Arboleda-Tham Syndrome

Mendelian MONDO:0014558 Pathograph 46 Show in embeddings browser autosomal dominant syndromic intellectual disability multiple congenital anomalies/dysmorphic syndrome-intellectual disability

Arboleda-Tham syndrome (KAT6A syndrome) is an autosomal dominant neurodevelopmental disorder caused by heterozygous, usually de novo, pathogenic variants in KAT6A, a MYST-family lysine acetyltransferase that acetylates histone H3 (notably H3K9 and H3K18) within a multi-subunit complex with BRPF1/2/3, ING5, and hEAF6 to drive developmental transcriptional programs. The core phenotype comprises global developmental delay with usually co-occurring intellectual disability and marked expressive speech delay, neonatal hypotonia, early feeding and oromotor difficulties, recognizable craniofacial dysmorphism (broad nasal tip and thin, tented upper lip), and congenital cardiac defects, most often septal defects. Gastrointestinal dysmotility (reflux, constipation, and an increased risk of intestinal obstruction), microcephaly, ophthalmologic anomalies (notably strabismus), recurrent infections, and variable behavioral features complete the spectrum. A genotype-phenotype correlation is recognized: early-truncating variants (exons 1-15) are predicted to trigger nonsense-mediated decay and haploinsufficiency and are associated with milder disease, whereas late-truncating variants (exons 16-17) escape nonsense-mediated decay and are associated with more severe developmental delay and a higher frequency of several syndromic features.

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1
Inheritance
11
Pathophys.
32
Phenotypes
3
Hypotheses
5
Gaps
46
Pathograph
1
Genes
5
Medical Actions
1
Differentials
3
Datasets
13
References
1
Deep Research
1
Hyp. Reports
👪

Inheritance

1
Autosomal dominant inheritance HP:0000006
Arboleda-Tham syndrome is autosomal dominant and is almost always caused by a de novo heterozygous pathogenic KAT6A variant.
Autosomal dominant inheritance Expressivity: VARIABLE
Show evidence (2 references)
PMID:25728775 SUPPORT Human Clinical
"Here, we report a syndrome caused by de novo heterozygous nonsense mutations in KAT6A (a.k.a., MOZ, MYST3) identified by clinical exome sequencing (CES) in four independent families."
The founding series establishes heterozygous, de novo KAT6A variants as the cause, consistent with autosomal dominant inheritance.
PMID:39740728 SUPPORT Human Clinical
"Here, we report a Danish family, where an inherited KAT6A frameshift variant c.2710dup (p.(Glu904Glyfs∗12)) show clinical variability in disease phenotype expression among three family members."
This family demonstrates that vertical transmission of a constitutional frameshift allele can occur and that expression is variable; de novo occurrence is usual rather than universal.
◈

Mechanistic Hypotheses

3
Early-Truncating NMD / Haploinsufficiency Branch
early_truncating_nmd_haploinsufficiency CANONICAL
Evidence balance 1 support
Truncating variants in exons 1-15 are predicted to trigger nonsense-mediated decay of the mutant transcript, producing KAT6A haploinsufficiency. This branch is associated with a milder phenotype, with a majority of early-truncating cases rated as having mild intellectual disability.
Pathograph links
Heterozygous KAT6A Pathogenic Variation -> NMD-Mediated KAT6A Haploinsufficiency DIRECT
NMD-Mediated KAT6A Haploinsufficiency -> Dysregulated Histone H3 Acetylation DIRECT
Show evidence (1 reference)
PMID:30245513 SUPPORT Human Clinical
"This suggests a potential role for nonsense mediated decay (NMD), where truncating mutations in the first 15 exons trigger NMD mechanisms and result in haploinsufficiency while mutations in exons 16 and 17 would not result in NMD, therefore the mRNA would result in a translated but dysfunctional..."
The genotype-phenotype study proposes NMD-mediated haploinsufficiency for early-truncating variants as the basis for milder disease.
Late-Truncating NMD-Escape Branch
late_truncating_nmd_escape ALTERNATIVE
Evidence balance 1 support
Truncating variants in the last two exons (16-17) escape nonsense-mediated decay and are predicted to yield a translated but dysfunctional protein with possible gain-of-function or dominant-negative effects. This branch is associated with more severe developmental delay and a higher frequency of several syndromic features. Direct demonstration of mutant protein and its mode of action in patient tissue remains an evidence gap. The two halves of this branch are not equally supported: the clinical severity gradient is reproduced across independent cohorts, while the molecular claim is unproven. KAT6A is among the most loss-of-function-intolerant genes in the genome and early decay-competent truncations are unambiguously pathogenic, so haploinsufficiency is the baseline mechanism and this branch is better read as a severity modifier layered on it than as a competing primary mechanism.
