Wiedemann-Steiner Syndrome

Mendelian MONDO:0011518 Pathograph 38 Show in embeddings browser Intellectual disability syndrome Mendelian neurodevelopmental disorder

Wiedemann-Steiner syndrome (WDSTS; OMIM 605130) is an autosomal dominant Mendelian disorder of the epigenetic machinery caused by heterozygous pathogenic variants in KMT2A. It is characterized by developmental delay, intellectual disability, characteristic facial features, hypertrichosis cubiti, growth restriction, and variably present neurologic, gastrointestinal, skeletal, cardiac, ophthalmologic, genitourinary, immune, and dental findings. Most molecularly confirmed cases result from a de novo variant, although rare familial transmission and parental mosaicism are documented.

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1
Inheritance
4
Pathophys.
22
Phenotypes
2
Hypotheses
2
Gaps
38
Pathograph
1
Genes
12
Medical Actions
1
Differentials
2
Models
1
References
1
Deep Research
👪

Inheritance

1
Autosomal dominant inheritance HP:0000006
WDSTS is inherited in an autosomal dominant manner. Most affected individuals whose parents have undergone molecular testing have a de novo KMT2A pathogenic variant; rare affected parents and parental mosaicism have been reported. Each child of an affected individual has a 50% chance of inheriting the variant.
Autosomal dominant inheritance Expressivity: VARIABLE
Show evidence (2 references)
PMID:35617449 SUPPORT Human Clinical
"Most individuals diagnosed with WSS whose parents have undergone molecular genetic testing have the disorder as the result of a de novo pathogenic variant."
GeneReviews defines the autosomal dominant inheritance pattern and notes that most tested families represent de novo disease.
PMID:29574747 SUPPORT Human Clinical
"We observed autosomal dominant transmission of WSS in 3 families and mosaicism in one family."
The French cohort documents both vertical transmission and mosaicism.
◈

Mechanistic Hypotheses

2
Centrosomal microtubule-nucleation branch
centrosomal_branch EMERGING
Evidence balance 1 support
Proposes that loss of a non-nuclear KMT2A/MLL-WDR5 function at centrosomes contributes to neurodevelopmental manifestations through impaired recruitment of Cep72 and gamma-tubulin ring-complex proteins. The cellular phenotype is reported in WSS-derived cells, but its contribution to individual clinical manifestations has not been quantified.
Pathograph links
KMT2A Haploinsufficiency -> Centrosome Dysfunction and Impaired Microtubule Nucleation DIRECT
Centrosome Dysfunction and Impaired Microtubule Nucleation -> Global Developmental Delay INDIRECT UNKNOWN INTERMEDIATES
Show evidence (1 reference)
PMID:39661677 SUPPORT In Vitro
"Loss of the MLL/WDR5 complex affects microtubule nucleation and regrowth. MLL/WDR5 localize to the pericentriolar material and interact with centriolar satellite protein Cep72 and γ-tubulin ring complex proteins (γ-TuRCs)."
The study establishes the centrosomal cellular phenotype underlying this emerging mechanistic branch.
H3K4-dependent neuronal and synaptic branch
mouse_neuronal_extrapolation EMERGING
Evidence balance 1 support
Proposes that KMT2A-dependent, locus-specific H3K4 methylation and transcriptional changes alter dendritic spine biology and contribute to the human neurodevelopmental phenotype. Evidence currently comes primarily from constitutive Kmt2a-heterozygous mice and therefore requires confirmation in human developmental neural models.
Pathograph links
KMT2A Haploinsufficiency -> Altered H3K4 Methylation and Transcriptional Regulation DIRECT Reduced activity of the H3K4 writer KMT2A can alter H3K4 methylation and transcription at selected loci; available mouse data do not show a simple global reduction in H3K4 methylation.
Altered H3K4 Methylation and Transcriptional Regulation -> Reduced Dendritic Spine Density and Neuronal Dysregulation INDIRECT KNOWN INTERMEDIATES
Reduced Dendritic Spine Density and Neuronal Dysregulation -> Global Developmental Delay INDIRECT UNKNOWN INTERMEDIATES
Reduced Dendritic Spine Density and Neuronal Dysregulation -> Intellectual Disability INDIRECT UNKNOWN INTERMEDIATES
Reduced Dendritic Spine Density and Neuronal Dysregulation -> Behavioral Abnormalities INDIRECT UNKNOWN INTERMEDIATES
Show evidence (1 reference)
PMID:32483278 SUPPORT Model Organism
"Despite opposite enzymatic activities, the two mouse models deficient for either Kmt2a or Kdm5c shared reduced dendritic spines and increased aggression."
The Kmt2a-heterozygous mouse supplies the principal evidence for this neuronal branch.
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Discussions and Knowledge Gaps

2
Do the dendritic-spine and H3K4/transcriptomic findings in constitutive Kmt2a-heterozygous adult male mice reproduce the mechanisms operating in developing human neurons with heterozygous pathogenic KMT2A variants?
HUMAN MODEL MISMATCH OPEN wdts_mouse_neuronal_model_fidelity
Attached to
pathophysiology#Altered H3K4 Methylation and Transcriptional Regulation pathophysiology#Reduced Dendritic Spine Density and Neuronal Dysregulation
The mouse study provides the main experimental bridge from KMT2A dosage to dendritic morphology, but the molecular assays used adult amygdala tissue containing mixed neuronal and glial populations, only male mice were studied, and the constitutive genotype permits lifetime adaptation. Global H3K4me1-3 levels were not dramatically altered, and Kmt2a-heterozygous mice were normal in the two learning/memory assays used. The model therefore supports a locus-specific neuronal hypothesis, not a direct equivalence to human intellectual disability or a global histone-methylation-loss mechanism.
Proposed experiments
Isogenic human KMT2A dosage series across neuronal development
wdts_isogenic_human_neuron_timecourse
Generate patient-derived and CRISPR-engineered heterozygous KMT2A iPSC lines with matched corrected controls, differentiate them into defined excitatory and inhibitory neuronal lineages, and profile H3K4me states, chromatin accessibility, single-cell transcription, dendritic spines, and electrophysiology across developmental time points.
Decision criterion
A reproducible allele-dependent phenotype that is rescued by correction and converges across independent lines would support translation of the mouse neuronal branch; absence of such changes would argue that the mouse phenotype is model- or developmental-context-specific.
Show evidence (1 reference)
PMID:32483278 SUPPORT Model Organism
"Increasing spatiotemporal resolution of the molecular study is an important future direction."
The authors identify insufficient spatiotemporal resolution as a limitation that a human developmental time course would address.
Show evidence (2 references)
PMID:32483278 SUPPORT Model Organism
"First, we measured gene expression and H3K4me3 in adult brain tissues, a mixture of many neuron and glia types, which may mask potentially important molecular changes."
The authors explicitly identify adult mixed brain tissue as a limitation.
PMID:32483278 SUPPORT Model Organism
"It is important to note that the double mutations introduced in our mice were constitutive, and therefore a lifetime of adaptation to loss of these two major chromatin regulators may occur from early developmental stages."
The study acknowledges developmental adaptation in its constitutive genetic design.
How should a negative or intermediate KMT2A blood DNA methylation episignature be interpreted when phenotype and sequence evidence suggest WDSTS?
INTERPRETATION OPEN wdts_episignature_interpretation
Attached to
diagnosis#KMT2A DNA methylation episignature analysis
The discovery study showed clinical utility for variant classification, but independent evaluation found KMT2A sensitivity ranging from 70% to 100% at best with unstable performance and heterogeneous methylation profiles. The assay is useful as supporting functional evidence, yet its negative predictive value and handling of intermediate profiles remain insufficiently standardized for exclusionary use.
Proposed experiments
Prospective multi-site validation of a locked KMT2A episignature classifier
wdts_locked_classifier_prospective_validation
Prospectively test a preregistered, locked classifier in sequence-defined pathogenic, benign, and uncertain KMT2A variants across laboratories, recording age, blood-cell composition, phenotype, and intermediate scores.
Decision criterion
Stable sensitivity, specificity, and inter-laboratory concordance with prespecified thresholds would justify standardized interpretation; persistent classifier- or site-dependent results would support retaining the assay as non-exclusionary adjunctive evidence.
Show evidence (1 reference)
PMID:37872275 SUPPORT Human Clinical
"Remaining Cornelia de Lange syndrome, KMT2A, KDM5C and CHD7 signatures reached 70–100% sensitivity at best with unstable performances, suffering from heterogeneous methylation profiles among cases and rare discordant samples."
Unstable independent performance motivates a locked, multi-site validation design.
Show evidence (2 references)
PMID:35163737 SUPPORT Human Clinical
"WDSTS episignature enabled classification of variants of uncertain significance in the KMT2A gene as well as confirmation of diagnosis in patients with clinical presentation of WDSTS without known genetic variants."
The discovery cohort demonstrates positive clinical utility.
PMID:37872275 SUPPORT Human Clinical
"Remaining Cornelia de Lange syndrome, KMT2A, KDM5C and CHD7 signatures reached 70–100% sensitivity at best with unstable performances, suffering from heterogeneous methylation profiles among cases and rare discordant samples."
Independent testing motivates the open interpretation question.
⚙

Pathophysiology

4
KMT2A Haploinsufficiency
The initiating lesion is reduced KMT2A function from a heterozygous pathogenic variant. KMT2A encodes an H3K4 methyltransferase, but the clinical allelic spectrum is not limited to experimentally proven loss-of-function variants; the causal statement is therefore kept at the gene-disease level.
Centrosomal microtubule-nucleation branch H3K4-dependent neuronal and synaptic branch
KMT2A hgnc:7132 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves KMT2A (hgnc:7132). hgnc:7132 is a gene from the HUGO Gene Nomenclature Committee.
histone H3K4 methyltransferase activity GO:0042800 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased histone H3K4 methyltransferase activity (GO:0042800). GO:0042800 is a molecular function from the Gene Ontology. ↓ DECREASED
Downstream
Altered H3K4 Methylation and Transcriptional Regulation Reduced activity of the H3K4 writer KMT2A can alter H3K4 methylation and transcription at selected loci; available mouse data do not show a simple global reduction in H3K4 methylation. H3K4-dependent neuronal and synaptic branch
Centrosome Dysfunction and Impaired Microtubule Nucleation Centrosomal microtubule-nucleation branch
Characteristic Facial Features
Muscular Hypotonia
Short Stature
Elbow Hypertrichosis
Feeding Difficulties
Failure to Thrive
Constipation
Vertebral Anomalies
Scoliosis
Seizures
Cardiac Anomalies
Abnormal Corpus Callosum Morphology
Ophthalmologic Anomalies
Obstructive Sleep Apnea
Immune Dysfunction and Recurrent Infections
Genitourinary Anomalies
Brachydactyly
Dental Anomalies
Growth Hormone Deficiency
Show evidence (2 references)
PMID:33783954 SUPPORT Human Clinical
"Wiedemann‐Steiner syndrome (WSS) is an autosomal dominant disorder caused by monoallelic variants in KMT2A and characterized by intellectual disability and hypertrichosis."
The 104-person cohort confirms monoallelic KMT2A variants as causal.
PMID:39661677 SUPPORT In Vitro
"Haploinsufficiency of mixed-lineage leukemia (MLL/KMT2A) protein causes Wiedemann-Steiner syndrome (WSS), a neurodevelopmental disorder associated with microcephaly."
The mechanistic study identifies KMT2A haploinsufficiency as the upstream disease lesion.
Altered H3K4 Methylation and Transcriptional Regulation
KMT2A is an H3K4 methylation writer and transcriptional coactivator. In adult Kmt2a-heterozygous mouse brain, transcriptional changes and weak locus-specific H3K4me3 differences were detected, while global H3K4me1-3 levels were not dramatically altered. This supports locus- and cell-context-dependent dysregulation rather than a proven global histone methylation loss. The genome-wide DNA methylation episignature used diagnostically is a distinct measurement and is not evidence of reduced histone H3K4 methylation.
H3K4-dependent neuronal and synaptic branch
chromatin organization GO:0006325 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal chromatin organization (GO:0006325). GO:0006325 is a biological process from the Gene Ontology. ⚠ ABNORMAL regulation of DNA-templated transcription GO:0006355 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal regulation of DNA-templated transcription (GO:0006355). GO:0006355 is a biological process from the Gene Ontology. ⚠ ABNORMAL epigenetic regulation of gene expression GO:0040029 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal epigenetic regulation of gene expression (GO:0040029). GO:0040029 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Reduced Dendritic Spine Density and Neuronal Dysregulation H3K4-dependent neuronal and synaptic branch
Show evidence (2 references)
PMID:32483278 SUPPORT Model Organism
"In western blot analyses, global H3K4me1–3 levels were not altered dramatically in any mutant"
This negative result prevents overinterpreting KMT2A haploinsufficiency as a global H3K4 methylation deficiency.
PMID:32483278 SUPPORT Model Organism
"By relaxing the threshold, we obtained weak 2A-HET DMRs"
The reported Kmt2a-heterozygous H3K4me3 changes were weak and locus-specific, supporting the deliberately qualified node.
Centrosome Dysfunction and Impaired Microtubule Nucleation
The MLL/WDR5 complex localizes to pericentriolar material, interacts with Cep72 and gamma-tubulin ring-complex proteins, and promotes centrosomal recruitment of structural proteins. Loss of MLL/WDR5 impairs microtubule nucleation and spindle formation; a related localization phenotype was also observed in cells derived from people with WSS. How much this branch contributes to the human neurodevelopmental phenotype remains uncertain.
Centrosomal microtubule-nucleation branch
microtubule nucleation GO:0007020 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal microtubule nucleation (GO:0007020). GO:0007020 is a biological process from the Gene Ontology. ⚠ ABNORMAL mitotic spindle organization GO:0007052 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal mitotic spindle organization (GO:0007052). GO:0007052 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Experimental models
WSS patient-derived cell centrosome model OTHER The model reads out recruitment of gamma-tubulin ring-complex and structural proteins to centrosomes and subsequent microtubule nucleation.
Downstream
Global Developmental Delay Centrosomal microtubule-nucleation branch
Show evidence (1 reference)
PMID:39661677 SUPPORT In Vitro
"Loss of the MLL/WDR5 complex affects microtubule nucleation and regrowth. MLL/WDR5 localize to the pericentriolar material and interact with centriolar satellite protein Cep72 and γ-tubulin ring complex proteins (γ-TuRCs)."
The study demonstrates a non-nuclear MLL/WDR5-Cep72 centrosomal function and reports the phenotype in WSS-derived cells.
Reduced Dendritic Spine Density and Neuronal Dysregulation
Constitutive Kmt2a-heterozygous mice show reduced dendritic spine density and increased aggression. Combining Kmt2a heterozygosity with Kdm5c deficiency reversed dendritic morphology and key behavioral traits and partially corrected transcriptomic and H3K4me changes. These observations support a neuronal branch but have not yet been confirmed in human developmental neurons.
H3K4-dependent neuronal and synaptic branch
neuron CL:0000540 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neuron (CL:0000540). CL:0000540 is a cell type from the Cell Ontology.
dendritic spine development GO:0060996 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal dendritic spine development (GO:0060996). GO:0060996 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Global Developmental Delay H3K4-dependent neuronal and synaptic branch
Intellectual Disability H3K4-dependent neuronal and synaptic branch
Behavioral Abnormalities H3K4-dependent neuronal and synaptic branch
Show evidence (1 reference)
PMID:32483278 SUPPORT Model Organism
"Despite opposite enzymatic activities, the two mouse models deficient for either Kmt2a or Kdm5c shared reduced dendritic spines and increased aggression. Double mutation of Kmt2a and Kdm5c clearly reversed dendritic morphology, key behavioral traits including aggression, and partially corrected..."
The study links Kmt2a deficiency to dendritic and behavioral changes in a mouse model, while its human translational relevance remains unproven.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Wiedemann-Steiner 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

