Steiner, Coffin-Siris, Kabuki and Cornelia de Lange syndromes
  • White-Sutton syndrome, CDK13-related disorder, ADNP-related disorder and SETD5-related NDD
  • Imprinting disorders involving chromosome 14, particularly in large deletions
  • Monogenic movement disorders when dystonia/myoclonus dominates
  • Syndromic craniosynostosis or Pierre Robin sequence when craniofacial findings dominate

Distinguishing GADEVS ultimately depends on YY1 testing and, when uncertain, segregation and functional/episignature evidence.

Screening

  • Not included in routine newborn biochemical screening.
  • Population carrier screening is not appropriate.
  • Cascade testing is limited because most cases are de novo.
  • Test both parents to establish inheritance and assess recurrence.
  • Prenatal or preimplantation testing is possible once the familial/proband variant is known.

11. Outcome and prognosis

Survival

No 5-year/10-year survival rate, standardized mortality rate, disease-specific mortality estimate, or reliable life-expectancy calculation exists. Published individuals have survived into adulthood, including people assessed in their third and fourth decades. There is no current evidence that uncomplicated GADEVS is inevitably life-limiting.

Morbidity and function

The principal long-term burdens are:

  • Lifelong cognitive and adaptive disability
  • Speech/communication impairment
  • Feeding and gastrointestinal problems
  • Motor delay, hypotonia and gait impairment
  • Behavioral or psychiatric morbidity
  • Visual/hearing impairment
  • Progressive dystonia in a subset
  • Complications of individual congenital anomalies

Recovery from the underlying genetic condition is not expected. Nevertheless, acquisition of skills, improved communication, safer feeding, mobility gains, behavioral stabilization and correction of structural anomalies are realistic treatment goals.

Prognostic indicators

No validated biomarker or prediction model exists. Likely practical indicators include:

  • Baseline developmental severity
  • Presence of severe feeding/aspiration difficulty
  • Major congenital brain or cardiac anomaly
  • Severe/progressive movement disorder
  • Hearing/vision impairment
  • Access to early developmental intervention
  • Size and gene content of a 14q32 deletion

There is no established variant-specific prognosis.

12. Treatment

General principle

There is no approved disease-modifying therapy for YY1 haploinsufficiency. Care is individualized and multidisciplinary. The 2024 review stated that symptomatic treatment and comprehensive rehabilitation may improve quality of life. [54]

Manifestation/intervention Approach and evidence Suggested NCIT term
Developmental delay/ID Early intervention, individualized education, developmental pediatrics Developmental Therapy; Early Intervention
Gross-motor delay/hypotonia Physical therapy, orthotics, walkers or wheelchairs as required Physical Therapy NCIT:C15309
Fine-motor/adaptive limitation Occupational therapy Occupational Therapy NCIT:C15310
Speech/language impairment Speech-language therapy; AAC evaluation for limited speech Speech Therapy NCIT:C15308
Feeding dysfunction Feeding therapy, dietitian input, swallow assessment, texture modification Nutritional Support NCIT:C15440
Persistent unsafe/inadequate feeding Gastrostomy where necessary Gastrostomy NCIT:C52004
GERD/constipation Standard pediatric/adult therapy Supportive Care
Seizures Standard antiseizure medication selected by seizure type; no GADEVS-specific agent Anticonvulsant Therapy
ADHD/anxiety/autism-related behavior Behavioral intervention; standard psychotropic treatment when appropriate Behavioral Therapy NCIT:C15185
Dystonia PT, standard dystonia medications, botulinum toxin for focal symptoms; specialist movement-disorder care Botulinum Toxin Therapy
Severe refractory generalized dystonia Consider bilateral GPi deep-brain stimulation in highly selected cases Deep Brain Stimulation NCIT:C116507
Strabismus/refractive error Glasses, patching or surgery as indicated Ophthalmic Procedure
Hearing impairment Audiology, amplification/communication support Hearing Aid Device
Cleft palate/craniosynostosis Multidisciplinary craniofacial surgery Surgical Procedure NCIT:C15329
Cardiac/renal anomalies Lesion-specific cardiology, nephrology or urology care Supportive/Corrective Surgery
Cryptorchidism Standard orchiopexy timing Orchiopexy
Hypothyroidism/GH deficiency Standard endocrine replacement after confirmation Thyroid Hormone Replacement; Growth Hormone Therapy

GeneReviews recommends PT, OT, speech and feeding therapies from infancy, individualized education, augmentative communication, standard management of seizures and congenital anomalies, and gastrostomy when persistent feeding difficulty warrants it. [46]

Deep-brain stimulation evidence

Evidence is limited to case reports. A 2021 report described long-term response of YY1-related dystonia to DBS, PMID 33638881. [183] A later case documented a 35-year-old man whose Burke-Fahn-Marsden motor score improved from 100 to 50 at six months and to 46 at four years after bilateral GPi-DBS; disability score improved from 20 to 14. This supports consideration for medication-refractory severe dystonia, not routine GADEVS treatment. [181]

Experimental therapies

No validated gene replacement, CRISPR editing, RNA therapy, cell therapy, targeted anti-inflammatory therapy, or syndrome-specific pharmacotherapy is available. The organoid/co-culture work raises hypotheses involving inflammatory modulation and astrocyte–neuron signaling, but the investigators explicitly note that preclinical validation is required. [1]

No clearly verified GADEVS-specific interventional ClinicalTrials.gov study or treatment-response trial was identified. Generic natural-history or sequencing studies should not be represented as therapeutic trials.