Pathograph links
Heterozygous KAT6A Pathogenic Variation -> NMD-Escaping Dysfunctional KAT6A Protein DIRECT
NMD-Escaping Dysfunctional KAT6A Protein -> Dysregulated Histone H3 Acetylation DIRECT
Deep research
OpenScientist citations 10 citations 2026-09-07T06:06:44.220361
Show evidence (1 reference)
PMID:30245513 SUPPORT Human Clinical
"95% of late truncating cases (exon 16 and 17) were rated as moderate or severe, while 60% of early truncating cases (exons 1-15) were rated as mild"
The cohort documents the more severe developmental phenotype associated with the NMD-escaping late-truncating branch.
KAT6A-RSPO2-Wnt Hippocampal Signaling Branch
kat6a_rspo2_wnt_hippocampal EMERGING
Evidence balance 1 support
An emerging mechanism, so far demonstrated only in mice, links KAT6A deficiency to impaired cognition through a specific transcriptional target: KAT6A activates the CA3-enriched Wnt activator R-spondin 2 (RSPO2), and its loss reduces hippocampal CA3 synaptic structure, plasticity, and Wnt signaling. Restoring RSPO2 in CA3 neurons rescues Wnt signaling and learning behaviors in Kat6a mutant mice, nominating the KAT6A-RSPO2-Wnt axis as a candidate therapeutic target. Fidelity to human KAT6A-syndrome cognition is not yet established.
Pathograph links
Altered Developmental Transcriptional Programs -> KAT6A-RSPO2-Wnt Hippocampal Signaling Deficit DIRECT
KAT6A-RSPO2-Wnt Hippocampal Signaling Deficit -> Intellectual Disability INDIRECT UNKNOWN INTERMEDIATES
Show evidence (1 reference)
PMID:38758792 SUPPORT Model Organism
"Collectively, our results demonstrate that KAT6A-RSPO2-Wnt signaling plays a critical role in regulating hippocampal CA3 synaptic plasticity and cognitive function, providing potential therapeutic targets for KAT6A syndrome and related neurodevelopmental diseases."
A mouse study defines the KAT6A-RSPO2-Wnt hippocampal axis as an emerging mechanism of the cognitive phenotype and a candidate therapeutic target.
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Discussions and Knowledge Gaps

5
Do the neural-progenitor, hippocampal RSPO2-Wnt, and histone-acetylation abnormalities found in Kat6a mouse models reproduce human neural pathology, and can acetyl-L-carnitine safely improve clinically meaningful outcomes?
HUMAN MODEL MISMATCH OPEN gap_kat6a_preclinical_translation
Attached to
pathophysiology#Impaired Neural Progenitor Proliferation and Differentiation pathophysiology#KAT6A-RSPO2-Wnt Hippocampal Signaling Deficit treatments#Acetyl-L-Carnitine
The mechanistic and intervention results are from mouse neural cells or whole animals. Patient fibroblasts establish chromatin abnormalities but do not validate the neural circuit mechanisms, clinical endpoints, dose, or variant-specific treatment response in people.
Show evidence (1 reference)
PMID:41702672 SUPPORT Model Organism
"Treatment with the acetyl-donor, acetyl-L-carnitine (ALCAR) resulted in the rescue of H3K23ac levels in mouse brain and amelioration of the hyperactivity and learning impairments."
Mouse rescue motivates translation but cannot establish human benefit.
What are the incidence, age-specific natural history, predictors, and evidence-based surveillance thresholds for neutropenia, marrow failure, and other hematologic abnormalities in Arboleda-Tham syndrome?
KNOWLEDGE GAP OPEN gap_kat6a_hematologic_natural_history
Attached to
phenotypes#Neutropenia phenotypes#Aplastic Anemia
The first quantified cohort reports a broad severity range in only three affected participants. It does not define longitudinal risk or justify a uniform blood-count schedule or intervention threshold.
Show evidence (1 reference)
PMID:42040242 SUPPORT Human Clinical
"Notably, 3 of 11 patients (27%) exhibited hematologic abnormalities, ranging from transient neonatal neutropenia to severe aplastic anemia requiring hematopoietic stem cell transplantation."
This small retrospective denominator establishes the signal while leaving prevalence, trajectory, predictors, and surveillance unresolved.
Do recurrent infections in Arboleda-Tham syndrome reflect a primary KAT6A-dependent immune defect, secondary or structural factors, or ordinary childhood infection rates?
KNOWLEDGE GAP OPEN gap_kat6a_recurrent_infection_mechanism
Attached to
phenotypes#Recurrent Infections
The largest cohort explicitly cautions that the common childhood infections reported by a subset of patients are not necessarily indicative of immunodysfunction, while isolated patients had hypogammaglobulinemia, unusual infections, or structural predispositions. Mouse studies show KAT6A-dependent memory B-cell formation and CD8 T-cell responses, but no human immunophenotyping study has tested that bridge, so no causal edge is asserted for this phenotype.
Show evidence (2 references)
PMID:30245513 SUPPORT Human Clinical
"Many children experience recurrent infections of these types, so this is not necessarily indicative of immunodysfunction."
The cohort's own caution is the reason the infection phenotype is left without a mechanistic edge.
PMID:30245513 SUPPORT Model Organism
"Further studies demonstrated that KAT6A-mediated acetylation promotes memory B-cell formation and the CD8 T-cell response to viral infection"
Mouse immunology supplies a candidate mechanism that human studies have not yet tested.