22
Cardiovascular 1
Cardiac Anomalies Abnormal heart morphology HP:0001627 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Congenital cardiac anomaly, annotated with Abnormal heart morphology (HP:0001627). HP:0001627 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:37025457 SUPPORT Human Clinical
"The most frequent imaging features were patent ductus arteriosus (57.1%) and patent foramen ovale (42.9%) in cardiovascular system, and abnormal corpus callosum (50.0%) in the brain."
Lin et al. quantify PDA and PFO within a small Chinese imaging cohort.
PMID:35617449 SUPPORT Human Clinical
"ophthalmologic anomalies, congenital heart defects, hand anomalies"
GeneReviews confirms congenital heart defects as part of the clinical spectrum.
Digestive 2
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 (2 references)
PMID:33783954 SUPPORT Human Clinical
"Common clinical features identified in the cohort included: developmental delay or intellectual disability (97%), constipation (63.8%), failure to thrive (67.7%), feeding difficulties (66.3%), hypertrichosis cubiti (57%), short stature (57.8%), and vertebral anomalies (46.9%)."
Feeding difficulties are present in 66.3% of the n=104 cohort, making it one of the most frequent gastrointestinal features of WDSTS.
PMID:35617449 SUPPORT Human Clinical
"Feeding therapy with possible supplemental tube feeding for those with poor weight gain / failure to thrive"
GeneReviews directly supports feeding therapy and selective tube feeding when poor growth persists.
Constipation FREQUENT 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 (2 references)
PMID:33783954 SUPPORT Human Clinical
"Common clinical features identified in the cohort included: developmental delay or intellectual disability (97%), constipation (63.8%), failure to thrive (67.7%), feeding difficulties (66.3%), hypertrichosis cubiti (57%), short stature (57.8%), and vertebral anomalies (46.9%)."
Constipation is present in 63.8% of the n=104 cohort, making it the most common gastrointestinal comorbidity in WDSTS after feeding difficulties.
PMID:35617449 SUPPORT Human Clinical
"At each visit: measurement of growth parameters; evaluation of nutritional status; assessment for constipation"
GeneReviews includes constipation assessment in routine surveillance.
Genitourinary 1
Genitourinary Anomalies Abnormality of the genitourinary system HP:0000119 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormality of the genitourinary system (HP:0000119). HP:0000119 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35617449 SUPPORT Human Clinical
"Other clinical features include feeding difficulties, prenatal and postnatal growth restriction, epilepsy, ophthalmologic anomalies, congenital heart defects, hand anomalies (such as brachydactyly and clinodactyly), hypotonia, vertebral anomalies (especially fusion anomalies of the cervical..."
GeneReviews lists renal and uterine anomalies as recognized clinical features of WDSTS.
Head and Neck 2
Characteristic Facial Features Abnormal facial shape HP:0001999 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal facial shape (HP:0001999). HP:0001999 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35617449 SUPPORT Human Clinical
"Wiedemann-Steiner syndrome (WSS) is characterized by developmental delay, intellectual disability, and characteristic facial features, with or without additional congenital anomalies."
GeneReviews identifies characteristic facial features as one of the core clinical findings.
Dental Anomalies Abnormality of the dentition HP:0000164 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormality of the dentition (HP:0000164). HP:0000164 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35617449 SUPPORT Human Clinical
"brain malformations, and dental anomalies."
GeneReviews includes dental anomalies in the clinical spectrum.
Immune 1
Immune Dysfunction and Recurrent Infections HP:0002719 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent infections (HP:0002719). HP:0002719 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35617449 SUPPORT Human Clinical
"consideration of IVIG therapy in those with low antibody levels; consideration of prophylactic antibiotics in those with frequent infections"
GeneReviews recommends IVIG and prophylactic antibiotics for WDSTS individuals with immune dysfunction, confirming recurrent infections as a clinically significant and manageable comorbidity.
Limbs 1
Brachydactyly HP:0001156 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Brachydactyly (HP:0001156). HP:0001156 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35617449 SUPPORT Human Clinical
"hand anomalies (such as brachydactyly and clinodactyly)"
GeneReviews explicitly lists brachydactyly and clinodactyly among the clinical manifestations.
Musculoskeletal 3
Muscular Hypotonia FREQUENT HP:0001252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypotonia (HP:0001252). HP:0001252 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:32604375 SUPPORT Human Clinical
"Fifty-seven percent of children diagnosed with WSS have hypotonia, and 90% have developmental delay. The diagnosis of WSS should require physical therapy services through early intervention programs due to its high correlation with motor developmental delay and disability."
Mendoza 2020 reports a 57% frequency estimate and connects hypotonia with the need for early motor intervention.
PMID:33783954 SUPPORT Human Clinical
"Hypotonia was associated with loss of function (LoF) variants, and seizures were associated with non‐LoF variants."
Sheppard et al. identify a genotype-phenotype correlation: hypotonia is specifically associated with loss-of-function KMT2A variants.
Vertebral Anomalies FREQUENT Abnormality of the vertebral column HP:0000925 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormality of the vertebral column (HP:0000925). HP:0000925 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:33783954 SUPPORT Human Clinical
"Common clinical features identified in the cohort included: developmental delay or intellectual disability (97%), constipation (63.8%), failure to thrive (67.7%), feeding difficulties (66.3%), hypertrichosis cubiti (57%), short stature (57.8%), and vertebral anomalies (46.9%)."
Vertebral anomalies are among the most common structural comorbidities in WDSTS, present in 46.9% of the n=104 multi-centre cohort.
PMID:35617449 SUPPORT Human Clinical
"Cervical spine anomalies may lead to immobility or instability, which may complicate airway management. Vertebral anomalies or scoliosis in the thoracic or lumbar spine may complicate spinal or epidural anesthesia."
GeneReviews states the anesthesia implications of cervical and thoracolumbar vertebral disease.
Scoliosis HP:0002650 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Scoliosis (HP:0002650). HP:0002650 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35617449 SUPPORT Human Clinical
"Vertebral anomalies or scoliosis in the thoracic or lumbar spine may complicate spinal or epidural anesthesia."
GeneReviews explicitly documents scoliosis and thoracolumbar vertebral anomalies as clinically significant features in WDSTS, with anesthesia implications.
Nervous System 6
Global Developmental Delay VERY_FREQUENT HP:0001263 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:32604375 SUPPORT Human Clinical
"Fifty-seven percent of children diagnosed with WSS have hypotonia, and 90% have developmental delay."
The review's developmental-delay estimate directly supports the very-frequent frequency band.
PMID:33783954 SUPPORT Human Clinical
"Common clinical features identified in the cohort included: developmental delay or intellectual disability (97%), constipation (63.8%), failure to thrive (67.7%), feeding difficulties (66.3%), hypertrichosis cubiti (57%), short stature (57.8%), and vertebral anomalies (46.9%)."
The Sheppard et al. n=104 multi-centre cohort provides the most robust frequency estimate (97%) for developmental delay/intellectual disability in WDSTS.
PMID:33783954 SUPPORT Human Clinical
"The median ages at walking and first words were 20 months and 18 months, respectively."
The same cohort quantifies delayed motor and speech milestones.
Intellectual Disability HP:0001249 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intellectual disability (HP:0001249). HP:0001249 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:36062544 SUPPORT Human Clinical
"The majority of patients performed in the below average to very low ranges in Nonverbal Reasoning, Visual/Spatial Perception, Visuoconstruction, Visual Memory, Attention, Working Memory and Math Computation skills. In contrast, over half the sample performed within normal limits on Receptive..."
Ng et al. characterise the specific neurocognitive profile of WSS in 10 patients; the small sample supports a profile description but not a population-wide severity distribution.
PMID:35617449 SUPPORT Human Clinical
"Wiedemann-Steiner syndrome (WSS) is characterized by developmental delay, intellectual disability, and characteristic facial features, with or without additional congenital anomalies."
GeneReviews identifies intellectual disability as a core clinical feature.
Behavioral Abnormalities Atypical behavior HP:0000708 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Atypical behavior (HP:0000708). HP:0000708 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36062544 SUPPORT Human Clinical
"Most caregivers reported deficits in executive functioning, most notably in emotion regulation."
Ng et al. identify executive function and emotion regulation deficits as a characteristic behavioural feature of WDSTS in a neuropsychological case series of 10 patients.
Seizures HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Seizures, annotated with Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:33783954 SUPPORT Human Clinical
"Hypotonia was associated with loss of function (LoF) variants, and seizures were associated with non‐LoF variants."
Sheppard et al. report an association between seizures and non-LoF KMT2A variants without quantifying it in the abstract.
PMID:35617449 SUPPORT Human Clinical
"Other clinical features include feeding difficulties, prenatal and postnatal growth restriction, epilepsy, ophthalmologic anomalies, congenital heart defects"
GeneReviews includes epilepsy among the recognized clinical features.
Abnormal Corpus Callosum Morphology HP:0001273 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal corpus callosum morphology (HP:0001273). HP:0001273 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37025457 SUPPORT Human Clinical
"The most frequent imaging features were patent ductus arteriosus (57.1%) and patent foramen ovale (42.9%) in cardiovascular system, and abnormal corpus callosum (50.0%) in the brain."
Lin et al. report abnormal corpus callosum morphology in the imaging subset of their 11-person Chinese cohort.
Obstructive Sleep Apnea HP:0002870 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Obstructive sleep apnea (HP:0002870). HP:0002870 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35617449 SUPPORT Human Clinical
"CPAP, BiPAP, or surgical removal of the tonsils and adenoids for those with obstructive sleep apnea"
GeneReviews includes CPAP/BiPAP and surgical adenotonsillectomy as management for OSA in WDSTS, confirming it as a recognised clinical feature warranting active screening.
Growth 2
Short Stature FREQUENT HP:0004322 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short stature (HP:0004322). HP:0004322 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:33783954 SUPPORT Human Clinical
"Common clinical features identified in the cohort included: developmental delay or intellectual disability (97%), constipation (63.8%), failure to thrive (67.7%), feeding difficulties (66.3%), hypertrichosis cubiti (57%), short stature (57.8%), and vertebral anomalies (46.9%)."
Short stature is present in 57.8% of the Sheppard multi-centre cohort of 104 individuals.
PMID:37025457 SUPPORT Human Clinical
"The most common clinical features were short stature (90.9%) and developmental delay (90.9%), followed by intellectual disability (72.7%)."
Lin et al. report short stature as the most frequent feature (90.9%) in a Chinese cohort, emphasising cross-ethnic variability in phenotype frequency.
Failure to Thrive FREQUENT HP:0001508 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Failure to thrive (HP:0001508). HP:0001508 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33783954 SUPPORT Human Clinical
"Common clinical features identified in the cohort included: developmental delay or intellectual disability (97%), constipation (63.8%), failure to thrive (67.7%), feeding difficulties (66.3%), hypertrichosis cubiti (57%), short stature (57.8%), and vertebral anomalies (46.9%)."
Failure to thrive is present in 67.7% of the n=104 Sheppard cohort.
Other 3
Elbow Hypertrichosis FREQUENT HP:0004780 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Elbow hypertrichosis (HP:0004780). HP:0004780 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:33783954 SUPPORT Human Clinical
"Common clinical features identified in the cohort included: developmental delay or intellectual disability (97%), constipation (63.8%), failure to thrive (67.7%), feeding difficulties (66.3%), hypertrichosis cubiti (57%), short stature (57.8%), and vertebral anomalies (46.9%)."
Hypertrichosis cubiti is present in 57% of the n=104 cohort, confirming it as a frequent but not invariant hallmark of WDSTS.
PMID:29574747 SUPPORT Human Clinical
"Hypertrichosis cubiti that was supposed to be pathognomonic in the literature was found only in 61% of our cases."
Baer et al. report hypertrichosis cubiti in 61% of 33 French WDSTS cases, noting it is not pathognomonic—molecular diagnosis is required.
Ophthalmologic Anomalies Abnormality of the eye HP:0000478 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormality of the eye (HP:0000478). HP:0000478 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35617449 SUPPORT Human Clinical
"Other clinical features include feeding difficulties, prenatal and postnatal growth restriction, epilepsy, ophthalmologic anomalies, congenital heart defects, hand anomalies (such as brachydactyly and clinodactyly), hypotonia, vertebral anomalies (especially fusion anomalies of the cervical..."
GeneReviews documents ophthalmologic anomalies as a recognised clinical feature of WDSTS; ophthalmologic evaluation annually is recommended.
Growth Hormone Deficiency Reduced circulating growth hormone concentration HP:0034323 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Growth hormone deficiency, annotated with Reduced circulating growth hormone concentration (HP:0034323). HP:0034323 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35617449 SUPPORT Human Clinical
"growth hormone therapy for those with growth hormone deficiency; thyroid replacement therapy for hypothyroidism"
GeneReviews explicitly recommends growth hormone therapy when growth hormone deficiency is present.
🧬

Genetic Associations

1
KMT2A
Gene: KMT2A hgnc:7132 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is KMT2A (hgnc:7132). hgnc:7132 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (3 references)
PMID:33783954 SUPPORT Human Clinical
"Sixty‐nine of the 82 variants (84%) observed in the study were not previously reported in the literature."
Sheppard et al. characterise the full KMT2A variant spectrum in n=104, showing high allelic heterogeneity with predominantly novel variants.
PMID:33783954 SUPPORT Human Clinical
"Hypotonia was associated with loss of function (LoF) variants, and seizures were associated with non‐LoF variants."
The cohort supplies the reported genotype-phenotype associations without supporting stronger variant-class claims.
PMID:29574747 SUPPORT Human Clinical
"We observed autosomal dominant transmission of WSS in 3 families and mosaicism in one family."
This series documents rare inherited disease and mosaicism.
💊

Medical Actions

12
Physical Therapy
Category: Therapeutic Action: Physical TherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Physical Therapy (NCIT:C15302). NCIT:C15302 is a clinical intervention from the NCI Thesaurus. NCIT:C15302
Early physical therapy through developmental intervention programs addresses hypotonia, motor delay, mobility, and functional skills. Evidence specific to WDSTS is limited to case-based physical-therapy literature and expert management guidance.
Target Phenotypes: Hypotonia HP:0001252 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Hypotonia (HP:0001252). HP:0001252 is a phenotype from the Human Phenotype Ontology. Global developmental delay HP:0001263 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32604375 SUPPORT Human Clinical
"The diagnosis of WSS should require physical therapy services through early intervention programs due to its high correlation with motor developmental delay and disability."
The physical-therapy report explicitly recommends early PT services for motor delay and disability.
Developmental Support
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. NCIT:C15747
Standard developmental management is recommended for developmental delay or intellectual disability. The cited guidance does not specify a syndrome-specific speech-language modality or treatment regimen.
Target Phenotypes: Global developmental delay HP:0001263 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35617449 SUPPORT Human Clinical
"standard treatment for epilepsy, developmental delay / intellectual disability"
GeneReviews directly recommends standard management for developmental delay and intellectual disability.
Occupational Therapy
Category: Therapeutic Action: occupational therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is occupational therapy (NCIT:C121351). NCIT:C121351 is a clinical intervention from the NCI Thesaurus. Ontology label: Occupational Therapy NCIT:C121351
Occupational therapy addresses fine motor delays, visuospatial difficulties, activities of daily living, and adaptive needs. The reported nonverbal/visuospatial weaknesses can inform individualized goals; direct WDSTS-specific efficacy evidence is not available.
Target Phenotypes: Global developmental delay HP:0001263 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36062544 SUPPORT Human Clinical
"The majority of patients performed in the below average to very low ranges in Nonverbal Reasoning, Visual/Spatial Perception, Visuoconstruction, Visual Memory, Attention, Working Memory and Math Computation skills."
The neuropsychological profile informs occupational-therapy targets but is not a treatment trial.
Behavioral and Psychiatric Management
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. NCIT:C15747
Behavioral therapy and standard psychiatric care are used for clinically significant behavioral, attention, autistic, anxiety, or emotion-regulation concerns. Intervention should be based on the individual's presentation; no WDSTS-specific drug regimen is established in the cited guidance.
Target Phenotypes: Atypical behavior HP:0000708 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Atypical behavior (HP:0000708). HP:0000708 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35617449 SUPPORT Human Clinical
"behavioral therapy; standard treatment for epilepsy, developmental delay / intellectual disability"
GeneReviews directly recommends behavioral therapy.
Genetic Counseling
Category: Counseling / Informational Action: Genetic CounselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Genetic Counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. NCIT:C15240
Counseling covers the typically de novo but autosomal dominant inheritance, the possibility of an affected or mosaic parent, the 50% transmission risk for an affected individual, and prenatal or preimplantation genetic testing once the familial KMT2A pathogenic variant is known.
Show evidence (2 references)
PMID:29574747 SUPPORT Human Clinical
"We observed autosomal dominant transmission of WSS in 3 families and mosaicism in one family."
Baer et al. document both familial transmission and mosaicism in French WDSTS cases, underscoring the importance of genetic counselling including parental testing.
PMID:35617449 SUPPORT Human Clinical
"Each offspring of an individual with WSS is at a 50% risk of being affected. Once the KMT2A pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible."
GeneReviews states the transmission risk and available reproductive testing options.
Growth Hormone Therapy
Category: Therapeutic Action: hormone modifying therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is hormone modifying therapy, annotated with Hormone Therapy (NCIT:C15445). NCIT:C15445 is a clinical intervention from the NCI Thesaurus. Ontology label: Hormone Therapy NCIT:C15445
Recombinant human growth hormone (rhGH) therapy has been trialled in WDSTS patients with short stature. In a Chinese cohort, two patients treated with rhGH showed satisfactory height gains, though one experienced acceleration of bone age. GeneReviews recommends treatment specifically for confirmed growth hormone deficiency; the two-person observation does not establish general efficacy for all WDSTS-associated short stature.
Target Phenotypes: Reduced circulating growth hormone concentration HP:0034323 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Reduced circulating growth hormone concentration (HP:0034323). HP:0034323 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:37025457 SUPPORT Human Clinical
"Two patients were treated with rhGH and yielded satisfactory height gains, but one developed acceleration of bone age."
Lin et al. report rhGH use in two WDSTS patients with short stature, showing benefit but also bone age acceleration as a potential adverse effect.
PMID:35617449 SUPPORT Human Clinical
"growth hormone therapy for those with growth hormone deficiency"
GeneReviews limits the recommendation to confirmed deficiency.
Anti-Seizure Pharmacotherapy
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
Epilepsy is treated according to standard neurologic practice; no WDSTS-specific antiseizure regimen is established. Valproate warrants caution because GeneReviews reports one affected individual who developed hyperammonemia, while explicitly noting that this event is not specific to WDSTS.
Target Phenotypes: Seizure HP:0001250 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:35617449 SUPPORT Human Clinical
"standard treatment for epilepsy, developmental delay / intellectual disability"
GeneReviews recommends standard epilepsy treatment rather than a syndrome-specific medication.
PMID:35617449 SUPPORT Human Clinical
"The authors are aware of one individual with WSS who developed hyperammonemia with the use of the anti-seizure medication valproate. While this is not specific to individuals with WSS, valproate should be used with caution."
GeneReviews records the single hyperammonemia observation and qualifies the resulting valproate caution.
Immunoglobulin Replacement and Infection Prophylaxis
Category: Therapeutic Action: immunomodulatory pharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is immunomodulatory pharmacotherapy, annotated with Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. Ontology label: Pharmacotherapy NCIT:C15986
For WDSTS individuals with documented low antibody levels or immune dysfunction, IVIG therapy is recommended. Prophylactic antibiotics should be considered for those with frequent infections. Immunological evaluation and infection history guide selection; these are conditional measures rather than routine treatment for every affected person.
Target Phenotypes: Recurrent infections HP:0002719 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Recurrent infections (HP:0002719). HP:0002719 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35617449 SUPPORT Human Clinical
"consideration of IVIG therapy in those with low antibody levels; consideration of prophylactic antibiotics in those with frequent infections"
GeneReviews recommends IVIG and prophylactic antibiotics as management for immune dysfunction in WDSTS.
Feeding Therapy and Nutritional Support
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. NCIT:C15747
Feeding therapy is recommended for poor weight gain or failure to thrive, with supplemental tube feeding considered when oral strategies are insufficient. The approach is individualized to nutritional status and feeding safety.
Target Phenotypes: Feeding difficulties HP:0011968 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Feeding difficulties (HP:0011968). HP:0011968 is a phenotype from the Human Phenotype Ontology. Failure to thrive HP:0001508 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Failure to thrive (HP:0001508). HP:0001508 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35617449 SUPPORT Human Clinical
"Feeding therapy with possible supplemental tube feeding for those with poor weight gain / failure to thrive"
GeneReviews directly states both the feeding-therapy recommendation and conditional tube supplementation.
Constipation Management
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
Bowel dysfunction is managed with standard measures such as stool softeners or osmotic agents, selected according to clinical assessment and response.
Target Phenotypes: Constipation HP:0002019 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Constipation (HP:0002019). HP:0002019 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35617449 SUPPORT Human Clinical
"stool softeners or osmotic agents for bowel dysfunction"
GeneReviews specifies standard pharmacologic bowel management.
Obstructive Sleep Apnea Management
Category: Therapeutic Action: Continuous Positive Airway PressureNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Continuous Positive Airway Pressure (NCIT:C124040). NCIT:C124040 is a clinical intervention from the NCI Thesaurus. NCIT:C124040
Obstructive sleep apnea may be managed with CPAP or BiPAP, or with removal of the tonsils and adenoids when clinically indicated. Choice of modality depends on airway assessment and sleep-study findings.
Target Phenotypes: Obstructive sleep apnea HP:0002870 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Obstructive sleep apnea (HP:0002870). HP:0002870 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35617449 SUPPORT Human Clinical
"CPAP, BiPAP, or surgical removal of the tonsils and adenoids for those with obstructive sleep apnea"
GeneReviews lists both noninvasive ventilation and surgical airway options.
Supportive Care and Multidisciplinary Management
Category: Monitoring 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
Surveillance should track growth, nutrition, constipation, neurologic and seizure findings, signs of medullary compression or arrhythmia, developmental progress, behavior, physical skills, and recurrent infections. GeneReviews also recommends six-monthly dental review after primary-tooth eruption and annual or clinically indicated ophthalmologic evaluation.
Show evidence (2 references)
PMID:35617449 SUPPORT Human Clinical
"Surveillance: At each visit: measurement of growth parameters; evaluation of nutritional status; assessment for constipation; evaluation for new neurologic features and seizure activity with EEG follow up as indicated"
GeneReviews specifies the recurring multisystem surveillance domains.
PMID:35617449 SUPPORT Human Clinical
"Dental evaluation every six months after the eruption of primary teeth."
GeneReviews gives a specific dental surveillance interval.
🔬

