Kabuki syndrome is a multisystem Mendelian chromatin disorder caused primarily by heterozygous pathogenic variants in KMT2D and less commonly by pathogenic variants in KDM6A. The syndrome combines characteristic craniofacial dysmorphism, infantile hypotonia, developmental delay or intellectual disability, postnatal growth deficiency, congenital heart disease, and frequent humoral immune dysfunction. Its core mechanism is impaired epigenetic control of developmental gene expression with downstream effects on neural crest-derived tissues, skeletal growth, cardiovascular development, and B-cell maturation.
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name: Kabuki Syndrome
creation_date: '2026-03-15T23:04:41Z'
updated_date: '2026-04-30T20:04:42Z'
category: Mendelian
description: >-
Kabuki syndrome is a multisystem Mendelian chromatin disorder caused primarily
by heterozygous pathogenic variants in KMT2D and less commonly by pathogenic
variants in KDM6A. The syndrome combines characteristic craniofacial
dysmorphism, infantile hypotonia, developmental delay or intellectual
disability, postnatal growth deficiency, congenital heart disease, and
frequent humoral immune dysfunction. Its core mechanism is impaired epigenetic
control of developmental gene expression with downstream effects on neural
crest-derived tissues, skeletal growth, cardiovascular development, and B-cell
maturation.
disease_term:
preferred_term: Kabuki syndrome
term:
id: MONDO:0016512
label: Kabuki syndrome
classifications:
harrisons_chapter:
- classification_value: GENETICS_ENVIRONMENT_DISEASE
evidence:
- reference: PMID:20711175
reference_title: "Exome sequencing identifies MLL2 mutations as a cause of Kabuki syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We demonstrate the successful application of exome sequencing to discover
a gene for an autosomal dominant disorder, Kabuki syndrome
(OMIM%147920).
explanation: Supports classification as a hereditary genetic disorder.
- classification_value: NEUROLOGIC
evidence:
- reference: PMID:30514738
reference_title: "Kabuki syndrome: international consensus diagnostic criteria."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The authors propose that a definitive diagnosis can be made in an
individual of any age with a history of infantile hypotonia,
developmental delay and/or intellectual disability, and one or both of
the following major criteria: (1) a pathogenic or likely pathogenic
variant in KMT2D or KDM6A; and (2) typical dysmorphic features (defined
below) at some point of life.
explanation: Supports classification as a neurodevelopmental/nervous system disorder.
parents:
- Neurodevelopmental Disorder
- Chromatin Disorder
- Multiple Congenital Anomaly Syndrome
synonyms:
- Kabuki make-up syndrome
- Niikawa-Kuroki syndrome
- KMS
definitions:
- name: International consensus clinical definition
definition_type: CASE_DEFINITION
description: >-
Kabuki syndrome is clinically defined by infantile hypotonia with
developmental delay or intellectual disability together with either a
pathogenic KMT2D or KDM6A variant or the characteristic evolving Kabuki
facial gestalt.
scope: Molecularly confirmed and clinically recognizable Kabuki syndrome
evidence:
- reference: PMID:30514738
reference_title: "Kabuki syndrome: international consensus diagnostic criteria."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The authors propose that a definitive diagnosis can be made in an
individual of any age with a history of infantile hypotonia,
developmental delay and/or intellectual disability, and one or both of
the following major criteria: (1) a pathogenic or likely pathogenic
variant in KMT2D or KDM6A; and (2) typical dysmorphic features (defined
below) at some point of life.
explanation: Supports a modern consensus case definition for Kabuki syndrome.
has_subtypes:
- name: KMT2D-related Kabuki syndrome
subtype_term:
preferred_term: Kabuki syndrome 1
term:
id: MONDO:0007843
label: Kabuki syndrome 1
classification: molecular
description: >-
Autosomal dominant Kabuki syndrome caused by pathogenic KMT2D variants and
representing the major molecular subtype.
genes:
- preferred_term: KMT2D
term:
id: hgnc:7133
label: KMT2D
evidence:
- reference: PMID:20711175
reference_title: "Exome sequencing identifies MLL2 mutations as a cause of Kabuki syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Our results strongly suggest that mutations in MLL2 are a major cause of
Kabuki syndrome.
explanation: Supports KMT2D as the principal disease gene and major subtype.
- reference: ORPHA:2322
reference_title: "Kabuki syndrome (Orphanet structured-database record)"
supports: SUPPORT
snippet: "KMT2D | lysine methyltransferase 2D | hgnc:7133 | Disease-causing germline mutation(s) in"
explanation: Orphanet lists KMT2D as a disease-causing gene for Kabuki syndrome.
- name: KDM6A-related Kabuki syndrome
subtype_term:
preferred_term: Kabuki syndrome 2
term:
id: MONDO:0010465
label: Kabuki syndrome 2
classification: molecular
description: >-
Less common Kabuki syndrome subtype caused by pathogenic KDM6A variants.
genes:
- preferred_term: KDM6A
term:
id: hgnc:12637
label: KDM6A
evidence:
- reference: PMID:22197486
reference_title: "Deletion of KDM6A, a histone demethylase interacting with MLL2, in three patients with Kabuki syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
This study identifies KDM6A mutations as another cause of KS and
highlights the growing role of histone methylases and histone
demethylases in multiple-congenital-anomaly and intellectual-disability
syndromes.
explanation: Supports a distinct KDM6A-related molecular subtype.
- reference: ORPHA:2322
reference_title: "Kabuki syndrome (Orphanet structured-database record)"
supports: SUPPORT
snippet: "KDM6A | lysine demethylase 6A | hgnc:12637 | Disease-causing germline mutation(s) in"
explanation: Orphanet lists KDM6A as a disease-causing gene for Kabuki syndrome.
inheritance:
- name: Autosomal dominant inheritance
inheritance_term:
preferred_term: Autosomal dominant inheritance
term:
id: HP:0000006
label: Autosomal dominant inheritance
description: >-
Most Kabuki syndrome cases are caused by heterozygous KMT2D variants and
behave as an autosomal dominant disorder, usually arising de novo.
evidence:
- reference: PMID:20711175
reference_title: "Exome sequencing identifies MLL2 mutations as a cause of Kabuki syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We demonstrate the successful application of exome sequencing to discover
a gene for an autosomal dominant disorder, Kabuki syndrome
(OMIM%147920).
explanation: Supports autosomal dominant inheritance for the common KMT2D-related form.
- reference: ORPHA:2322
reference_title: "Kabuki syndrome (Orphanet structured-database record)"
supports: SUPPORT
snippet: "Autosomal dominant"
explanation: Orphanet classifies Kabuki syndrome inheritance as autosomal dominant.
- name: X-linked dominant inheritance
inheritance_term:
preferred_term: X-linked dominant inheritance
term:
id: HP:0001423
label: X-linked dominant inheritance
description: >-
A minority of cases are caused by heterozygous pathogenic variants or
deletions in the X-linked gene KDM6A.
evidence:
- reference: PMID:22197486
reference_title: "Deletion of KDM6A, a histone demethylase interacting with MLL2, in three patients with Kabuki syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Here, we describe three KS individuals with de novo partial or complete
deletions of an X chromosome gene, KDM6A, that encodes a histone
demethylase that interacts with MLL2.
explanation: Supports an X-linked disease mechanism for the KDM6A-related form.
pathophysiology:
- name: Chromatin dysregulation from KMT2D and KDM6A haploinsufficiency
description: >-
Kabuki syndrome is a disorder of epigenetic regulation in which loss of
KMT2D or KDM6A function perturbs COMPASS-associated chromatin control.
Truncating KMT2D variants frequently undergo nonsense-mediated decay,
reducing KMT2D dosage and dysregulating developmental target genes.
KDM6A lesions disrupt a cooperating histone demethylase in the same
chromatin-regulatory pathway.
cell_types:
- preferred_term: neural crest cell
term:
id: CL:0011012
label: neural crest cell
- preferred_term: B cell
term:
id: CL:0000236
label: B cell
biological_processes:
- preferred_term: chromatin organization
term:
id: GO:0006325
label: chromatin organization
- preferred_term: regulation of gene expression
term:
id: GO:0010468
label: regulation of gene expression
downstream:
- target: Neural crest developmental dysregulation
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
description: >-
KMT2D/KDM6A haploinsufficiency reduces enhancer H3K4me1 deposition
and H3K27me3 demethylation, dysregulating developmental enhancers
required for neural crest specification and migration.
- target: Cardiomyocyte gene-expression dysregulation
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
description: >-
Reduced KMT2D activity in cardiomyocytes lowers H3K4me1/me2 at
enhancers controlling ion-transport and cell-cycle programs.
- target: Chondrocyte differentiation defect
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
description: >-
KMT2D/KDM6A loss disrupts H3K4me1 deposition at SOX9/RUNX2 enhancers
controlling chondrogenic differentiation and growth-plate hypertrophy.
- target: B-cell terminal differentiation defect
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
description: >-
KMT2D loss alters enhancer activity at immune loci, including
class-switch and integrin genes, impairing terminal B-cell maturation.
- target: Postnatal neurogenesis deficit
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
description: >-
Reduced KMT2D activity decreases dentate gyrus H3K4me3 and impairs
adult hippocampal neurogenesis.
- target: Pancreatic beta-cell dysfunction
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
KMT2D/KDM6A loss in pancreatic beta cells perturbs insulin secretion
regulation, predisposing to congenital hyperinsulinism.
- target: Cochlear outer hair cell dysfunction
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
KMT2D loss in cochlear hair cells contributes to sensorineural
hearing loss independent of structural ear malformation.
evidence:
- reference: PMID:24633898
reference_title: "Molecular analysis, pathogenic mechanisms, and readthrough therapy on a large cohort of Kabuki syndrome patients."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Kabuki syndrome (KS) is a multiple congenital anomalies syndrome
characterized by characteristic facial features and varying degrees of
mental retardation, caused by mutations in KMT2D/MLL2 and KDM6A/UTX
genes.
explanation: Establishes the two principal disease genes and the syndrome's developmental basis.
- reference: PMID:24633898
reference_title: "Molecular analysis, pathogenic mechanisms, and readthrough therapy on a large cohort of Kabuki syndrome patients."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
We found that a number of KMT2D truncating mutations result in mRNA
degradation through the nonsense-mediated mRNA decay, contributing to
protein haploinsufficiency.
explanation: Supports haploinsufficiency as a core molecular mechanism.
- reference: PMID:22197486
reference_title: "Deletion of KDM6A, a histone demethylase interacting with MLL2, in three patients with Kabuki syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Here, we describe three KS individuals with de novo partial or complete
deletions of an X chromosome gene, KDM6A, that encodes a histone
demethylase that interacts with MLL2.
explanation: Connects KDM6A loss to the same chromatin-regulatory disease mechanism.
- reference: PMID:37043208
reference_title: "Characterizing the molecular impact of KMT2D variants on the epigenetic and transcriptional landscapes in Kabuki syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Our analysis identified unique enhancer signatures in H3K4me1 and
H3K4me2 in KS compared with controls.
explanation: Direct human evidence that KMT2D haploinsufficiency disrupts enhancer H3K4me1/me2 signatures in patient PBMCs.
- reference: PMID:37043208
reference_title: "Characterizing the molecular impact of KMT2D variants on the epigenetic and transcriptional landscapes in Kabuki syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
31% of super-enhancers of normal blood cells overlapped with disrupted
enhancers in KS, supporting an association of reduced enhancer activity
of immune-related genes with immune deficiency phenotypes.
explanation: Mechanistically links chromatin dysregulation to the immune phenotype via super-enhancer overlap.
- reference: PMID:28669924
reference_title: "Histone H3 lysine 4 methyltransferase KMT2D."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
KMT2D is a major mammalian H3K4 mono-methyltransferase and co-localizes
with lineage determining transcription factors on transcriptional
enhancers. It is required for the binding of histone H3K27
acetyltransferases CBP and p300 on enhancers, enhancer activation and
cell-type specific gene expression during differentiation.
explanation: Establishes KMT2D's molecular role as an H3K4 mono-methyltransferase coupling enhancer activation with H3K27 acetylation.
- name: Neural crest developmental dysregulation
description: >-
Experimental models indicate that Kabuki syndrome is a neurocristopathy.
Impaired chromatin regulation in neural crest derivatives disrupts
craniofacial morphogenesis, left-sided cardiovascular development, and
postnatal growth, helping explain the characteristic facial gestalt,
congenital heart disease, and growth deficiency seen clinically.
cell_types:
- preferred_term: neural crest cell
term:
id: CL:0011012
label: neural crest cell
- preferred_term: chondrocyte
term:
id: CL:0000138
label: chondrocyte
biological_processes:
- preferred_term: neural crest cell migration
term:
id: GO:0001755
label: neural crest cell migration
- preferred_term: neural crest cell migration involved in heart formation
term:
id: GO:0003147
label: neural crest cell migration involved in heart formation
downstream:
- target: Long Palpebral Fissures
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
description: Disrupted cranial neural crest patterning produces the elongated palpebral fissure phenotype.
- target: Arched Broad Eyebrows
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
description: Altered cranial neural crest morphogenesis contributes to the characteristic eyebrow gestalt.
- target: Cleft Palate
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
description: KMT2D loss in neural crest impairs secondary palatal shelf elevation and ECM expression, producing cleft palate.
- target: Prominent Fingertip Pads
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: Persistent fetal fingertip pads are part of the broader neurocristopathy phenotype but specific molecular intermediates are not fully defined.
- target: Congenital Heart Defects
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
description: Cardiac neural crest dysfunction contributes to outflow-tract and left-sided obstructive lesions.
intermediate_mechanisms:
- Impaired cardiac neural crest migration into outflow tract
- Notch pathway dysregulation during endocardial patterning
evidence:
- reference: PMID:29073101
reference_title: "UTX-guided neural crest function underlies craniofacial features of Kabuki syndrome."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
We now establish Kabuki syndrome as a neurocristopathy, whereby the
majority of clinical features are modeled in mice carrying neural crest
(NC) deletion of UTX, including craniofacial dysmorphism, cardiac
defects, and postnatal growth retardation.
explanation: Supports neural crest dysfunction as a unifying developmental mechanism.
- reference: PMID:31479440
reference_title: "Inhibition of Notch signaling rescues cardiovascular development in Kabuki Syndrome."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Our zebrafish Kabuki Syndrome model reveals a regulatory link between the
Notch pathway and Kmt2d during endothelium and endocardium patterning and
shows that pharmacological inhibition of Notch signaling rebalances Rbpj
protein levels and rescues the cardiovascular phenotype by enhancing
endothelial and endocardial cell proliferation and stabilizing
endocardial patterning.
explanation: Supports a specific cardiovascular mechanism downstream of KMT2D deficiency.