What developmental mechanism produces type 1 Chiari malformation and cerebral white-matter hyperintensities in Arboleda-Tham syndrome, and are these neuroimaging findings KAT6A-specific or coincidental?
KNOWLEDGE GAP OPEN gap_kat6a_neuroanatomic_findings_mechanism
Attached to
phenotypes#Chiari Malformation phenotypes#Cerebral White Matter Hyperintensities
Both findings come from a small retrospective imaging denominator (2 of 10 imaged patients, reported jointly) with a single corroborating Chiari case in the earlier 76-person cohort, where major structural brain anomalies were described as rare. No study links these findings to KAT6A-dependent skull-base, hindbrain, or white-matter development, so no causal edge is asserted for either phenotype.
Show evidence (1 reference)
PMID:42040242 SUPPORT Human Clinical
"Brain imaging revealed type 1 Chiari malformation and white matter hyperintensities in 2 of the 10 assessed (20%), suggesting a broader neuroanatomic involvement."
The observation is quantified but mechanistically unexplained, so it is recorded as a knowledge gap rather than a manufactured causal edge.
Do late-truncating KAT6A alleles that escape nonsense-mediated decay act through a dysfunctional protein with gain-of-function or dominant-negative activity, or is Arboleda-Tham syndrome a haploinsufficiency disorder across the whole allelic series with position effects explained by residual dosage?
CONTROVERSY OPEN kat6a_truncation_position_mechanism_controversy
Attached to
pathophysiology#Heterozygous KAT6A Pathogenic Variation pathophysiology#NMD-Mediated KAT6A Haploinsufficiency pathophysiology#NMD-Escaping Dysfunctional KAT6A Protein mechanistic_hypotheses#early_truncating_nmd_haploinsufficiency mechanistic_hypotheses#late_truncating_nmd_escape
The genotype-phenotype correlation (late truncations more severe) and patient-cell multi-omics showing HOXC derepression point toward an active truncated protein, while the earliest truncations behave as nulls and a heterozygous Kat6a null mouse reproduces core behavioural features. Neither truncated protein in patient cells nor a same-background comparison of early, late and null alleles has been published, so the variant's functional_impact_category is UNKNOWN and the two hypotheses are kept as separate branches.
Proposed experiments
Truncated-KAT6A protein detection and early- versus late-truncation isogenic comparison
Patient-cell proteomics plus isogenic iPSC allelic series stratified by truncation position Relation: this experiment is of type this experiment type This experiment is of type Patient-cell proteomics plus isogenic iPSC allelic series stratified by truncation position.
exp_arths_truncation_position_isogenic_panel
Test for truncated KAT6A protein in patient lymphoblastoid or fibroblast lines carrying early (exon 1-15) and late (exon 16-17) truncations by N-terminal immunoblot and targeted proteomics, with and without nonsense-mediated-decay inhibition. Then derive isogenic human iPSC lines carrying a representative early truncation, a representative late truncation, a heterozygous KAT6A null, and a corrected control; differentiate to neural progenitors; and compare H3K9/H3K23 acetylation, posterior HOXC cluster expression, and neural-progenitor proliferation, with wild-type add-back and mutant-selective knockdown arms.
Decision criterion
The late-truncation branch is dominant or gain of function if truncated protein is detected for late but not early alleles and the late knock-in line diverges from the null on HOXC and acetylation readouts in a way that mutant-selective knockdown corrects; both branches are loss of function if early, late and null lines match and wild-type add-back rescues each.
Would support
mechanistic_hypotheses#late_truncating_nmd_escape mechanistic_hypotheses#early_truncating_nmd_haploinsufficiency
Would refute
mechanistic_hypotheses#early_truncating_nmd_haploinsufficiency mechanistic_hypotheses#late_truncating_nmd_escape
Supporting outcome
  • Late alleles express truncated protein and behave differently from the null with mutant-selective rescue: the entry should carry two contexts, LOSS_OF_FUNCTION for early and GAIN_OF_FUNCTION or DOMINANT_NEGATIVE for late truncations.
Refuting outcome
  • No truncated protein for either class and all mutant lines match the null: a single LOSS_OF_FUNCTION context covers the allelic series.
Posed by claude-code Posed 2026-09-05T00:00:00Z
Show evidence (3 references)
PMID:41702672 SUPPORT Model Organism
"very early truncations, which are likely to represent complete loss of function of one allele"
The haploinsufficient-mouse study assigns the earliest human truncations to a null-like class, the loss-of-function pole of the controversy.
PMID:37861717 SUPPORT In Vitro
"our study suggests that KAT6A truncating mutations may have some abnormal, potentially gain-of-function effects causing upregulation of specific HOX genes and clusters."
Patient-cell multi-omics raises a gain-of-function reading for truncating alleles, the opposite pole.
PMID:37861717 SUPPORT In Vitro
"However, this molecular role requires additional study to demonstrate definitive proof of the gain-of-function effects in model systems."
The same authors mark the gain-of-function reading as undemonstrated, which is why the category stays UNKNOWN.