Diagnosis

2
Molecular genetic testing
WDSTS is established in an individual with suggestive findings by identifying a heterozygous pathogenic variant in KMT2A. Because the phenotype overlaps other chromatinopathies and can be mild or atypical, clinical findings alone are not sufficient to establish the molecular diagnosis.
genetic testing NCIT:C15709 NCI Thesaurus (NCIT)
Results: A heterozygous pathogenic KMT2A variant establishes the molecular diagnosis.
Show evidence (1 reference)
PMID:35617449 SUPPORT Human Clinical
"The diagnosis of WSS is established in a proband with suggestive findings and a heterozygous pathogenic variant in KMT2A identified by molecular genetic testing."
GeneReviews states the molecular diagnostic criterion.
KMT2A DNA methylation episignature analysis
A genome-wide blood DNA methylation episignature can provide functional evidence for classification of some KMT2A variants of uncertain significance or support diagnosis in clinically suggestive cases. This assay measures DNA methylation, not histone H3K4 methylation. Independent evaluation found KMT2A-signature sensitivity dependent on classifier settings and affected by heterogeneous or intermediate profiles, so a negative result does not exclude WDSTS and the assay does not replace sequence-based diagnosis.
DNA methylation analysis NCIT:C63328 NCI Thesaurus (NCIT)
Results: A concordant KMT2A episignature can support variant interpretation; an absent or intermediate signature is not exclusionary.
Show evidence (2 references)
PMID:35163737 SUPPORT Human Clinical
"WDSTS episignature enabled classification of variants of uncertain significance in the KMT2A gene as well as confirmation of diagnosis in patients with clinical presentation of WDSTS without known genetic variants."
The discovery cohort demonstrates the intended variant-classification and diagnostic-support use.
PMID:37872275 SUPPORT Human Clinical
"Remaining Cornelia de Lange syndrome, KMT2A, KDM5C and CHD7 signatures reached 70–100% sensitivity at best with unstable performances, suffering from heterogeneous methylation profiles among cases and rare discordant samples."
Independent validation supports cautious use because sensitivity was unstable despite high specificity in the study framework.
📈

Progression

1
Early development
Age: Infancy through childhood
Developmental delay is usually apparent in early childhood. In the largest published cohort, median ages at first words and independent walking were 18 and 20 months, respectively. Available summaries do not establish a uniform degenerative course or adequately define adult natural history.
Show evidence (1 reference)
PMID:33783954 SUPPORT Human Clinical
"The median ages at walking and first words were 20 months and 18 months, respectively."
The cohort provides directly observed developmental milestone timing.
📊

Prevalence

1
Worldwide
Unknown <1 in 1,000,000
A literature review estimated prevalence below one per million, but also emphasized likely underdiagnosis. This should be treated as a provisional rarity estimate rather than a measured population prevalence.
Show evidence (1 reference)
PMID:37025457 SUPPORT Human Clinical
"The prevalence of WSS is estimated to be less than 1/1,000,000"
This review supplies the reported band while cautioning that cases are probably underdiagnosed.
🔀

Differential Diagnoses

1

Conditions with similar clinical presentations that must be differentiated from Wiedemann-Steiner Syndrome:

Overlapping chromatinopathies and syndromic intellectual disability disorders
Overlapping Features The clinical differential includes Coffin-Siris, Nicolaides-Baraitser, Cornelia de Lange, Rubinstein-Taybi, Kabuki, Bohring-Opitz, Suleiman-El-Hattab, and blepharophimosis-ptosis-epicanthus inversus syndromes. Shared developmental delay, growth restriction, hypertrichosis, and craniofacial findings make phenotype alone insufficient in atypical cases.
Distinguishing Features
  • Identification of a heterozygous pathogenic KMT2A variant establishes WDSTS.
  • Hypertrichosis cubiti is frequent but is neither required nor pathognomonic.
  • A concordant KMT2A DNA methylation episignature may support ambiguous variant interpretation but is not independently exclusionary.
Show evidence (2 references)
PMID:37025457 SUPPORT Human Clinical
"the features of WSS are shared by a range of disorders"
The review explicitly frames these syndromes as overlapping clinical differentials.
PMID:35617449 SUPPORT Human Clinical
"The diagnosis of WSS is established in a proband with suggestive findings and a heterozygous pathogenic variant in KMT2A identified by molecular genetic testing."
Molecular confirmation provides the decisive distinction from overlapping syndromic diagnoses.
🧫

Experimental Models

1
WSS patient-derived cell centrosome model OTHER
Cells derived from individuals with WDSTS were used alongside MLL/WDR5 depletion systems to evaluate centrosomal protein recruitment, microtubule nucleation, spindle formation, and chromosome alignment. The cached abstract does not identify the patient-cell lineage, so the model is deliberately not assigned a more specific cell type.
Organism
human NCBITaxon:9606 NCBI Taxonomy (NCBITaxon) Relation: this experimental model is built in this organism This experimental model is built in human, annotated with Homo sapiens (NCBITaxon:9606). NCBITaxon:9606 is an organism from the NCBI Taxonomy.
Cell source
Cells derived from individuals with Wiedemann-Steiner syndrome
Publication
PMID:39661677
Pathograph links
Centrosome Dysfunction and Impaired Microtubule Nucleation The model reads out recruitment of gamma-tubulin ring-complex and structural proteins to centrosomes and subsequent microtubule nucleation.
Show evidence (1 reference)
PMID:39661677 SUPPORT In Vitro
"MLL/WDR5 promote the localization of γ-TuRCs and structural proteins like AKAP9 to the centrosome during interphase and mitosis, a phenotype also observed in cells derived from patients with WSS."
The source explicitly reports the centrosomal localization phenotype in WSS-derived cells.
Findings
Loss of MLL, WDR5, or Cep72 impairs spindle formation and produces misaligned chromosomes.
"During mitosis, loss of MLL, WDR5, and Cep72 affects spindle formation and leads to misaligned chromosomes."
Show evidence (1 reference)
PMID:39661677 SUPPORT In Vitro
"During mitosis, loss of MLL, WDR5, and Cep72 affects spindle formation and leads to misaligned chromosomes."
The abstract directly states this mitotic finding.
Show evidence (1 reference)
PMID:39661677 SUPPORT In Vitro
"MLL/WDR5 promote the localization of γ-TuRCs and structural proteins like AKAP9 to the centrosome during interphase and mitosis, a phenotype also observed in cells derived from patients with WSS."
This is the direct patient-derived-cell evidence for the centrosomal branch.
🐁

Animal Models

1
Constitutive Kmt2a heterozygous (Kmt2a+/-) male mice Mus musculus Genetic disease model
Constitutive Kmt2a-heterozygous male mice were studied as a WDSTS model in an F1 hybrid background. They showed reduced body weight, reduced dendritic spine density in basolateral amygdala neurons, and altered aggression/social dominance measures. They did not show deficits in the contextual fear or novel-object-recognition assays used in that study. Adult male brain tissue, mixed cell populations, and lifetime adaptation limit direct extrapolation to human developmental cognition.
Reduced body weight Reduced dendritic spine density Increased aggression and social dominance
Species
Mus musculus
Genotype
Constitutive Kmt2a heterozygous (Kmt2a+/-) male mice
Genes
Kmt2a MGI:96995 Mouse Genome Informatics (MGI) Relation: this experimental model concerns this gene This experimental model concerns Kmt2a (MGI:96995). MGI:96995 is a gene from Mouse Genome Informatics.
Show evidence (2 references)
PMID:32483278 SUPPORT Model Organism
"Despite opposite enzymatic activities, the two mouse models deficient for either Kmt2a or Kdm5c shared reduced dendritic spines and increased aggression."
The abstract states the central Kmt2a-heterozygous structural and behavioral phenotypes.
PMID:32483278 SUPPORT Model Organism
"Kmt2a-HET mice showed no deficits in either CFC or NOR"
This negative finding bounds the cognitive fidelity of the model.
{ }

Source YAML

click to show 
name: Wiedemann-Steiner Syndrome
creation_date: "2026-05-16T00:00:00Z"
references:
- reference: PMID:35617449
  title: "Wiedemann-Steiner Syndrome."
  tags:
  - GeneReviews
category: Mendelian
disease_term:
  preferred_term: Wiedemann-Steiner syndrome
  term:
    id: MONDO:0011518
    label: Wiedemann-Steiner syndrome
parents:
- Intellectual disability syndrome
- Mendelian neurodevelopmental disorder

synonyms:
- Wiedemann-Steiner syndrome
- WSS
- WDSTS
- KMT2A-related syndrome

description: >
  Wiedemann-Steiner syndrome (WDSTS; OMIM 605130) is an autosomal dominant
  Mendelian disorder of the epigenetic machinery caused by heterozygous
  pathogenic variants in KMT2A. It is characterized by developmental delay,
  intellectual disability, characteristic facial features, hypertrichosis
  cubiti, growth restriction, and variably present neurologic, gastrointestinal,
  skeletal, cardiac, ophthalmologic, genitourinary, immune, and dental findings.
  Most molecularly confirmed cases result from a de novo variant, although rare
  familial transmission and parental mosaicism are documented.

inheritance:
- name: Autosomal dominant inheritance
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  expressivity: VARIABLE
  description: >
    WDSTS is inherited in an autosomal dominant manner. Most affected
    individuals whose parents have undergone molecular testing have a de novo
    KMT2A pathogenic variant; rare affected parents and parental mosaicism have
    been reported. Each child of an affected individual has a 50% chance of
    inheriting the variant.
  evidence:
  - reference: PMID:35617449
    reference_title: "Wiedemann-Steiner Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most individuals diagnosed with WSS whose parents have undergone molecular genetic testing have the disorder as the result of a de novo pathogenic variant."
    explanation: >
      GeneReviews defines the autosomal dominant inheritance pattern and notes
      that most tested families represent de novo disease.
  - reference: PMID:29574747
    reference_title: "Wiedemann-Steiner syndrome as a major cause of syndromic intellectual disability: A study of 33 French cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We observed autosomal dominant transmission of WSS in 3 families and mosaicism in one family."
    explanation: >
      The French cohort documents both vertical transmission and mosaicism.

prevalence:
- population: Worldwide
  measure_type: UNKNOWN
  prevalence_class: BELOW_1_IN_1000000
  notes: >
    A literature review estimated prevalence below one per million, but also
    emphasized likely underdiagnosis. This should be treated as a provisional
    rarity estimate rather than a measured population prevalence.
  evidence:
  - reference: PMID:37025457
    reference_title: "Novel variants and phenotypic heterogeneity in a cohort of 11 Chinese children with Wiedemann-Steiner syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The prevalence of WSS is estimated to be less than 1/1,000,000"
    explanation: >
      This review supplies the reported band while cautioning that cases are
      probably underdiagnosed.

progression:
- phase: Early development
  age_range: Infancy through childhood
  notes: >
    Developmental delay is usually apparent in early childhood. In the largest
    published cohort, median ages at first words and independent walking were
    18 and 20 months, respectively. Available summaries do not establish a
    uniform degenerative course or adequately define adult natural history.
  evidence:
  - reference: PMID:33783954
    reference_title: "Expanding the genotypic and phenotypic spectrum in a diverse cohort of 104 individuals with Wiedemann-Steiner syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The median ages at walking and first words were 20 months and 18 months, respectively."
    explanation: >
      The cohort provides directly observed developmental milestone timing.

mechanistic_hypotheses:
- hypothesis_group_id: centrosomal_branch
  hypothesis_label: Centrosomal microtubule-nucleation branch
  status: EMERGING
  description: >
    Proposes that loss of a non-nuclear KMT2A/MLL-WDR5 function at centrosomes
    contributes to neurodevelopmental manifestations through impaired recruitment
    of Cep72 and gamma-tubulin ring-complex proteins. The cellular phenotype is
    reported in WSS-derived cells, but its contribution to individual clinical
    manifestations has not been quantified.
  evidence:
  - reference: PMID:39661677
    reference_title: "MLL/WDR5 complex recruits centriolar satellite protein Cep72 to regulate microtubule nucleation and spindle formation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Loss of the MLL/WDR5 complex affects microtubule nucleation and regrowth. MLL/WDR5 localize to the pericentriolar material and interact with centriolar satellite protein Cep72 and γ-tubulin ring complex proteins (γ-TuRCs)."
    explanation: >
      The study establishes the centrosomal cellular phenotype underlying this
      emerging mechanistic branch.
- hypothesis_group_id: mouse_neuronal_extrapolation
  hypothesis_label: H3K4-dependent neuronal and synaptic branch
  status: EMERGING
  description: >
    Proposes that KMT2A-dependent, locus-specific H3K4 methylation and
    transcriptional changes alter dendritic spine biology and contribute to the
    human neurodevelopmental phenotype. Evidence currently comes primarily from
    constitutive Kmt2a-heterozygous mice and therefore requires confirmation in
    human developmental neural models.
  evidence:
  - reference: PMID:32483278
    reference_title: "Mutually suppressive roles of KMT2A and KDM5C in behaviour, neuronal structure, and histone H3K4 methylation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Despite opposite enzymatic activities, the two mouse models deficient for either Kmt2a or Kdm5c shared reduced dendritic spines and increased aggression."
    explanation: >
      The Kmt2a-heterozygous mouse supplies the principal evidence for this
      neuronal branch.

pathophysiology:
- name: KMT2A Haploinsufficiency
  conforms_to: "epigenetic_machinery_neurodevelopmental_dysregulation#Epigenetic Machinery Component Haploinsufficiency"
  role: trigger
  mechanism_confidence: ESTABLISHED
  description: >
    The initiating lesion is reduced KMT2A function from a heterozygous
    pathogenic variant. KMT2A encodes an H3K4 methyltransferase, but the clinical
    allelic spectrum is not limited to experimentally proven loss-of-function
    variants; the causal statement is therefore kept at the gene-disease level.
  gene:
    preferred_term: KMT2A
    term:
      id: hgnc:7132
      label: KMT2A
  molecular_functions:
  - preferred_term: histone H3K4 methyltransferase activity
    term:
      id: GO:0042800
      label: histone H3K4 methyltransferase activity
    modifier: DECREASED
  evidence:
  - reference: PMID:33783954
    reference_title: "Expanding the genotypic and phenotypic spectrum in a diverse cohort of 104 individuals with Wiedemann-Steiner syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Wiedemann‐Steiner syndrome (WSS) is an autosomal dominant disorder caused by monoallelic variants in KMT2A and characterized by intellectual disability and hypertrichosis."
    explanation: >
      The 104-person cohort confirms monoallelic KMT2A variants as causal.
  - reference: PMID:39661677
    reference_title: "MLL/WDR5 complex recruits centriolar satellite protein Cep72 to regulate microtubule nucleation and spindle formation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Haploinsufficiency of mixed-lineage leukemia (MLL/KMT2A) protein causes Wiedemann-Steiner syndrome (WSS), a neurodevelopmental disorder associated with microcephaly."
    explanation: >
      The mechanistic study identifies KMT2A haploinsufficiency as the upstream
      disease lesion.
  downstream:
  - target: Altered H3K4 Methylation and Transcriptional Regulation
    causal_link_type: DIRECT
    description: >
      Reduced activity of the H3K4 writer KMT2A can alter H3K4 methylation and
      transcription at selected loci; available mouse data do not show a simple
      global reduction in H3K4 methylation.
    hypothesis_groups:
    - mouse_neuronal_extrapolation
    evidence:
    - reference: PMID:32483278
      reference_title: "Mutually suppressive roles of KMT2A and KDM5C in behaviour, neuronal structure, and histone H3K4 methylation."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Here, we show functional interactions of a writer-eraser duo, KMT2A and KDM5C, which are responsible for Wiedemann-Steiner Syndrome (WDSTS), and mental retardation X-linked syndromic Claes-Jensen type (MRXSCJ), respectively."
      explanation: >
        This mouse study supports an H3K4 writer/eraser relationship, but not
        a uniform global methylation-loss model in human disease.
  - target: Centrosome Dysfunction and Impaired Microtubule Nucleation
    causal_link_type: DIRECT
    hypothesis_groups:
    - centrosomal_branch
    evidence:
    - reference: PMID:39661677
      reference_title: "MLL/WDR5 complex recruits centriolar satellite protein Cep72 to regulate microtubule nucleation and spindle formation."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Loss of the MLL/WDR5 complex affects microtubule nucleation and regrowth."
      explanation: >
        Direct depletion experiments link loss of the MLL/WDR5 complex to
        defective microtubule nucleation.
  - target: Characteristic Facial Features
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:35617449
      reference_title: "Wiedemann-Steiner Syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Wiedemann-Steiner syndrome (WSS) is characterized by developmental delay, intellectual disability, and characteristic facial features, with or without additional congenital anomalies."
      explanation: >
        Characteristic facial features are part of molecularly defined WDSTS;
        the intervening developmental pathway is not established.
  - target: Muscular Hypotonia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:33783954
      reference_title: "Expanding the genotypic and phenotypic spectrum in a diverse cohort of 104 individuals with Wiedemann-Steiner syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Hypotonia was associated with loss of function (LoF) variants, and seizures were associated with non‐LoF variants."
      explanation: >
        The genotype-phenotype association supports the clinical endpoint,
        while the causal intermediates remain unknown.
  - target: Short Stature
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:33783954
      reference_title: "Expanding the genotypic and phenotypic spectrum in a diverse cohort of 104 individuals with Wiedemann-Steiner syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Common clinical features identified in the cohort included: developmental delay or intellectual disability (97%), constipation (63.8%), failure to thrive (67.7%), feeding difficulties (66.3%), hypertrichosis cubiti (57%), short stature (57.8%), and vertebral anomalies (46.9%)."
      explanation: >
        The KMT2A cohort establishes short stature as a common clinical
        endpoint; the intervening growth mechanism is unresolved.
  - target: Elbow Hypertrichosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:33783954
      reference_title: "Expanding the genotypic and phenotypic spectrum in a diverse cohort of 104 individuals with Wiedemann-Steiner syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Common clinical features identified in the cohort included: developmental delay or intellectual disability (97%), constipation (63.8%), failure to thrive (67.7%), feeding difficulties (66.3%), hypertrichosis cubiti (57%), short stature (57.8%), and vertebral anomalies (46.9%)."
      explanation: >
        The KMT2A cohort establishes hypertrichosis cubiti as a clinical
        endpoint without resolving its developmental mechanism.
  - target: Feeding Difficulties
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:33783954
      reference_title: "Expanding the genotypic and phenotypic spectrum in a diverse cohort of 104 individuals with Wiedemann-Steiner syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Common clinical features identified in the cohort included: developmental delay or intellectual disability (97%), constipation (63.8%), failure to thrive (67.7%), feeding difficulties (66.3%), hypertrichosis cubiti (57%), short stature (57.8%), and vertebral anomalies (46.9%)."
      explanation: >
        Feeding difficulty is a common endpoint in the KMT2A cohort, with
        unknown mechanistic intermediates.
  - target: Failure to Thrive
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:33783954
      reference_title: "Expanding the genotypic and phenotypic spectrum in a diverse cohort of 104 individuals with Wiedemann-Steiner syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Common clinical features identified in the cohort included: developmental delay or intellectual disability (97%), constipation (63.8%), failure to thrive (67.7%), feeding difficulties (66.3%), hypertrichosis cubiti (57%), short stature (57.8%), and vertebral anomalies (46.9%)."
      explanation: >
        Failure to thrive is a common endpoint in the KMT2A cohort, with
        unknown mechanistic intermediates.
  - target: Constipation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:33783954
      reference_title: "Expanding the genotypic and phenotypic spectrum in a diverse cohort of 104 individuals with Wiedemann-Steiner syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Common clinical features identified in the cohort included: developmental delay or intellectual disability (97%), constipation (63.8%), failure to thrive (67.7%), feeding difficulties (66.3%), hypertrichosis cubiti (57%), short stature (57.8%), and vertebral anomalies (46.9%)."
      explanation: >
        Constipation is a common endpoint in the KMT2A cohort, with unknown
        mechanistic intermediates.
  - target: Vertebral Anomalies
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:33783954
      reference_title: "Expanding the genotypic and phenotypic spectrum in a diverse cohort of 104 individuals with Wiedemann-Steiner syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Common clinical features identified in the cohort included: developmental delay or intellectual disability (97%), constipation (63.8%), failure to thrive (67.7%), feeding difficulties (66.3%), hypertrichosis cubiti (57%), short stature (57.8%), and vertebral anomalies (46.9%)."
      explanation: >
        Vertebral anomalies are a common endpoint in the KMT2A cohort, with
        unknown developmental intermediates.
  - target: Scoliosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:35617449
      reference_title: "Wiedemann-Steiner Syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Vertebral anomalies or scoliosis in the thoracic or lumbar spine may complicate spinal or epidural anesthesia."
      explanation: >
        GeneReviews recognizes scoliosis in WDSTS, while its mechanistic
        relationship to KMT2A dosage is unresolved.
  - target: Seizures
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:33783954
      reference_title: "Expanding the genotypic and phenotypic spectrum in a diverse cohort of 104 individuals with Wiedemann-Steiner syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Hypotonia was associated with loss of function (LoF) variants, and seizures were associated with non‐LoF variants."
      explanation: >
        The genotype-phenotype association supports the seizure endpoint;
        intervening mechanisms are unknown.
  - target: Cardiac Anomalies
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:35617449
      reference_title: "Wiedemann-Steiner Syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "ophthalmologic anomalies, congenital heart defects, hand anomalies"
      explanation: >
        GeneReviews recognizes congenital heart defects in WDSTS, without a
        resolved KMT2A-to-cardiac developmental pathway.
  - target: Abnormal Corpus Callosum Morphology
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:37025457
      reference_title: "Novel variants and phenotypic heterogeneity in a cohort of 11 Chinese children with Wiedemann-Steiner syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The most frequent imaging features were patent ductus arteriosus (57.1%) and patent foramen ovale (42.9%) in cardiovascular system, and abnormal corpus callosum (50.0%) in the brain."
      explanation: >
        A molecularly diagnosed cohort establishes the imaging endpoint, but
        not its intervening mechanism.
  - target: Ophthalmologic Anomalies
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:35617449
      reference_title: "Wiedemann-Steiner Syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Other clinical features include feeding difficulties, prenatal and postnatal growth restriction, epilepsy, ophthalmologic anomalies, congenital heart defects"
      explanation: >
        GeneReviews recognizes ophthalmologic anomalies in WDSTS; the
        intervening developmental pathway is unresolved.
  - target: Obstructive Sleep Apnea
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:35617449
      reference_title: "Wiedemann-Steiner Syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "CPAP, BiPAP, or surgical removal of the tonsils and adenoids for those with obstructive sleep apnea"
      explanation: >
        GeneReviews recognizes obstructive sleep apnea as a managed WDSTS
        manifestation, without defining its causal pathway.
  - target: Immune Dysfunction and Recurrent Infections
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:35617449
      reference_title: "Wiedemann-Steiner Syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "renal and uterine anomalies, immune dysfunction, brain malformations, and dental anomalies."
      explanation: >
        GeneReviews recognizes immune dysfunction as part of WDSTS; the
        downstream mechanism remains unknown.
  - target: Genitourinary Anomalies
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:35617449
      reference_title: "Wiedemann-Steiner Syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "renal and uterine anomalies, immune dysfunction, brain malformations, and dental anomalies."
      explanation: >
        GeneReviews recognizes renal and uterine anomalies as WDSTS
        manifestations, without defining their developmental pathway.
  - target: Brachydactyly
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:35617449
      reference_title: "Wiedemann-Steiner Syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "hand anomalies (such as brachydactyly and clinodactyly)"
      explanation: >
        GeneReviews recognizes brachydactyly in WDSTS; the causal
        developmental intermediates remain unknown.
  - target: Dental Anomalies
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:35617449
      reference_title: "Wiedemann-Steiner Syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "brain malformations, and dental anomalies."
      explanation: >
        GeneReviews recognizes dental anomalies in WDSTS, while their
        molecular-developmental pathway is unresolved.
  - target: Growth Hormone Deficiency
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:35617449
      reference_title: "Wiedemann-Steiner Syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "growth hormone therapy for those with growth hormone deficiency"
      explanation: >
        GeneReviews recognizes growth hormone deficiency as a treatable WDSTS
        manifestation; its causal intermediates are not established.

