Kabuki Syndrome

Mendelian MONDO:0016512 Neurodevelopmental Disorder Chromatin Disorder Multiple Congenital Anomaly Syndrome

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.

0
Mappings
1
Definitions
2
Inheritance
4
Pathophysiology
0
Histopathology
14
Phenotypes
0
Pathograph
2
Genes
5
Treatments
2
Subtypes
0
Differentials
0
Datasets
0
Trials
0
Models
🏷

Classifications

Harrison's Chapter
hereditary disease nervous system disorder
📘

Definitions

1
International consensus clinical definition
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.
CASE_DEFINITION Molecularly confirmed and clinically recognizable Kabuki syndrome
Show evidence (1 reference)
PMID:30514738 SUPPORT Human Clinical
"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..."
Supports a modern consensus case definition for Kabuki syndrome.
👪

Inheritance

2
Autosomal dominant inheritance HP:0000006
Most Kabuki syndrome cases are caused by heterozygous KMT2D variants and behave as an autosomal dominant disorder, usually arising de novo.
Autosomal dominant inheritance
Show evidence (1 reference)
PMID:20711175 SUPPORT Human Clinical
"We demonstrate the successful application of exome sequencing to discover a gene for an autosomal dominant disorder, Kabuki syndrome (OMIM%147920)."
Supports autosomal dominant inheritance for the common KMT2D-related form.
X-linked dominant inheritance HP:0001423
A minority of cases are caused by heterozygous pathogenic variants or deletions in the X-linked gene KDM6A.
X-linked dominant inheritance
Show evidence (1 reference)
PMID:22197486 SUPPORT Human Clinical
"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."
Supports an X-linked disease mechanism for the KDM6A-related form.
◆

Subtypes

2
KMT2D-related Kabuki syndrome MONDO:0007843
KMT2D
Autosomal dominant Kabuki syndrome caused by pathogenic KMT2D variants and representing the major molecular subtype.
Show evidence (1 reference)
PMID:20711175 SUPPORT Human Clinical
"Our results strongly suggest that mutations in MLL2 are a major cause of Kabuki syndrome."
Supports KMT2D as the principal disease gene and major subtype.
KDM6A-related Kabuki syndrome MONDO:0010465
KDM6A
Less common Kabuki syndrome subtype caused by pathogenic KDM6A variants.
Show evidence (1 reference)
PMID:22197486 SUPPORT Human Clinical
"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."
Supports a distinct KDM6A-related molecular subtype.
⚙

Pathophysiology

4
Chromatin dysregulation from KMT2D and KDM6A haploinsufficiency
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.
neural crest cell link B cell link
chromatin organization link regulation of gene expression link
Show evidence (3 references)
PMID:24633898 SUPPORT Human Clinical
"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."
Establishes the two principal disease genes and the syndrome's developmental basis.
PMID:24633898 SUPPORT In Vitro
"We found that a number of KMT2D truncating mutations result in mRNA degradation through the nonsense-mediated mRNA decay, contributing to protein haploinsufficiency."
Supports haploinsufficiency as a core molecular mechanism.
PMID:22197486 SUPPORT Human Clinical
"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."
Connects KDM6A loss to the same chromatin-regulatory disease mechanism.
Neural crest developmental dysregulation
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.
neural crest cell link chondrocyte link
neural crest cell migration link neural crest cell migration involved in heart formation link
Show evidence (2 references)
PMID:29073101 SUPPORT Model Organism
"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."
Supports neural crest dysfunction as a unifying developmental mechanism.
PMID:31479440 SUPPORT Model Organism
"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..."
Supports a specific cardiovascular mechanism downstream of KMT2D deficiency.
B-cell terminal differentiation defect
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.
B cell link
B cell differentiation link somatic hypermutation of immunoglobulin genes link
Show evidence (3 references)
PMID:26194542 SUPPORT Human Clinical
"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."
Supports a high-burden humoral immunodeficiency phenotype in KMT2D-related disease.
PMID:26194542 SUPPORT In Vitro
"Impaired terminal differentiation was noted in primary B cells from patients with KMT2D(Mut/+) mutations."
Supports a cell-intrinsic B-cell maturation defect.
PMID:31363182 SUPPORT Human Clinical
"Overall, 44.1% (78/177) and 58.2% (46/79) of KS individuals exhibited infection susceptibility and hypogammaglobulinemia, respectively;"
Confirms that immune dysfunction and autoimmunity are common in a large registry cohort.
Postnatal neurogenesis deficit
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.
neuron link
neuron development link
Show evidence (1 reference)
PMID:25273096 SUPPORT Model Organism
"In vivo, deficiency of H3K4me3 in the dentate gyrus granule cell layer of Kmt2d(+/βGeo) mice correlated with reduced neurogenesis and hippocampal memory defects."
Supports a mechanistic link between KMT2D-dependent chromatin defects and cognitive impairment.
●