⚙

Pathophysiology

11
Heterozygous KAT6A Pathogenic Variation
Mechanism confidence: Established
The initiating lesion is a heterozygous, usually de novo, pathogenic KAT6A variant. Most established alleles are protein-truncating (nonsense or frameshift), with recurrent hotspots in the arginine-rich acidic domain, and are distributed across the gene with a bias toward the last two exons.
Early-Truncating NMD / Haploinsufficiency Branch Late-Truncating NMD-Escape Branch
KAT6A hgnc:13013 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves KAT6A (hgnc:13013). hgnc:13013 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context KAT6A hgnc:13013 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns KAT6A (hgnc:13013). hgnc:13013 is a gene from the HUGO Gene Nomenclature Committee. variant_origin: DE_NOVO zygosity: HETEROZYGOUS functional_impact_category: UNKNOWN
De novo heterozygous protein-truncating KAT6A alleles. Recorded as UNKNOWN because the mechanism depends on truncation position and neither branch has been demonstrated at the protein level: early truncations (exons 1-15) are expected to trigger nonsense-mediated decay and act by haploinsufficiency (mechanistic_hypotheses#early_truncating_nmd_haploinsufficiency), while late truncations (exons 16-17) escape decay and may act through a dysfunctional, possibly gain-of-function or dominant-negative, protein (mechanistic_hypotheses#late_truncating_nmd_escape). Once demonstrated, the two branches warrant separate contexts rather than one category.
Downstream
Mitochondrial and Bioenergetic Dysfunction
NMD-Mediated KAT6A Haploinsufficiency Early-Truncating NMD / Haploinsufficiency Branch
NMD-Escaping Dysfunctional KAT6A Protein Late-Truncating NMD-Escape Branch
Show evidence (1 reference)
PMID:25728777 SUPPORT Human Clinical
"All five different de novo heterozygous truncating mutations were located in the C-terminal transactivation domain of KAT6A"
The founding series establishes heterozygous, de novo truncating KAT6A variants clustered in the C-terminal domain.
NMD-Mediated KAT6A Haploinsufficiency
Mechanism confidence: Provisional
Early-truncating variants (exons 1-15) are predicted to trigger nonsense-mediated decay of the mutant transcript, reducing functional KAT6A dosage (haploinsufficiency). This is the canonical route and is associated with milder disease.
Early-Truncating NMD / Haploinsufficiency Branch
Downstream
Dysregulated Histone H3 Acetylation Early-Truncating NMD / Haploinsufficiency Branch
NMD-Escaping Dysfunctional KAT6A Protein
Mechanism confidence: Provisional
Late-truncating variants (exons 16-17) escape nonsense-mediated decay and are predicted to produce a translated but dysfunctional protein that may act by gain-of-function or dominant-negative mechanisms. This is the alternative route and is associated with more severe disease. Direct demonstration of mutant protein and its mode of action in patient tissue remains an evidence gap.
Late-Truncating NMD-Escape Branch
Downstream
Dysregulated Histone H3 Acetylation Late-Truncating NMD-Escape Branch
Dysregulated Histone H3 Acetylation
Mechanism confidence: Established
KAT6A (MOZ/MYST3) is a MYST-family histone acetyltransferase that, within a complex containing BRPF1/2/3, ING5, and hEAF6, acetylates lysine residues on histone H3 tails (notably H3K9 and H3K18). Pathogenic variants dysregulate H3K9 and H3K18 acetylation, altering the chromatin state that governs developmental gene expression. (GO lacks a current, non-obsolete histone-H3-specific acetylation biological-process term; the H3 specificity is carried by the H3K9 and H3K18 molecular-function annotations.)
chromatin organization GO:0006325 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal chromatin organization (GO:0006325). GO:0006325 is a biological process from the Gene Ontology. ⚠ ABNORMAL
histone acetyltransferase activity GO:0004402 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves histone acetyltransferase activity (GO:0004402). GO:0004402 is a molecular function from the Gene Ontology. histone H3K9 acetyltransferase activity GO:0043992 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves dysregulated histone H3K9 acetyltransferase activity (GO:0043992). GO:0043992 is a molecular function from the Gene Ontology. ↕ DYSREGULATED histone H3K18 acetyltransferase activity GO:0043993 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves dysregulated histone H3K18 acetyltransferase activity (GO:0043993). GO:0043993 is a molecular function from the Gene Ontology. ↕ DYSREGULATED
Downstream
Altered p53 Signaling
Altered Developmental Transcriptional Programs
Posterior HOXC Cluster Overexpression
Impaired Neural Progenitor Proliferation and Differentiation
Show evidence (3 references)
PMID:25728775 SUPPORT In Vitro
"We further demonstrate that KAT6A mutations result in dysregulation of H3K9 and H3K18 acetylation and altered P53 signaling."
Directly supports dysregulated H3K9/H3K18 acetylation as the molecular consequence of KAT6A mutation.
PMID:30245513 SUPPORT Other
"KAT6A and KAT6B each function in a multi-subunit complex with three other proteins: BRPF1/2/3, ING5 and hEAF6"
Establishes the KAT6A histone-acetyltransferase complex through which the enzyme acts on histone H3.