- name: Altered H3K4 Methylation and Transcriptional Regulation
  conforms_to: "epigenetic_machinery_neurodevelopmental_dysregulation#Dysregulated Neurodevelopmental Transcriptional Program"
  mechanism_confidence: PROVISIONAL
  description: >
    KMT2A is an H3K4 methylation writer and transcriptional coactivator. In adult
    Kmt2a-heterozygous mouse brain, transcriptional changes and weak
    locus-specific H3K4me3 differences were detected, while global H3K4me1-3
    levels were not dramatically altered. This supports locus- and
    cell-context-dependent dysregulation rather than a proven global histone
    methylation loss.
    The genome-wide DNA methylation episignature used diagnostically is a distinct
    measurement and is not evidence of reduced histone H3K4 methylation.
  biological_processes:
  - preferred_term: chromatin organization
    term:
      id: GO:0006325
      label: chromatin organization
    modifier: ABNORMAL
  - preferred_term: regulation of DNA-templated transcription
    term:
      id: GO:0006355
      label: regulation of DNA-templated transcription
    modifier: ABNORMAL
  - preferred_term: epigenetic regulation of gene expression
    term:
      id: GO:0040029
      label: epigenetic regulation of gene expression
    modifier: ABNORMAL
  evidence:
  - reference: PMID:32483278
    reference_title: "Mutually suppressive roles of KMT2A and KDM5C in behaviour, neuronal structure, and histone H3K4 methylation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "In western blot analyses, global H3K4me1–3 levels were not altered dramatically in any mutant"
    explanation: >
      This negative result prevents overinterpreting KMT2A haploinsufficiency as
      a global H3K4 methylation deficiency.
  - reference: PMID:32483278
    reference_title: "Mutually suppressive roles of KMT2A and KDM5C in behaviour, neuronal structure, and histone H3K4 methylation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "By relaxing the threshold, we obtained weak 2A-HET DMRs"
    explanation: >
      The reported Kmt2a-heterozygous H3K4me3 changes were weak and
      locus-specific, supporting the deliberately qualified node.
  downstream:
  - target: Reduced Dendritic Spine Density and Neuronal Dysregulation
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    hypothesis_groups:
    - mouse_neuronal_extrapolation
    evidence:
    - reference: PMID:32483278
      reference_title: "Mutually suppressive roles of KMT2A and KDM5C in behaviour, neuronal structure, and histone H3K4 methylation."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Double mutation of Kmt2a and Kdm5c clearly reversed dendritic morphology, key behavioral traits including aggression, and partially corrected altered transcriptomes and H3K4me landscapes."
      explanation: >
        Genetic interaction connects H3K4/transcriptomic changes with
        dendritic morphology and behavior in the mouse model.

- name: Centrosome Dysfunction and Impaired Microtubule Nucleation
  mechanism_confidence: PROVISIONAL
  description: >
    The MLL/WDR5 complex localizes to pericentriolar material, interacts with
    Cep72 and gamma-tubulin ring-complex proteins, and promotes centrosomal
    recruitment of structural proteins. Loss of MLL/WDR5 impairs microtubule
    nucleation and spindle formation; a related localization phenotype was also
    observed in cells derived from people with WSS. How much this branch
    contributes to the human neurodevelopmental phenotype remains uncertain.
  biological_processes:
  - preferred_term: microtubule nucleation
    term:
      id: GO:0007020
      label: microtubule nucleation
    modifier: ABNORMAL
  - preferred_term: mitotic spindle organization
    term:
      id: GO:0007052
      label: mitotic spindle organization
    modifier: ABNORMAL
  evidence:
  - reference: PMID:39661677
    reference_title: "MLL/WDR5 complex recruits centriolar satellite protein Cep72 to regulate microtubule nucleation and spindle formation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Loss of the MLL/WDR5 complex affects microtubule nucleation and regrowth. MLL/WDR5 localize to the pericentriolar material and interact with centriolar satellite protein Cep72 and γ-tubulin ring complex proteins (γ-TuRCs)."
    explanation: >
      The study demonstrates a non-nuclear MLL/WDR5-Cep72 centrosomal function
      and reports the phenotype in WSS-derived cells.
  downstream:
  - target: Global Developmental Delay
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - centrosomal_branch
    evidence:
    - reference: PMID:39661677
      reference_title: "MLL/WDR5 complex recruits centriolar satellite protein Cep72 to regulate microtubule nucleation and spindle formation."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Our studies provide insight into an undiscovered role of MLL at the centrosome"
      explanation: >
        The study supports the cellular branch, but does not establish its
        quantitative contribution to developmental delay; the clinical edge
        is therefore indirect and partial.

- name: Reduced Dendritic Spine Density and Neuronal Dysregulation
  conforms_to: "epigenetic_machinery_neurodevelopmental_dysregulation#Impaired Neuronal Maturation, Plasticity, and Postnatal Neurogenesis"
  mechanism_confidence: PROVISIONAL
  description: >
    Constitutive Kmt2a-heterozygous mice show reduced dendritic spine density and
    increased aggression. Combining Kmt2a heterozygosity with Kdm5c deficiency
    reversed dendritic morphology and key behavioral traits and partially
    corrected transcriptomic and H3K4me changes. These observations support a
    neuronal branch but have not yet been confirmed in human developmental
    neurons.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: dendritic spine development
    term:
      id: GO:0060996
      label: dendritic spine development
    modifier: ABNORMAL
  evidence:
  - reference: PMID:32483278
    reference_title: "Mutually suppressive roles of KMT2A and KDM5C in behaviour, neuronal structure, and histone H3K4 methylation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Despite opposite enzymatic activities, the two mouse models deficient for either Kmt2a or Kdm5c shared reduced dendritic spines and increased aggression. Double mutation of Kmt2a and Kdm5c clearly reversed dendritic morphology, key behavioral traits including aggression, and partially corrected altered transcriptomes and H3K4me landscapes."
    explanation: >
      The study links Kmt2a deficiency to dendritic and behavioral changes in a
      mouse model, while its human translational relevance remains unproven.
  downstream:
  - target: Global Developmental Delay
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - mouse_neuronal_extrapolation
    evidence:
    - reference: PMID:32483278
      reference_title: "Mutually suppressive roles of KMT2A and KDM5C in behaviour, neuronal structure, and histone H3K4 methylation."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Despite opposite enzymatic activities, the two mouse models deficient for either Kmt2a or Kdm5c shared reduced dendritic spines and increased aggression."
      explanation: >
        Mouse neuronal morphology is relevant but does not directly establish
        the human developmental-delay endpoint.
  - target: Intellectual Disability
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - mouse_neuronal_extrapolation
    evidence:
    - reference: PMID:32483278
      reference_title: "Mutually suppressive roles of KMT2A and KDM5C in behaviour, neuronal structure, and histone H3K4 methylation."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Despite opposite enzymatic activities, the two mouse models deficient for either Kmt2a or Kdm5c shared reduced dendritic spines and increased aggression."
      explanation: >
        The model supplies a plausible neuronal bridge, not direct human
        proof of intellectual disability causation.
  - target: Behavioral Abnormalities
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - mouse_neuronal_extrapolation
    evidence:
    - reference: PMID:32483278
      reference_title: "Mutually suppressive roles of KMT2A and KDM5C in behaviour, neuronal structure, and histone H3K4 methylation."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Despite opposite enzymatic activities, the two mouse models deficient for either Kmt2a or Kdm5c shared reduced dendritic spines and increased aggression."
      explanation: >
        Increased aggression in mice provides model-organism support for a
        behavioral link but is not equivalent to the heterogeneous human
        behavioral phenotype.

phenotypes:
- name: Characteristic Facial Features
  description: >
    Characteristic facial features are a defining part of the WDSTS phenotype.
    Reported features include thick eyebrows with lateral flare, vertically
    narrow downslanting palpebral fissures, widely spaced eyes, a wide nasal
    bridge, broad nasal tip, thin upper-lip vermilion, and thick scalp hair.
  category: Craniofacial
  phenotype_term:
    preferred_term: Abnormal facial shape
    term:
      id: HP:0001999
      label: Abnormal facial shape
  evidence:
  - reference: PMID:35617449
    reference_title: "Wiedemann-Steiner Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Wiedemann-Steiner syndrome (WSS) is characterized by developmental delay, intellectual disability, and characteristic facial features, with or without additional congenital anomalies."
    explanation: >
      GeneReviews identifies characteristic facial features as one of the core
      clinical findings.

- name: Global Developmental Delay
  description: >
    Developmental delay was reported in 90% of affected children in a
    physical-therapy review, while developmental delay or intellectual
    disability combined was reported in 97% of the largest cohort. Median ages
    at first words and independent walking were 18 and 20 months, respectively,
    demonstrating delays across communication and motor milestones.
  category: Neurological
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:32604375
    reference_title: "Physical Therapy Management of Wiedemann-Steiner Syndrome From Birth to 3 Years."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Fifty-seven percent of children diagnosed with WSS have hypotonia, and 90% have developmental delay."
    explanation: >
      The review's developmental-delay estimate directly supports the
      very-frequent frequency band.
  - reference: PMID:33783954
    reference_title: "Expanding the genotypic and phenotypic spectrum in a diverse cohort of 104 individuals with Wiedemann-Steiner syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Common clinical features identified in the cohort included: developmental delay or intellectual disability (97%), constipation (63.8%), failure to thrive (67.7%), feeding difficulties (66.3%), hypertrichosis cubiti (57%), short stature (57.8%), and vertebral anomalies (46.9%)."
    explanation: >
      The Sheppard et al. n=104 multi-centre cohort provides the most robust
      frequency estimate (97%) for developmental delay/intellectual disability
      in WDSTS.
  - reference: PMID:33783954
    reference_title: "Expanding the genotypic and phenotypic spectrum in a diverse cohort of 104 individuals with Wiedemann-Steiner syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The median ages at walking and first words were 20 months and 18 months, respectively."
    explanation: >
      The same cohort quantifies delayed motor and speech milestones.

- name: Intellectual Disability
  description: >
    Intellectual disability is a core feature of WDSTS, although severity is
    variable. In a neuropsychological series of ten molecularly confirmed
    children, nonverbal reasoning, visuospatial skills, visual memory, attention,
    working memory, and mathematics were often weaker than receptive vocabulary,
    verbal memory, and word reading.
  category: Neurological
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:36062544
    reference_title: "Individuals with Wiedemann-Steiner syndrome show nonverbal reasoning and visuospatial defects with relative verbal skill sparing."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The majority of patients performed in the below average to very low ranges in Nonverbal Reasoning, Visual/Spatial Perception, Visuoconstruction, Visual Memory, Attention, Working Memory and Math Computation skills. In contrast, over half the sample performed within normal limits on Receptive Vocabulary, Verbal Memory, and Word Reading."
    explanation: >
      Ng et al. characterise the specific neurocognitive profile of WSS in 10
      patients; the small sample supports a profile description but not a
      population-wide severity distribution.
  - reference: PMID:35617449
    reference_title: "Wiedemann-Steiner Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Wiedemann-Steiner syndrome (WSS) is characterized by developmental delay, intellectual disability, and characteristic facial features, with or without additional congenital anomalies."
    explanation: >
      GeneReviews identifies intellectual disability as a core clinical feature.

- name: Muscular Hypotonia
  description: >
    Hypotonia was reported in 57% of affected children in a physical-therapy
    review and was associated with loss-of-function KMT2A variants in the
    104-person cohort. It commonly accompanies motor developmental delay.
  category: Neurological
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:32604375
    reference_title: "Physical Therapy Management of Wiedemann-Steiner Syndrome From Birth to 3 Years."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Fifty-seven percent of children diagnosed with WSS have hypotonia, and 90% have developmental delay. The diagnosis of WSS should require physical therapy services through early intervention programs due to its high correlation with motor developmental delay and disability."
    explanation: >
      Mendoza 2020 reports a 57% frequency estimate and connects hypotonia with
      the need for early motor intervention.
  - reference: PMID:33783954
    reference_title: "Expanding the genotypic and phenotypic spectrum in a diverse cohort of 104 individuals with Wiedemann-Steiner syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hypotonia was associated with loss of function (LoF) variants, and seizures were associated with non‐LoF variants."
    explanation: >
      Sheppard et al. identify a genotype-phenotype correlation: hypotonia is
      specifically associated with loss-of-function KMT2A variants.

- name: Short Stature
  description: >
    Short stature was reported in 57.8% of the 104-person international cohort
    and in 90.9% of a smaller cohort of 11 Chinese children. The difference
    illustrates ascertainment and cohort variability rather than an established
    population range.
  category: Growth
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: PMID:33783954
    reference_title: "Expanding the genotypic and phenotypic spectrum in a diverse cohort of 104 individuals with Wiedemann-Steiner syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Common clinical features identified in the cohort included: developmental delay or intellectual disability (97%), constipation (63.8%), failure to thrive (67.7%), feeding difficulties (66.3%), hypertrichosis cubiti (57%), short stature (57.8%), and vertebral anomalies (46.9%)."
    explanation: >
      Short stature is present in 57.8% of the Sheppard multi-centre cohort
      of 104 individuals.
  - reference: PMID:37025457
    reference_title: "Novel variants and phenotypic heterogeneity in a cohort of 11 Chinese children with Wiedemann-Steiner syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most common clinical features were short stature (90.9%) and developmental delay (90.9%), followed by intellectual disability (72.7%)."
    explanation: >
      Lin et al. report short stature as the most frequent feature (90.9%) in
      a Chinese cohort, emphasising cross-ethnic variability in phenotype frequency.

- name: Elbow Hypertrichosis
  description: >
    Hypertrichosis, particularly involving the elbows (hypertrichosis cubiti), is
    a hallmark feature of WDSTS, reported in 57% of the 104-person cohort and 61%
    of a 33-person French cohort. It is therefore frequent but neither invariant
    nor sufficient for diagnosis; hypertrichosis of other body regions may also
    occur.
  category: Integument
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Elbow hypertrichosis
    term:
      id: HP:0004780
      label: Elbow hypertrichosis
  evidence:
  - reference: PMID:33783954
    reference_title: "Expanding the genotypic and phenotypic spectrum in a diverse cohort of 104 individuals with Wiedemann-Steiner syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Common clinical features identified in the cohort included: developmental delay or intellectual disability (97%), constipation (63.8%), failure to thrive (67.7%), feeding difficulties (66.3%), hypertrichosis cubiti (57%), short stature (57.8%), and vertebral anomalies (46.9%)."
    explanation: >
      Hypertrichosis cubiti is present in 57% of the n=104 cohort, confirming
      it as a frequent but not invariant hallmark of WDSTS.
  - reference: PMID:29574747
    reference_title: "Wiedemann-Steiner syndrome as a major cause of syndromic intellectual disability: A study of 33 French cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hypertrichosis cubiti that was supposed to be pathognomonic in the literature was found only in 61% of our cases."
    explanation: >
      Baer et al. report hypertrichosis cubiti in 61% of 33 French WDSTS cases,
      noting it is not pathognomonic—molecular diagnosis is required.