- reference: PMID:32541010
reference_title: "The KMT2D Kabuki syndrome histone methylase controls neural crest cell differentiation and facial morphology."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
KMT2D NCC knockout mice demonstrate hypoplasia with reductions in
frontonasal bone lengths.
explanation: Establishes that conditional KMT2D loss in neural crest is sufficient to produce the craniofacial phenotype.
- reference: PMID:32541010
reference_title: "The KMT2D Kabuki syndrome histone methylase controls neural crest cell differentiation and facial morphology."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
KMT2D NCC loss-of-function does exhibit unique phenotypes distinct from
UTX mutation, including fully penetrant cleft palate, mandible
hypoplasia and deficits in cranial base ossification.
explanation: Identifies KMT2D-specific neural crest phenotypes that distinguish KS1 from KS2.
- reference: PMID:31813957
reference_title: "The histone methyltransferase KMT2D, mutated in Kabuki syndrome patients, is required for neural crest cell formation and migration."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Kmt2d knockdown correlates with a decrease in H3K4 monomethylation and
H3K27 acetylation supporting a role of Kmt2d in the transcriptional
activation of target genes.
explanation: Provides the chromatin-mark mechanism (H3K4me1/H3K27ac loss) by which Kmt2d activates neural crest target genes.
- reference: PMID:31813957
reference_title: "The histone methyltransferase KMT2D, mutated in Kabuki syndrome patients, is required for neural crest cell formation and migration."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Kmt2d loss-of-function inhibits Xenopus Sema3F expression, and
overexpression of Sema3F can partially rescue Kmt2d loss-of-function
defects.
explanation: Identifies Sema3F as a downstream Kmt2d target gene whose restoration rescues neural crest defects.
- reference: PMID:39327125
reference_title: "KMT2D deficiency leads to cellular developmental disorders and enhancer dysregulation in neural-crest-containing brain organoids."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
GREE identified that KMT2D targets a roof-plate-like niche cell and
activates the niche cell-specific WNT3A enhancer, providing the
microenvironment for neural crest and neuronal development.
explanation: Identifies the WNT3A enhancer as a primary KMT2D target whose loss disrupts neural crest and neuronal development.
- name: B-cell terminal differentiation defect
description: >-
KMT2D deficiency impairs terminal B-cell maturation, class-switched memory
B-cell formation, and humoral immune competence. This creates a clinically
important immune phenotype with hypogammaglobulinemia, IgA deficiency,
recurrent infections, and in a subset of patients autoimmune disease.
cell_types:
- preferred_term: B cell
term:
id: CL:0000236
label: B cell
biological_processes:
- preferred_term: B cell differentiation
term:
id: GO:0030183
label: B cell differentiation
- preferred_term: somatic hypermutation of immunoglobulin genes
term:
id: GO:0016446
label: somatic hypermutation of immunoglobulin genes
downstream:
- target: Decreased Serum IgA
causal_link_type: DIRECT
description: Impaired terminal B-cell maturation reduces class-switched IgA-producing plasma cells.
- target: Recurrent Infections
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
description: Hypogammaglobulinemia and impaired class switching predispose to recurrent sinopulmonary and otologic infections.
intermediate_mechanisms:
- Reduced class-switched memory B cells
- Hypogammaglobulinemia
- target: Autoimmunity
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: B-cell tolerance and selection defects predispose a subset of patients to autoimmune cytopenias.
evidence:
- reference: PMID:26194542
reference_title: "Defects of B-cell terminal differentiation in patients with type-1 Kabuki syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Among the patients with KMT2D mutations (KMT2D(Mut/+)),
hypogammaglobulinemia was detected in all but 1 patient, with IgA
deficiency affecting 90% of patients and a deficiency in at least 1 other
isoform seen in 40% of patients.
explanation: Supports a high-burden humoral immunodeficiency phenotype in KMT2D-related disease.
- reference: PMID:26194542
reference_title: "Defects of B-cell terminal differentiation in patients with type-1 Kabuki syndrome."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Impaired terminal differentiation was noted in primary B cells from
patients with KMT2D(Mut/+) mutations.
explanation: Supports a cell-intrinsic B-cell maturation defect.
- reference: PMID:31363182
reference_title: "Immunopathological manifestations in Kabuki syndrome: a registry study of 177 individuals."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Overall, 44.1% (78/177) and 58.2% (46/79) of KS individuals exhibited
infection susceptibility and hypogammaglobulinemia, respectively;
explanation: Confirms that immune dysfunction and autoimmunity are common in a large registry cohort.
- reference: PMID:38765012
reference_title: "KMT2D regulates activation, localization, and integrin expression by T-cells."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
we reveal decreased expression (both at the transcriptional and
translational levels) of a cluster of leukocyte-specific integrins,
which perturb aspects of T-cell activation, maturation,
adhesion/localization, and effector function.
explanation: Extends the immune mechanism beyond B cells, showing KMT2D directly regulates leukocyte integrin expression and T-cell function.
- reference: PMID:38765012
reference_title: "KMT2D regulates activation, localization, and integrin expression by T-cells."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
H3K4me3 ChIP-PCR suggests that these evolutionary similar integrins are
under direct control of KMT2D.
explanation: Direct chromatin evidence (H3K4me3) for KMT2D control of integrin loci in lymphocytes.
- reference: PMID:38765012
reference_title: "KMT2D regulates activation, localization, and integrin expression by T-cells."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
KMT2D deficiency is
associated with the accumulation of murine CD8+ single-positive (SP)
thymocytes and shifts in both human and murine peripheral T-cell
populations, including the reduction of the CD4+ recent thymic emigrant
(RTE) population.
explanation: Shows KMT2D loss perturbs T-cell development (CD8+ single-positive thymocyte accumulation and reduced CD4+ recent thymic emigrants), extending the immune mechanism to thymic T-cell maturation alongside the B-cell defect.
- name: Postnatal neurogenesis deficit
description: >-
Animal data support a chromatin-based neurodevelopmental mechanism in which
reduced KMT2D activity decreases dentate gyrus H3K4me3, impairs postnatal
neurogenesis, and contributes to hippocampal-dependent memory deficits.
cell_types:
- preferred_term: neuron
term:
id: CL:0000540
label: neuron
biological_processes:
- preferred_term: neuron development
term:
id: GO:0048666
label: neuron development
downstream:
- target: Intellectual Disability
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
description: Reduced adult hippocampal neurogenesis contributes to learning and memory deficits underlying intellectual disability.
intermediate_mechanisms:
- Reduced dentate gyrus H3K4me3
- Decreased doublecortin-positive newborn neurons
- target: Speech Delay
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
description: Neurodevelopmental chromatin disruption affecting postnatal neurogenesis contributes to delayed speech and language development beyond purely structural (hearing/oromotor) causes.
- target: Seizures
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: Neuron-specific chromatin disruption may predispose a subset of patients to seizures; precise epileptogenic mechanism in Kabuki syndrome is not fully defined.
evidence:
- reference: PMID:25273096
reference_title: "Histone deacetylase inhibition rescues structural and functional brain deficits in a mouse model of Kabuki syndrome."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
In vivo, deficiency of H3K4me3 in the dentate gyrus granule cell layer of
Kmt2d(+/βGeo) mice correlated with reduced neurogenesis and hippocampal
memory defects.
explanation: Supports a mechanistic link between KMT2D-dependent chromatin defects and cognitive impairment.
- reference: PMID:33738331
reference_title: "Inhibition of KDM1A activity restores adult neurogenesis and improves hippocampal memory in a mouse model of Kabuki syndrome."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
orally administered TAK-418 increases the numbers of newly born
doublecortin (DCX)+ cells and processes in the hippocampus in a
dose-dependent manner.
explanation: Confirms postnatal neurogenesis deficit can be reversed by restoring H3K4 methylation balance via KDM1A inhibition.
- reference: PMID:38702196
reference_title: "Neuron-specific chromatin disruption at CpG islands and aging-related regions in Kabuki syndrome mice."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Neurons, but not B or T cells, show preferential chromatin disruption at
CpG islands and at regulatory elements linked to aging.
explanation: Demonstrates that neuronal chromatin disruption in Kabuki syndrome is cell-type specific and distinct from blood cell episignatures.
- name: Cardiomyocyte gene-expression dysregulation
description: >-
Beyond a neural-crest contribution, KMT2D acts cell-autonomously in cardiac
precursors and cardiomyocytes during cardiogenesis. Myocardial Kmt2d
deletion in mice reduces enhancer/promoter H3K4me1 and H3K4me2, downregulates
ion-transport and cell-cycle genes, and produces altered calcium handling.
Zebrafish models additionally implicate Notch dysregulation during
endocardial patterning, contributing to congenital heart disease.
cell_types:
- preferred_term: cardiac muscle cell
term:
id: CL:0000746
label: cardiac muscle cell
biological_processes:
- preferred_term: heart development
term:
id: GO:0007507
label: heart development
- preferred_term: Notch signaling pathway
term:
id: GO:0007219
label: Notch signaling pathway
- preferred_term: outflow tract morphogenesis
term:
id: GO:0003151
label: outflow tract morphogenesis
downstream:
- target: Congenital Heart Defects
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
description: KMT2D-dependent enhancer activation in cardiomyocytes is required for normal cardiac gene expression; loss produces septal and outflow-tract defects.
intermediate_mechanisms:
- Reduced H3K4me1/me2 at cardiac enhancers
- Dysregulated ion transport and cell-cycle gene expression
- Notch pathway imbalance in endocardium
evidence:
- reference: PMID:26932671
reference_title: "KMT2D regulates specific programs in heart development via histone H3 lysine 4 di-methylation."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
we demonstrate a requirement for KMT2D in cardiac precursors and
cardiomyocytes during cardiogenesis in mice.
explanation: Establishes cell-autonomous KMT2D requirement in cardiomyocytes during heart development.
- reference: PMID:26932671
reference_title: "KMT2D regulates specific programs in heart development via histone H3 lysine 4 di-methylation."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
myocardial Kmt2d deletion led to decreased H3K4me1 and H3K4me2 at
enhancers and promoters.
explanation: Demonstrates the chromatin-level molecular consequence of KMT2D loss in cardiomyocytes.
- reference: PMID:31479440
reference_title: "Inhibition of Notch signaling rescues cardiovascular development in Kabuki Syndrome."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Our zebrafish Kabuki Syndrome model reveals a regulatory link between the
Notch pathway and Kmt2d during endothelium and endocardium patterning
explanation: Implicates Notch dysregulation as a downstream cardiovascular mechanism in Kabuki syndrome.
- reference: PMID:31479440
reference_title: "Inhibition of Notch signaling rescues cardiovascular development in Kabuki Syndrome."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
zebrafish kmt2d null mutants have robust Notch signaling hyperactivation in
endocardial and endothelial cells, including increased protein levels of the
Notch transcription factor Rbpj.
explanation: Specifies the direction of the cardiovascular Notch defect - Kmt2d loss causes Notch pathway hyperactivation with elevated Rbpj in endocardial/endothelial cells, the substrate for the endocardial patterning defect.
- name: Chondrocyte differentiation defect
description: >-
KMT2D is required for hypertrophic chondrocyte differentiation and
endochondral ossification. KS1 and KS2 cellular models exhibit precocious
chondrocyte differentiation, shortened growth-plate hypertrophic zones,
and convergent transcriptomic dysregulation downstream of SOX9 and RUNX2
enhancer programs. This contributes to postnatal growth deficiency,
skeletal anomalies, and cleft palate via cranial-base ossification defects.
cell_types:
- preferred_term: chondrocyte
term:
id: CL:0000138
label: chondrocyte
- preferred_term: hypertrophic chondrocyte
term:
id: CL:0000138
label: chondrocyte
biological_processes:
- preferred_term: chondrocyte differentiation
term:
id: GO:0002062
label: chondrocyte differentiation
- preferred_term: endochondral ossification
term:
id: GO:0001958
label: endochondral ossification
downstream:
- target: Short Stature
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
description: Premature/dysregulated chondrocyte differentiation and shortened growth-plate hypertrophic zones contribute to postnatal growth deficiency.
- target: Cleft Palate
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
description: Cranial-base chondrocyte differentiation defects impair endochondral ossification and palatal shelf elevation.
- target: Scoliosis
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: Generalized chondrocyte differentiation defects contribute to skeletal anomalies including scoliosis.
evidence:
- reference: PMID:38857303
reference_title: "Growth deficiency in a mouse model of Kabuki syndrome 2 bears mechanistic similarities to Kabuki syndrome 1."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Kdm6atm1d/+ growth plates are also shorter, due to decreases in
hypertrophic chondrocyte size and hypertrophic zone height.
explanation: Demonstrates a growth-plate hypertrophic chondrocyte defect underlying KS2 short stature.
- reference: PMID:38857303
reference_title: "Growth deficiency in a mouse model of Kabuki syndrome 2 bears mechanistic similarities to Kabuki syndrome 1."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
RNA-seq simultaneously on Kmt2d-/-, Kdm6a-/-, and control lines at Days 7
and 14 of differentiation. This revealed surprising resemblance in gene
expression between Kmt2d-/- and Kdm6a-/-
explanation: Supports a convergent KS1/KS2 chondrocyte transcriptomic program.
- reference: PMID:38857303
reference_title: "Growth deficiency in a mouse model of Kabuki syndrome 2 bears mechanistic similarities to Kabuki syndrome 1."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
we found that Kdm6a-/- cells undergo premature, enhanced
differentiation towards chondrocytes compared to Kdm6a+/+ controls.
explanation: Direct in vitro evidence that KDM6A loss drives premature, enhanced chondrocyte differentiation, mirroring the precocious differentiation seen in KS1 Kmt2d-/- chondrocytes and underlying the growth-plate defect.
- reference: PMID:32541010
reference_title: "The KMT2D Kabuki syndrome histone methylase controls neural crest cell differentiation and facial morphology."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
KMT2D mutant chondrocytes in the cranial base fail to properly
differentiate, leading to defective endochondral ossification.
explanation: Connects KMT2D loss in chondrocytes to cranial-base ossification defects.
- name: Pancreatic beta-cell dysfunction
description: >-
Pathogenic variants in KMT2D and KDM6A predispose to congenital
hyperinsulinism through dysregulated insulin secretion in pancreatic
beta cells. Hypoglycemia frequently presents in the neonatal period and
is typically diazoxide-responsive.
cell_types:
- preferred_term: pancreatic beta cell
term:
id: CL:0000169
label: type B pancreatic cell
biological_processes:
- preferred_term: insulin secretion
term:
id: GO:0030073
label: insulin secretion
- preferred_term: regulation of insulin secretion
term:
id: GO:0050796
label: regulation of insulin secretion
downstream:
- target: Hyperinsulinemic Hypoglycemia
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: Dysregulated insulin secretion in KMT2D/KDM6A-deficient beta cells produces persistent neonatal hypoglycemia.
evidence:
- reference: PMID:29907798
reference_title: "Congenital hyperinsulinism as the presenting feature of Kabuki syndrome: clinical and molecular characterization of 9 affected individuals."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Molecular diagnoses of KS were established by identification of
pathogenic variants in KMT2D (n = 5) and KDM6A (n = 4).
explanation: Confirms that both KMT2D and KDM6A loss can present with hyperinsulinism, supporting a shared beta-cell mechanism.