PMID:37861717 SUPPORT In Vitro
"Finally, we used unbiased proteomic mass spectrometry and identified two new histone post-translational modifications (PTMs) that are disrupted in ARTHS: H2A and H3K56 acetylation."
Patient-derived fibroblast multi-omics extends the established acetylation defect beyond H3K9/H3K18 to H2A and H3K56 marks.
Posterior HOXC Cluster Overexpression
Mechanism confidence: Provisional
Multi-omic profiling of eight patient-derived dermal fibroblast lines found increased chromatin accessibility, H3K23 acetylation, gene-body DNA methylation, and overexpression across a posterior HOXC gene cluster. This is a reproducible human-cell molecular readout; fibroblasts do not establish which developmental tissues carry the same signature or whether HOXC overexpression causes particular clinical features.
gene expression GO:0010467 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased gene expression (GO:0010467). GO:0010467 is a biological process from the Gene Ontology. ↑ INCREASED
Show evidence (1 reference)
PMID:37861717 SUPPORT In Vitro
"The genomic loci harboring HOXC genes are epigenetically regulated with increased chromatin accessibility, high levels of H3K23ac, and increased gene-body DNA methylation compared to controls, all of which are consistent with transcriptomic overexpression."
This directly supports the coupled chromatin and transcriptional HOXC phenotype in patient fibroblasts while not assigning an unproven organ-level consequence.
Impaired Neural Progenitor Proliferation and Differentiation
Mechanism confidence: Provisional
In mouse neural stem and progenitor cells, loss of one or both Kat6a alleles disrupts H3K23 acetylation and MLL1 recruitment at developmental genes, impairing normal proliferation and neuronal differentiation. The result strengthens the developmental-neurobiology bridge but has not yet been demonstrated in patient-derived neural progenitors or human brain tissue.
neural stem cell CL:0000047 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neural stem cell (CL:0000047). CL:0000047 is a cell type from the Cell Ontology.
neural precursor cell proliferation GO:0061351 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased neural precursor cell proliferation (GO:0061351). GO:0061351 is a biological process from the Gene Ontology. ↓ DECREASED neuron differentiation GO:0030182 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased neuron differentiation (GO:0030182). GO:0030182 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Global Developmental Delay
Show evidence (1 reference)
PMID:42081590 SUPPORT Model Organism
"Our data suggests two modes of action for KAT6A: (1) acetylation of histone H3 on lysine 23 at promoters and enhancers and (2) recruitment of the trithorax group protein MLL1 (KMT2A) to promote the expression of developmental genes, including SOX and homeodomain genes."
The mouse study identifies the two chromatin functions upstream of the neural-progenitor proliferation and differentiation defect.
Altered p53 Signaling
Mechanism confidence: Provisional
Beyond its direct catalytic effect on histone H3, KAT6A dysfunction perturbs p53-associated transcriptional programs. Patient-derived fibroblasts show altered expression of p53-associated genes, a downstream transcriptional consequence distinct from the direct loss of histone acetylation. The specific disease-level consequences downstream of altered p53 signaling in KAT6A syndrome are not established, so this node is intentionally left as a terminal molecular readout.
signal transduction by p53 class mediator GO:0072331 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal signal transduction by p53 class mediator (GO:0072331). GO:0072331 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Show evidence (1 reference)
PMID:30245513 SUPPORT In Vitro
"demonstrated altered expression of p53- associated genes"
Patient fibroblast transcriptomics show altered p53-associated gene expression downstream of KAT6A dysfunction.
Altered Developmental Transcriptional Programs
Mechanism confidence: Provisional
Disrupted KAT6A-dependent histone acetylation alters the transcriptional programs that pattern the developing brain, craniofacial skeleton, heart, and other organs, producing the multisystem congenital and neurodevelopmental phenotype. The intervening steps from chromatin dysregulation to each organ-level endpoint are not individually resolved in humans.
KAT6A-RSPO2-Wnt Hippocampal Signaling Branch
regulation of transcription by RNA polymerase II GO:0006357 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal regulation of transcription by RNA polymerase II (GO:0006357). GO:0006357 is a biological process from the Gene Ontology. ⚠ ABNORMAL nervous system development GO:0007399 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal nervous system development (GO:0007399). GO:0007399 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Global Developmental Delay
Intellectual Disability
Expressive Speech Delay
Craniofacial Dysmorphism
Congenital Cardiac Defects
Hypotonia
Feeding Difficulties
Microcephaly
Gastroesophageal Reflux
Constipation
KAT6A-RSPO2-Wnt Hippocampal Signaling Deficit KAT6A-RSPO2-Wnt Hippocampal Signaling Branch
Atrial Septal Defect Specific cardiac lesion within the congenital cardiac phenotype already attributed to disrupted developmental transcription; the intervening cardiogenic steps are unresolved.
Ventricular Septal Defect Specific cardiac lesion within the congenital cardiac phenotype already attributed to disrupted developmental transcription; the intervening cardiogenic steps are unresolved.