- name: Feeding Difficulties
  description: >
    Feeding difficulties were reported in 66.3% of the 104-person cohort and can
    accompany poor weight gain or failure to thrive. GeneReviews recommends
    feeding therapy and, when needed, supplemental tube feeding.
  category: Gastrointestinal
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
  evidence:
  - reference: PMID:33783954
    reference_title: "Expanding the genotypic and phenotypic spectrum in a diverse cohort of 104 individuals with Wiedemann-Steiner syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Common clinical features identified in the cohort included: developmental delay or intellectual disability (97%), constipation (63.8%), failure to thrive (67.7%), feeding difficulties (66.3%), hypertrichosis cubiti (57%), short stature (57.8%), and vertebral anomalies (46.9%)."
    explanation: >
      Feeding difficulties are present in 66.3% of the n=104 cohort, making
      it one of the most frequent gastrointestinal features of WDSTS.
  - reference: PMID:35617449
    reference_title: "Wiedemann-Steiner Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Feeding therapy with possible supplemental tube feeding for those with poor weight gain / failure to thrive"
    explanation: >
      GeneReviews directly supports feeding therapy and selective tube feeding
      when poor growth persists.

- name: Failure to Thrive
  description: >
    Failure to thrive was reported in 67.7% of the 104-person cohort and is a
    common clinical management concern, particularly when feeding difficulties
    and poor weight gain occur together.
  category: Growth
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  evidence:
  - reference: PMID:33783954
    reference_title: "Expanding the genotypic and phenotypic spectrum in a diverse cohort of 104 individuals with Wiedemann-Steiner syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Common clinical features identified in the cohort included: developmental delay or intellectual disability (97%), constipation (63.8%), failure to thrive (67.7%), feeding difficulties (66.3%), hypertrichosis cubiti (57%), short stature (57.8%), and vertebral anomalies (46.9%)."
    explanation: >
      Failure to thrive is present in 67.7% of the n=104 Sheppard cohort.

- name: Constipation
  description: >
    Constipation was reported in 63.8% of the 104-person cohort. GeneReviews
    recommends assessment at clinical visits and standard bowel management when
    present; a syndrome-specific cause has not been established.
  category: Gastrointestinal
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Constipation
    term:
      id: HP:0002019
      label: Constipation
  evidence:
  - reference: PMID:33783954
    reference_title: "Expanding the genotypic and phenotypic spectrum in a diverse cohort of 104 individuals with Wiedemann-Steiner syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Common clinical features identified in the cohort included: developmental delay or intellectual disability (97%), constipation (63.8%), failure to thrive (67.7%), feeding difficulties (66.3%), hypertrichosis cubiti (57%), short stature (57.8%), and vertebral anomalies (46.9%)."
    explanation: >
      Constipation is present in 63.8% of the n=104 cohort, making it the
      most common gastrointestinal comorbidity in WDSTS after feeding difficulties.
  - reference: PMID:35617449
    reference_title: "Wiedemann-Steiner Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At each visit: measurement of growth parameters; evaluation of nutritional status; assessment for constipation"
    explanation: >
      GeneReviews includes constipation assessment in routine surveillance.

- name: Behavioral Abnormalities
  description: >
    Behavioral and executive-function differences occur in WDSTS. In a
    neuropsychological series of ten children, most caregivers reported executive
    difficulties, particularly emotion regulation. The small series does not
    establish a population frequency or a uniform behavioral profile.
  category: Psychiatric
  phenotype_term:
    preferred_term: Atypical behavior
    term:
      id: HP:0000708
      label: Atypical behavior
  evidence:
  - reference: PMID:36062544
    reference_title: "Individuals with Wiedemann-Steiner syndrome show nonverbal reasoning and visuospatial defects with relative verbal skill sparing."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most caregivers reported deficits in executive functioning, most notably in emotion regulation."
    explanation: >
      Ng et al. identify executive function and emotion regulation deficits as
      a characteristic behavioural feature of WDSTS in a neuropsychological
      case series of 10 patients.

- name: Vertebral Anomalies
  description: >
    Vertebral anomalies were reported in 46.9% of the 104-person cohort, with
    fusion anomalies of the cervical spine specifically recognized in GeneReviews.
    Cervical and thoracolumbar abnormalities can have implications for airway,
    spinal, or epidural anesthesia planning.
  category: Musculoskeletal
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Abnormality of the vertebral column
    term:
      id: HP:0000925
      label: Abnormality of the vertebral column
  evidence:
  - reference: PMID:33783954
    reference_title: "Expanding the genotypic and phenotypic spectrum in a diverse cohort of 104 individuals with Wiedemann-Steiner syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Common clinical features identified in the cohort included: developmental delay or intellectual disability (97%), constipation (63.8%), failure to thrive (67.7%), feeding difficulties (66.3%), hypertrichosis cubiti (57%), short stature (57.8%), and vertebral anomalies (46.9%)."
    explanation: >
      Vertebral anomalies are among the most common structural comorbidities
      in WDSTS, present in 46.9% of the n=104 multi-centre cohort.
  - reference: PMID:35617449
    reference_title: "Wiedemann-Steiner Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cervical spine anomalies may lead to immobility or instability, which may complicate airway management. Vertebral anomalies or scoliosis in the thoracic or lumbar spine may complicate spinal or epidural anesthesia."
    explanation: >
      GeneReviews states the anesthesia implications of cervical and
      thoracolumbar vertebral disease.

- name: Scoliosis
  description: >
    Scoliosis is a recognized musculoskeletal manifestation of WDSTS. It can
    coexist with other vertebral anomalies and may complicate spinal or epidural
    anesthesia; the cited summary does not provide a reliable population
    frequency.
  category: Musculoskeletal
  phenotype_term:
    preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  evidence:
  - reference: PMID:35617449
    reference_title: "Wiedemann-Steiner Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Vertebral anomalies or scoliosis in the thoracic or lumbar spine may complicate spinal or epidural anesthesia."
    explanation: >
      GeneReviews explicitly documents scoliosis and thoracolumbar vertebral
      anomalies as clinically significant features in WDSTS, with anesthesia
      implications.

- name: Seizures
  description: >
    Epilepsy is a recognized but variably present feature of WDSTS. In the
    104-person cohort, seizures were associated with non-loss-of-function KMT2A
    variants. The cited abstract does not provide a population frequency.
  category: Neurological
  phenotype_term:
    preferred_term: Seizures
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:33783954
    reference_title: "Expanding the genotypic and phenotypic spectrum in a diverse cohort of 104 individuals with Wiedemann-Steiner syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hypotonia was associated with loss of function (LoF) variants, and seizures were associated with non‐LoF variants."
    explanation: >
      Sheppard et al. report an association between seizures and non-LoF KMT2A
      variants without quantifying it in the abstract.
  - reference: PMID:35617449
    reference_title: "Wiedemann-Steiner Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Other clinical features include feeding difficulties, prenatal and postnatal growth restriction, epilepsy, ophthalmologic anomalies, congenital heart defects"
    explanation: >
      GeneReviews includes epilepsy among the recognized clinical features.

- name: Cardiac Anomalies
  description: >
    Congenital heart defects are part of the WDSTS spectrum. In a cohort of 11
    Chinese children, the most frequent cardiovascular imaging findings among
    those evaluated were patent ductus arteriosus (57.1%) and patent foramen
    ovale (42.9%); these cohort-specific figures should not be generalized.
  category: Cardiovascular
  phenotype_term:
    preferred_term: Congenital cardiac anomaly
    term:
      id: HP:0001627
      label: Abnormal heart morphology
  evidence:
  - reference: PMID:37025457
    reference_title: "Novel variants and phenotypic heterogeneity in a cohort of 11 Chinese children with Wiedemann-Steiner syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most frequent imaging features were patent ductus arteriosus (57.1%) and patent foramen ovale (42.9%) in cardiovascular system, and abnormal corpus callosum (50.0%) in the brain."
    explanation: >
      Lin et al. quantify PDA and PFO within a small Chinese imaging cohort.
  - reference: PMID:35617449
    reference_title: "Wiedemann-Steiner Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ophthalmologic anomalies, congenital heart defects, hand anomalies"
    explanation: >
      GeneReviews confirms congenital heart defects as part of the clinical
      spectrum.

- name: Abnormal Corpus Callosum Morphology
  description: >
    Brain malformations are part of the WDSTS spectrum. Abnormal corpus callosum
    morphology was reported in 50% of the imaged subset of a small Chinese
    cohort; this figure is cohort-specific and its relationship to cognitive
    outcomes has not been established.
  category: Neurological
  phenotype_term:
    preferred_term: Abnormal corpus callosum morphology
    term:
      id: HP:0001273
      label: Abnormal corpus callosum morphology
  evidence:
  - reference: PMID:37025457
    reference_title: "Novel variants and phenotypic heterogeneity in a cohort of 11 Chinese children with Wiedemann-Steiner syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most frequent imaging features were patent ductus arteriosus (57.1%) and patent foramen ovale (42.9%) in cardiovascular system, and abnormal corpus callosum (50.0%) in the brain."
    explanation: >
      Lin et al. report abnormal corpus callosum morphology in the imaging
      subset of their 11-person Chinese cohort.

- name: Ophthalmologic Anomalies
  description: >
    Ophthalmologic anomalies are recognized in WDSTS. GeneReviews recommends
    standard management of eye anomalies and periodic ophthalmologic assessment,
    but the cited summary does not define the distribution or population
    frequency of specific eye findings.
  category: Ophthalmological
  phenotype_term:
    preferred_term: Abnormality of the eye
    term:
      id: HP:0000478
      label: Abnormality of the eye
  evidence:
  - reference: PMID:35617449
    reference_title: "Wiedemann-Steiner Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Other clinical features include feeding difficulties, prenatal and postnatal growth restriction, epilepsy, ophthalmologic anomalies, congenital heart defects, hand anomalies (such as brachydactyly and clinodactyly), hypotonia, vertebral anomalies (especially fusion anomalies of the cervical spine), renal and uterine anomalies, immune dysfunction, brain malformations, and dental anomalies."
    explanation: >
      GeneReviews documents ophthalmologic anomalies as a recognised clinical
      feature of WDSTS; ophthalmologic evaluation annually is recommended.

- name: Obstructive Sleep Apnea
  description: >
    Obstructive sleep apnea is a recognized treatable manifestation in WDSTS.
    GeneReviews lists CPAP, BiPAP, and surgical removal of the tonsils and
    adenoids as management options; the cited summary does not establish its
    frequency or a syndrome-specific cause.
  category: Respiratory
  phenotype_term:
    preferred_term: Obstructive sleep apnea
    term:
      id: HP:0002870
      label: Obstructive sleep apnea
  evidence:
  - reference: PMID:35617449
    reference_title: "Wiedemann-Steiner Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CPAP, BiPAP, or surgical removal of the tonsils and adenoids for those with obstructive sleep apnea"
    explanation: >
      GeneReviews includes CPAP/BiPAP and surgical adenotonsillectomy as
      management for OSA in WDSTS, confirming it as a recognised clinical
      feature warranting active screening.

- name: Immune Dysfunction and Recurrent Infections
  description: >
    Immune dysfunction and recurrent infections occur in some individuals with
    WDSTS. GeneReviews recommends considering IVIG for low antibody levels and
    prophylactic antibiotics for frequent infections; the cited summary does not
    provide a population frequency.
  category: Immunological
  phenotype_term:
    preferred_term: Recurrent infections
    term:
      id: HP:0002719
      label: Recurrent infections
  evidence:
  - reference: PMID:35617449
    reference_title: "Wiedemann-Steiner Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "consideration of IVIG therapy in those with low antibody levels; consideration of prophylactic antibiotics in those with frequent infections"
    explanation: >
      GeneReviews recommends IVIG and prophylactic antibiotics for WDSTS
      individuals with immune dysfunction, confirming recurrent infections
      as a clinically significant and manageable comorbidity.

- name: Genitourinary Anomalies
  description: >
    Renal and uterine anomalies are recognized manifestations of WDSTS, with
    additional genitourinary findings reported in cohorts. The cited GeneReviews
    summary does not provide a frequency or justify a single aggregate estimate
    for all genitourinary anomalies.
  category: Genitourinary
  phenotype_term:
    preferred_term: Abnormality of the genitourinary system
    term:
      id: HP:0000119
      label: Abnormality of the genitourinary system
  evidence:
  - reference: PMID:35617449
    reference_title: "Wiedemann-Steiner Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Other clinical features include feeding difficulties, prenatal and postnatal growth restriction, epilepsy, ophthalmologic anomalies, congenital heart defects, hand anomalies (such as brachydactyly and clinodactyly), hypotonia, vertebral anomalies (especially fusion anomalies of the cervical spine), renal and uterine anomalies, immune dysfunction, brain malformations, and dental anomalies."
    explanation: >
      GeneReviews lists renal and uterine anomalies as recognized clinical
      features of WDSTS.

- name: Brachydactyly
  description: >
    Hand anomalies, especially brachydactyly and clinodactyly, are recognized
    components of the WDSTS phenotype. Available summary evidence establishes
    their presence but does not provide a reliable population frequency.
  category: Musculoskeletal
  phenotype_term:
    preferred_term: Brachydactyly
    term:
      id: HP:0001156
      label: Brachydactyly
  evidence:
  - reference: PMID:35617449
    reference_title: "Wiedemann-Steiner Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "hand anomalies (such as brachydactyly and clinodactyly)"
    explanation: >
      GeneReviews explicitly lists brachydactyly and clinodactyly among the
      clinical manifestations.

- name: Dental Anomalies
  description: >
    Dental anomalies are part of the variable multisystem WDSTS phenotype. The
    available GeneReviews summary establishes their presence but does not define
    a syndrome-specific pattern or population frequency.
  category: Craniofacial
  phenotype_term:
    preferred_term: Abnormality of the dentition
    term:
      id: HP:0000164
      label: Abnormality of the dentition
  evidence:
  - reference: PMID:35617449
    reference_title: "Wiedemann-Steiner Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "brain malformations, and dental anomalies."
    explanation: >
      GeneReviews includes dental anomalies in the clinical spectrum.

- name: Growth Hormone Deficiency
  description: >
    Growth hormone deficiency occurs in a subset of individuals with WDSTS and
    is clinically relevant because growth hormone therapy may be considered when
    the deficiency is confirmed. The cited summary does not provide a population
    frequency.
  category: Endocrine
  phenotype_term:
    preferred_term: Growth hormone deficiency
    term:
      id: HP:0034323
      label: Reduced circulating growth hormone concentration
  evidence:
  - reference: PMID:35617449
    reference_title: "Wiedemann-Steiner Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "growth hormone therapy for those with growth hormone deficiency; thyroid replacement therapy for hypothyroidism"
    explanation: >
      GeneReviews explicitly recommends growth hormone therapy when growth
      hormone deficiency is present.

genetic:
- name: KMT2A
  notes: >
    Heterozygous pathogenic KMT2A variants cause WDSTS. The allelic spectrum is
    highly heterogeneous: 69 of 82 variants in the 104-person cohort were novel.
    Most tested families represent de novo disease, but vertical autosomal
    dominant transmission and parental mosaicism occur. In that cohort,
    hypotonia was associated with loss-of-function variants and seizures with
    non-loss-of-function variants; the abstract does not support more granular
    variant-class percentages or a universal functional mechanism.
  gene_term:
    preferred_term: KMT2A
    term:
      id: hgnc:7132
      label: KMT2A
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  evidence:
  - reference: PMID:33783954
    reference_title: "Expanding the genotypic and phenotypic spectrum in a diverse cohort of 104 individuals with Wiedemann-Steiner syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sixty‐nine of the 82 variants (84%) observed in the study were not previously reported in the literature."
    explanation: >
      Sheppard et al. characterise the full KMT2A variant spectrum in n=104,
      showing high allelic heterogeneity with predominantly novel variants.
  - reference: PMID:33783954
    reference_title: "Expanding the genotypic and phenotypic spectrum in a diverse cohort of 104 individuals with Wiedemann-Steiner syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hypotonia was associated with loss of function (LoF) variants, and seizures were associated with non‐LoF variants."
    explanation: >
      The cohort supplies the reported genotype-phenotype associations without
      supporting stronger variant-class claims.
  - reference: PMID:29574747
    reference_title: "Wiedemann-Steiner syndrome as a major cause of syndromic intellectual disability: A study of 33 French cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We observed autosomal dominant transmission of WSS in 3 families and mosaicism in one family."
    explanation: >
      This series documents rare inherited disease and mosaicism.

diagnosis:
- name: Molecular genetic testing
  description: >
    WDSTS is established in an individual with suggestive findings by identifying
    a heterozygous pathogenic variant in KMT2A. Because the phenotype overlaps
    other chromatinopathies and can be mild or atypical, clinical findings alone
    are not sufficient to establish the molecular diagnosis.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  results: A heterozygous pathogenic KMT2A variant establishes the molecular diagnosis.
  evidence:
  - reference: PMID:35617449
    reference_title: "Wiedemann-Steiner Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The diagnosis of WSS is established in a proband with suggestive findings and a heterozygous pathogenic variant in KMT2A identified by molecular genetic testing."
    explanation: >
      GeneReviews states the molecular diagnostic criterion.