- reference: PMID:38859884
reference_title: "Clinical and Molecular Characterization of Hyperinsulinism in Kabuki Syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Diazoxide trial was conducted in 25 children, 92% of whom were
responsive.
explanation: Demonstrates that hyperinsulinism in KS is typically diazoxide-responsive, consistent with a regulatory rather than structural beta-cell defect.
- name: Cochlear outer hair cell dysfunction
description: >-
KMT2D loss causes cell-intrinsic cochlear outer hair cell dysfunction,
contributing to sensorineural hearing loss in addition to the conductive
component from recurrent otitis media. Mouse models show diminished
distortion product otoacoustic emissions despite no gross cochlear
structural malformation on micro-CT.
cell_types:
- preferred_term: outer hair cell of cochlea
term:
id: CL:0000855
label: sensory hair cell
biological_processes:
- preferred_term: inner ear development
term:
id: GO:0048839
label: inner ear development
downstream:
- target: Sensorineural Hearing Loss
causal_link_type: DIRECT
description: KMT2D loss in cochlear hair cells produces cell-intrinsic outer hair cell dysfunction underlying sensorineural hearing loss.
- target: Hearing Impairment
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
description: Combined sensorineural (hair cell) and conductive (recurrent otitis media) components produce the overall Kabuki hearing impairment phenotype.
evidence:
- reference: PMID:38254937
reference_title: "KMT2D Deficiency Causes Sensorineural Hearing Loss in Mice and Humans."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
The KS1 mice also display diminished distortion product otoacoustic
emission levels, which suggests outer hair cell dysfunction.
explanation: Demonstrates a cell-intrinsic outer hair cell mechanism for sensorineural hearing loss in KS1.
- reference: PMID:38254937
reference_title: "KMT2D Deficiency Causes Sensorineural Hearing Loss in Mice and Humans."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
our data suggests that KMT2D dysfunction causes sensorineural hearing
loss compounded with external factors, such as infection.
explanation: Supports a cell-intrinsic chromatin-based mechanism for the sensorineural hearing component of Kabuki syndrome.
phenotypes:
- name: Long Palpebral Fissures
category: Craniofacial
diagnostic: true
description: >-
Long palpebral fissures with eversion of the lateral lower eyelid are a core
component of the characteristic Kabuki facial gestalt.
phenotype_term:
preferred_term: Long palpebral fissure
term:
id: HP:0000637
label: Long palpebral fissure
evidence:
- reference: PMID:30514738
reference_title: "Kabuki syndrome: international consensus diagnostic criteria."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Typical dysmorphic features include long palpebral fissures with eversion
of the lateral third of the lower eyelid and two or more of the
following: (1) arched and broad eyebrows with the lateral third
displaying notching or sparseness; (2) short columella with depressed
nasal tip; (3) large, prominent or cupped ears; and (4) persistent
fingertip pads.
explanation: Supports long palpebral fissures as a defining clinical feature.
- reference: ORPHA:2322
reference_title: "Kabuki syndrome (Orphanet structured-database record)"
supports: SUPPORT
snippet: "HP:0000637 | Long palpebral fissure | Frequent (79-30%)"
explanation: Orphanet classifies long palpebral fissures as frequent in Kabuki syndrome.
- name: Arched Broad Eyebrows
category: Craniofacial
diagnostic: true
description: >-
Arched and broad eyebrows with lateral third notching or sparseness are a
core component of the characteristic Kabuki facial gestalt.
phenotype_term:
preferred_term: Arched broad eyebrows
term:
id: HP:0002553
label: Highly arched eyebrow
evidence:
- reference: PMID:30514738
reference_title: "Kabuki syndrome: international consensus diagnostic criteria."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Typical dysmorphic features include long palpebral fissures with eversion
of the lateral third of the lower eyelid and two or more of the
following: (1) arched and broad eyebrows with the lateral third
displaying notching or sparseness; (2) short columella with depressed
nasal tip; (3) large, prominent or cupped ears; and (4) persistent
fingertip pads.
explanation: Lists arched broad eyebrows as a primary diagnostic dysmorphic feature.
- reference: ORPHA:2322
reference_title: "Kabuki syndrome (Orphanet structured-database record)"
supports: SUPPORT
snippet: "HP:0002553 | Highly arched eyebrow | Very frequent (99-80%)"
explanation: Orphanet classifies highly arched eyebrows as very frequent in Kabuki syndrome.
- name: Intellectual Disability
category: Neurological
frequency: VERY_FREQUENT
description: >-
Developmental delay and usually mild-to-moderate intellectual disability are
central neurodevelopmental manifestations.
phenotype_term:
preferred_term: Intellectual disability
term:
id: HP:0001249
label: Intellectual disability
evidence:
- reference: PMID:30514738
reference_title: "Kabuki syndrome: international consensus diagnostic criteria."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The authors propose that a definitive diagnosis can be made in an
individual of any age with a history of infantile hypotonia,
developmental delay and/or intellectual disability, and one or both of
the following major criteria: (1) a pathogenic or likely pathogenic
variant in KMT2D or KDM6A; and (2) typical dysmorphic features (defined
below) at some point of life.
explanation: Places intellectual disability in the core diagnostic phenotype.
- reference: PMID:15523636
reference_title: "Developmental outcome in Kabuki syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Based on these patients and a review of the literature, in the absence of
major structural brain anomalies, the average intelligence quotient (IQ)
in patients with this condition fall within the mild mental retardation
range, however, specific developmental outcomes are widely variable,
ranging from severe MR to normal intelligence.
explanation: Supports the typical severity range and variable developmental outcome.
- reference: ORPHA:2322
reference_title: "Kabuki syndrome (Orphanet structured-database record)"
supports: SUPPORT
snippet: "HP:0001249 | Intellectual disability | Very frequent (99-80%)"
explanation: Orphanet classifies intellectual disability as very frequent in Kabuki syndrome.
- name: Short Stature
category: Growth
frequency: FREQUENT
description: >-
Postnatal growth deficiency commonly leads to short stature. About 28%
of KS children meet biochemical criteria for growth hormone deficiency,
and growth-plate hypertrophic chondrocyte abnormalities are documented
in both KS1 and KS2 mouse models.
phenotype_term:
preferred_term: Short stature
term:
id: HP:0004322
label: Short stature
evidence:
- reference: PMID:21607748
reference_title: "A mutation screen in patients with Kabuki syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Kabuki syndrome (KS) is one of the classical, clinically well-known
multiple anomalies/mental retardation syndromes, mainly characterized by
a very distinctive facial appearance in combination with additional
clinical signs such as developmental delay, short stature, persistent
fingerpads, and urogenital tract anomalies.
explanation: Supports short stature as a common core feature.
- reference: PMID:27649541
reference_title: "Growth Hormone Stimulation Tests in Children with Kabuki Syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Five of the 18 children (27.8%) were biochemically GH deficient.
explanation: Documents biochemical GH deficiency in approximately one-quarter of KS children studied, supporting an endocrine contribution to short stature.
- reference: ORPHA:2322
reference_title: "Kabuki syndrome (Orphanet structured-database record)"
supports: SUPPORT
snippet: "HP:0004322 | Short stature | Frequent (79-30%)"
explanation: Orphanet classifies short stature as frequent in Kabuki syndrome.
- name: Hypotonia
category: Neurological
frequency: FREQUENT
description: >-
Infantile hypotonia is part of the consensus clinical definition and
contributes to motor delay and feeding difficulties. Reported in 69.6%
of a Taiwanese KMT2D cohort.
phenotype_term:
preferred_term: Hypotonia
term:
id: HP:0001252
label: Hypotonia
evidence:
- reference: PMID:30514738
reference_title: "Kabuki syndrome: international consensus diagnostic criteria."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The authors propose that a definitive diagnosis can be made in an
individual of any age with a history of infantile hypotonia,
developmental delay and/or intellectual disability, and one or both of
the following major criteria: (1) a pathogenic or likely pathogenic
variant in KMT2D or KDM6A; and (2) typical dysmorphic features (defined
below) at some point of life.
explanation: Supports hypotonia as a core early-life phenotype.
- reference: ORPHA:2322
reference_title: "Kabuki syndrome (Orphanet structured-database record)"
supports: SUPPORT
snippet: "HP:0001252 | Hypotonia | Frequent (79-30%)"
explanation: Orphanet classifies hypotonia as frequent in Kabuki syndrome.
- name: Congenital Heart Defects
category: Cardiovascular
frequency: FREQUENT
description: >-
Congenital heart disease is common in Kabuki syndrome, especially
left-sided obstructive lesions and septal defects. Detected in 70% of
KMT2D-positive patients in one cohort and 69.6% in a Taiwanese
23-patient series.
phenotype_term:
preferred_term: Abnormal heart morphology
term:
id: HP:0001627
label: Abnormal heart morphology
evidence:
- reference: PMID:28884922
reference_title: "Congenital heart defects in molecularly proven Kabuki syndrome patients."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
In conclusion, a CHD is detected in 70% of patients with KMT2D (MLL2)
pathogenic variants, most commonly left-sided obstructive lesions,
including multiple left-sided obstructions similar to those observed in
the spectrum of the Shone complex, and septal defects.
explanation: Supports congenital heart disease as a frequent and clinically important manifestation.
- reference: ORPHA:2322
reference_title: "Kabuki syndrome (Orphanet structured-database record)"
supports: SUPPORT
snippet: "HP:0001627 | Abnormal heart morphology | Frequent (79-30%)"
explanation: Orphanet classifies abnormal heart morphology as frequent in Kabuki syndrome.
- name: Decreased Serum IgA
category: Immunological
frequency: VERY_FREQUENT
description: >-
Humoral immune dysfunction often includes decreased serum IgA levels with
broader hypogammaglobulinemia in a subset of patients. IgA deficiency
affects 90% of KMT2D-positive patients in a French cohort, and
hypogammaglobulinemia 58.2% in a 177-patient registry.
phenotype_term:
preferred_term: Decreased serum IgA
term:
id: HP:0002720
label: Decreased circulating IgA concentration
evidence:
- reference: PMID:26194542
reference_title: "Defects of B-cell terminal differentiation in patients with type-1 Kabuki syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Among the patients with KMT2D mutations (KMT2D(Mut/+)),
hypogammaglobulinemia was detected in all but 1 patient, with IgA
deficiency affecting 90% of patients and a deficiency in at least 1 other
isoform seen in 40% of patients.
explanation: Supports IgA deficiency as a prevalent immunologic phenotype.
- reference: ORPHA:2322
reference_title: "Kabuki syndrome (Orphanet structured-database record)"
supports: PARTIAL
snippet: "HP:0002720 | Decreased circulating IgA level | Occasional (29-5%)"
explanation: >-
Orphanet classifies decreased circulating IgA as occasional (29-5%).
This frequency estimate is lower than the 90% IgA deficiency rate
reported in molecularly confirmed KMT2D cohorts (PMID:26194542),
possibly reflecting ascertainment differences.
- name: Recurrent Infections
category: Immunological
frequency: FREQUENT
description: >-
Recurrent sinopulmonary and otologic infections are common clinical
consequences of the associated antibody deficiency. Reported in 44.1%
of a 177-patient KS registry and 65.2% of a 23-patient Taiwanese
cohort.
phenotype_term:
preferred_term: Recurrent infections
term:
id: HP:0002719
label: Recurrent infections
evidence:
- reference: PMID:31363182
reference_title: "Immunopathological manifestations in Kabuki syndrome: a registry study of 177 individuals."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Overall, 44.1% (78/177) and 58.2% (46/79) of KS individuals exhibited
infection susceptibility and hypogammaglobulinemia, respectively;
explanation: Supports recurrent infection susceptibility in a large cohort.
- reference: ORPHA:2322
reference_title: "Kabuki syndrome (Orphanet structured-database record)"
supports: SUPPORT
snippet: "HP:0002719 | Recurrent infections | Frequent (79-30%)"
explanation: Orphanet classifies recurrent infections as frequent in Kabuki syndrome.
- name: Prominent Fingertip Pads
category: Musculoskeletal
diagnostic: true
description: >-
Persistent fetal fingertip pads are a hallmark feature included in the
consensus diagnostic criteria.
phenotype_term:
preferred_term: Prominent fingertip pads
term:
id: HP:0001212
label: Prominent fingertip pads
evidence:
- reference: PMID:30514738
reference_title: "Kabuki syndrome: international consensus diagnostic criteria."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Typical dysmorphic features include long palpebral fissures with eversion
of the lateral third of the lower eyelid and two or more of the
following: (1) arched and broad eyebrows with the lateral third
displaying notching or sparseness; (2) short columella with depressed
nasal tip; (3) large, prominent or cupped ears; and (4) persistent
fingertip pads.
explanation: Persistent fingertip pads are listed as one of the core diagnostic dysmorphic features.
- reference: ORPHA:2322
reference_title: "Kabuki syndrome (Orphanet structured-database record)"
supports: SUPPORT
snippet: "HP:0001212 | Prominent fingertip pads | Frequent (79-30%)"
explanation: Orphanet classifies prominent fingertip pads as frequent in Kabuki syndrome.
- name: Scoliosis
category: Musculoskeletal
description: >-
Skeletal anomalies including scoliosis are well-documented manifestations
of Kabuki syndrome, linked to altered neural crest and chondrocyte
development.
phenotype_term:
preferred_term: Scoliosis
term:
id: HP:0002650
label: Scoliosis
evidence:
- reference: PMID:33805950
reference_title: "Kabuki Syndrome-Clinical Review with Molecular Aspects."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
hypertrichosis and scoliosis.
explanation: Lists scoliosis among the core skeletal manifestations of Kabuki syndrome in a clinical/molecular review.
- reference: PMID:11343317
reference_title: "Congenital heart defects in Kabuki syndrome."
supports: PARTIAL
evidence_source: HUMAN_CLINICAL
snippet: >-
Kabuki makeup (Niikawa-Kuroki) syndrome (KS) is characterized by
distinct facial anomalies, mental retardation, congenital heart defect
(CHD), and skeletal malformations.
explanation: >-
Supports skeletal malformations broadly as a cardinal KS feature;
scoliosis is a documented manifestation but not specifically named
in this CHD-focused paper.
- reference: ORPHA:2322
reference_title: "Kabuki syndrome (Orphanet structured-database record)"
supports: SUPPORT
snippet: "HP:0002650 | Scoliosis | Frequent (79-30%)"
explanation: Orphanet classifies scoliosis as frequent in Kabuki syndrome.