Patent Ductus Arteriosus Persistence of fetal cardiovascular anatomy within the congenital cardiac phenotype attributed to disrupted developmental transcription.
Patent Foramen Ovale Persistence of fetal cardiovascular anatomy within the congenital cardiac phenotype attributed to disrupted developmental transcription.
Broad Nasal Tip Specific facial feature within the craniofacial dysmorphism already attributed to disrupted developmental transcription.
Thin, Tented Upper Lip Specific facial feature within the craniofacial dysmorphism already attributed to disrupted developmental transcription.
Low-Set, Posteriorly Rotated Ears Specific facial feature within the craniofacial dysmorphism already attributed to disrupted developmental transcription.
Craniosynostosis Skull development anomaly within the craniofacial spectrum attributed to disrupted developmental transcription.
Dental Anomalies Dentition anomalies within the craniofacial spectrum attributed to disrupted developmental transcription.
Hearing Impairment Congenital hearing defects are a developmental anomaly within the multisystem congenital phenotype; the otologic developmental bridge is unresolved.
Strabismus Ocular anomaly within the multisystem congenital and neurodevelopmental phenotype; whether the defect is primarily oculomotor-neural or muscular is unresolved.
Cryptorchidism Congenital genitourinary anomaly within the multisystem congenital phenotype; the developmental bridge is unresolved.
Intestinal Obstruction Structural gastrointestinal malformations (malrotation, duodenal web) underlie several obstruction cases, indicating a developmental origin; dysmotility may contribute in others.
Autistic Behavior Neurobehavioral manifestation of the neurodevelopmental phenotype, at the same epistemic level as the wired intellectual-disability and developmental-delay edges.
Sleep Disturbance Neurobehavioral manifestation of the neurodevelopmental phenotype; no sleep-specific mechanism has been studied.
Seizures Uncommon neurologic manifestation of abnormal brain development; no consistent seizure type or epileptogenic mechanism has been identified.
Impaired Hematopoietic Stem Cell Function
Show evidence (1 reference)
PMID:30245513 SUPPORT Other
"These proteins form a complex to acetylate lysine residues on histone H3 tails, thereby promoting a wide range of developmental programs."
Supports the link between the KAT6A acetyltransferase complex and broad developmental transcriptional programs.
KAT6A-RSPO2-Wnt Hippocampal Signaling Deficit
Mechanism confidence: Provisional
In a mouse model, KAT6A deficiency lowers transcription of the CA3-enriched Wnt activator R-spondin 2 (RSPO2), impairing canonical Wnt signaling and synaptic structure and plasticity in hippocampal CA3 pyramidal neurons and producing memory deficits. Restoring RSPO2 in CA3 neurons rescues Wnt signaling and learning behaviors, nominating this axis as a candidate therapeutic target. This mechanism is currently established only in mice; its fidelity to human KAT6A-syndrome cognition is unproven.
KAT6A-RSPO2-Wnt Hippocampal Signaling Branch
hippocampal CA3 pyramidal neuron CL:1001571 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves hippocampal CA3 pyramidal neuron, annotated with hippocampal pyramidal neuron (CL:1001571). CL:1001571 is a cell type from the Cell Ontology.
canonical Wnt signaling pathway GO:0060070 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased canonical Wnt signaling pathway (GO:0060070). GO:0060070 is a biological process from the Gene Ontology. ↓ DECREASED regulation of synaptic plasticity GO:0048167 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal regulation of synaptic plasticity (GO:0048167). GO:0048167 is a biological process from the Gene Ontology. ⚠ ABNORMAL learning or memory GO:0007611 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal learning or memory (GO:0007611). GO:0007611 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Intellectual Disability KAT6A-RSPO2-Wnt Hippocampal Signaling Branch
Show evidence (1 reference)
PMID:38758792 SUPPORT Model Organism
"Here, we find that KAT6A deficiency impairs synaptic structure and plasticity in hippocampal CA3, but not in CA1 region, resulting in memory deficits in mice."
The mouse model localizes the KAT6A cognitive mechanism to CA3 synaptic structure and plasticity.
Mitochondrial and Bioenergetic Dysfunction
Mechanism confidence: Provisional
Patient-derived fibroblasts carrying KAT6A mutations show impaired cellular bioenergetics alongside the histone-acetylation defect. This cellular bioenergetic deficit is the mechanistic rationale for the experimental pantothenate and L-carnitine intervention, which corrects it in vitro. The finding is from patient fibroblast models; its contribution to the clinical phenotype in vivo is not established.
Show evidence (1 reference)
PMID:36553567 SUPPORT In Vitro
"the cell bioenergetics of mutant cells was significantly improved"
That bioenergetics of mutant cells could be significantly improved by treatment establishes a baseline bioenergetic deficit in KAT6A-mutant fibroblasts.