- name: KMT2A DNA methylation episignature analysis
  description: >
    A genome-wide blood DNA methylation episignature can provide functional
    evidence for classification of some KMT2A variants of uncertain significance
    or support diagnosis in clinically suggestive cases. This assay measures DNA
    methylation, not histone H3K4 methylation. Independent evaluation found
    KMT2A-signature sensitivity dependent on classifier settings and affected by
    heterogeneous or intermediate profiles, so a negative result does not exclude
    WDSTS and the assay does not replace sequence-based diagnosis.
  diagnosis_term:
    preferred_term: DNA methylation analysis
    term:
      id: NCIT:C63328
      label: DNA Methylation Analysis
  results: >
    A concordant KMT2A episignature can support variant interpretation; an
    absent or intermediate signature is not exclusionary.
  evidence:
  - reference: PMID:35163737
    reference_title: "Clinical Utility of a Unique Genome-Wide DNA Methylation Signature for KMT2A-Related Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "WDSTS episignature enabled classification of variants of uncertain significance in the KMT2A gene as well as confirmation of diagnosis in patients with clinical presentation of WDSTS without known genetic variants."
    explanation: >
      The discovery cohort demonstrates the intended variant-classification and
      diagnostic-support use.
  - reference: PMID:37872275
    reference_title: "Episignatures in practice: independent evaluation of published episignatures for the molecular diagnostics of ten neurodevelopmental disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Remaining Cornelia de Lange syndrome, KMT2A, KDM5C and CHD7 signatures reached 70–100% sensitivity at best with unstable performances, suffering from heterogeneous methylation profiles among cases and rare discordant samples."
    explanation: >
      Independent validation supports cautious use because sensitivity was
      unstable despite high specificity in the study framework.

differential_diagnoses:
- name: Overlapping chromatinopathies and syndromic intellectual disability disorders
  description: >
    The clinical differential includes Coffin-Siris, Nicolaides-Baraitser,
    Cornelia de Lange, Rubinstein-Taybi, Kabuki, Bohring-Opitz,
    Suleiman-El-Hattab, and blepharophimosis-ptosis-epicanthus inversus
    syndromes. Shared developmental delay, growth restriction, hypertrichosis,
    and craniofacial findings make phenotype alone insufficient in atypical
    cases.
  distinguishing_features:
  - Identification of a heterozygous pathogenic KMT2A variant establishes WDSTS.
  - Hypertrichosis cubiti is frequent but is neither required nor pathognomonic.
  - A concordant KMT2A DNA methylation episignature may support ambiguous variant interpretation but is not independently exclusionary.
  evidence:
  - reference: PMID:37025457
    reference_title: "Novel variants and phenotypic heterogeneity in a cohort of 11 Chinese children with Wiedemann-Steiner syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the features of WSS are shared by a range of disorders"
    explanation: >
      The review explicitly frames these syndromes as overlapping clinical
      differentials.
  - reference: PMID:35617449
    reference_title: "Wiedemann-Steiner Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The diagnosis of WSS is established in a proband with suggestive findings and a heterozygous pathogenic variant in KMT2A identified by molecular genetic testing."
    explanation: >
      Molecular confirmation provides the decisive distinction from overlapping
      syndromic diagnoses.

treatments:
- name: Physical Therapy
  description: >
    Early physical therapy through developmental intervention programs addresses
    hypotonia, motor delay, mobility, and functional skills. Evidence specific to
    WDSTS is limited to case-based physical-therapy literature and expert
    management guidance.
  action_category: THERAPEUTIC
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Physical Therapy
    term:
      id: NCIT:C15302
      label: Physical Therapy
  target_phenotypes:
  - preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  - preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:32604375
    reference_title: "Physical Therapy Management of Wiedemann-Steiner Syndrome From Birth to 3 Years."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The diagnosis of WSS should require physical therapy services through early intervention programs due to its high correlation with motor developmental delay and disability."
    explanation: >
      The physical-therapy report explicitly recommends early PT services for
      motor delay and disability.

- name: Developmental Support
  description: >
    Standard developmental management is recommended for developmental delay
    or intellectual disability. The cited guidance does not specify a
    syndrome-specific speech-language modality or treatment regimen.
  action_category: THERAPEUTIC
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_phenotypes:
  - preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:35617449
    reference_title: "Wiedemann-Steiner Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "standard treatment for epilepsy, developmental delay / intellectual disability"
    explanation: >
      GeneReviews directly recommends standard management for developmental
      delay and intellectual disability.

- name: Occupational Therapy
  description: >
    Occupational therapy addresses fine motor delays, visuospatial difficulties,
    activities of daily living, and adaptive needs. The reported
    nonverbal/visuospatial weaknesses can inform individualized goals; direct
    WDSTS-specific efficacy evidence is not available.
  action_category: THERAPEUTIC
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: occupational therapy
    term:
      id: NCIT:C121351
      label: Occupational Therapy
  target_phenotypes:
  - preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:36062544
    reference_title: "Individuals with Wiedemann-Steiner syndrome show nonverbal reasoning and visuospatial defects with relative verbal skill sparing."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The majority of patients performed in the below average to very low ranges in Nonverbal Reasoning, Visual/Spatial Perception, Visuoconstruction, Visual Memory, Attention, Working Memory and Math Computation skills."
    explanation: >
      The neuropsychological profile informs occupational-therapy targets but
      is not a treatment trial.

- name: Behavioral and Psychiatric Management
  description: >
    Behavioral therapy and standard psychiatric care are used for clinically
    significant behavioral, attention, autistic, anxiety, or emotion-regulation
    concerns. Intervention should be based on the individual's presentation; no
    WDSTS-specific drug regimen is established in the cited guidance.
  action_category: THERAPEUTIC
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_phenotypes:
  - preferred_term: Atypical behavior
    term:
      id: HP:0000708
      label: Atypical behavior
  evidence:
  - reference: PMID:35617449
    reference_title: "Wiedemann-Steiner Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "behavioral therapy; standard treatment for epilepsy, developmental delay / intellectual disability"
    explanation: >
      GeneReviews directly recommends behavioral therapy.

- name: Genetic Counseling
  description: >
    Counseling covers the typically de novo but autosomal dominant inheritance,
    the possibility of an affected or mosaic parent, the 50% transmission risk
    for an affected individual, and prenatal or preimplantation genetic testing
    once the familial KMT2A pathogenic variant is known.
  action_category: COUNSELING_INFORMATIONAL
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:29574747
    reference_title: "Wiedemann-Steiner syndrome as a major cause of syndromic intellectual disability: A study of 33 French cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We observed autosomal dominant transmission of WSS in 3 families and mosaicism in one family."
    explanation: >
      Baer et al. document both familial transmission and mosaicism in French
      WDSTS cases, underscoring the importance of genetic counselling including
      parental testing.
  - reference: PMID:35617449
    reference_title: "Wiedemann-Steiner Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Each offspring of an individual with WSS is at a 50% risk of being affected. Once the KMT2A pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible."
    explanation: >
      GeneReviews states the transmission risk and available reproductive
      testing options.

- name: Growth Hormone Therapy
  description: >
    Recombinant human growth hormone (rhGH) therapy has been trialled in WDSTS
    patients with short stature. In a Chinese cohort, two patients treated with
    rhGH showed satisfactory height gains, though one experienced acceleration
    of bone age. GeneReviews recommends treatment specifically for confirmed
    growth hormone deficiency; the two-person observation does not establish
    general efficacy for all WDSTS-associated short stature.
  action_category: THERAPEUTIC
  therapeutic_modality: PROTEIN_REPLACEMENT
  treatment_term:
    preferred_term: hormone modifying therapy
    term:
      id: NCIT:C15445
      label: Hormone Therapy
  target_phenotypes:
  - preferred_term: Reduced circulating growth hormone concentration
    term:
      id: HP:0034323
      label: Reduced circulating growth hormone concentration
  evidence:
  - reference: PMID:37025457
    reference_title: "Novel variants and phenotypic heterogeneity in a cohort of 11 Chinese children with Wiedemann-Steiner syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Two patients were treated with rhGH and yielded satisfactory height gains, but one developed acceleration of bone age."
    explanation: >
      Lin et al. report rhGH use in two WDSTS patients with short stature,
      showing benefit but also bone age acceleration as a potential adverse effect.
  - reference: PMID:35617449
    reference_title: "Wiedemann-Steiner Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "growth hormone therapy for those with growth hormone deficiency"
    explanation: >
      GeneReviews limits the recommendation to confirmed deficiency.

- name: Anti-Seizure Pharmacotherapy
  description: >
    Epilepsy is treated according to standard neurologic practice; no
    WDSTS-specific antiseizure regimen is established. Valproate warrants caution
    because GeneReviews reports one affected individual who developed
    hyperammonemia, while explicitly noting that this event is not specific to
    WDSTS.
  action_category: THERAPEUTIC
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_phenotypes:
  - preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:35617449
    reference_title: "Wiedemann-Steiner Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "standard treatment for epilepsy, developmental delay / intellectual disability"
    explanation: >
      GeneReviews recommends standard epilepsy treatment rather than a
      syndrome-specific medication.
  - reference: PMID:35617449
    reference_title: "Wiedemann-Steiner Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The authors are aware of one individual with WSS who developed hyperammonemia with the use of the anti-seizure medication valproate. While this is not specific to individuals with WSS, valproate should be used with caution."
    explanation: >
      GeneReviews records the single hyperammonemia observation and qualifies
      the resulting valproate caution.

- name: Immunoglobulin Replacement and Infection Prophylaxis
  description: >
    For WDSTS individuals with documented low antibody levels or immune
    dysfunction, IVIG therapy is recommended. Prophylactic antibiotics
    should be considered for those with frequent infections. Immunological
    evaluation and infection history guide selection; these are conditional
    measures rather than routine treatment for every affected person.
  action_category: THERAPEUTIC
  treatment_term:
    preferred_term: immunomodulatory pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_phenotypes:
  - preferred_term: Recurrent infections
    term:
      id: HP:0002719
      label: Recurrent infections
  evidence:
  - reference: PMID:35617449
    reference_title: "Wiedemann-Steiner Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "consideration of IVIG therapy in those with low antibody levels; consideration of prophylactic antibiotics in those with frequent infections"
    explanation: >
      GeneReviews recommends IVIG and prophylactic antibiotics as management
      for immune dysfunction in WDSTS.

- name: Feeding Therapy and Nutritional Support
  description: >
    Feeding therapy is recommended for poor weight gain or failure to thrive,
    with supplemental tube feeding considered when oral strategies are
    insufficient. The approach is individualized to nutritional status and
    feeding safety.
  action_category: THERAPEUTIC
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_phenotypes:
  - preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
  - preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  evidence:
  - reference: PMID:35617449
    reference_title: "Wiedemann-Steiner Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Feeding therapy with possible supplemental tube feeding for those with poor weight gain / failure to thrive"
    explanation: >
      GeneReviews directly states both the feeding-therapy recommendation and
      conditional tube supplementation.

- name: Constipation Management
  description: >
    Bowel dysfunction is managed with standard measures such as stool softeners
    or osmotic agents, selected according to clinical assessment and response.
  action_category: THERAPEUTIC
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_phenotypes:
  - preferred_term: Constipation
    term:
      id: HP:0002019
      label: Constipation
  evidence:
  - reference: PMID:35617449
    reference_title: "Wiedemann-Steiner Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "stool softeners or osmotic agents for bowel dysfunction"
    explanation: >
      GeneReviews specifies standard pharmacologic bowel management.

- name: Obstructive Sleep Apnea Management
  description: >
    Obstructive sleep apnea may be managed with CPAP or BiPAP, or with removal
    of the tonsils and adenoids when clinically indicated. Choice of modality
    depends on airway assessment and sleep-study findings.
  action_category: THERAPEUTIC
  treatment_term:
    preferred_term: Continuous Positive Airway Pressure
    term:
      id: NCIT:C124040
      label: Continuous Positive Airway Pressure
  target_phenotypes:
  - preferred_term: Obstructive sleep apnea
    term:
      id: HP:0002870
      label: Obstructive sleep apnea
  evidence:
  - reference: PMID:35617449
    reference_title: "Wiedemann-Steiner Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CPAP, BiPAP, or surgical removal of the tonsils and adenoids for those with obstructive sleep apnea"
    explanation: >
      GeneReviews lists both noninvasive ventilation and surgical airway
      options.

- name: Supportive Care and Multidisciplinary Management
  description: >
    Surveillance should track growth, nutrition, constipation, neurologic and
    seizure findings, signs of medullary compression or arrhythmia, developmental
    progress, behavior, physical skills, and recurrent infections. GeneReviews
    also recommends six-monthly dental review after primary-tooth eruption and
    annual or clinically indicated ophthalmologic evaluation.
  action_category: MONITORING
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:35617449
    reference_title: "Wiedemann-Steiner Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Surveillance: At each visit: measurement of growth parameters; evaluation of nutritional status; assessment for constipation; evaluation for new neurologic features and seizure activity with EEG follow up as indicated"
    explanation: >
      GeneReviews specifies the recurring multisystem surveillance domains.
  - reference: PMID:35617449
    reference_title: "Wiedemann-Steiner Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Dental evaluation every six months after the eruption of primary teeth."
    explanation: >
      GeneReviews gives a specific dental surveillance interval.

animal_models:
- species: Mus musculus
  genotype: Constitutive Kmt2a heterozygous (Kmt2a+/-) male mice
  category: Genetic disease model
  genes:
  - preferred_term: Kmt2a
    term:
      id: MGI:96995
      label: Kmt2a
  associated_phenotypes:
  - Reduced body weight
  - Reduced dendritic spine density
  - Increased aggression and social dominance
  description: >
    Constitutive Kmt2a-heterozygous male mice were studied as a WDSTS model in
    an F1 hybrid background. They showed reduced body weight, reduced dendritic
    spine density in basolateral amygdala neurons, and altered aggression/social
    dominance measures. They did not show deficits in the contextual fear or
    novel-object-recognition assays used in that study. Adult male brain tissue,
    mixed cell populations, and lifetime adaptation limit direct extrapolation to
    human developmental cognition.
  evidence:
  - reference: PMID:32483278
    reference_title: "Mutually suppressive roles of KMT2A and KDM5C in behaviour, neuronal structure, and histone H3K4 methylation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Despite opposite enzymatic activities, the two mouse models deficient for either Kmt2a or Kdm5c shared reduced dendritic spines and increased aggression."
    explanation: >
      The abstract states the central Kmt2a-heterozygous structural and
      behavioral phenotypes.
  - reference: PMID:32483278
    reference_title: "Mutually suppressive roles of KMT2A and KDM5C in behaviour, neuronal structure, and histone H3K4 methylation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Kmt2a-HET mice showed no deficits in either CFC or NOR"
    explanation: >
      This negative finding bounds the cognitive fidelity of the model.

experimental_models:
- name: WSS patient-derived cell centrosome model
  description: >
    Cells derived from individuals with WDSTS were used alongside MLL/WDR5
    depletion systems to evaluate centrosomal protein recruitment, microtubule
    nucleation, spindle formation, and chromosome alignment. The cached abstract
    does not identify the patient-cell lineage, so the model is deliberately not
    assigned a more specific cell type.
  experimental_model_type: OTHER
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_source: Cells derived from individuals with Wiedemann-Steiner syndrome
  publication: PMID:39661677
  modeled_mechanisms:
  - target: Centrosome Dysfunction and Impaired Microtubule Nucleation
    description: >
      The model reads out recruitment of gamma-tubulin ring-complex and
      structural proteins to centrosomes and subsequent microtubule nucleation.
    evidence:
    - reference: PMID:39661677
      reference_title: "MLL/WDR5 complex recruits centriolar satellite protein Cep72 to regulate microtubule nucleation and spindle formation."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "MLL/WDR5 promote the localization of γ-TuRCs and structural proteins like AKAP9 to the centrosome during interphase and mitosis, a phenotype also observed in cells derived from patients with WSS."
      explanation: >
        The source explicitly reports the centrosomal localization phenotype
        in WSS-derived cells.
  findings:
  - statement: >
      Loss of MLL, WDR5, or Cep72 impairs spindle formation and produces
      misaligned chromosomes.
    supporting_text: "During mitosis, loss of MLL, WDR5, and Cep72 affects spindle formation and leads to misaligned chromosomes."
    evidence:
    - reference: PMID:39661677
      reference_title: "MLL/WDR5 complex recruits centriolar satellite protein Cep72 to regulate microtubule nucleation and spindle formation."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "During mitosis, loss of MLL, WDR5, and Cep72 affects spindle formation and leads to misaligned chromosomes."
      explanation: >
        The abstract directly states this mitotic finding.
  evidence:
  - reference: PMID:39661677
    reference_title: "MLL/WDR5 complex recruits centriolar satellite protein Cep72 to regulate microtubule nucleation and spindle formation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "MLL/WDR5 promote the localization of γ-TuRCs and structural proteins like AKAP9 to the centrosome during interphase and mitosis, a phenotype also observed in cells derived from patients with WSS."
    explanation: >
      This is the direct patient-derived-cell evidence for the centrosomal
      branch.

datasets: []

discussions:
- discussion_id: wdts_mouse_neuronal_model_fidelity
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: >
    Do the dendritic-spine and H3K4/transcriptomic findings in constitutive
    Kmt2a-heterozygous adult male mice reproduce the mechanisms operating in
    developing human neurons with heterozygous pathogenic KMT2A variants?
  attaches_to:
  - pathophysiology#Altered H3K4 Methylation and Transcriptional Regulation
  - pathophysiology#Reduced Dendritic Spine Density and Neuronal Dysregulation
  rationale: >
    The mouse study provides the main experimental bridge from KMT2A dosage to
    dendritic morphology, but the molecular assays used adult amygdala tissue
    containing mixed neuronal and glial populations, only male mice were studied,
    and the constitutive genotype permits lifetime adaptation. Global H3K4me1-3
    levels were not dramatically altered, and Kmt2a-heterozygous mice were normal
    in the two learning/memory assays used. The model therefore supports a
    locus-specific neuronal hypothesis, not a direct equivalence to human
    intellectual disability or a global histone-methylation-loss mechanism.
  evidence:
  - reference: PMID:32483278
    reference_title: "Mutually suppressive roles of KMT2A and KDM5C in behaviour, neuronal structure, and histone H3K4 methylation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "First, we measured gene expression and H3K4me3 in adult brain tissues, a mixture of many neuron and glia types, which may mask potentially important molecular changes."
    explanation: >
      The authors explicitly identify adult mixed brain tissue as a limitation.
  - reference: PMID:32483278
    reference_title: "Mutually suppressive roles of KMT2A and KDM5C in behaviour, neuronal structure, and histone H3K4 methylation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "It is important to note that the double mutations introduced in our mice were constitutive, and therefore a lifetime of adaptation to loss of these two major chromatin regulators may occur from early developmental stages."
    explanation: >
      The study acknowledges developmental adaptation in its constitutive
      genetic design.
  proposed_experiments:
  - experiment_id: wdts_isogenic_human_neuron_timecourse
    name: Isogenic human KMT2A dosage series across neuronal development
    description: >
      Generate patient-derived and CRISPR-engineered heterozygous KMT2A iPSC
      lines with matched corrected controls, differentiate them into defined
      excitatory and inhibitory neuronal lineages, and profile H3K4me states,
      chromatin accessibility, single-cell transcription, dendritic spines, and
      electrophysiology across developmental time points.
    decision_criterion: >
      A reproducible allele-dependent phenotype that is rescued by correction
      and converges across independent lines would support translation of the
      mouse neuronal branch; absence of such changes would argue that the mouse
      phenotype is model- or developmental-context-specific.
    evidence:
    - reference: PMID:32483278
      reference_title: "Mutually suppressive roles of KMT2A and KDM5C in behaviour, neuronal structure, and histone H3K4 methylation."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Increasing spatiotemporal resolution of the molecular study is an important future direction."
      explanation: >
        The authors identify insufficient spatiotemporal resolution as a
        limitation that a human developmental time course would address.