- name: Hearing Impairment
category: Otological
frequency: FREQUENT
description: >-
Hearing loss is common in Kabuki syndrome and combines conductive
components (driven by recurrent otitis media) with cell-intrinsic
sensorineural components (cochlear outer hair cell dysfunction). Mean
age of presentation is approximately 7 years; reported in 39.1% of a
Taiwanese cohort.
phenotype_term:
preferred_term: Hearing impairment
term:
id: HP:0000365
label: Hearing impairment
evidence:
- reference: PMID:34570271
reference_title: "Kidney and urinary tract findings among patients with Kabuki (make-up) syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Kabuki syndrome (KS) is a genetic disorder caused mainly by de novo
pathogenic variants in KMT2D or KDM6A, characterized by recognizable
facial features, intellectual disability, and multi-systemic involvement,
including short stature, microcephaly, hearing loss, cardiac defects, and
additional congenital anomalies.
explanation: Identifies hearing loss as a recognized multisystem feature.
- reference: PMID:15523636
reference_title: "Developmental outcome in Kabuki syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The presence or absence of hearing loss or major malformations, other
than those involving the brain, was not predictive of developmental
outcome.
explanation: Acknowledges hearing loss as a feature while noting it does not predict cognitive outcome.
- reference: PMID:38254937
reference_title: "KMT2D Deficiency Causes Sensorineural Hearing Loss in Mice and Humans."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
individuals have both sensorineural and conductive hearing loss, with
the average age of presentation being 7 years.
explanation: Documents the mixed conductive/sensorineural character of Kabuki hearing loss with mean age of presentation around 7 years.
- reference: PMID:39202303
reference_title: "Genetic and Phenotypic Spectrum of KMT2D Variants in Taiwanese Case Series of Kabuki Syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Other abnormalities included hearing loss (39.1%), seizures (26.1%),
cleft palate (26.1%), and renal anomalies (21.7%).
explanation: Quantifies hearing loss prevalence at 39.1% in a 23-patient Taiwanese KMT2D cohort.
- reference: ORPHA:2322
reference_title: "Kabuki syndrome (Orphanet structured-database record)"
supports: SUPPORT
snippet: "HP:0000405 | Conductive hearing impairment | Frequent (79-30%)"
explanation: Orphanet classifies conductive hearing impairment as frequent in Kabuki syndrome.
- reference: ORPHA:2322
reference_title: "Kabuki syndrome (Orphanet structured-database record)"
supports: SUPPORT
snippet: "HP:0000407 | Sensorineural hearing impairment | Frequent (79-30%)"
explanation: Orphanet classifies sensorineural hearing impairment as frequent in Kabuki syndrome.
- name: Cleft Palate
category: Craniofacial
description: >-
Cleft palate occurs in a subset of patients, consistent with the
neurocristopathy and chondrocyte-differentiation mechanisms. Reported
at 26.1% in a Taiwanese cohort. Mouse models with conditional KMT2D
loss in neural crest exhibit fully penetrant cleft palate driven by
defective secondary palatal shelf elevation and cranial-base
ossification deficits.
phenotype_term:
preferred_term: Cleft palate
term:
id: HP:0000175
label: Cleft palate
evidence:
- reference: PMID:39202303
reference_title: "Genetic and Phenotypic Spectrum of KMT2D Variants in Taiwanese Case Series of Kabuki Syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Other abnormalities included hearing loss (39.1%), seizures (26.1%),
cleft palate (26.1%), and renal anomalies (21.7%).
explanation: Documents cleft palate prevalence at 26.1% in a 23-patient KMT2D cohort.
- reference: PMID:32541010
reference_title: "The KMT2D Kabuki syndrome histone methylase controls neural crest cell differentiation and facial morphology."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
KMT2D mutant NCCs lead to defective secondary palatal shelf elevation
with reduced expression of extracellular matrix components.
explanation: Identifies the developmental mechanism (palatal shelf elevation defect) underlying the cleft palate phenotype.
- reference: ORPHA:2322
reference_title: "Kabuki syndrome (Orphanet structured-database record)"
supports: SUPPORT
snippet: "HP:0000175 | Cleft palate | Frequent (79-30%)"
explanation: Orphanet classifies cleft palate as frequent in Kabuki syndrome.
- reference: PMID:17105332
reference_title: "Cleft palate in Kabuki syndrome: a report of six cases."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Although cleft palate is a feature that is sometimes observed in patients
with Kabuki syndrome, there are few clinical reports of cleft palate
associated with Kabuki syndrome.
explanation: Supports cleft palate as a recognized craniofacial manifestation of Kabuki syndrome.
- name: Congenital Anomalies of the Kidney and Urinary Tract
category: Genitourinary
description: >-
Renal and urinary tract malformations are frequent, ranging from
hydronephrosis and double collecting systems to horseshoe kidney
and kidney agenesis.
phenotype_term:
preferred_term: Abnormality of the urinary system
term:
id: HP:0000079
label: Abnormality of the urinary system
evidence:
- reference: PMID:34570271
reference_title: "Kidney and urinary tract findings among patients with Kabuki (make-up) syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
CAKUT were detected in 8/13 (61.5%) of patients and varied from
hypospadias, hydronephrosis, or double collecting systems to pelvic
kidney, kidney asymmetry, horseshoe kidney, or kidney agenesis.
explanation: Demonstrates a high prevalence of CAKUT in a single-center cohort of KS patients.
- reference: PMID:21607748
reference_title: "A mutation screen in patients with Kabuki syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
MLL2 mutation carriers significantly more often presented with short
stature and renal anomalies (p = 0.026 and 0.031, respectively)
explanation: Renal anomalies are significantly associated with KMT2D mutation-positive patients.
- reference: ORPHA:2322
reference_title: "Kabuki syndrome (Orphanet structured-database record)"
supports: SUPPORT
snippet: "HP:0000079 | Abnormality of the urinary system | Frequent (79-30%)"
explanation: Orphanet classifies urinary system abnormalities as frequent in Kabuki syndrome.
- name: Autoimmunity
category: Immunological
description: >-
A subset of patients develop autoimmune manifestations including
immune thrombocytopenic purpura, autoimmune hemolytic anemia, and
vitiligo, reflecting the paradox of concurrent immunodeficiency and
immune dysregulation. Registry data quantify autoimmune disease in
13.6% overall and 25.6% of adults.
phenotype_term:
preferred_term: Autoimmunity
term:
id: HP:0002960
label: Autoimmunity
evidence:
- reference: PMID:31363182
reference_title: "Immunopathological manifestations in Kabuki syndrome: a registry study of 177 individuals."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
13.6% (24/177) had autoimmune disease
explanation: Quantifies autoimmune disease prevalence in a 177-patient KS registry.
- reference: PMID:31363182
reference_title: "Immunopathological manifestations in Kabuki syndrome: a registry study of 177 individuals."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The most frequent AID manifestations were immune
thrombocytopenic purpura
explanation: Identifies immune thrombocytopenic purpura as the most common autoimmune manifestation in KS.
- reference: PMID:31363182
reference_title: "Immunopathological manifestations in Kabuki syndrome: a registry study of 177 individuals."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Among nonhematological manifestations, vitiligo was frequent.
explanation: Documents vitiligo as a frequent non-hematological autoimmune manifestation in KS.
- name: Hyperinsulinemic Hypoglycemia
category: Endocrine
description: >-
Congenital hyperinsulinism causing persistent neonatal hypoglycemia is a
recognized presenting feature of Kabuki syndrome. Reported in both KMT2D
and KDM6A patients, frequently diazoxide-responsive.
phenotype_term:
preferred_term: Hyperinsulinemic hypoglycemia
term:
id: HP:0000825
label: Hyperinsulinemic hypoglycemia
evidence:
- reference: PMID:29907798
reference_title: "Congenital hyperinsulinism as the presenting feature of Kabuki syndrome: clinical and molecular characterization of 9 affected individuals."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The incidence of HI among patients with KS may be higher than
previously reported, and KS may account for as much as 1% of patients
diagnosed with HI.
explanation: Establishes congenital hyperinsulinism as a recognized presenting feature of Kabuki syndrome.
- reference: ORPHA:2322
reference_title: "Kabuki syndrome (Orphanet structured-database record)"
supports: SUPPORT
snippet: "HP:0000825 | Hyperinsulinemic hypoglycemia | Very rare (<4-1%)"
explanation: Orphanet classifies hyperinsulinemic hypoglycemia as very rare in Kabuki syndrome.
- reference: PMID:38859884
reference_title: "Clinical and Molecular Characterization of Hyperinsulinism in Kabuki Syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Hypoglycemia was recognized on the first day of life in 25 children
(76%).
explanation: Documents hyperinsulinism timing and prevalence in a 33-patient KS cohort, with 92% diazoxide responsiveness.
- name: Sensorineural Hearing Loss
category: Otological
description: >-
Sensorineural hearing loss is documented in Kabuki syndrome and arises
from cochlear hair cell dysfunction independent of recurrent otitis
media or structural ear anomalies. Mouse models show diminished
distortion product otoacoustic emissions consistent with outer hair
cell dysfunction.
phenotype_term:
preferred_term: Sensorineural hearing impairment
term:
id: HP:0000407
label: Sensorineural hearing impairment
evidence:
- reference: PMID:38254937
reference_title: "KMT2D Deficiency Causes Sensorineural Hearing Loss in Mice and Humans."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
individuals have both sensorineural and conductive hearing loss, with
the average age of presentation being 7 years.
explanation: Documents sensorineural hearing loss as a recurring component of the Kabuki hearing phenotype.
- reference: PMID:38254937
reference_title: "KMT2D Deficiency Causes Sensorineural Hearing Loss in Mice and Humans."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
The KS1 mice also display diminished distortion product otoacoustic
emission levels, which suggests outer hair cell dysfunction.
explanation: Supports a cell-intrinsic outer hair cell mechanism for sensorineural hearing loss.
- name: Seizures
category: Neurological
frequency: OCCASIONAL
description: >-
Seizures occur in a minority of patients with Kabuki syndrome,
reported at 26.1% in a Taiwanese cohort.
phenotype_term:
preferred_term: Seizure
term:
id: HP:0001250
label: Seizure
evidence:
- reference: PMID:39202303
reference_title: "Genetic and Phenotypic Spectrum of KMT2D Variants in Taiwanese Case Series of Kabuki Syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Other abnormalities included hearing loss (39.1%), seizures (26.1%),
cleft palate (26.1%), and renal anomalies (21.7%).
explanation: Quantifies seizure prevalence at 26.1% in a 23-patient Taiwanese KS cohort.
- reference: ORPHA:2322
reference_title: "Kabuki syndrome (Orphanet structured-database record)"
supports: SUPPORT
snippet: "HP:0001250 | Seizure | Occasional (29-5%)"
explanation: Orphanet classifies seizures as occasional in Kabuki syndrome.
- name: Speech Delay
category: Neurological
frequency: VERY_FREQUENT
description: >-
Delayed speech and language development is a near-universal feature of
Kabuki syndrome, reported in 78.3% of a 23-patient Taiwanese cohort.
Reflects both intellectual disability and the structural/oromotor
contributions of cleft palate, hearing loss, and hypotonia.
phenotype_term:
preferred_term: Speech delay
term:
id: HP:0000750
label: Delayed speech and language development
evidence:
- reference: PMID:39202303
reference_title: "Genetic and Phenotypic Spectrum of KMT2D Variants in Taiwanese Case Series of Kabuki Syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The most common clinical characteristics included distinct facial
features (100%), intellectual disability (100%), developmental delay
(95.7%), speech delay (78.3%), hypotonia (69.6%), congenital heart
abnormalities (69.6%), and recurrent infections (65.2%).
explanation: Quantifies speech delay at 78.3% in a 23-patient Taiwanese KS cohort.
- reference: ORPHA:2322
reference_title: "Kabuki syndrome (Orphanet structured-database record)"
supports: SUPPORT
snippet: "HP:0012758 | Neurodevelopmental delay | Very frequent (99-80%)"
explanation: Orphanet classifies neurodevelopmental delay (encompassing speech delay) as very frequent in Kabuki syndrome.
- name: Feeding Difficulties
category: Gastrointestinal
frequency: FREQUENT
description: >-
Feeding difficulties are common in infancy and early childhood, often
requiring thickened feeds and positioning strategies.
phenotype_term:
preferred_term: Feeding difficulties
term:
id: HP:0011968
label: Feeding difficulties
evidence:
- reference: ORPHA:2322
reference_title: "Kabuki syndrome (Orphanet structured-database record)"
supports: SUPPORT
snippet: "HP:0011968 | Feeding difficulties | Frequent (79-30%)"
explanation: Orphanet classifies feeding difficulties as frequent in Kabuki syndrome.
- name: Failure to Thrive
category: Growth
frequency: FREQUENT
description: >-
Failure to thrive in infancy is common in Kabuki syndrome,
often preceding a shift to overweight or obesity in later childhood.
phenotype_term:
preferred_term: Failure to thrive
term:
id: HP:0001508
label: Failure to thrive
evidence:
- reference: ORPHA:2322
reference_title: "Kabuki syndrome (Orphanet structured-database record)"
supports: SUPPORT
snippet: "HP:0001508 | Failure to thrive | Frequent (79-30%)"
explanation: Orphanet classifies failure to thrive as frequent in Kabuki syndrome.
- reference: PMID:15108197
reference_title: "Growth, behavior, and clinical findings in 27 patients with Kabuki (Niikawa-Kuroki) syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Six of these eight patients had failure to thrive in infancy.
explanation: Documents failure to thrive in infancy in over half of patients studied.
- name: Joint Hypermobility
category: Musculoskeletal
frequency: FREQUENT
description: >-
Joint hypermobility and laxity are frequently observed, contributing
to motor delays and joint dislocations.
phenotype_term:
preferred_term: Joint hypermobility
term:
id: HP:0001382
label: Joint hypermobility
evidence:
- reference: ORPHA:2322
reference_title: "Kabuki syndrome (Orphanet structured-database record)"
supports: SUPPORT
snippet: "HP:0001382 | Joint hypermobility | Frequent (79-30%)"
explanation: Orphanet classifies joint hypermobility as frequent in Kabuki syndrome.
- name: Strabismus
category: Ophthalmological
frequency: FREQUENT
description: >-
Strabismus is a frequent ophthalmological finding in Kabuki syndrome.
phenotype_term:
preferred_term: Strabismus
term:
id: HP:0000486
label: Strabismus
evidence:
- reference: ORPHA:2322
reference_title: "Kabuki syndrome (Orphanet structured-database record)"
supports: SUPPORT
snippet: "HP:0000486 | Strabismus | Frequent (79-30%)"
explanation: Orphanet classifies strabismus as frequent in Kabuki syndrome.
