Kabuki Syndrome (MONDO:0016512) — Disease Characteristics Research Report

1. Disease Information

1.1 Overview (definition and current understanding)

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)

1.2 Key identifiers and synonyms

A structured list of identifiers available from the retrieved sources is provided here:

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)

1.3 Consensus diagnostic framing (expert consensus)

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)

2. Etiology

2.1 Primary causal factors (genetic)

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)

2.2 Risk factors / protective factors / gene–environment interactions

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)

3. Phenotypes (with HPO suggestions)

3.1 Core phenotypic domains

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)

3.2 Recent cohort statistics (2024 Taiwanese case series)

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)

3.3 Hearing phenotype (recent 2023 human+mouse study)

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)

3.4 Immune/autoimmune phenotype statistics (registry)

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)

3.5 Quality of life / humanistic burden

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)

3.6 HPO term suggestions (non-exhaustive; ontology mapping suggestions)

(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

4. Genetic / Molecular Information

4.1 Causal genes and inheritance

• KMT2D (KS1): autosomal dominant; typically de novo but familial transmission occurs. (barry2022fromgenotypeto pages 1-2, dugan2021kabukisyndrome pages 1-3)
• KDM6A (KS2): X-linked; sex-dependent expressivity is reported in recent KS2 cohorts. (wang2024sexspecificdifferencein pages 2-4, wang2024sexspecificdifferencein pages 5-6)

4.2 Variant classes and spectrum

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)

4.3 Epigenetic and transcriptional consequences (human evidence; 2023)

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)

4.4 Immune mechanism: integrin regulation in T cells (2024)

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)

4.5 Cell-type specificity of chromatin disruption (2024)

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)

4.6 KS2 growth mechanism and convergence with KS1 (2024)

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)

5. Environmental Information

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)

6. Mechanism / Pathophysiology

6.1 Chromatin and histone-mark dysregulation (core causal chain)

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)

6.2 Immune pathway mechanism (integrin/MST1 axis)

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)

6.3 Neurodevelopment: tissue specificity and episignature caveat

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)

6.4 Growth-plate biology and endochondral ossification

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)

6.5 Suggested ontology terms (mechanism structuring; not exhaustively validated here)

• GO biological process (suggested): chromatin organization; histone H3-K4 methylation; regulation of transcription by RNA polymerase II; T cell activation; leukocyte migration; endochondral ossification; chondrocyte differentiation.
• Cell Ontology (suggested): B cell; T cell; CD4-positive T cell; CD8-positive T cell; thymocyte; natural killer cell; chondrocyte; hypertrophic chondrocyte; neuron.

7. Anatomical Structures Affected

7.1 Organ/system involvement (supported)

• Central nervous system / neurodevelopment: developmental delay, intellectual disability, hypotonia. (barry2022fromgenotypeto pages 1-2, lee2024geneticandphenotypic pages 1-2)
• Immune system: recurrent infections, hypogammaglobulinemia, autoimmune cytopenias. (margot2020immunopathologicalmanifestationsin pages 1-2)
• Cardiovascular system: congenital heart abnormalities (e.g., ASD, VSD, coarctation). (lee2024geneticandphenotypic pages 1-2)
• Auditory system: mixed conductive and sensorineural hearing loss. (kalinousky2023kmt2ddeficiencycauses pages 5-7)
• Skeletal system / growth plates: growth deficiency and altered long-bone and growth-plate parameters (mouse models; mechanistic relevance). (gao2024growthdeficiencyin pages 3-6)

7.2 UBERON / GO-CC suggestions (not asserted as extracted identifiers)

• UBERON (suggested): heart; cochlea; thymus; bone growth plate; hippocampus
• GO cellular component (suggested): nucleus; chromatin; histone methyltransferase complex

8. Temporal Development

8.1 Typical onset

KS is congenital with early-life hypotonia and developmental delay emphasized in diagnostic criteria. (adam2019kabukisyndromeinternational pages 1-2)

8.2 Hearing temporal profile (example)

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)

9. Inheritance and Population

9.1 Inheritance patterns

• KS1 (KMT2D): autosomal dominant. (barry2022fromgenotypeto pages 1-2, dugan2021kabukisyndrome pages 1-3)
• KS2 (KDM6A): X-linked; recent cohort work suggests sex-modified severity. (wang2024sexspecificdifferencein pages 2-4, wang2024sexspecificdifferencein pages 5-6)

9.2 Sex-specific severity in KS2 (2024 matched case–control)

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)

10. Diagnostics

10.1 Clinical criteria and confirmatory testing

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)

10.2 Genetic testing (real-world implementation)

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)

10.3 Epigenomic “episignature” as a diagnostic adjunct

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)

10.4 Differential diagnosis

This run did not retrieve differential-diagnosis tables or guideline-style differential lists; therefore no specific differentials are asserted here.