- discussion_id: wdts_episignature_interpretation
  kind: INTERPRETATION
  status: OPEN
  prompt: >
    How should a negative or intermediate KMT2A blood DNA methylation
    episignature be interpreted when phenotype and sequence evidence suggest
    WDSTS?
  attaches_to:
  - diagnosis#KMT2A DNA methylation episignature analysis
  rationale: >
    The discovery study showed clinical utility for variant classification, but
    independent evaluation found KMT2A sensitivity ranging from 70% to 100% at
    best with unstable performance and heterogeneous methylation profiles. The
    assay is useful as supporting functional evidence, yet its negative predictive
    value and handling of intermediate profiles remain insufficiently standardized
    for exclusionary use.
  evidence:
  - reference: PMID:35163737
    reference_title: "Clinical Utility of a Unique Genome-Wide DNA Methylation Signature for KMT2A-Related Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "WDSTS episignature enabled classification of variants of uncertain significance in the KMT2A gene as well as confirmation of diagnosis in patients with clinical presentation of WDSTS without known genetic variants."
    explanation: >
      The discovery cohort demonstrates positive clinical utility.
  - reference: PMID:37872275
    reference_title: "Episignatures in practice: independent evaluation of published episignatures for the molecular diagnostics of ten neurodevelopmental disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Remaining Cornelia de Lange syndrome, KMT2A, KDM5C and CHD7 signatures reached 70–100% sensitivity at best with unstable performances, suffering from heterogeneous methylation profiles among cases and rare discordant samples."
    explanation: >
      Independent testing motivates the open interpretation question.
  proposed_experiments:
  - experiment_id: wdts_locked_classifier_prospective_validation
    name: Prospective multi-site validation of a locked KMT2A episignature classifier
    description: >
      Prospectively test a preregistered, locked classifier in sequence-defined
      pathogenic, benign, and uncertain KMT2A variants across laboratories,
      recording age, blood-cell composition, phenotype, and intermediate scores.
    decision_criterion: >
      Stable sensitivity, specificity, and inter-laboratory concordance with
      prespecified thresholds would justify standardized interpretation;
      persistent classifier- or site-dependent results would support retaining
      the assay as non-exclusionary adjunctive evidence.
    evidence:
    - reference: PMID:37872275
      reference_title: "Episignatures in practice: independent evaluation of published episignatures for the molecular diagnostics of ten neurodevelopmental disorders."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Remaining Cornelia de Lange syndrome, KMT2A, KDM5C and CHD7 signatures reached 70–100% sensitivity at best with unstable performances, suffering from heterogeneous methylation profiles among cases and rare discordant samples."
      explanation: >-
        Unstable independent performance motivates a locked, multi-site
        validation design.
📚

References & Deep Research

References

1
PMID:35617449
Wiedemann-Steiner Syndrome.
No top-level findings curated for this source.

Deep Research

1
Falcon ▸
Wiedemann–Steiner Syndrome (WSS; KMT2A-related) — Disease Characteristics Research Report
Edison Scientific Literature 40 citations 2026-05-16T19:22:53.897266

Wiedemann–Steiner Syndrome (WSS; KMT2A-related) — Disease Characteristics Research Report

Executive Summary

Wiedemann–Steiner syndrome (WSS; also written WDSTS) is an autosomal-dominant Mendelian neurodevelopmental disorder caused primarily by heterozygous pathogenic variants in KMT2A (also known historically as MLL), a histone H3 lysine 4 (H3K4) methyltransferase and core component of the epigenetic “writer” machinery. Clinically, WSS features global developmental delay/intellectual disability, postnatal growth deficiency/short stature, hypertrichosis (often including hypertrichosis cubiti), and characteristic craniofacial dysmorphism, with frequent gastrointestinal, skeletal, cardiac, genitourinary, endocrine, and immune comorbidities in cohort studies. The largest multi-continental cohort (n=104) provides robust phenotype frequencies and milestone distributions; recent (2023–2024) advances emphasize neurocognitive profiling, and clinical implementation of DNA methylation episignatures as functional biomarkers for variant interpretation.

Key quantitative points (largest cohort, n=104): developmental delay/intellectual disability 97%, hypotonia 72.4%, failure to thrive 67.7%, feeding difficulties 66.3%, constipation 63.8%, short stature 57.8%, hypertrichosis cubiti 57%, seizures ~20%, cardiac abnormalities ~35.8% among those evaluated; median milestone ages: first words 18 months, independent walking 20 months. (sheppard2021expandingthegenotypic pages 3-4, sheppard2021expandingthegenotypic pages 11-13, sheppard2021expandingthegenotypic pages 6-11)

1. Disease Information

1.1 Concise overview

WSS is a rare autosomal-dominant disorder of the epigenetic machinery (a “chromatinopathy/MDEM”) caused by heterozygous pathogenic variants in KMT2A, characterized by neurodevelopmental impairment (developmental delay/intellectual disability), hypertrichosis (often including hypertrichosis cubiti), facial dysmorphism, and growth deficiency with multi-system congenital anomalies. (ng2023individualswithwiedemannsteiner pages 1-2, foroutan2022clinicalutilityof pages 2-3)

Recent clinical neuropsychology evidence (2023) indicates a characteristic cognitive pattern with prominent nonverbal/visuospatial weaknesses and relative sparing of some verbal skills in a pediatric series, supporting syndrome-specific educational planning. (ng2023individualswithwiedemannsteiner pages 1-2)

1.2 Key identifiers

  • MONDO: MONDO_0011518 (OpenTargets disease identifier) (OpenTargets Search: Wiedemann-Steiner syndrome-KMT2A)
  • OMIM (phenotype): 605130 (explicitly cited in neuropsychology and chromatin clinic literature) (ng2023individualswithwiedemannsteiner pages 1-2, harris2024fiveyearsof pages 7-9)
  • Causal gene: KMT2A (lysine methyltransferase 2A; H3K4 methyltransferase; 11q23 locus referenced across studies) (foroutan2022clinicalutilityof pages 2-3, lin2023novelvariantsand pages 2-3)

Not available in retrieved evidence (tool-limited): Orphanet ID, MeSH descriptor ID, ICD-10/ICD-11 mappings. These should be added from OMIM/Orphanet/ICD resources directly.

1.3 Synonyms / alternative names

  • Wiedemann–Steiner syndrome (WSS)
  • Wiedemann-Steiner syndrome (WDSTS)
  • KMT2A-related syndrome (often used in epigenetic/episignature literature) (foroutan2022clinicalutilityof pages 2-3)

1.4 Evidence provenance

The report draws primarily from: - Aggregated cohort studies (e.g., Sheppard et al. multicenter cohort of 104 individuals) (sheppard2021expandingthegenotypic pages 3-4, sheppard2021expandingthegenotypic pages 11-13, sheppard2021expandingthegenotypic pages 6-11) - Disease-focused reviews/case series (e.g., Yu et al. 2022 review; Ng et al. 2023 neuropsychology case series) (yu2022wiedemann–steinersyndromecase pages 7-8, ng2023individualswithwiedemannsteiner pages 1-2) - Clinical diagnostic-method studies (e.g., DNA methylation episignature validation papers) (foroutan2022clinicalutilityof pages 2-3, husson2024episignaturesinpractice pages 1-2) - Real-world specialized clinic cohort (Johns Hopkins Epigenetics and Chromatin Clinic experience) (harris2024fiveyearsof pages 7-9, harris2024fiveyearsof pages 5-7)

2. Etiology

2.1 Disease causal factors

Primary cause: Germline heterozygous pathogenic variants in KMT2A leading predominantly to haploinsufficiency (loss-of-function via premature stop codons and/or nonsense-mediated decay is emphasized in reviews and cohort studies). (yu2022wiedemann–steinersyndromecase pages 1-2, sheppard2021expandingthegenotypic pages 4-6)

Direct abstract quote (diagnostic episignature paper): “Wiedemann–Steiner syndrome (WDSTS) is a Mendelian syndromic intellectual disability (ID) condition… caused by pathogenic variants in the KMT2A gene.” (foroutan2022clinicalutilityof pages 2-3)

2.2 Risk factors

For a monogenic, typically de novo disorder, “risk factors” are primarily genetic and reproductive: - De novo occurrence is common. In the 104-person cohort, 55.8% were confirmed de novo (likely an underestimate due to incomplete parental testing). (sheppard2021expandingthegenotypic pages 6-11) - Familial transmission and mosaicism occur but are uncommon. Baer et al. reported autosomal-dominant transmission in three families and mosaicism in one family. (baer2018wiedemann‐steinersyndromeas pages 1-2)

Environmental risk factors are not established in the retrieved literature.

2.3 Protective factors / gene–environment interactions

No validated protective variants or gene–environment interactions specific to WSS were identified in the retrieved evidence.

3. Phenotypes

3.1 Core phenotype spectrum and frequencies

The largest available cohort data (n=104) provide the most stable frequency estimates: - Neurodevelopmental: developmental delay/intellectual disability 97%; hypotonia 72.4%; autism spectrum disorder 21.3%; seizures 20.0% (surveyed subset). (sheppard2021expandingthegenotypic pages 3-4, sheppard2021expandingthegenotypic pages 6-11) - Growth/nutrition: failure to thrive 67.7%; feeding difficulties 66.3%; tube feeds 25.5%. (sheppard2021expandingthegenotypic pages 3-4, sheppard2021expandingthegenotypic pages 11-13) - Gastrointestinal: constipation 63.8%. (sheppard2021expandingthegenotypic pages 3-4) - Growth: short stature 57.8%. (sheppard2021expandingthegenotypic pages 3-4) - Hair/skin: hypertrichosis cubiti 57%; additional hypertrichosis patterns summarized visually in cohort figures. (sheppard2021expandingthegenotypic pages 3-4, sheppard2021expandingthegenotypic media eacdfc98) - Skeletal: vertebral anomalies 46.9%; scoliosis 21.3%. (sheppard2021expandingthegenotypic pages 3-4, sheppard2021expandingthegenotypic pages 11-13) - Cardiac: cardiac abnormalities 35.8% among those evaluated. (sheppard2021expandingthegenotypic pages 6-11) - Genitourinary: GU anomalies 46.8%; renal anomalies 28.6% in cohort subset. (sheppard2021expandingthegenotypic pages 11-13) - Immunologic: in a small tested subset (n=13), abnormal immunoglobulins 53.8% and insufficient pneumococcal response 30.8%; recurrent infections 25.7% overall. (sheppard2021expandingthegenotypic pages 11-13)

Visual evidence: Cohort phenotype distributions and dysmorphism/hypertrichosis patterns are summarized in Sheppard et al. Figures 2–3. (sheppard2021expandingthegenotypic media eacdfc98, sheppard2021expandingthegenotypic media 4a2ea034)

Population-specific variability: In a Chinese cohort (n=11), short stature and developmental delay were each 90.9%; PDA 57.1%, PFO 42.9%, and abnormal corpus callosum 50% were frequent imaging findings. (lin2023novelvariantsand pages 1-2)

3.2 Neurocognitive and behavioral phenotype (recent, 2023–2024 priority)

Neuropsychological profile (2023): Most patients performed in “below average to very low” ranges for nonverbal reasoning, visuospatial skills, attention/working memory, and math; >50% had normal-range receptive vocabulary/verbal memory/word reading; nonverbal reasoning weaker than verbal reasoning (p = .005). (ng2023individualswithwiedemannsteiner pages 1-2)

Clinic-based severity distribution (2024 real-world cohort): In a specialized Epigenetics and Chromatin Clinic, among 14 WSS patients, cognitive impairment was distributed as borderline/GDD above cutoff 21.4%, mild ID 57.1%, moderate ID 21.4%. (harris2024fiveyearsof pages 7-9)

3.3 Phenotype characteristics: onset, progression, and severity

  • Onset: typically congenital/early childhood with early developmental delay and postnatal growth deficiency. (ng2023individualswithwiedemannsteiner pages 1-2, sheppard2021expandingthegenotypic pages 3-4)
  • Developmental trajectory: median age at walking 20 months and first words 18 months; ranges can extend to 60 months. (sheppard2021expandingthegenotypic pages 11-13)
  • Adulthood: adult outcomes are variable; in one cohort summary of 23 adults, most completed high school (17/18 with schooling data), few attended tertiary education (3), and employment was limited (10 unemployed). (sheppard2021expandingthegenotypic pages 11-13)

3.4 HPO term suggestions (non-exhaustive)

(Representative mappings for knowledge-base entry) - Global developmental delay — HP:0001263 - Intellectual disability — HP:0001249 - Hypotonia — HP:0001252 - Seizures — HP:0001250 - Short stature — HP:0004322 - Failure to thrive — HP:0001508 - Feeding difficulties — HP:0011968 - Constipation — HP:0002019 - Hypertrichosis cubiti — HP:0004558 (commonly used clinically for elbow hypertrichosis) - Abnormal corpus callosum morphology — HP:0001273 - Patent ductus arteriosus — HP:0001643 - Patent foramen ovale — HP:0001655 - Scoliosis — HP:0002650 - Strabismus — HP:0000486

(HPO codes are standard; specific HPO coding was not enumerated in the retrieved text and is provided as ontology mapping consistent with phenotype names.)

4. Genetic / Molecular Information

4.1 Causal gene

  • KMT2A (lysine methyltransferase 2A; histone H3K4 methyltransferase; epigenetic “writer”). (foroutan2022clinicalutilityof pages 2-3, ng2023individualswithwiedemannsteiner pages 1-2)

4.2 Pathogenic variant classes and frequencies

Largest cohort variant spectrum (n=104; 82 distinct variants): - Frameshift 37.8% - Nonsense 29.3% - Missense 20.7% - Splice-site 11% - Most variants detected by exome sequencing; 80/82 absent from gnomAD v2.1.1. (sheppard2021expandingthegenotypic pages 4-6)

Genotype–phenotype correlations: hypotonia associated with loss-of-function variants; seizures associated with non-loss-of-function variants. (sheppard2021expandingthegenotypic pages 3-4)

4.3 Variant interpretation challenges and epigenetic functional testing

Variant classification can be difficult for rare missense/VUS in KMT2A; a genome-wide DNA methylation episignature has been proposed/used as a functional biomarker to classify VUS and confirm diagnoses. (foroutan2022clinicalutilityof pages 2-3)

Independent validation (2024): Husson et al. reported that their leave-one-out episignature approach achieved 100% specificity overall but that signatures vary widely; the KMT2A episignature reached “70–100% sensitivity at best with unstable performances,” suggesting it can be useful but requires cautious interpretation and larger validation datasets. (husson2024episignaturesinpractice pages 1-2)

5. Environmental Information

No specific environmental contributors, lifestyle factors, or infectious triggers for disease onset are supported by the retrieved evidence; WSS is primarily a genetic haploinsufficiency syndrome.

6. Mechanism / Pathophysiology

6.1 Epigenetic/transcriptional dysregulation (upstream mechanism)

KMT2A encodes an H3K4 methyltransferase essential for development; pathogenic variants cause chromatin remodeling defects and dysregulated gene expression. (foroutan2022clinicalutilityof pages 2-3, yu2022wiedemann–steinersyndromecase pages 1-2)

Methylation biomarker insight: Foroutan et al. reported that the methylation changes “involve global reduction in methylation in various genes, including homeobox gene promoters,” supporting developmental transcriptional dysregulation as a unifying mechanism for pleiotropy. (foroutan2022clinicalutilityof pages 2-3)

6.2 Centrosome and microtubule nucleation dysfunction (2024 mechanistic advance)

A major recent mechanistic development is the demonstration that KMT2A/MLL1 has a centrosomal function via WDR5 and Cep72: - The MLL/KMT2A–WDR5 complex localizes to pericentriolar material and interacts with Cep72 and γ-TuRC components. - Loss of MLL/WDR5 impairs microtubule nucleation/regrowth and disrupts spindle formation. - Importantly, similar defects were observed in patient-derived cells from WSS individuals (reduced centrosomal localization of AKAP9, NEDD1, γ-tubulin, and Cep72, with impaired microtubule nucleation), providing disease-relevant cellular pathophysiology. (chodisetty2024mllwdr5complexrecruits pages 1-2, chodisetty2024mllwdr5complexrecruits pages 13-14)

6.3 Transcriptomic profiling in patient-derived fibroblasts

RNA-seq of fibroblasts from 4 WSS patients (vs 5 controls) identified 1,181 DEGs (p<0.05) and 188 DEGs (p<0.01; fold change>2) with predominance of downregulation; pathway analysis highlighted eNOS signaling and axonal guidance among enriched pathways, linking KMT2A loss to neurodevelopmental and hair-growth pathways. (mietton2018rnasequencingand pages 4-5)

6.4 Model organism evidence (translational mechanisms)

Mouse models demonstrate neurobehavioral and neuronal-structure phenotypes consistent with WSS biology: - Kmt2a haploinsufficiency and Kdm5c deficiency share reduced dendritic spines and increased aggression; double mutants partially rescue dendritic morphology, behavior, transcriptomes, and H3K4me landscapes—supporting the concept that balancing writer/eraser activity can ameliorate phenotypes in principle. (vallianatos2020mutuallysuppressiveroles pages 1-2)

6.5 Suggested ontology terms

GO Biological Process (examples): - Histone H3-K4 methylation — GO:0051568 - Chromatin organization — GO:0006325 - Regulation of transcription, DNA-templated — GO:0006355 - Microtubule nucleation — GO:0007020 - Mitotic spindle organization — GO:0007052

Cell types (CL examples; context-dependent): - Neuron — CL:0000540 - Neural progenitor cell — CL:0000047 - B cell (patient-derived lymphocytes used in mechanism study) — CL:0000236

Anatomy (UBERON examples): - Brain — UBERON:0000955 - Cerebral cortex — UBERON:0001851 - Pituitary gland — UBERON:0000007

(These ontology IDs are standard mappings of terms used in studies; the retrieved texts did not enumerate ontology IDs explicitly.)

7. Anatomical Structures Affected

Based on phenotype distributions and mechanistic studies, WSS primarily affects: - Central nervous system/brain (neurodevelopmental delay, structural brain abnormalities such as corpus callosum anomalies) (sheppard2021expandingthegenotypic pages 6-11, lin2023novelvariantsand pages 1-2) - Endocrine/growth axis (short stature, GH deficiency, pituitary MRI abnormalities in subset) (sheppard2021expandingthegenotypic pages 11-13) - Cardiovascular system (cardiac anomalies; PDA/PFO in some cohorts) (sheppard2021expandingthegenotypic pages 6-11, lin2023novelvariantsand pages 1-2) - GI system (feeding difficulties, constipation) (sheppard2021expandingthegenotypic pages 3-4) - Musculoskeletal system (vertebral anomalies, scoliosis) (sheppard2021expandingthegenotypic pages 3-4, sheppard2021expandingthegenotypic pages 11-13) - Integument/hair (hypertrichosis patterns) (sheppard2021expandingthegenotypic media eacdfc98)

Subcellular localization/mechanisms implicated include nuclear chromatin regulation and centrosome/pericentriolar material functions. (foroutan2022clinicalutilityof pages 2-3, chodisetty2024mllwdr5complexrecruits pages 1-2)

8. Temporal Development

  • Typical onset: congenital/infancy with developmental delay and growth deficiency. (sheppard2021expandingthegenotypic pages 3-4)
  • Course: chronic/lifelong neurodevelopmental disorder with variable severity; adults show variable independence and employment outcomes. (sheppard2021expandingthegenotypic pages 11-13)

9. Inheritance and Population

9.1 Inheritance

  • Autosomal dominant with predominantly de novo pathogenic variants. (ng2023individualswithwiedemannsteiner pages 1-2, sheppard2021expandingthegenotypic pages 6-11)
  • Familial transmission and mosaicism reported in a minority. (baer2018wiedemann‐steinersyndromeas pages 1-2, ng2023individualswithwiedemannsteiner pages 1-2)

9.2 Epidemiology

Published estimates vary across sources: - Lin et al. (2023) state prevalence <1/1,000,000 and <400 reported cases worldwide (reflecting underdiagnosis and earlier ascertainment). (lin2023novelvariantsand pages 2-3) - Yu et al. (2022 review) reports a revised estimate from 1/100,000 to ~1/25,000–40,000 with increasing identification through sequencing. (yu2022wiedemann–steinersyndromecase pages 1-2)

These discrepancies likely reflect ascertainment differences and evolving molecular diagnosis; robust population prevalence remains uncertain in the retrieved evidence.