Pharmacogenomics

No YY1-specific CPIC/PharmGKB prescribing guideline or reproducible genotype-dependent drug response is known.

13. Prevention

Primary prevention

Because most cases arise from a de novo germline event, lifestyle change, vaccination, diet or exposure avoidance cannot prevent occurrence.

Secondary prevention and early detection

  • Prompt genomic testing in children with unexplained DD/ID plus feeding difficulty, growth restriction, dysmorphism or congenital anomalies
  • Parental testing after diagnosis
  • Prenatal diagnosis by chorionic-villus sampling or amniocentesis when a familial/proband variant is known
  • Preimplantation genetic testing for monogenic disease
  • Early developmental, feeding, hearing, vision, renal and cardiac assessment

Tertiary prevention

  • Swallow-safety intervention to reduce aspiration/malnutrition
  • Seizure recognition and treatment
  • Early PT/OT/speech/AAC to reduce secondary functional limitation
  • Growth and thyroid monitoring
  • Behavioral and sleep surveillance
  • Prompt treatment of visual, auditory, cardiac, renal, orthopedic and movement complications

Genetic counseling

After a confirmed de novo variant absent from both parents’ blood, counsel an approximate 1% sibling recurrence risk because of possible germline mosaicism. If a parent is found to carry the variant, each pregnancy has a 50% transmission risk, with unpredictable severity. Prenatal and preimplantation testing are technically feasible once the causal variant is known. [46]

Vaccines, antimicrobial prophylaxis and public-health/environmental control measures are not disease-specific; routine age-appropriate immunization remains appropriate.

14. Other species and natural disease

No naturally occurring veterinary syndrome clearly homologous to human GADEVS and no breed-specific OMIA entry were identified. There is no infectious transmission, zoonotic potential or cross-species contagion.

Orthologs

Species Taxon ID Ortholog/resource Relevance
Human, Homo sapiens 9606 YY1; NCBI Gene 7528 Disease gene
Mouse, Mus musculus 10090 Yy1; NCBI Gene 22632; MGI:99150 Principal developmental model
Rat, Rattus norvegicus 10116 Yy1; NCBI Gene 24919 Conserved ortholog; no natural GADEVS model
Zebrafish, Danio rerio 7955 yy1b, NCBI Gene 406394; a second paralog also exists Developmental knockdown model [162]
Dog, Canis lupus familiaris 9615 YY1, NCBI Gene 611171 Conserved ortholog; no established natural disease
Cat, Felis catus 9685 YY1, NCBI Gene 101080802 Conserved ortholog; no established natural disease
Fruit fly, Drosophila melanogaster 7227 pho/pleiohomeotic, with phol as a related homolog Polycomb recruitment/comparative chromatin biology

Mammalian YY1 can partially rescue loss of Drosophila pho, demonstrating evolutionary conservation of parts of its Polycomb-related function, although mammalian and fly genomic targeting are not identical. [151][163]

15. Model organisms and experimental models

Model Manipulation Phenotype/mechanistic contribution Limitations/resource
Germline Yy1-null mouse Homozygous targeted disruption Peri-implantation lethality; establishes essential embryonic role Too severe to model heterozygous human disease; PMID 10490658 [168]
Yy1+/− mouse Heterozygous disruption Incomplete growth retardation, exencephaly, pseudoventricles and brain asymmetry; approximately 24% affected in one backcross Variable penetrance; not a complete behavioral model; MGI:99150 [153][171]
Dorsal-cortex conditional mouse Emx1-Cre Yy1 deletion Reduced forebrain/cortical thickness, G1/S arrest and p53-dependent progenitor apoptosis Biallelic tissue-specific loss exceeds human haploinsufficiency [172]
Mid-hindbrain conditional mouse Region-specific deletion Reduced proliferation, p53 accumulation, apoptosis and cerebellar agenesis Models severe regional loss, not systemic heterozygosity [177]
Neural-crest conditional mouse Premigratory neural-crest deletion Embryonic death with midbrain and craniofacial defects Useful for craniofacial mechanism; severe knockout [165]
Oligodendrocyte-lineage models Conditional Yy1 loss Impaired oligodendrocyte differentiation/myelination program Relevance to GADEVS white-matter findings remains indirect
Zebrafish yy1a/yy1 knockdown Morpholino/experimental knockdown Abnormal brain and heart development, linked in one study to phosphatidylserine-receptor regulation Knockdown artifacts and paralog redundancy; not variant-specific [175]
Patient lymphoblastoid cells Endogenous pathogenic variants/deletion Reduced YY1 binding, altered H3K27ac/H3K27me3 and transcription; GEO GSE98478 Blood-derived transformed cells do not model corticogenesis
Patient-derived iPSCs Reprogrammed cells carrying YY1 variants Dosage, occupancy and pluripotent-stage transcription studies Reprogramming and line-to-line variability
Neural crest stem cells Differentiated patient iPSCs Differentiation failure and apoptotic blebbing In-vitro approximation
Cortical organoids Patient-derived 3D organoids Irregular ventricle-like structures and cell-type-specific corticogenesis defects No vasculature, microglial completeness or whole-body physiology
NGN2-induced cortical neurons Patient iPSC-derived excitatory neurons Synaptic transcriptomic disturbance and increased synaptic puncta Forced differentiation may bypass developmental stages
Neuron–astrocyte co-culture Patient neurons plus normal mouse astrocytes Non-cell-autonomous inflammatory/astrogliosis-like astrocyte response Cross-species, in-vitro system