- reference: PMID:21882399
reference_title: "Kabuki Syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
ptosis and strabismus, and widely spaced teeth and hypodontia.
explanation: GeneReviews lists strabismus among recognized Kabuki syndrome findings.
- name: Ptosis
category: Ophthalmological
frequency: FREQUENT
description: >-
Ptosis is a frequently reported ophthalmological feature of Kabuki
syndrome.
phenotype_term:
preferred_term: Ptosis
term:
id: HP:0000508
label: Ptosis
evidence:
- reference: ORPHA:2322
reference_title: "Kabuki syndrome (Orphanet structured-database record)"
supports: SUPPORT
snippet: "HP:0000508 | Ptosis | Frequent (79-30%)"
explanation: Orphanet classifies ptosis as frequent in Kabuki syndrome.
- reference: PMID:21882399
reference_title: "Kabuki Syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
ptosis and strabismus, and widely spaced teeth and hypodontia.
explanation: GeneReviews lists ptosis among recognized Kabuki syndrome findings.
- name: Premature Thelarche
category: Endocrine
frequency: FREQUENT
description: >-
Premature breast development (isolated premature thelarche) is
frequently reported in female infants and young girls with Kabuki
syndrome.
phenotype_term:
preferred_term: Premature thelarche
term:
id: HP:0010314
label: Premature thelarche
evidence:
- reference: ORPHA:2322
reference_title: "Kabuki syndrome (Orphanet structured-database record)"
supports: SUPPORT
snippet: "HP:0010314 | Premature thelarche | Frequent (79-30%)"
explanation: Orphanet classifies premature thelarche as frequent in Kabuki syndrome.
- reference: PMID:3067577
reference_title: "Kabuki make-up (Niikawa-Kuroki) syndrome: a study of 62 patients."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
early breast development in infant girls (23%)
explanation: Niikawa et al. documented premature thelarche in 23% of the original 62-patient cohort.
- name: Cryptorchidism
category: Genitourinary
frequency: OCCASIONAL
description: >-
Cryptorchidism is an occasional genitourinary finding in males
with Kabuki syndrome.
phenotype_term:
preferred_term: Cryptorchidism
term:
id: HP:0000028
label: Cryptorchidism
evidence:
- reference: ORPHA:2322
reference_title: "Kabuki syndrome (Orphanet structured-database record)"
supports: SUPPORT
snippet: "HP:0000028 | Cryptorchidism | Occasional (29-5%)"
explanation: Orphanet classifies cryptorchidism as occasional in Kabuki syndrome.
- name: Obesity
category: Growth
frequency: OCCASIONAL
description: >-
Obesity may develop in later childhood or adolescence, often
following infantile failure to thrive.
phenotype_term:
preferred_term: Obesity
term:
id: HP:0001513
label: Obesity
evidence:
- reference: ORPHA:2322
reference_title: "Kabuki syndrome (Orphanet structured-database record)"
supports: SUPPORT
snippet: "HP:0001513 | Obesity | Occasional (29-5%)"
explanation: Orphanet classifies obesity as occasional in Kabuki syndrome.
- reference: PMID:15108197
reference_title: "Growth, behavior, and clinical findings in 27 patients with Kabuki (Niikawa-Kuroki) syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Eight of 14 patients over the age of 5 years were overweight or obese.
explanation: Documents the characteristic growth trajectory from infantile failure to thrive to later obesity.
- name: Abnormal Dental Morphology
category: Craniofacial
frequency: FREQUENT
description: >-
Dental anomalies including hypodontia, widely spaced teeth, and
microdontia are frequent findings in Kabuki syndrome.
phenotype_term:
preferred_term: Abnormal dental morphology
term:
id: HP:0006482
label: Abnormal dental morphology
evidence:
- reference: ORPHA:2322
reference_title: "Kabuki syndrome (Orphanet structured-database record)"
supports: SUPPORT
snippet: "HP:0006482 | Abnormal dental morphology | Frequent (79-30%)"
explanation: Orphanet classifies abnormal dental morphology as frequent in Kabuki syndrome.
- reference: PMID:21882399
reference_title: "Kabuki Syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
widely spaced teeth and hypodontia.
explanation: GeneReviews lists dental anomalies among recognized Kabuki syndrome findings.
- name: Gastroesophageal Reflux
category: Gastrointestinal
frequency: OCCASIONAL
description: >-
Gastroesophageal reflux is an occasional finding, particularly in
infancy, often concurrent with feeding difficulties.
phenotype_term:
preferred_term: Gastroesophageal reflux
term:
id: HP:0002020
label: Gastroesophageal reflux
evidence:
- reference: ORPHA:2322
reference_title: "Kabuki syndrome (Orphanet structured-database record)"
supports: SUPPORT
snippet: "HP:0002020 | Gastroesophageal reflux | Occasional (29-5%)"
explanation: Orphanet classifies gastroesophageal reflux as occasional in Kabuki syndrome.
- reference: PMID:21882399
reference_title: "Kabuki Syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Thickened feedings and positioning after meals to treat gastroesophageal reflux
explanation: GeneReviews recommends management of gastroesophageal reflux as part of Kabuki syndrome care.
prevalence:
- population: Worldwide
measure_type: BIRTH_PREVALENCE
prevalence_class: BAND_1_9_PER_100000
rate_per_100000: 3.0
percentage: 0.003
notes: >-
Estimated prevalence of approximately 1 in 32,000 live births. This is
likely an underestimate as milder cases may go undiagnosed.
evidence:
- reference: ORPHA:2322
reference_title: "Kabuki syndrome (Orphanet structured-database record)"
supports: SUPPORT
snippet: "1-9 / 100 000 | Japan | Prevalence at birth | PMID:3067577"
explanation: Orphanet cites prevalence at birth of 1-9 per 100,000 in Japan.
- reference: ORPHA:2322
reference_title: "Kabuki syndrome (Orphanet structured-database record)"
supports: SUPPORT
snippet: "1-9 / 100 000 | Australia | Prevalence at birth | PMID:15108197"
explanation: Orphanet cites prevalence at birth of 1-9 per 100,000 in Australia.
- reference: ORPHA:2322
reference_title: "Kabuki syndrome (Orphanet structured-database record)"
supports: SUPPORT
snippet: "1-9 / 100 000 | Europe | Point prevalence | EXPERT,PMID:21882399"
explanation: Orphanet cites a European point prevalence of 1-9 per 100,000.
- reference: PMID:3067577
reference_title: "Kabuki make-up (Niikawa-Kuroki) syndrome: a study of 62 patients."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
It was estimated that its prevalence in Japanese newborn infants is
1/32,000.
explanation: Original Japanese epidemiological estimate of 1 in 32,000 live births.
- reference: PMID:15108197
reference_title: "Growth, behavior, and clinical findings in 27 patients with Kabuki (Niikawa-Kuroki) syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The minimum birth prevalence was calculated at 1 in 86,000.
explanation: Australian/New Zealand estimate of minimum birth prevalence at 1 in 86,000.
datasets:
- accession: geo:GSE149688
title: The KMT2D Kabuki syndrome histone methylase controls neural crest cell differentiation and facial morphology
description: >-
RNA-seq from E14.25 wild-type and Kmt2d neural crest cell knockout mouse
palatal shelves, supporting analysis of KMT2D-dependent craniofacial
developmental gene expression.
organism:
preferred_term: mouse
term:
id: NCBITaxon:10090
label: Mus musculus
data_type: BULK_RNA_SEQ
conditions:
- E14.25 wild-type palatal shelves
- E14.25 Kmt2d neural crest cell knockout palatal shelves
publication: PMID:32541010
notes: >-
GEO series linked to the KMT2D neural crest and palatal shelf model used to
study craniofacial features of Kabuki syndrome.
evidence:
- reference: PMID:32541010
reference_title: "The KMT2D Kabuki syndrome histone methylase controls neural crest cell differentiation and facial morphology."
supports: PARTIAL
evidence_source: MODEL_ORGANISM
snippet: >-
We mutated KMT2D in neural crest cells (NCCs) to study cellular and
molecular functions in craniofacial development with respect to UTX.
explanation: >-
Supports the mouse neural crest experimental context for this GEO RNA-seq
dataset; the GEO accession identifies the deposited series.
treatments:
- name: HDAC Inhibitor Therapy (Experimental)
description: >-
Histone deacetylase inhibitors such as AR-42 have shown preclinical
promise in rescuing structural and functional brain deficits in Kmt2d
haploinsufficient mouse models. By promoting histone acetylation, HDAC
inhibitors can partially compensate for the reduced H3K4 methylation
caused by KMT2D deficiency.
treatment_term:
preferred_term: HDAC inhibitor therapy
term:
id: NCIT:C15986
label: Pharmacotherapy
target_mechanisms:
- target: Postnatal neurogenesis deficit
treatment_effect: RESTORES
description: HDAC inhibition increases histone acetylation, partially compensating for reduced H3K4 methylation and rescuing adult neurogenesis.
evidence:
- reference: PMID:25273096
reference_title: "Histone deacetylase inhibition rescues structural and functional brain deficits in a mouse model of Kabuki syndrome."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
These abnormalities improved upon postnatal treatment with AR-42.
explanation: Demonstrates rescue of neurogenesis-related abnormalities by HDAC inhibition.
evidence:
- reference: PMID:25273096
reference_title: "Histone deacetylase inhibition rescues structural and functional brain deficits in a mouse model of Kabuki syndrome."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
These abnormalities improved upon postnatal treatment with AR-42. Our
work suggests that a reversible deficiency in postnatal neurogenesis
underlies intellectual disability in Kabuki syndrome.
explanation: >-
Demonstrates that HDAC inhibitor treatment can rescue neurogenesis and
memory deficits in a Kabuki syndrome mouse model.
- name: Growth Hormone Therapy
description: >-
Growth hormone replacement may be considered for patients with
documented growth hormone deficiency contributing to postnatal growth
retardation.
treatment_term:
preferred_term: Growth hormone replacement therapy
term:
id: MAXO:0000780
label: human growth hormone replacement therapy
target_mechanisms:
- target: Chondrocyte differentiation defect
treatment_effect: BYPASSES
description: Exogenous GH/IGF-1 stimulation drives chondrocyte proliferation at the growth plate, partially bypassing the KMT2D/KDM6A-dependent enhancer defect in chondrocyte differentiation.
notes: >-
Short stature is a core feature of KS. Growth hormone therapy has been
used in patients with documented GH deficiency, though abstract-level
evidence for efficacy is limited.
evidence:
- reference: PMID:28793284
reference_title: "Growth Hormone Therapy in Children with Kabuki Syndrome: 1-year Treatment Results."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
All participants experienced catch-up growth during the year of rhGH
treatment, but without an influence on body proportions.
explanation: Supports recombinant human growth hormone as a treatment that can improve linear growth in children with Kabuki syndrome.
- name: Speech Therapy
description: >-
Speech and language therapy is an important component of developmental
support given the high prevalence of speech delay and intellectual
disability.
treatment_term:
preferred_term: Speech therapy
term:
id: MAXO:0000930
label: speech therapy
evidence:
- reference: PMID:15523636
reference_title: "Developmental outcome in Kabuki syndrome."
supports: PARTIAL
evidence_source: HUMAN_CLINICAL
snippet: >-
Based on these patients and a review of the literature, in the absence
of major structural brain anomalies, the average intelligence quotient
(IQ) in patients with this condition fall within the mild mental
retardation range, however, specific developmental outcomes are widely
variable, ranging from severe MR to normal intelligence.
explanation: >-
Supports significant developmental variability warranting early
intervention; speech therapy specifically is not discussed in this paper.
- name: Cardiac Surgery
description: >-
Surgical repair of congenital heart defects including septal defects,
coarctation of the aorta, and other structural cardiac anomalies.
treatment_term:
preferred_term: Cardiac surgery
term:
id: MAXO:0025001
label: surgical procedure on cardiovascular system
target_mechanisms:
- target: Cardiomyocyte gene-expression dysregulation
treatment_effect: BYPASSES
description: Surgical repair corrects the structural consequence of cardiomyocyte and neural crest developmental defects without addressing the upstream chromatin mechanism.
- target: Neural crest developmental dysregulation
treatment_effect: BYPASSES
description: Surgery addresses outflow-tract and septal defects produced by cardiac neural crest dysfunction.
evidence:
- reference: PMID:11343317
reference_title: "Congenital heart defects in Kabuki syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
CHD was diagnosed in 35 (58%) of our patients. Aortic coarctation (COA)
(23%), atrial septal defect (ASD) (20%), and ventricular septal defect
(VSD) (17%) were the most frequent CHDs
explanation: >-
High frequency of congenital heart defects necessitates surgical
evaluation and repair.
- name: Immunoglobulin Replacement
description: >-
Intravenous or subcutaneous immunoglobulin replacement therapy for
patients with severe hypogammaglobulinemia and recurrent infections.
treatment_term:
preferred_term: Immunoglobulin replacement therapy
term:
id: MAXO:0001480
label: immunoglobulin infusion therapy
therapeutic_agent:
- preferred_term: therapeutic immune globulin
term:
id: NCIT:C2701
label: Therapeutic Immune Globulin
target_mechanisms:
- target: B-cell terminal differentiation defect
treatment_effect: BYPASSES
description: Exogenous immunoglobulin compensates for impaired endogenous antibody production from defective terminal B-cell differentiation.
evidence:
- reference: PMID:15887282
reference_title: "Immune abnormalities are a frequent manifestation of Kabuki syndrome."
supports: PARTIAL
evidence_source: HUMAN_CLINICAL
snippet: >-
Due to this increased susceptibility to infection, children with KS
should have immunologic evaluations at the time of diagnosis in order to
reduce preventable morbidity and mortality.
explanation: >-
Supports the clinical need for immunologic work-up but does not
explicitly recommend immunoglobulin replacement therapy.
- name: KDM1A Inhibitor (Experimental)
description: >-
Lysine-specific demethylase 1A (KDM1A/LSD1) normally removes H3K4 methyl
marks added by KMT2D. Pharmacologic KDM1A inhibition (e.g., TAK-418)
rebalances H3K4 methylation, restores postnatal neurogenesis, and
rescues hippocampal memory in Kmt2d-haploinsufficient mice. Targets the
upstream chromatin defect more directly than HDAC inhibition.