Phenotypes

14
Blood 1
Decreased Serum IgA Decreased circulating IgA concentration (HP:0002720)
Show evidence (1 reference)
PMID:26194542 SUPPORT Human Clinical
"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."
Supports IgA deficiency as a prevalent immunologic phenotype.
Cardiovascular 1
Congenital Heart Defects Abnormal heart morphology (HP:0001627)
Show evidence (1 reference)
PMID:28884922 SUPPORT Human Clinical
"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."
Supports congenital heart disease as a frequent and clinically important manifestation.
Ear 1
Hearing Impairment Hearing impairment (HP:0000365)
Show evidence (2 references)
PMID:34570271 SUPPORT Human Clinical
"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..."
Identifies hearing loss as a recognized multisystem feature.
PMID:15523636 SUPPORT Human Clinical
"The presence or absence of hearing loss or major malformations, other than those involving the brain, was not predictive of developmental outcome."
Acknowledges hearing loss as a feature while noting it does not predict cognitive outcome.
Genitourinary 1
Congenital Anomalies of the Kidney and Urinary Tract Abnormality of the urinary system (HP:0000079)
Show evidence (2 references)
PMID:34570271 SUPPORT Human Clinical
"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."
Demonstrates a high prevalence of CAKUT in a single-center cohort of KS patients.
PMID:21607748 SUPPORT Human Clinical
"MLL2 mutation carriers significantly more often presented with short stature and renal anomalies (p = 0.026 and 0.031, respectively)"
Renal anomalies are significantly associated with KMT2D mutation-positive patients.
Head and Neck 3
Long Palpebral Fissures Long palpebral fissure (HP:0000637)
Show evidence (1 reference)
PMID:30514738 SUPPORT Human Clinical
"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,..."
Supports long palpebral fissures as a defining clinical feature.
Arched Broad Eyebrows Highly arched eyebrow (HP:0002553)
Show evidence (1 reference)
PMID:30514738 SUPPORT Human Clinical
"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,..."
Lists arched broad eyebrows as a primary diagnostic dysmorphic feature.
Cleft Palate Cleft palate (HP:0000175)
Palatal anomalies are recognized within the broader craniofacial phenotype of Kabuki syndrome but are less frequently documented in abstract-level evidence.
Immune 2
Recurrent Infections Recurrent infections (HP:0002719)
Show evidence (1 reference)
PMID:31363182 SUPPORT Human Clinical
"Overall, 44.1% (78/177) and 58.2% (46/79) of KS individuals exhibited infection susceptibility and hypogammaglobulinemia, respectively;"
Supports recurrent infection susceptibility in a large cohort.
Autoimmunity Autoimmunity (HP:0002960)
Autoimmune manifestations are documented in the clinical literature but specific abstract-level quantification is limited. Registry data from PMID:31363182 confirms broad immune dysregulation in KS.
Integument 1
Prominent Fingertip Pads Prominent fingertip pads (HP:0001212)
Show evidence (1 reference)
PMID:30514738 SUPPORT Human Clinical
"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,..."
Persistent fingertip pads are listed as one of the core diagnostic dysmorphic features.
Musculoskeletal 2
Hypotonia Hypotonia (HP:0001252)
Show evidence (1 reference)
PMID:30514738 SUPPORT Human Clinical
"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..."
Supports hypotonia as a core early-life phenotype.
Scoliosis Scoliosis (HP:0002650)
Show evidence (1 reference)
PMID:11343317 PARTIAL Human Clinical
"Kabuki makeup (Niikawa-Kuroki) syndrome (KS) is characterized by distinct facial anomalies, mental retardation, congenital heart defect (CHD), and skeletal malformations."
Supports skeletal malformations broadly as a cardinal KS feature; scoliosis is a documented manifestation but not specifically named in this CHD-focused paper.
Nervous System 1
Intellectual Disability Intellectual disability (HP:0001249)
Show evidence (2 references)
PMID:30514738 SUPPORT Human Clinical
"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..."
Places intellectual disability in the core diagnostic phenotype.
PMID:15523636 SUPPORT Human Clinical
"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..."
Supports the typical severity range and variable developmental outcome.
Growth 1
Short Stature Short stature (HP:0004322)
Show evidence (1 reference)
PMID:21607748 SUPPORT Human Clinical
"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..."
Supports short stature as a common core feature.
🧬

Genetic Associations

2
KMT2D (Causative)
Show evidence (2 references)
PMID:20711175 SUPPORT Human Clinical
"Our results strongly suggest that mutations in MLL2 are a major cause of Kabuki syndrome."
Establishes KMT2D as the major causative gene.
PMID:24633898 SUPPORT In Vitro
"We found that a number of KMT2D truncating mutations result in mRNA degradation through the nonsense-mediated mRNA decay, contributing to protein haploinsufficiency."
Supports KMT2D haploinsufficiency as the dominant genetic mechanism.
KDM6A (Causative)
Show evidence (1 reference)
PMID:22197486 SUPPORT Human Clinical
"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."
Establishes KDM6A as a causative Kabuki syndrome gene.
💊