The 2024 organoid study is currently the most disease-proximal experimental platform because it uses endogenous patient variants and resolves affected radial-glial, progenitor, neuronal and astrocytic programs at single-cell level. However, its regulatory networks and dominant-negative interpretation are partly computational or inferential and require in-vivo validation. [18]

Selected primary literature and current authoritative resources

Publication/resource Publication date Key contribution URL/identifier
Gabriele M, et al. “YY1 Haploinsufficiency Causes an Intellectual Disability Syndrome Featuring Transcriptional and Chromatin Dysfunction” June 1, 2017 Foundational 23-person cohort; haploinsufficiency, YY1 ChIP-seq, H3K27ac and transcriptomics PMID 28575647; DOI 10.1016/j.ajhg.2017.05.006 [20]
Khamirani HJ, et al. “Clinical features of patients with Yin Yang 1 deficiency…” January 2022; online November 3, 2021 Iranian case and 13-case literature review; c.690del PMID 34729769; DOI 10.1111/ahg.12448 [105]
Cherik F, et al. “DNA methylation episignature in Gabriele-de Vries syndrome” April 2022; online January 10, 2022 13-person methylation analysis; blood episignature; expanded phenotype PMID 35027293; DOI 10.1016/j.gim.2021.12.003 [76]
dos Santos SR, et al. “A de novo YY1 missense variant…” October 2022; online July 13, 2022 Phenotypic expansion and altered X-chromosome inactivation PMID 35829845; DOI 10.1007/s11011-022-01024-2 [43]
Koruga N, et al. “First Reported Case…with Spinal Dysraphism” March 26, 2023 Single-case expansion: meningomyelocele, hydrocephalus and Chiari II PMID 37189872; DOI 10.3390/children10040623 [238]
Yang J, et al. “Clinical analysis of Gabriele-de Vries caused by YY1 mutations…” January 2024; online September 1, 2023 Novel c.458_476del frameshift and review of 28 reported patients PMID 37658636; DOI 10.1002/mgg3.2281 [16]
Pereira MF, et al. “YY1 mutations disrupt corticogenesis…” Online February 17, 2024; journal version 2025 Patient iPSCs, cortical organoids, single-cell multiomics and neuron–astrocyte signaling PMID 38405909; DOI 10.1038/s41380-025-02929-x [18]
GeneReviews: “Gabriele-de Vries Syndrome” Initial posting May 30, 2019 Diagnostic strategy, genetic counseling, evaluations, management and surveillance https://europepmc.org/books/n/gene/gabriele-devries/ [46]
Orphanet GADEVS Current database entry ORPHA identifier, concise definition, inheritance and onset https://www.orpha.net/en/disease/detail/506358 [32]

Overall interpretation

The strongest current model is that GADEVS is a YY1 dosage-dependent developmental enhanceropathy. Reduced effective YY1 binding destabilizes enhancer activation and cell-type-specific transcriptional networks during organogenesis, with the cerebral cortex—particularly radial glia, intermediate progenitors, excitatory neurons and their interaction with astrocytes—showing marked vulnerability. Clinical care remains supportive and surveillance-based; molecular diagnosis, early developmental intervention, feeding safety, and individualized management of movement, behavioral, sensory and congenital abnormalities are presently the most actionable measures.

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome Count
References checked 25
Resolved 25
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 25
On topic 10
Off topic 0

All extracted references resolved successfully.

Term Validation

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

Outcome Count
Terms checked 99
Resolved 93
Unresolved (possible confabulation) 0
Obsolete 3
Unverifiable 3
Terms whose name was checked 1
Terms named correctly 0
Terms named as a different term 1

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

  • MONDO:0044738 (3 mentions) - the report calls it "MONDO"; MONDO calls it Gabriele de Vries syndrome

Obsolete terms

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

  • GO:0016573 (obsolete histone acetylation) (1 mention)
  • GO:0044237 (obsolete cellular metabolic process) (1 mention) - replaced by GO:0008152
  • CL:0002609 (obsolete neuron of cerebral cortex) (1 mention) - replaced by CL:0010012

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA, MGI.