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
target_mechanisms:
- target: Postnatal neurogenesis deficit
treatment_effect: RESTORES
description: KDM1A inhibition restores the H3K4me-balance lost in KMT2D haploinsufficiency, rescuing adult hippocampal neurogenesis.
evidence:
- reference: PMID:33738331
reference_title: "Inhibition of KDM1A activity restores adult neurogenesis and improves hippocampal memory in a mouse model of Kabuki syndrome."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
After 2 weeks of TAK-418, Kmt2d +/βGeo mice demonstrated
normalization of hippocampal memory defects.
explanation: Direct mechanism-targeted rescue of the neurogenesis-memory phenotype in a Kabuki mouse model.
evidence:
- reference: PMID:33738331
reference_title: "Inhibition of KDM1A activity restores adult neurogenesis and improves hippocampal memory in a mouse model of Kabuki syndrome."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
our data suggest that KDM1A inhibition is a plausible treatment
strategy for KS
explanation: Establishes KDM1A inhibition as a rational chromatin-targeted treatment strategy for Kabuki syndrome.
- name: Modified Atkins Diet (Investigational)
description: >-
Ketogenic/Modified Atkins dietary intervention is being investigated as
a chromatin-modulating therapy in Kabuki syndrome. Multi-omics data
show partial reversal of ribosomal protein dysregulation in a treated
KMT2D KS patient. A completed 12-week adult phase-1 trial (NCT04722315)
evaluated cognitive and methylation outcomes.
treatment_term:
preferred_term: dietary intervention
term:
id: MAXO:0000088
label: dietary intervention
target_mechanisms:
- target: Chromatin dysregulation from KMT2D and KDM6A haploinsufficiency
treatment_effect: MODULATES
description: Ketogenic state alters histone acetylation and chromatin accessibility, partially compensating for KMT2D-driven enhancer dysregulation.
evidence:
- reference: PMID:38768529
reference_title: "Ketogenic diet modifies ribosomal protein dysregulation in KMT2D Kabuki syndrome."
supports: PARTIAL
evidence_source: HUMAN_CLINICAL
snippet: >-
A 12-year-old boy with KS, suffering from recurrent episodes of
cognitive decline, exhibited improved cognitive function and
neuropsychological assessment performance after 12 months on the
ketogenic diet, with concomitant improvement in transcriptomic
ribosomal protein dysregulation.
explanation: Demonstrates that ketogenic diet can modulate KMT2D-related ribosomal protein dysregulation with concurrent clinical improvement, supporting chromatin-modulating treatment targeting.
- name: Diazoxide
description: >-
First-line pharmacotherapy for hyperinsulinemic hypoglycemia in Kabuki
syndrome. Activates pancreatic beta-cell K-ATP channels to suppress
insulin secretion. Approximately 92% of children with KS-associated
hyperinsulinism respond to a diazoxide trial.
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_agent:
- preferred_term: diazoxide
term:
id: CHEBI:4495
label: diazoxide
target_mechanisms:
- target: Pancreatic beta-cell dysfunction
treatment_effect: INHIBITS
description: Diazoxide opens beta-cell K-ATP channels, suppressing dysregulated insulin secretion in KS-associated hyperinsulinism.
evidence:
- reference: PMID:38859884
reference_title: "Clinical and Molecular Characterization of Hyperinsulinism in Kabuki Syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Diazoxide trial was conducted in 25 children, 92% of whom were
responsive.
explanation: Demonstrates high clinical response rate to diazoxide for KS-associated hyperinsulinism.
evidence:
- reference: PMID:38859884
reference_title: "Clinical and Molecular Characterization of Hyperinsulinism in Kabuki Syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
HI treatment was discontinued in 46% of the cohort at median age 2.8
years
explanation: Documents that medical management of KS-associated hyperinsulinism, primarily with diazoxide, frequently allows treatment discontinuation in early childhood.
clinical_trials:
- name: NCT04722315
phase: PHASE_I
status: COMPLETED
description: >-
Single-group early phase 1 trial evaluating a 12-week Modified Atkins
Diet in adults with genetically confirmed Kabuki syndrome, with
cognitive/visuospatial/memory outcomes plus serial genome-wide DNA
methylation measurements.
target_phenotypes:
- preferred_term: Intellectual disability
term:
id: HP:0001249
label: Intellectual disability
evidence:
- reference: clinicaltrials:NCT04722315
reference_title: "Pilot Clinical Trial of Modified Atkins Diet for Kabuki Syndrome"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
This study aims to examine a small number of adults with Kabuki
syndrome before and after 12 weeks on a modified Atkins diet to
determine if there is any cognitive improvement and if the diet can
be tolerated.
explanation: Documents the trial's design and primary cognitive endpoint, anchoring the Modified Atkins Diet treatment in completed human evidence.
- reference: clinicaltrials:NCT04722315
reference_title: "Pilot Clinical Trial of Modified Atkins Diet for Kabuki Syndrome"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Modified Atkins diet is safer and easier tolerated than full
ketogenic diet and still has the histone deacetylase inhibition
believed to be responsible for the cognitive improvement.
explanation: Provides the mechanistic rationale (HDAC inhibition via ketones) for testing Modified Atkins Diet in Kabuki syndrome.
genetic:
- name: KMT2D
gene_term:
preferred_term: KMT2D
term:
id: hgnc:7133
label: KMT2D
association: Causative
notes: >-
KMT2D is the major Kabuki syndrome gene. Many pathogenic variants are
truncating and reduce KMT2D dosage through nonsense-mediated decay,
consistent with haploinsufficiency.
evidence:
- reference: PMID:20711175
reference_title: "Exome sequencing identifies MLL2 mutations as a cause of Kabuki syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Our results strongly suggest that mutations in MLL2 are a major cause of
Kabuki syndrome.
explanation: Establishes KMT2D as the major causative gene.
- reference: PMID:24633898
reference_title: "Molecular analysis, pathogenic mechanisms, and readthrough therapy on a large cohort of Kabuki syndrome patients."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
We found that a number of KMT2D truncating mutations result in mRNA
degradation through the nonsense-mediated mRNA decay, contributing to
protein haploinsufficiency.
explanation: Supports KMT2D haploinsufficiency as the dominant genetic mechanism.
- reference: ORPHA:2322
reference_title: "Kabuki syndrome (Orphanet structured-database record)"
supports: SUPPORT
snippet: "KMT2D | lysine methyltransferase 2D | hgnc:7133 | Disease-causing germline mutation(s) in"
explanation: Orphanet lists KMT2D as a disease-causing gene for Kabuki syndrome.
- name: KDM6A
gene_term:
preferred_term: KDM6A
term:
id: hgnc:12637
label: KDM6A
association: Causative
notes: >-
KDM6A is a less common Kabuki syndrome gene that encodes a histone
demethylase functionally linked to KMT2D.
evidence:
- reference: PMID:22197486
reference_title: "Deletion of KDM6A, a histone demethylase interacting with MLL2, in three patients with Kabuki syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Here, we describe three KS individuals with de novo partial or complete
deletions of an X chromosome gene, KDM6A, that encodes a histone
demethylase that interacts with MLL2.
explanation: Establishes KDM6A as a causative Kabuki syndrome gene.
- reference: ORPHA:2322
reference_title: "Kabuki syndrome (Orphanet structured-database record)"
supports: SUPPORT
snippet: "KDM6A | lysine demethylase 6A | hgnc:12637 | Disease-causing germline mutation(s) in"
explanation: Orphanet lists KDM6A as a disease-causing gene for Kabuki syndrome.
Kabuki syndrome (KS) is a rare, congenital, multisystem neurodevelopmental disorder characterized by a recognizable facial gestalt, developmental delay/intellectual disability, skeletal anomalies, dermatoglyphic anomalies (including persistent fetal fingertip pads), and postnatal growth deficiency, with additional frequent involvement of cardiac, renal, hearing, immune, endocrine, and gastrointestinal systems. (barry2022fromgenotypeto pages 1-2, dugan2021kabukisyndrome pages 1-3, boniel2021kabukisyndrome—clinicalreview pages 1-2)
Epidemiologic frequency (range reported in large review): estimated frequency ~1:32,000–1:86,000. (barry2022fromgenotypeto pages 1-2)
Evidence type: aggregated disease-level literature review synthesizing 152 publications and 1369 individuals. (barry2022fromgenotypeto pages 1-2, barry2022fromgenotypeto pages 2-4)
A structured list of identifiers available from the retrieved sources is provided here:
| Identifier system | Identifier/value | Notes |
|---|---|---|
| MONDO | MONDO:0016512 | User-provided disease identifier for Kabuki syndrome. Not independently verified in retrieved evidence. |
| OMIM | Kabuki syndrome 1 (KS1): 147920 | KMT2D-related Kabuki syndrome; autosomal dominant in retrieved reviews/management sources (dugan2021kabukisyndrome pages 1-3, boniel2021kabukisyndrome—clinicalreview pages 1-2) |
| OMIM | Kabuki syndrome 2 (KS2): 300867 | KDM6A-related Kabuki syndrome; X-linked in retrieved reviews/management sources (dugan2021kabukisyndrome pages 1-3, boniel2021kabukisyndrome—clinicalreview pages 1-2) |
| OMIM / gene | KMT2D: 602113 | Major causal gene for KS1; cited in recent mechanistic and clinical reviews (golden2023molecularinsightsof pages 1-3, golden2023molecularinsightsof pages 9-11) |
| OMIM / gene | KDM6A: 300128 | Causal gene for KS2; X-linked histone demethylase noted in retrieved reviews and KS2 cohort study (golden2023molecularinsightsof pages 1-3, wang2024sexspecificdifferencein pages 2-4) |
| Disease name | Kabuki syndrome | Preferred disease name across retrieved sources (barry2022fromgenotypeto pages 1-2, adam2019kabukisyndromeinternational pages 1-2) |
| Synonym | Kabuki make-up syndrome | Explicit synonym in management/review sources (dugan2021kabukisyndrome pages 1-3, boniel2021kabukisyndrome—clinicalreview pages 8-9) |
| Synonym | Niikawa–Kuroki syndrome | Historical synonym in review sources (barry2022fromgenotypeto pages 1-2, dugan2021kabukisyndrome pages 1-3) |
| Orphanet | Not in retrieved sources | No Orphanet identifier was present in the gathered evidence. |
| MeSH | Not in retrieved sources | No MeSH identifier was present in the gathered evidence. |
| ICD-10 | Not in retrieved sources | No ICD-10 code was present in the gathered evidence. |
| ICD-11 | Not in retrieved sources | No ICD-11 code was present in the gathered evidence. |
Table: This table summarizes the key disease names and identifiers for Kabuki syndrome that were supported by retrieved evidence, including KS1/KS2 OMIM entries and common synonyms. Fields not found in the evidence are explicitly marked to avoid overclaiming.
Synonyms supported by retrieved sources include Kabuki make-up syndrome and Niikawa–Kuroki syndrome. (barry2022fromgenotypeto pages 1-2, dugan2021kabukisyndrome pages 1-3, boniel2021kabukisyndrome—clinicalreview pages 8-9)
Note on missing identifiers: Orphanet IDs, MeSH IDs, and ICD-10/ICD-11 codes were not present in the retrieved documents available to this run; therefore they are not asserted here. (artifact-00)
The international consensus diagnostic criteria emphasize a recognisable clinical pattern plus molecular confirmation when available.