Impaired Hematopoietic Stem Cell Function
Mechanism confidence: Provisional
KAT6A (MOZ) was originally characterized as a master regulator of hematopoiesis: complete-knockout mice die in embryogenesis from a failure of hematopoiesis, and tissue-specific knockouts show KAT6A-dependent transcriptional programs in blood lineages. In heterozygous patients an emerging hematologic spectrum (transient neonatal neutropenia through severe aplastic anemia) is consistent with impaired hematopoietic stem cell function, but the causal bridge from heterozygous KAT6A variation to human cytopenias and marrow failure has not been directly demonstrated, so this node and its outgoing edges are provisional.
hematopoietic stem cell CL:0000037 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves hematopoietic stem cell (CL:0000037). CL:0000037 is a cell type from the Cell Ontology.
hemopoiesis GO:0030097 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal hemopoiesis (GO:0030097). GO:0030097 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Neutropenia
Aplastic Anemia
Show evidence (2 references)
PMID:30245513 SUPPORT Model Organism
"Complete knockout mouse models result in embryonic lethality, due to a failure of hematopoiesis."
Mouse knockouts establish KAT6A as essential for hematopoiesis; the human heterozygous state is a partial, not complete, loss of function.
PMID:30245513 SUPPORT INDIRECT Human Clinical
"One hypothesis is that KAT6A syndrome may result in a variety of abnormalities of blood cell lines."
The clinical cohort explicitly frames blood-lineage abnormalities as a hypothesis rather than an established mechanism, which is why this node is provisional.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Arboleda-Tham Syndrome Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

32
Blood 2
Neutropenia OCCASIONAL Decreased total neutrophil count HP:0001875 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Neutropenia, annotated with Decreased total neutrophil count (HP:0001875). HP:0001875 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:30245513 SUPPORT Human Clinical
"three individuals report isolated moderate to severe neutropenia5,13."
The 76-person cohort consolidates three reports of isolated moderate-to-severe neutropenia, supporting an occasional frequency band.
PMID:42040242 SUPPORT Human Clinical
"Notably, 3 of 11 patients (27%) exhibited hematologic abnormalities, ranging from transient neonatal neutropenia to severe aplastic anemia requiring hematopoietic stem cell transplantation."
The molecularly confirmed cohort independently includes transient neonatal neutropenia within an emerging hematologic spectrum. The pathograph link through impaired hematopoietic stem cell function is provisional, resting on mouse hematopoiesis data rather than a demonstrated human bridge.
Aplastic Anemia OCCASIONAL HP:0001915 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Aplastic anemia (HP:0001915). HP:0001915 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42040242 SUPPORT Human Clinical
"Notably, 3 of 11 patients (27%) exhibited hematologic abnormalities, ranging from transient neonatal neutropenia to severe aplastic anemia requiring hematopoietic stem cell transplantation."
This establishes aplastic anemia as a specifically observed severe manifestation while leaving its individual prevalence unresolved.
Cardiovascular 5
Congenital Cardiac Defects FREQUENT Abnormal heart morphology HP:0001627 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal heart morphology (HP:0001627). HP:0001627 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30245513 SUPPORT Human Clinical
"Cardiac malformations are present in half (51%) of our cohort."
The cohort documents cardiac malformations in 51% of patients.
Atrial Septal Defect FREQUENT HP:0001631 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Atrial septal defect (HP:0001631). HP:0001631 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30245513 SUPPORT Human Clinical
"Most frequent are septal defects including atrial septal defects (34%), ventricular septal defects in (8%), and persistence of the fetal anatomy (19%) (patent foreman ovale, and persistent ductus arteriosus)."
The cohort reports atrial septal defects in 34% of patients, the most frequent cardiac lesion.
Ventricular Septal Defect OCCASIONAL HP:0001629 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ventricular septal defect (HP:0001629). HP:0001629 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30245513 SUPPORT Human Clinical
"Most frequent are septal defects including atrial septal defects (34%), ventricular septal defects in (8%), and persistence of the fetal anatomy (19%) (patent foreman ovale, and persistent ductus arteriosus)."
The cohort reports ventricular septal defects in 8% of patients.
Patent Ductus Arteriosus HP:0001643 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Patent ductus arteriosus (HP:0001643). HP:0001643 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30245513 SUPPORT Human Clinical
"Most frequent are septal defects including atrial septal defects (34%), ventricular septal defects in (8%), and persistence of the fetal anatomy (19%) (patent foreman ovale, and persistent ductus arteriosus)."
Persistent ductus arteriosus is part of the persistence-of-fetal-anatomy category reported in 19% of the cohort (combined with patent foramen ovale).
Patent Foramen Ovale HP:0001655 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Patent foramen ovale (HP:0001655). HP:0001655 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30245513 SUPPORT Human Clinical
"Most frequent are septal defects including atrial septal defects (34%), ventricular septal defects in (8%), and persistence of the fetal anatomy (19%) (patent foreman ovale, and persistent ductus arteriosus)."
Patent foramen ovale is part of the persistence-of-fetal-anatomy category reported in 19% of the cohort (combined with patent ductus arteriosus).
Digestive 4
Feeding Difficulties FREQUENT HP:0011968 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Feeding difficulties (HP:0011968). HP:0011968 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30245513 SUPPORT Human Clinical
"78% of patients experienced feeding difficulties."