10. Diagnostics

10.1 Genetic testing (current practice)

  • Exome sequencing (WES) is heavily utilized in cohorts and case reports and captures diverse variant classes; in one Korean cohort, 9/10 were diagnosed by exome sequencing, with one microdeletion detected by chromosomal microarray. (lin2023novelvariantsand pages 2-3)
  • Copy-number testing (CMA/qPCR/MLPA as appropriate) is needed for intragenic/multi-exon deletions and 11q23.3 deletions encompassing KMT2A; Chinese cohort used qPCR to assess multi-exon deletions. (lin2023novelvariantsand pages 2-3)

10.2 DNA methylation episignature testing (2023–2024 development)

  • A KMT2A-related DNA methylation episignature has been proposed as a molecular biomarker to confirm diagnosis and classify VUS. (foroutan2022clinicalutilityof pages 2-3)
  • Independent evaluation emphasizes high specificity but variable sensitivity; for KMT2A “70–100% sensitivity at best with unstable performances.” (husson2024episignaturesinpractice pages 1-2)

10.3 Differential diagnosis

WSS overlaps with other chromatinopathies (e.g., Kabuki syndrome [KMT2D], Rubinstein–Taybi, Coffin–Siris, Kleefstra), complicating phenotype-only diagnosis. (vallianatos2020mutuallysuppressiveroles pages 1-2, foroutan2022clinicalutilityof pages 2-3)

11. Outcome / Prognosis

  • Survival/life expectancy: not quantified in retrieved evidence; no cohort-based mortality estimates available here.
  • Functional outcomes: variable; in the adult subset of the 104-person cohort, most completed high school but many required special education; tertiary education was uncommon and employment limited (10/23 adults unemployed). (sheppard2021expandingthegenotypic pages 11-13)
  • Complications: multi-system involvement is common (cardiac, endocrine, immunologic), supporting multidisciplinary surveillance. (sheppard2021expandingthegenotypic pages 11-13, sheppard2021expandingthegenotypic pages 6-11)

12. Treatment

12.1 Current standard of care (symptomatic/supportive)

WSS management is typically multidisciplinary and symptom-directed: - Developmental interventions: early intervention, PT/OT/speech therapy; PT case study supports early PT from infancy and goal-based functional outcome tracking. (mendoza2020physicaltherapymanagement pages 1-2) - Feeding/nutrition: management of feeding difficulties and tube feeding when necessary (25.5% in one cohort). (sheppard2021expandingthegenotypic pages 11-13) - Neurobehavioral care: educational supports, neuropsychological evaluation, ADHD/anxiety management as indicated; cognitive profile studies support targeted accommodations. (ng2023individualswithwiedemannsteiner pages 1-2, harris2024fiveyearsof pages 5-7) - System surveillance: cardiac evaluation, neuroimaging when indicated, endocrine evaluation for growth/pubertal abnormalities, and immune workup in those with recurrent infections. (baer2018wiedemann‐steinersyndromeas pages 10-11, sheppard2021expandingthegenotypic pages 11-13)

12.2 Recombinant human growth hormone (rhGH) for short stature / GH deficiency

Evidence is largely from case series and observational cohorts: - In Sheppard et al., GH deficiency was noted in 18.8% of an endocrine-evaluated subset; GH therapy was given to 3 and recommended to 3 more. (sheppard2021expandingthegenotypic pages 11-13) - A 2023 case report documented provocation peak GH 6.9 ng/mL and improvement of height to the 10th percentile after 1 year of rhGH. (kim2023growthhormonedeficiency pages 1-2)

(Additional rhGH quantitative outcomes exist in 2025 literature retrieved but post-date the requested 2023–2024 prioritization; they are not required to establish current practice trends.) (wang2025diagnosisandrecombinant pages 1-2)

12.3 Experimental / targeted therapeutics

No clinical trials were identified for treating WSS neurodevelopmental features directly in the retrieved evidence. The clinical trials retrieved for “KMT2A” primarily target KMT2A-rearranged leukemias and are not applicable to WSS.

12.4 MAXO term suggestions (examples)

  • Recombinant human growth hormone therapy — MAXO:0000600 (growth hormone therapy)
  • Physical therapy — MAXO:0000011
  • Occupational therapy — MAXO:0000012
  • Speech therapy — MAXO:0000026
  • Genetic counseling — MAXO:0000079

(MAXO codes are provided as standard mappings; not enumerated in retrieved text.)

13. Prevention

Primary prevention of de novo WSS is not established. Standard approaches include: - Genetic counseling regarding recurrence risk (generally low for de novo variants but higher with parental mosaicism). Mosaicism has been documented, supporting discussion of recurrence possibilities. (baer2018wiedemann‐steinersyndromeas pages 1-2, ng2023individualswithwiedemannsteiner pages 1-2) - Prenatal/preimplantation testing is feasible when a familial pathogenic variant is known (not directly evidenced in retrieved texts).

14. Other Species / Natural Disease

No naturally occurring veterinary WSS analogs were identified in retrieved evidence.

15. Model Organisms

  • Mouse models: Kmt2a haploinsufficient mice model aspects of WSS neurobiology, with behavioral and dendritic spine phenotypes; interaction with Kdm5c suggests potential compensatory mechanisms via epigenetic balance. (vallianatos2020mutuallysuppressiveroles pages 1-2, vallianatos2020mutuallysuppressiveroles pages 2-3)
  • Cell models: patient-derived B lymphocytes show centrosome/microtubule nucleation defects consistent with KMT2A/MLL1–WDR5 mechanism. (chodisetty2024mllwdr5complexrecruits pages 13-14, chodisetty2024mllwdr5complexrecruits pages 1-2)
  • Patient-derived fibroblasts: transcriptomic dysregulation and pathway enrichment (eNOS signaling, axonal guidance) with targeted H3K4me3 profiling. (mietton2018rnasequencingand pages 4-5)

Recent developments (2023–2024) — Highlights

  1. Neurocognitive profiling (2023): evidence for a syndrome-specific cognitive pattern emphasizing nonverbal/visuospatial weaknesses and relative verbal sparing, enabling targeted educational interventions. (ng2023individualswithwiedemannsteiner pages 1-2)
  2. Clinical adoption of episignatures (2024): independent validation underscores the promise and limitations of KMT2A episignature testing (high specificity; variable/unstable sensitivity), supporting cautious implementation in molecular diagnostics. (husson2024episignaturesinpractice pages 1-2)
  3. Mechanistic advance (2024): discovery of centrosomal role of KMT2A/MLL1–WDR5 with patient-cell phenocopy provides a new cellular disease axis beyond transcriptional regulation alone. (chodisetty2024mllwdr5complexrecruits pages 1-2)

Summary Table (curated)

The following artifact consolidates key quantitative findings (phenotype frequencies, milestones, variant spectrum) from the highest-yield cohort and supporting studies.

Domain Feature/Statistic Value Study/Population Notes
Clinical features Developmental delay and/or intellectual disability 97% Sheppard et al. 2021, multicenter cohort (n=104) (sheppard2021expandingthegenotypic pages 3-4) Core neurodevelopmental feature in the largest cohort
Clinical features Failure to thrive 67.7% Sheppard et al. 2021, multicenter cohort (n=104) (sheppard2021expandingthegenotypic pages 3-4) Common early growth problem
Clinical features Feeding difficulties 66.3% Sheppard et al. 2021, multicenter cohort (n=104) (sheppard2021expandingthegenotypic pages 3-4) Tube feeds reported in 25.5% in extended cohort summary (sheppard2021expandingthegenotypic pages 11-13)
Clinical features Constipation 63.8% Sheppard et al. 2021, multicenter cohort (n=104) (sheppard2021expandingthegenotypic pages 3-4) Frequent gastrointestinal comorbidity
Clinical features Short stature 57.8% Sheppard et al. 2021, multicenter cohort (n=104) (sheppard2021expandingthegenotypic pages 3-4) Postnatal growth deficiency is a hallmark finding
Clinical features Hypertrichosis cubiti 57.0% Sheppard et al. 2021, multicenter cohort (n=104) (sheppard2021expandingthegenotypic pages 3-4) Historically considered highly suggestive, but not universal
Clinical features Vertebral anomalies 46.9% Sheppard et al. 2021, multicenter cohort (n=104) (sheppard2021expandingthegenotypic pages 3-4) Supports skeletal surveillance
Clinical features Hypotonia 72.4% Sheppard et al. 2021, multicenter cohort (n=104) (sheppard2021expandingthegenotypic pages 6-11) Later associated with LoF variants in cohort analysis
Clinical features Hyperactivity 44.3% Sheppard et al. 2021, multicenter cohort (n=104) (sheppard2021expandingthegenotypic pages 6-11) Behavioral/psychiatric burden is substantial
Clinical features Aggressive behavior 33.0% Sheppard et al. 2021, multicenter cohort (n=104) (sheppard2021expandingthegenotypic pages 6-11) Behavioral support often needed
Clinical features Autism spectrum disorder 21.3% Sheppard et al. 2021, multicenter cohort (n=104) (sheppard2021expandingthegenotypic pages 6-11) Not universal but clinically relevant
Clinical features Seizures 20.0% Sheppard et al. 2021, surveyed subset of cohort (sheppard2021expandingthegenotypic pages 6-11) Reported association with non-LoF variants
Clinical features Structural brain abnormality on imaging 57.5% Sheppard et al. 2021, imaged subgroup (n=52) (sheppard2021expandingthegenotypic pages 6-11) Includes corpus callosum and myelination abnormalities
Clinical features Cardiac abnormalities 35.8% Sheppard et al. 2021, evaluated subgroup (29/81) (sheppard2021expandingthegenotypic pages 6-11) Structural anomalies also emphasized in review literature
Clinical features Genitourinary anomalies 46.8% Sheppard et al. 2021, multicenter cohort (n=104) (sheppard2021expandingthegenotypic pages 11-13) Renal anomaly 28.6%; uterine/testicular anomalies 16.9%
Clinical features Recurrent infections 25.7% Sheppard et al. 2021, multicenter cohort (n=104) (sheppard2021expandingthegenotypic pages 11-13) Supports consideration of immune evaluation
Clinical features Abnormal immunoglobulins 53.8% Sheppard et al. 2021, tested subgroup (n=13) (sheppard2021expandingthegenotypic pages 11-13) Small tested subset only
Developmental milestones Sitting independently Median 10 months (range 6-36) Sheppard et al. 2021, multicenter cohort (sheppard2021expandingthegenotypic pages 11-13) Delayed relative to typical development
Developmental milestones Standing independently Median 17 months (range 8-60) Sheppard et al. 2021, multicenter cohort (sheppard2021expandingthegenotypic pages 11-13) Marked gross motor delay
Developmental milestones Walking independently Median 20 months (range 11-60) Sheppard et al. 2021, multicenter cohort (sheppard2021expandingthegenotypic pages 3-4, sheppard2021expandingthegenotypic pages 11-13) Frequently cited milestone delay in WSS
Developmental milestones First words Median 18 months (range 8-60) Sheppard et al. 2021, multicenter cohort (sheppard2021expandingthegenotypic pages 3-4, sheppard2021expandingthegenotypic pages 11-13) Language delay common but variable
Clinical features Short stature 90.9% Lin et al. 2023, Chinese cohort (n=11) (lin2023novelvariantsand pages 1-2, lin2023novelvariantsand pages 2-3) Higher than in Sheppard cohort
Clinical features Developmental delay 90.9% Lin et al. 2023, Chinese cohort (n=11) (lin2023novelvariantsand pages 1-2, lin2023novelvariantsand pages 2-3) Confirms high frequency across populations
Clinical features Intellectual disability 72.7% Lin et al. 2023, Chinese cohort (n=11) (lin2023novelvariantsand pages 1-2, lin2023novelvariantsand pages 2-3) Smaller cohort, likely ascertainment effects
Clinical features Patent ductus arteriosus 57.1% Lin et al. 2023, Chinese cohort imaging findings (lin2023novelvariantsand pages 1-2) Frequent cardiovascular imaging finding in this cohort
Clinical features Patent foramen ovale 42.9% Lin et al. 2023, Chinese cohort imaging findings (lin2023novelvariantsand pages 1-2) Common but potentially incidental in some children
Clinical features Abnormal corpus callosum 50.0% Lin et al. 2023, Chinese cohort imaging findings (lin2023novelvariantsand pages 1-2) Supports neuroimaging when clinically indicated
Clinical features Developmental delay 84.6% Lin et al. 2023, combined Chinese cases (n=52) (lin2023novelvariantsand pages 1-2) Review-level estimate across reported Chinese patients
Clinical features Intellectual disability 84.6% Lin et al. 2023, combined Chinese cases (n=52) (lin2023novelvariantsand pages 1-2) Similar to developmental delay frequency
Clinical features Short stature 80.8% Lin et al. 2023, combined Chinese cases (n=52) (lin2023novelvariantsand pages 1-2) Suggests growth phenotype may be prominent in Chinese reports
Clinical features Delayed bone age 68.0% Lin et al. 2023, combined Chinese cases (n=52) (lin2023novelvariantsand pages 1-2) Bone age may be delayed or, in other reports, advanced
Variant spectrum Distinct KMT2A variants identified 82 Sheppard et al. 2021, multicenter cohort (n=104) (sheppard2021expandingthegenotypic pages 3-4, sheppard2021expandingthegenotypic pages 4-6) 69/82 were novel
Variant spectrum Novel variants among distinct variants 84% (69/82) Sheppard et al. 2021, multicenter cohort (sheppard2021expandingthegenotypic pages 3-4, sheppard2021expandingthegenotypic pages 4-6) Highlights allelic heterogeneity
Variant spectrum De novo variants 55.8% Sheppard et al. 2021, cohort summary (sheppard2021expandingthegenotypic pages 6-11) Likely underestimate due to incomplete parental testing
Variant spectrum Frameshift variants 37.8% Sheppard et al. 2021, variant spectrum (sheppard2021expandingthegenotypic pages 4-6) Largest variant class in this cohort
Variant spectrum Nonsense variants 29.3% Sheppard et al. 2021, variant spectrum (sheppard2021expandingthegenotypic pages 4-6) Supports haploinsufficiency mechanism
Variant spectrum Missense variants 20.7% Sheppard et al. 2021, variant spectrum (sheppard2021expandingthegenotypic pages 4-6) Missense variants often cluster in functional domains
Variant spectrum Splice-site variants 11.0% Sheppard et al. 2021, variant spectrum (sheppard2021expandingthegenotypic pages 4-6) Rounded from reported 11%
Variant spectrum Variants absent from gnomAD v2.1.1 80/82 Sheppard et al. 2021, variant spectrum (sheppard2021expandingthegenotypic pages 4-6) Consistent with rarity and pathogenic enrichment
Variant spectrum Variants identified 11 total (3 known, 8 novel) Lin et al. 2023, Chinese cohort (n=11) (lin2023novelvariantsand pages 1-2) No hotspot variant detected
Variant spectrum HGMD-listed KMT2A variants 349 total Lin et al. 2023 background summary (lin2023novelvariantsand pages 1-2) 273 disease-causing, 76 possible disease-causing
Variant spectrum Reported KMT2A variants in review 322 Yu et al. 2022 review (yu2022wiedemann–steinersyndromecase pages 7-8) Included missense, nonsense, frameshift, and splicing variants
Variant spectrum Variants in exons 3 and 27 >50% of pathogenic variants Yu et al. 2022 review (yu2022wiedemann–steinersyndromecase pages 7-8) Review-level observation, not cohort-specific
Treatment/management rhGH-treated patients with satisfactory height gain 2/2 Lin et al. 2023, Chinese cohort (lin2023novelvariantsand pages 1-2) One patient developed accelerated bone age
Treatment/management Growth hormone deficiency 18.8% Sheppard et al. 2021, endocrine subgroup (sheppard2021expandingthegenotypic pages 11-13) Supports endocrine assessment in selected patients
Treatment/management Growth hormone deficiency 18.8%-50% Yu et al. 2022 review (yu2022wiedemann–steinersyndromecase pages 7-8) Range reflects literature variability
Epidemiology Estimated prevalence <1/1,000,000 Lin et al. 2023 background summary (lin2023novelvariantsand pages 2-3) Authors also noted <400 reported cases worldwide at that time
Epidemiology Revised prevalence estimate ~1 in 25,000-40,000 Yu et al. 2022 review (yu2022wiedemann–steinersyndromecase pages 1-2) Review noted ascertainment likely increased with sequencing

Table: This table compiles key quantitative findings for Wiedemann–Steiner syndrome across major cohort and review papers, emphasizing phenotype frequencies, developmental milestones, and KMT2A variant spectrum statistics. It is useful as a quick-reference evidence summary for clinical and knowledge-base curation.

Key URLs and publication dates (from retrieved evidence)

  • Sheppard et al., Am J Med Genet A (2021-03): https://doi.org/10.1002/ajmg.a.62124 (sheppard2021expandingthegenotypic pages 3-4)
  • Lin et al., Front Genet (2023-03): https://doi.org/10.3389/fgene.2023.1085210 (lin2023novelvariantsand pages 1-2)
  • Ng et al., J Int Neuropsychol Soc (2023-09): https://doi.org/10.1017/S1355617722000467 (ng2023individualswithwiedemannsteiner pages 1-2)
  • Husson et al., Eur J Hum Genet (2024-10): https://doi.org/10.1038/s41431-023-01474-x (husson2024episignaturesinpractice pages 1-2)
  • Harris et al., Human Genetics (2024-03): https://doi.org/10.1007/s00439-023-02537-1 (harris2024fiveyearsof pages 7-9)
  • Chodisetty et al., Science Advances (2024-12): https://doi.org/10.1126/sciadv.adn0086 (chodisetty2024mllwdr5complexrecruits pages 1-2)
  • Foroutan et al., Int J Mol Sci (2022-02): https://doi.org/10.3390/ijms23031815 (foroutan2022clinicalutilityof pages 2-3)
  • Mietton et al., NeuroMolecular Medicine (2018-07): https://doi.org/10.1007/s12017-018-8502-1 (mietton2018rnasequencingand pages 4-5)

Limitations of this tool-based report

  • Not all requested identifiers (Orphanet, ICD-10/ICD-11, MeSH) were retrievable with the available tool evidence; they should be added from OMIM/Orphanet/WHO ICD resources.
  • Some “expert opinions” (e.g., consensus guidelines, GeneReviews) were not obtained in the current retrieval set.
  • Prevalence estimates vary substantially across sources; robust population epidemiology remains uncertain in the retrieved evidence set. (lin2023novelvariantsand pages 2-3, yu2022wiedemann–steinersyndromecase pages 1-2)

References

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  26. (vallianatos2020mutuallysuppressiveroles pages 2-3): Christina N. Vallianatos, Brynne Raines, Robert S. Porter, Katherine M. Bonefas, Michael C. Wu, Patricia M. Garay, Katie M. Collette, Young Ah Seo, Yali Dou, Catherine E. Keegan, Natalie C. Tronson, and Shigeki Iwase. Mutually suppressive roles of kmt2a and kdm5c in behaviour, neuronal structure, and histone h3k4 methylation. Communications Biology, Mar 2020. URL: https://doi.org/10.1038/s42003-020-1001-6, doi:10.1038/s42003-020-1001-6. This article has 61 citations and is from a peer-reviewed journal.

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