11. Outcome / Prognosis

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)

12. Treatment

12.1 Standard of care (current practice)

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)

12.2 Dietary/metabolic interventions (recent developments and real-world implementation)

12.2.1 2024 multi-omics + Modified Atkins/ketogenic diet report (KMT2D)

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)

12.2.2 ClinicalTrials.gov: Modified Atkins Diet trial (adults; completed)

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)

12.3 MAXO term suggestions (treatment action structuring)

• Multidisciplinary care coordination
• Genetic counseling
• Developmental therapy (speech therapy; physical therapy; occupational therapy)
• Dietary therapy (Modified Atkins diet / ketogenic diet)
• Immunologic monitoring and management (screening for hypogammaglobulinemia; management of autoimmune cytopenias)

13. Prevention

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)

14. Other Species / Natural Disease

No naturally occurring non-human Kabuki syndrome cases were retrieved in this run.

15. Model Organisms

15.1 Mouse models (key recent 2023–2024 studies)

• KS1 hearing model: Kmt2d+/βGeo mice show progressive hearing impairment; ABR thresholds diverge after hearing onset and DPOAEs are diminished at multiple frequencies, consistent with outer hair cell dysfunction despite no gross cochlear malformations on micro-CT. (kalinousky2023kmt2ddeficiencycauses pages 7-9)
• KS2 growth model: Kdm6a tm1d/+ mice exhibit postnatal growth deficiency with shortened long bones and growth-plate hypertrophic-zone reductions; Kdm6a−/− and Kmt2d−/− chondrocyte models show convergent transcriptomic changes. (gao2024growthdeficiencyin pages 3-6)
• Cell-type chromatin comparisons: ATAC-seq across neurons vs B/T cells demonstrates cell-context-specific chromatin disruptions (neuronal CpG-island/aging enrichment), informing translational interpretation of blood-derived episignatures. (boukas2024neuronspecificchromatindisruption pages 1-2)

16. Recent Developments (2023–2024 highlights)

1. Human epigenomic profiling in KS PBMCs links KMT2D haploinsufficiency to enhancer dysregulation at immune genes, with super-enhancer overlap (~31%) and metabolic gene upregulation. (Jung et al., 2023; https://doi.org/10.1101/2022.10.25.22280882). (jung2023characterizingthemolecular pages 1-5)
2. T-cell intrinsic mechanism in KS: KMT2D control of leukocyte integrins and migration/egress programs, with corroborating human peripheral T-cell shifts (reduced naïve/RTE, expanded memory). (Potter et al., 2024; https://doi.org/10.3389/fimmu.2024.1341745). (potter2024kmt2dregulatesactivation pages 14-16, potter2024kmt2dregulatesactivation pages 1-2)
3. Neuron-specific chromatin disruption suggests mechanistic differences across tissues and cautions in interpreting blood episignatures mechanistically for neurodevelopment. (Boukas et al., 2024; https://doi.org/10.1101/gr.278416.123). (boukas2024neuronspecificchromatindisruption pages 1-2)
4. KS2 skeletal mechanism and convergence with KS1 via shared chondrocyte differentiation programs and growth-plate pathology. (Gao et al., 2024; https://doi.org/10.1371/journal.pgen.1011310). (gao2024growthdeficiencyin pages 3-6)
5. Dietary intervention translational efforts: 2024 multi-omics report linking ribosomal protein dysregulation to KMT2D KS and describing Modified Atkins/ketogenic diet-associated molecular and cognitive changes (hypothesis-generating) plus an adult MAD clinical trial completed (NCT04722315). (tsang2024ketogenicdietmodifies pages 8-10, NCT04722315 chunk 1)

17. Notes on evidence gaps for this run

• ICD-10/ICD-11, MeSH, Orphanet identifiers were not present in retrieved sources; they should be added from dedicated ontology resources (Orphanet/MeSH/ICD) in a follow-on extraction step.
• Survival/life expectancy statistics were not captured in the extracted evidence; robust natural history cohorts would be needed.
• Differential diagnosis lists and standardized care pathways were not extracted in this run.

References

1. (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.

2. (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.

3. (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.

4. (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.

5. (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.

6. (golden2023molecularinsightsof pages 9-11): 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.

7. (wang2024sexspecificdifferencein pages 2-4): 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.

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9. (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.

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12. (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.

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17. (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.

18. (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.

19. (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.

20. (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.

21. (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.

22. (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.

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25. (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.

26. (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.

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28. (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.

29. (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.

30. (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.