Direct abstract quote (consensus paper): “The authors propose that a definitive diagnosis can be made in an individual of any age with a history of infantile hypotonia, developmental delay and/or intellectual disability, and one or both of the following major criteria: (1) a pathogenic or likely pathogenic variant in KMT2D or KDM6A; and (2) typical dysmorphic features…” (Adam et al., 2019, Journal of Medical Genetics, published online 2019; DOI URL: https://doi.org/10.1136/jmedgenet-2018-105625). (adam2019kabukisyndromeinternational pages 1-2)
KS is primarily a Mendelian disorder caused by pathogenic variants in chromatin regulators: - KMT2D (KS1; autosomal dominant): heterozygous dominant loss-of-function variants are the most common cause (often de novo). (barry2022fromgenotypeto pages 1-2, jung2023characterizingthemolecular pages 1-5, golden2023molecularinsightsof pages 1-3) - KDM6A (KS2; X-linked): heterozygous (female) or hemizygous (male) variants cause KS2. (barry2022fromgenotypeto pages 1-2, dugan2021kabukisyndrome pages 1-3, wang2024sexspecificdifferencein pages 2-4)
Mechanistically, KMT2D is an H3K4 methyltransferase, and KDM6A is an H3K27 demethylase; both are key components of enhancer/promoter chromatin regulation during development. (golden2023molecularinsightsof pages 1-3, boniel2021kabukisyndrome—clinicalreview pages 2-3)
For KS (a monogenic syndrome), the predominant “risk factor” is carrying a pathogenic germline variant in KMT2D or KDM6A; additional environmental risk and protective factors are not well-defined in the retrieved sources. (barry2022fromgenotypeto pages 1-2, dugan2021kabukisyndrome pages 1-3)
A plausible gene–environment interaction discussed in recent intervention work is that metabolic state (ketosis via dietary intervention) may modulate downstream molecular phenotypes (e.g., ribosomal/protein-translation pathways) in KMT2D-related KS. (tsang2024ketogenicdietmodifies pages 8-10, tsang2024ketogenicdietmodifies pages 2-3)
Across large reviews and clinical management sources, commonly described domains include: - Craniofacial gestalt (long palpebral fissures with lower-lid eversion; arched/broad eyebrows with lateral sparseness; depressed nasal tip/short columella; prominent/cupped ears) (adam2019kabukisyndromeinternational pages 1-2, dugan2021kabukisyndrome pages 1-3) - Neurodevelopmental phenotype (developmental delay; intellectual disability; hypotonia) (barry2022fromgenotypeto pages 1-2, dugan2021kabukisyndrome pages 1-3) - Skeletal anomalies and persistent fingertip pads (barry2022fromgenotypeto pages 1-2, adam2019kabukisyndromeinternational pages 1-2) - Postnatal growth deficiency/short stature (barry2022fromgenotypeto pages 1-2, boniel2021kabukisyndrome—clinicalreview pages 1-2) - Congenital heart disease (barry2022fromgenotypeto pages 1-2, lee2024geneticandphenotypic pages 1-2) - Immune dysfunction (recurrent infections, hypogammaglobulinemia; autoimmunity in a subset) (margot2020immunopathologicalmanifestationsin pages 1-2) - Hearing loss (conductive and sensorineural components) (kalinousky2023kmt2ddeficiencycauses pages 5-7)
A 2024 Taiwanese case series (n=23) provides concrete phenotype frequencies (primarily KMT2D): - Distinct facial features: 100% - Intellectual disability: 100% - Developmental delay: 95.7% - Speech delay: 78.3% - Hypotonia: 69.6% - Congenital heart abnormalities: 69.6% - Recurrent infections: 65.2% - Hearing loss: 39.1% - Seizures: 26.1% - Cleft palate: 26.1% - Renal anomalies: 21.7% (Lee et al., 2024, Diagnostics, Aug 2024; DOI URL: https://doi.org/10.3390/diagnostics14161815). (lee2024geneticandphenotypic pages 1-2)
Cardiac lesion distribution within CHD subset (n=16): ASD 37.5% (6/16), VSD 18.8% (3/16), aortic coarctation 18.8% (3/16). (lee2024geneticandphenotypic pages 6-7, lee2024geneticandphenotypic pages 4-6)
A 2023 KS1 study (KMT2D; n=21 individuals) reported: - Current hearing loss in 71.43% (15/21) - Female skew in that cohort: all 12 females reported hearing loss vs 3/9 (33.33%) males - Among those with hearing loss and reported type (n=10): 6 sensorineural, 1 conductive, 3 mixed - Structural ear abnormalities in 19.05% (4/21) (Kalinousky et al., 2023, Genes, Dec 2023; DOI URL: https://doi.org/10.3390/genes15010048). (kalinousky2023kmt2ddeficiencycauses pages 5-7)
A registry study (n=177; molecularly confirmed KMT2D/KDM6A) quantified: - Susceptibility to infections: 44.1% (78/177) - Hypogammaglobulinemia: 58.2% (46/79 tested) - Autoimmune disease overall: 13.6% (24/177); in adults: 25.6% (11/43) - Immune thrombocytopenic purpura: 7.3% (13/177); autoimmune hemolytic anemia: 4.0% (7/177) (Margot et al., 2020, Genetics in Medicine, Jan 2020; DOI URL: https://doi.org/10.1038/s41436-019-0623-x). (margot2020immunopathologicalmanifestationsin pages 1-2)
Caregiver/adolescent report studies indicate substantial multidimensional burden; while this run did not extract instrument-level statistics (e.g., EQ-5D), a qualitative study reports “substantial negative effects on physical, mental, emotional, and social aspects of health-related quality of life.” (barry2022fromgenotypeto pages 1-2)
(These are suggested mappings for knowledge-base structuring; the retrieved sources support the clinical concepts but do not enumerate HPO IDs.) - Facial gestalt: Long palpebral fissures; Everted lower eyelids; Arched eyebrows; Large/protruding ears - Neurodevelopment: Global developmental delay; Intellectual disability; Hypotonia; Speech delay - Growth: Postnatal growth retardation; Short stature - Cardiac: Congenital heart defect; Atrial septal defect; Ventricular septal defect; Coarctation of aorta - Immune: Recurrent infections; Hypogammaglobulinemia; Immune thrombocytopenia; Autoimmune hemolytic anemia - Hearing: Hearing impairment; Sensorineural hearing loss; Conductive hearing loss
Large aggregated reviews and recent KS1-focused review note broad variant classes including nonsense, frameshift, splice-site, indels, CNVs, and missense (some clustering near functional domains). (barry2022fromgenotypeto pages 2-4, golden2023molecularinsightsof pages 9-11)
Examples of quantitative variant spectrum reporting: - In the 2024 Taiwanese series (n=23), variant class frequencies were reported (patient-level): missense 26.1%, nonsense 21.7%, frameshift 17.4%. (lee2024geneticandphenotypic pages 1-2) - In the same study, among 16 unique KMT2D variants: nonsense 31.3%, missense 18.7%, frameshift 18.7%, deletions 18.7%, splicing 6.3%, insertion/deletion 6.3%. (lee2024geneticandphenotypic pages 2-4)
A 2023 study profiled PBMCs from 33 individuals with KMT2D-related KS and 36 controls, finding: - Distinct enhancer signatures in H3K4me1/H3K4me2 - Reduced promoter-distal enhancer signals at immune-related genes and overlap with ~31% of normal blood-cell super-enhancers - Increased enhancer signals near promoters of metabolic genes, with elevated transcription (Jung et al., 2023, Human Molecular Genetics, Oct 2023; DOI URL: https://doi.org/10.1101/2022.10.25.22280882). (jung2023characterizingthemolecular pages 1-5)
Direct abstract quote: “…we profiled and characterized alterations in histone modification and gene transcription in peripheral blood mononuclear cells (PBMCs) from 33 patients with KMT2D mutations and 36 unaffected healthy controls.” (jung2023characterizingthemolecular pages 1-5)
A 2024 mechanistic immunology study reports that KMT2D directly regulates leukocyte integrin loci (chromatin and expression), with functional impact on thymocyte migration/egress and peripheral T-cell composition.
Key mechanistic findings include: - Reduced expression of integrins (e.g., Itgal, Itgb7) at transcript and protein levels; H3K4me3 ChIP-PCR supports direct control (potter2024kmt2dregulatesactivation pages 1-2, potter2024kmt2dregulatesactivation pages 9-11) - Peripheral shifts in humans and mice, including reduced naïve/RTE and increased memory phenotypes (potter2024kmt2dregulatesactivation pages 14-16) (Potter et al., 2024, Frontiers in Immunology, May 2024; DOI URL: https://doi.org/10.3389/fimmu.2024.1341745). (potter2024kmt2dregulatesactivation pages 1-2)
A 2024 Genome Research study in Kabuki mouse models indicates that chromatin accessibility abnormalities in neurons are largely distinct from those in peripheral B and T cells, with neuron-specific enrichment at CpG islands and aging-linked elements.
Direct abstract-level statement from retrieved text: “…chromatin accessibility abnormalities in neurons are mostly distinct from those in B or T cells… Neurons, but not B or T cells, show preferential chromatin disruption at CpG islands and at regulatory elements linked to aging.” (Boukas et al., 2024, Genome Research, May 2024; DOI URL: https://doi.org/10.1101/gr.278416.123). (boukas2024neuronspecificchromatindisruption pages 1-2)
A 2024 KS2 mouse study (Kdm6a tm1d/+), focusing on endochondral ossification, found: - Decreased femur/tibia length; cortical and trabecular structural changes - Shorter growth plates, driven by reduced hypertrophic chondrocyte size and hypertrophic zone height - In vitro Kdm6a−/− cells showed premature/enhanced chondrocyte differentiation - RNA-seq showed convergent gene expression between Kdm6a−/− and Kmt2d−/− lines, suggesting shared downstream pathways (Gao et al., 2024, PLOS Genetics, Jun 2024; DOI URL: https://doi.org/10.1371/journal.pgen.1011310). (gao2024growthdeficiencyin pages 1-2, gao2024growthdeficiencyin pages 3-6)
No specific, reproducible non-genetic environmental causal factors are described in the retrieved sources for Kabuki syndrome, consistent with its primary Mendelian etiology. (barry2022fromgenotypeto pages 1-2, dugan2021kabukisyndrome pages 1-3)
Dietary metabolic state (ketogenic/Modified Atkins) is an intervention rather than a causal environmental exposure and is covered under Treatment/Applications. (tsang2024ketogenicdietmodifies pages 8-10, NCT04722315 chunk 1)
Upstream trigger: germline loss-of-function (typically) variants in KMT2D (H3K4 methyltransferase) and/or KDM6A (H3K27 demethylase). (golden2023molecularinsightsof pages 1-3, boniel2021kabukisyndrome—clinicalreview pages 2-3)
Intermediate molecular consequence: altered enhancer/promoter chromatin state and transcriptional dysregulation, measurable in human immune cells as altered H3K4me1/H3K4me2 enhancer signatures with reduced enhancer activity at immune genes. (jung2023characterizingthemolecular pages 1-5)
Downstream cellular consequences: impaired maturation/function of immune cells (B- and T-cell defects; altered integrin programs and migration/egress), contributing to recurrent infections, hypogammaglobulinemia, and autoimmune manifestations. (margot2020immunopathologicalmanifestationsin pages 1-2, potter2024kmt2dregulatesactivation pages 14-16)
Clinical manifestations: multisystem developmental phenotype including neurodevelopmental delay, craniofacial anomalies, growth deficiency, heart defects, hearing loss, and immune disease. (barry2022fromgenotypeto pages 1-2, dugan2021kabukisyndrome pages 1-3, lee2024geneticandphenotypic pages 1-2, kalinousky2023kmt2ddeficiencycauses pages 5-7)
In Kmt2d-deficient murine thymocytes, transcriptomics implicate integrin-linked migration programs (including Mst1 pathway-related genes such as Rap1a/Vasp and integrin genes) as dysregulated, aligning with abnormal T-cell maturation and peripheral distribution shifts. (potter2024kmt2dregulatesactivation pages 11-13, potter2024kmt2dregulatesactivation pages 14-16)
The 2024 neuron-vs-blood chromatin accessibility study supports a model in which neurodevelopmental chromatin disruptions are not simply recapitulated by blood epigenomic patterns; neurons show preferential disruption at CpG islands and aging-linked regulatory elements. This helps explain why blood-derived episignatures can be diagnostically useful yet incomplete as mechanistic proxies for brain phenotypes. (boukas2024neuronspecificchromatindisruption pages 1-2)
KS2 growth failure can arise from impaired hypertrophic chondrocyte enlargement (hypertrophic-zone shortening) and premature chondrogenic differentiation, with transcriptional convergence between KS1 and KS2 models supporting a shared downstream program affecting cartilage development. (gao2024growthdeficiencyin pages 1-2, gao2024growthdeficiencyin pages 3-6)
KS is congenital with early-life hypotonia and developmental delay emphasized in diagnostic criteria. (adam2019kabukisyndromeinternational pages 1-2)
In a KS1 cohort, mean onset/presentation of hearing loss was reported as ~7 years, though some individuals had hearing loss at birth. (kalinousky2023kmt2ddeficiencycauses pages 5-7)
In a KS2 cohort (n=12; males=5, females=7): - CHD: 5/5 (100%) males vs 1/7 (14.29%) females (P=0.015) - Moderate-to-severe intellectual disability (IQ<55): 4/4 (100%) assessed males vs 0/7 females (P=0.003) - Median IQ: 41 in males vs 69 in females (P=0.029) (Wang et al., 2024, BMC Pediatrics, Feb 2024; DOI URL: https://doi.org/10.1186/s12887-024-04562-z). (wang2024sexspecificdifferencein pages 5-6)
The consensus criteria emphasize hypotonia and developmental delay/intellectual disability plus either a pathogenic/likely pathogenic variant in KMT2D/KDM6A and/or typical dysmorphism. (adam2019kabukisyndromeinternational pages 1-2)
Recent reviews describe clinical implementation of WES/trio-WES and targeted sequencing to detect SNVs/indels and CNVs, with interpretive challenges including VUS and complex variant classes. (golden2023molecularinsightsof pages 9-11)
DNA methylation episignatures are described as capable of identifying KS1 “regardless of variant class” in a review context, supporting clinical adoption of episignature testing when sequence findings are equivocal. (golden2023molecularinsightsof pages 9-11)
This run did not retrieve differential-diagnosis tables or guideline-style differential lists; therefore no specific differentials are asserted here.
The retrieved sources emphasize variable multisystem burden and the need for longitudinal adult natural history data, but did not provide robust survival or life-expectancy statistics in the extracted passages. (barry2022fromgenotypeto pages 1-2)
However, immune complications can be serious: immunopathological manifestations are described as “common and can be life-threatening,” supporting systematic screening and preventive management. (margot2020immunopathologicalmanifestationsin pages 1-2)
Clinical management is primarily supportive and multidisciplinary, including surveillance and treatment of congenital anomalies, developmental interventions, and management of immune dysfunction, feeding problems, endocrine issues, and seizures as they arise. (dugan2021kabukisyndrome pages 1-3, boniel2021kabukisyndrome—clinicalreview pages 1-2)
A 2024 eBioMedicine study combined proteomics (KS n=4 vs controls n=4; significant protein changes at FDR<0.05) and scRNA-seq with a single-patient Modified Atkins/ketogenic-style dietary intervention.
Molecular findings included large-scale proteomic dysregulation and downregulation of ribosomal proteins/translation pathways in KS, with partial reversal of ribosomal gene dysregulation after 12 months of diet in the treated participant. (tsang2024ketogenicdietmodifies pages 8-10, tsang2024ketogenicdietmodifies pages 6-8)
Reported clinical signals in the treated child included elimination of “brain fog” episodes, improved neuropsychological testing domains (e.g., attention/impulse control), reduced school absenteeism (8.5→3 days/semester), and reduced antibiotic courses (8.5/year→3.7/year), though this is uncontrolled n=1 evidence. (tsang2024ketogenicdietmodifies pages 8-10)
Intervention details included initial carbohydrate restriction to 15 g/day, ketosis tracking with urinary ketones and serum beta-hydroxybutyrate (BOHB ~1.90–4.86 mmol/L). (tsang2024ketogenicdietmodifies pages 2-3)
Evidence type: n=1 intervention with supporting multi-omics; hypothesis-generating. (tsang2024ketogenicdietmodifies pages 8-10, tsang2024ketogenicdietmodifies pages 2-3)
A single-group early phase 1 trial evaluated 12-week Modified Atkins Diet in adults with genetically confirmed KS. - ClinicalTrials.gov ID: NCT04722315 - Status: Completed - Enrollment: 10 - Primary completion: 2024-01-26 - Results posted: 2025-05-13 - Outcome domains: cognitive/visuospatial/memory testing plus serial genome-wide DNA methylation measures. (NCT04722315 chunk 1)
URL: https://clinicaltrials.gov/study/NCT04722315 (NCT04722315 chunk 1)
Note: numeric outcome results were not extracted from the record text available in this run. (NCT04722315 chunk 1)
Primary prevention (preventing occurrence) is not generally applicable for a de novo-dominant/X-linked congenital syndrome; however, secondary/tertiary prevention through surveillance and complication prevention is implied in management frameworks and supported by high rates of infection susceptibility and immune abnormalities. (margot2020immunopathologicalmanifestationsin pages 1-2, dugan2021kabukisyndrome pages 1-3)
No naturally occurring non-human Kabuki syndrome cases were retrieved in this run.
References
(barry2022fromgenotypeto pages 1-2): Kelly K. Barry, Michaelangelo Tsaparlis, Deborah Hoffman, Deborah Hartman, Margaret P. Adam, Christina Hung, and Olaf A. Bodamer. From genotype to phenotype—a review of kabuki syndrome. Genes, 13:1761, Sep 2022. URL: https://doi.org/10.3390/genes13101761, doi:10.3390/genes13101761. This article has 72 citations.
(dugan2021kabukisyndrome pages 1-3): Sarah Dugan. Kabuki syndrome. Cassidy and Allanson's Management of Genetic Syndromes, pages 529-538, Oct 2021. URL: https://doi.org/10.1002/9781119432692.ch34, doi:10.1002/9781119432692.ch34. This article has 152 citations.
(boniel2021kabukisyndrome—clinicalreview pages 1-2): Snir Boniel, Krystyna Szymańska, Robert Śmigiel, and Krzysztof Szczałuba. Kabuki syndrome—clinical review with molecular aspects. Genes, 12:468, Mar 2021. URL: https://doi.org/10.3390/genes12040468, doi:10.3390/genes12040468. This article has 121 citations.