Treatments

5
HDAC Inhibitor Therapy (Experimental)
Action: HDAC inhibitor therapy Ontology label: pharmacotherapy MAXO:0000058
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.
Show evidence (1 reference)
PMID:25273096 SUPPORT Model Organism
"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."
Demonstrates that HDAC inhibitor treatment can rescue neurogenesis and memory deficits in a Kabuki syndrome mouse model.
Growth Hormone Therapy
Action: Growth hormone replacement therapy Ontology label: human growth hormone replacement therapy MAXO:0000780
Growth hormone replacement may be considered for patients with documented growth hormone deficiency contributing to postnatal growth retardation.
Speech Therapy
Action: Speech therapy Ontology label: speech therapy MAXO:0000930
Speech and language therapy is an important component of developmental support given the high prevalence of speech delay and intellectual disability.
Show evidence (1 reference)
PMID:15523636 PARTIAL Human Clinical
"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..."
Supports significant developmental variability warranting early intervention; speech therapy specifically is not discussed in this paper.
Cardiac Surgery
Action: Cardiac surgery Ontology label: surgical procedure on cardiovascular system MAXO:0025001
Surgical repair of congenital heart defects including septal defects, coarctation of the aorta, and other structural cardiac anomalies.
Show evidence (1 reference)
PMID:11343317 SUPPORT Human Clinical
"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"
High frequency of congenital heart defects necessitates surgical evaluation and repair.
Immunoglobulin Replacement
Action: Immunoglobulin replacement therapy Ontology label: immunoglobulin infusion therapy MAXO:0001480
Agent: therapeutic immune globulin ↗
Intravenous or subcutaneous immunoglobulin replacement therapy for patients with severe hypogammaglobulinemia and recurrent infections.
Show evidence (1 reference)
PMID:15887282 PARTIAL Human Clinical
"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."
Supports the clinical need for immunologic work-up but does not explicitly recommend immunoglobulin replacement therapy.
{ }

Source YAML

click to show 
name: Kabuki Syndrome
creation_date: '2026-03-15T23:04:41Z'
updated_date: '2026-03-16T21:00:00Z'
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: hereditary 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: nervous system disorder
    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.
- 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.
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.
- 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
  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.
- 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
  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.
- 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
  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.
- 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
  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.
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.
- 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.
- name: Intellectual Disability
  category: Neurological
  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.
- name: Short Stature
  category: Growth
  description: >-
    Postnatal growth deficiency commonly leads to short stature.
  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.
- name: Hypotonia
  category: Neurological
  description: >-
    Infantile hypotonia is part of the consensus clinical definition and
    contributes to motor delay and feeding difficulties.
  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.
- name: Congenital Heart Defects
  category: Cardiovascular
  description: >-
    Congenital heart disease is common, especially left-sided obstructive
    lesions and septal defects.
  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.
- name: Decreased Serum IgA
  category: Immunological
  description: >-
    Humoral immune dysfunction often includes decreased serum IgA levels with
    broader hypogammaglobulinemia in a subset of patients.
  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.
- name: Recurrent Infections
  category: Immunological
  description: >-
    Recurrent sinopulmonary and otologic infections are common clinical
    consequences of the associated antibody deficiency.
  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.
- 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.
- name: Scoliosis
  category: Musculoskeletal
  description: >-
    Skeletal anomalies including scoliosis are well-documented manifestations
    linked to altered neural crest and chondrocyte development.
  phenotype_term:
    preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  evidence:
  - 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.
- name: Hearing Impairment
  category: Otological
  description: >-
    Hearing loss is common in Kabuki syndrome, often conductive due to
    recurrent otitis media, but sensorineural loss also occurs.
  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.
- name: Cleft Palate
  category: Craniofacial
  description: >-
    Cleft palate or high-arched palate occurs in a subset of patients,
    consistent with the neurocristopathy mechanism.
  phenotype_term:
    preferred_term: Cleft palate
    term:
      id: HP:0000175
      label: Cleft palate
  notes: >-
    Palatal anomalies are recognized within the broader craniofacial phenotype
    of Kabuki syndrome but are less frequently documented in abstract-level
    evidence.
- 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.
- name: Autoimmunity
  category: Immunological
  description: >-
    A subset of patients develop autoimmune manifestations including
    idiopathic thrombocytopenic purpura, hemolytic anemia, and other
    autoimmune cytopenias, reflecting the paradox of concurrent
    immunodeficiency and immune dysregulation.
  phenotype_term:
    preferred_term: Autoimmunity
    term:
      id: HP:0002960
      label: Autoimmunity
  notes: >-
    Autoimmune manifestations are documented in the clinical literature but
    specific abstract-level quantification is limited. Registry data from
    PMID:31363182 confirms broad immune dysregulation in KS.
prevalence:
- population: Worldwide
  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.
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: MAXO:0000058
      label: pharmacotherapy
  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
  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.
- 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
  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
  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.
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.
- 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.