(barry2022fromgenotypeto pages 2-4): Kelly K. Barry, Michaelangelo Tsaparlis, Deborah Hoffman, Deborah Hartman, Margaret P. Adam, Christina Hung, and Olaf A. Bodamer. From genotype to phenotype—a review of kabuki syndrome. Genes, 13:1761, Sep 2022. URL: https://doi.org/10.3390/genes13101761, doi:10.3390/genes13101761. This article has 72 citations.
(golden2023molecularinsightsof pages 1-3): Carly S. Golden, Saylor Williams, and Maria A. Serrano. Molecular insights of kmt2d and clinical aspects of kabuki syndrome type 1. Birth Defects Research, 115:1809-1824, May 2023. URL: https://doi.org/10.1002/bdr2.2183, doi:10.1002/bdr2.2183. This article has 10 citations and is from a peer-reviewed journal.
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(boniel2021kabukisyndrome—clinicalreview pages 8-9): Snir Boniel, Krystyna Szymańska, Robert Śmigiel, and Krzysztof Szczałuba. Kabuki syndrome—clinical review with molecular aspects. Genes, 12:468, Mar 2021. URL: https://doi.org/10.3390/genes12040468, doi:10.3390/genes12040468. This article has 121 citations.
(jung2023characterizingthemolecular pages 1-5): Youngsook L Jung, Christina Hung, Jaejoon Choi, Eunjung A Lee, and Olaf Bodamer. Characterizing the molecular impact of kmt2d variants on the epigenetic and transcriptional landscapes in kabuki syndrome. Human molecular genetics, Oct 2023. URL: https://doi.org/10.1101/2022.10.25.22280882, doi:10.1101/2022.10.25.22280882. This article has 18 citations and is from a domain leading peer-reviewed journal.
(boniel2021kabukisyndrome—clinicalreview pages 2-3): Snir Boniel, Krystyna Szymańska, Robert Śmigiel, and Krzysztof Szczałuba. Kabuki syndrome—clinical review with molecular aspects. Genes, 12:468, Mar 2021. URL: https://doi.org/10.3390/genes12040468, doi:10.3390/genes12040468. This article has 121 citations.
(tsang2024ketogenicdietmodifies pages 8-10): Erica Tsang, Velda X. Han, Chloe Flutter, Sarah Alshammery, Brooke A. Keating, Tracey Williams, Brian S. Gloss, Mark E. Graham, Nader Aryamanesh, Ignatius Pang, Melanie Wong, David Winlaw, Michael Cardamone, Shekeeb Mohammad, Wendy Gold, Shrujna Patel, and Russell C. Dale. Ketogenic diet modifies ribosomal protein dysregulation in kmt2d kabuki syndrome. eBioMedicine, 104:105156, Jun 2024. URL: https://doi.org/10.1016/j.ebiom.2024.105156, doi:10.1016/j.ebiom.2024.105156. This article has 16 citations and is from a peer-reviewed journal.
(tsang2024ketogenicdietmodifies pages 2-3): Erica Tsang, Velda X. Han, Chloe Flutter, Sarah Alshammery, Brooke A. Keating, Tracey Williams, Brian S. Gloss, Mark E. Graham, Nader Aryamanesh, Ignatius Pang, Melanie Wong, David Winlaw, Michael Cardamone, Shekeeb Mohammad, Wendy Gold, Shrujna Patel, and Russell C. Dale. Ketogenic diet modifies ribosomal protein dysregulation in kmt2d kabuki syndrome. eBioMedicine, 104:105156, Jun 2024. URL: https://doi.org/10.1016/j.ebiom.2024.105156, doi:10.1016/j.ebiom.2024.105156. This article has 16 citations and is from a peer-reviewed journal.
(lee2024geneticandphenotypic pages 1-2): Chung-Lin Lee, Chih-Kuang Chuang, Ming-Ren Chen, Ju-Li Lin, Huei-Ching Chiu, Ya-Hui Chang, Yuan-Rong Tu, Yun-Ting Lo, Hsiang-Yu Lin, and Shuan-Pei Lin. Genetic and phenotypic spectrum of kmt2d variants in taiwanese case series of kabuki syndrome. Diagnostics, 14:1815, Aug 2024. URL: https://doi.org/10.3390/diagnostics14161815, doi:10.3390/diagnostics14161815. This article has 0 citations.
(margot2020immunopathologicalmanifestationsin pages 1-2): Henri Margot, Guilaine Boursier, Claire Duflos, Elodie Sanchez, Jeanne Amiel, Jean-Christophe Andrau, Stéphanie Arpin, Elise Brischoux-Boucher, Odile Boute, Lydie Burglen, Charlotte Caille, Yline Capri, Patrick Collignon, Solène Conrad, Valérie Cormier-Daire, Geoffroy Delplancq, Klaus Dieterich, Hélène Dollfus, Mélanie Fradin, Laurence Faivre, Helder Fernandes, Christine Francannet, Vincent Gatinois, Marion Gerard, Alice Goldenberg, Jamal Ghoumid, Sarah Grotto, Anne-Marie Guerrot, Agnès Guichet, Bertrand Isidor, Marie-Line Jacquemont, Sophie Julia, Philippe Khau Van Kien, Marine Legendre, K.H. Le Quan Sang, Bruno Leheup, Stanislas Lyonnet, Virginie Magry, Sylvie Manouvrier, Dominique Martin, Godelieve Morel, Arnold Munnich, Sophie Naudion, Sylvie Odent, Laurence Perrin, Florence Petit, Nicole Philip, Marlène Rio, Julie Robbe, Massimiliano Rossi, Elisabeth Sarrazin, Annick Toutain, Julien Van Gils, Gabriella Vera, Alain Verloes, Sacha Weber, Sandra Whalen, Damien Sanlaville, Didier Lacombe, Nathalie Aladjidi, and David Geneviève. Immunopathological manifestations in kabuki syndrome: a registry study of 177 individuals. Genetics in Medicine, 22:181-188, Jan 2020. URL: https://doi.org/10.1038/s41436-019-0623-x, doi:10.1038/s41436-019-0623-x. This article has 73 citations and is from a highest quality peer-reviewed journal.
(kalinousky2023kmt2ddeficiencycauses pages 5-7): Allison J. Kalinousky, Teresa R. Luperchio, Katrina M. Schrode, Jacqueline R. Harris, Li Zhang, Valerie B. DeLeon, Jill A. Fahrner, Amanda M. Lauer, and Hans T. Bjornsson. Kmt2d deficiency causes sensorineural hearing loss in mice and humans. Genes, 15:48, Dec 2023. URL: https://doi.org/10.3390/genes15010048, doi:10.3390/genes15010048. This article has 2 citations.
(lee2024geneticandphenotypic pages 6-7): Chung-Lin Lee, Chih-Kuang Chuang, Ming-Ren Chen, Ju-Li Lin, Huei-Ching Chiu, Ya-Hui Chang, Yuan-Rong Tu, Yun-Ting Lo, Hsiang-Yu Lin, and Shuan-Pei Lin. Genetic and phenotypic spectrum of kmt2d variants in taiwanese case series of kabuki syndrome. Diagnostics, 14:1815, Aug 2024. URL: https://doi.org/10.3390/diagnostics14161815, doi:10.3390/diagnostics14161815. This article has 0 citations.
(lee2024geneticandphenotypic pages 4-6): Chung-Lin Lee, Chih-Kuang Chuang, Ming-Ren Chen, Ju-Li Lin, Huei-Ching Chiu, Ya-Hui Chang, Yuan-Rong Tu, Yun-Ting Lo, Hsiang-Yu Lin, and Shuan-Pei Lin. Genetic and phenotypic spectrum of kmt2d variants in taiwanese case series of kabuki syndrome. Diagnostics, 14:1815, Aug 2024. URL: https://doi.org/10.3390/diagnostics14161815, doi:10.3390/diagnostics14161815. This article has 0 citations.
(wang2024sexspecificdifferencein pages 5-6): Yirou Wang, Yufei Xu, Yao Chen, Yabin Hu, Qun Li, Shijian Liu, Jian Wang, and Xiumin Wang. Sex-specific difference in phenotype of kabuki syndrome type 2 patients: a matched case-control study. BMC Pediatrics, Feb 2024. URL: https://doi.org/10.1186/s12887-024-04562-z, doi:10.1186/s12887-024-04562-z. This article has 2 citations and is from a peer-reviewed journal.
(lee2024geneticandphenotypic pages 2-4): Chung-Lin Lee, Chih-Kuang Chuang, Ming-Ren Chen, Ju-Li Lin, Huei-Ching Chiu, Ya-Hui Chang, Yuan-Rong Tu, Yun-Ting Lo, Hsiang-Yu Lin, and Shuan-Pei Lin. Genetic and phenotypic spectrum of kmt2d variants in taiwanese case series of kabuki syndrome. Diagnostics, 14:1815, Aug 2024. URL: https://doi.org/10.3390/diagnostics14161815, doi:10.3390/diagnostics14161815. This article has 0 citations.
(potter2024kmt2dregulatesactivation pages 1-2): Sarah J. Potter, Li Zhang, Michael Kotliar, Yuehong Wu, Caitlin Schafer, Kurtis Stefan, Leandros Boukas, Dima Qu’d, Olaf Bodamer, Brittany N. Simpson, Artem Barski, Andrew W. Lindsley, and Hans T. Bjornsson. Kmt2d regulates activation, localization, and integrin expression by t-cells. Frontiers in Immunology, May 2024. URL: https://doi.org/10.3389/fimmu.2024.1341745, doi:10.3389/fimmu.2024.1341745. This article has 10 citations and is from a peer-reviewed journal.
(potter2024kmt2dregulatesactivation pages 9-11): Sarah J. Potter, Li Zhang, Michael Kotliar, Yuehong Wu, Caitlin Schafer, Kurtis Stefan, Leandros Boukas, Dima Qu’d, Olaf Bodamer, Brittany N. Simpson, Artem Barski, Andrew W. Lindsley, and Hans T. Bjornsson. Kmt2d regulates activation, localization, and integrin expression by t-cells. Frontiers in Immunology, May 2024. URL: https://doi.org/10.3389/fimmu.2024.1341745, doi:10.3389/fimmu.2024.1341745. This article has 10 citations and is from a peer-reviewed journal.
(potter2024kmt2dregulatesactivation pages 14-16): Sarah J. Potter, Li Zhang, Michael Kotliar, Yuehong Wu, Caitlin Schafer, Kurtis Stefan, Leandros Boukas, Dima Qu’d, Olaf Bodamer, Brittany N. Simpson, Artem Barski, Andrew W. Lindsley, and Hans T. Bjornsson. Kmt2d regulates activation, localization, and integrin expression by t-cells. Frontiers in Immunology, May 2024. URL: https://doi.org/10.3389/fimmu.2024.1341745, doi:10.3389/fimmu.2024.1341745. This article has 10 citations and is from a peer-reviewed journal.
(boukas2024neuronspecificchromatindisruption pages 1-2): Leandros Boukas, Teresa Romeo Luperchio, Afrooz Razi, Kasper D. Hansen, and Hans T. Bjornsson. Neuron-specific chromatin disruption at cpg islands and aging-related regions in kabuki syndrome mice. Genome Research, 34:696-710, May 2024. URL: https://doi.org/10.1101/gr.278416.123, doi:10.1101/gr.278416.123. This article has 3 citations and is from a highest quality peer-reviewed journal.
(gao2024growthdeficiencyin pages 1-2): Christine W. Gao, WanYing Lin, Ryan C. Riddle, Sheetal Chopra, Jiyoung Kim, Leandros Boukas, Kasper D. Hansen, Hans T. Björnsson, and Jill A. Fahrner. Growth deficiency in a mouse model of kabuki syndrome 2 bears mechanistic similarities to kabuki syndrome 1. PLOS Genetics, 20:e1011310, Jun 2024. URL: https://doi.org/10.1371/journal.pgen.1011310, doi:10.1371/journal.pgen.1011310. This article has 3 citations and is from a domain leading peer-reviewed journal.
(gao2024growthdeficiencyin pages 3-6): Christine W. Gao, WanYing Lin, Ryan C. Riddle, Sheetal Chopra, Jiyoung Kim, Leandros Boukas, Kasper D. Hansen, Hans T. Björnsson, and Jill A. Fahrner. Growth deficiency in a mouse model of kabuki syndrome 2 bears mechanistic similarities to kabuki syndrome 1. PLOS Genetics, 20:e1011310, Jun 2024. URL: https://doi.org/10.1371/journal.pgen.1011310, doi:10.1371/journal.pgen.1011310. This article has 3 citations and is from a domain leading peer-reviewed journal.
(NCT04722315 chunk 1): Study of Modified Atkins Diet in Kabuki Syndrome. Hugo W. Moser Research Institute at Kennedy Krieger, Inc.. 2021. ClinicalTrials.gov Identifier: NCT04722315
(potter2024kmt2dregulatesactivation pages 11-13): Sarah J. Potter, Li Zhang, Michael Kotliar, Yuehong Wu, Caitlin Schafer, Kurtis Stefan, Leandros Boukas, Dima Qu’d, Olaf Bodamer, Brittany N. Simpson, Artem Barski, Andrew W. Lindsley, and Hans T. Bjornsson. Kmt2d regulates activation, localization, and integrin expression by t-cells. Frontiers in Immunology, May 2024. URL: https://doi.org/10.3389/fimmu.2024.1341745, doi:10.3389/fimmu.2024.1341745. This article has 10 citations and is from a peer-reviewed journal.
(tsang2024ketogenicdietmodifies pages 6-8): Erica Tsang, Velda X. Han, Chloe Flutter, Sarah Alshammery, Brooke A. Keating, Tracey Williams, Brian S. Gloss, Mark E. Graham, Nader Aryamanesh, Ignatius Pang, Melanie Wong, David Winlaw, Michael Cardamone, Shekeeb Mohammad, Wendy Gold, Shrujna Patel, and Russell C. Dale. Ketogenic diet modifies ribosomal protein dysregulation in kmt2d kabuki syndrome. eBioMedicine, 104:105156, Jun 2024. URL: https://doi.org/10.1016/j.ebiom.2024.105156, doi:10.1016/j.ebiom.2024.105156. This article has 16 citations and is from a peer-reviewed journal.
(kalinousky2023kmt2ddeficiencycauses pages 7-9): Allison J. Kalinousky, Teresa R. Luperchio, Katrina M. Schrode, Jacqueline R. Harris, Li Zhang, Valerie B. DeLeon, Jill A. Fahrner, Amanda M. Lauer, and Hans T. Bjornsson. Kmt2d deficiency causes sensorineural hearing loss in mice and humans. Genes, 15:48, Dec 2023. URL: https://doi.org/10.3390/genes15010048, doi:10.3390/genes15010048. This article has 2 citations.