The cohort reports feeding difficulties in 78% of patients, within the frequent band.
Constipation FREQUENT HP:0002019 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Constipation (HP:0002019). HP:0002019 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30245513 SUPPORT Human Clinical
"Constipation is a significant issue for over half of our patients and many are on long term laxatives."
The cohort documents constipation in over half of patients.
Gastroesophageal Reflux FREQUENT HP:0002020 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Gastroesophageal reflux (HP:0002020). HP:0002020 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30245513 SUPPORT Human Clinical
"The high prevalence of reflux and constipation is suggestive of dysfunctional intestinal motility."
The cohort notes a high prevalence of reflux alongside constipation.
Intestinal Obstruction OCCASIONAL HP:0005214 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intestinal obstruction (HP:0005214). HP:0005214 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:30245513 SUPPORT Human Clinical
"novel associations, including an increased risk of gastrointestinal obstruction."
The cohort identifies an increased risk of gastrointestinal obstruction as a novel association.
PMID:30245513 SUPPORT Human Clinical
"four patients in this study (patients 6, 22, 42 and 46) had bowel obstruction."
Four of 76 participants (5.3%) had bowel obstruction, supporting the occasional frequency band.
Ear 2
Low-Set, Posteriorly Rotated Ears OCCASIONAL Abnormal pinna morphology HP:0000377 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Low-set, posteriorly rotated ears, annotated with Abnormal pinna morphology (HP:0000377). HP:0000377 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30245513 SUPPORT Human Clinical
"Notable features present in a significant minority are epicanthic folds and low set and posteriorly rotated ears, which are occasionally folded"
The cohort documents low-set, posteriorly rotated ears in a significant minority of patients.
Hearing Impairment HP:0000365 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hearing impairment (HP:0000365). HP:0000365 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30245513 SUPPORT Human Clinical
"These included microcephaly, neonatal hypotonia, feeding difficulties, reflux, constipation, congenital hearing defects, and frequent infections."
Congenital hearing defects are among the subphenotypes significantly more common in late-truncating variants; an overall cohort frequency is not given, so no frequency band is assigned.
Eye 2
Strabismus FREQUENT HP:0000486 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Strabismus (HP:0000486). HP:0000486 is a phenotype from the Human Phenotype Ontology.
Sequelae: Amblyopia
Show evidence (1 reference)
PMID:30245513 SUPPORT Human Clinical
"Strabismus is reported in 54% of patients."
The cohort reports strabismus in 54% of patients.
Amblyopia HP:0000646 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Amblyopia (HP:0000646). HP:0000646 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30245513 SUPPORT Human Clinical
"Amblyopia is reported in several patients."
The cohort documents amblyopia in several patients, an uncommon secondary complication of strabismus.
Genitourinary 1
Cryptorchidism HP:0000028 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cryptorchidism (HP:0000028). HP:0000028 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30245513 SUPPORT Human Clinical
"we found a small number of patients had undescended testes (boys), clinodactyly and/or brachydactyly."
The cohort documents undescended testes in a small number of male patients.
Head and Neck 6
Craniofacial Dysmorphism FREQUENT Abnormal facial shape HP:0001999 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Craniofacial dysmorphism, annotated with Abnormal facial shape (HP:0001999). HP:0001999 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:25728775 SUPPORT Human Clinical
"Common features among all four probands include primary microcephaly, global developmental delay including profound speech delay, and craniofacial dysmorphism"
The founding series lists craniofacial dysmorphism among the common features shared by all probands.
PMID:42040242 SUPPORT Human Clinical
"Craniofacial dysmorphisms were observed in 11 patients (79%)"
The 2026 cohort quantifies craniofacial dysmorphism at 79%, within the frequent band and below the threshold for a very-frequent assertion.
Broad Nasal Tip FREQUENT HP:0000455 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Broad nasal tip (HP:0000455). HP:0000455 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30245513 SUPPORT Human Clinical
"A broad nasal tip, which may become more obvious with age, and a thin, tented upper lip, are the most consistent facial features in patients with KAT6A syndrome."
The cohort identifies broad nasal tip as one of the two most consistent facial features.
Thin, Tented Upper Lip FREQUENT Thin upper lip vermilion HP:0000219 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Thin, tented upper lip vermilion, annotated with Thin upper lip vermilion (HP:0000219). HP:0000219 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30245513 SUPPORT Human Clinical
"A broad nasal tip, which may become more obvious with age, and a thin, tented upper lip, are the most consistent facial features in patients with KAT6A syndrome."
The cohort identifies a thin, tented upper lip as one of the two most consistent facial features.
Microcephaly OCCASIONAL HP:0000252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Microcephaly (HP:0000252). HP:0000252 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30245513 SUPPORT Human Clinical
"in our larger cohort, only 25% individuals had microcephaly, which was not always present at birth."
The larger cohort reports microcephaly in 25% of patients, within the occasional band.
Craniosynostosis OCCASIONAL HP:0001363 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Craniosynostosis (HP:0001363). HP:0001363 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30245513 SUPPORT Human Clinical
"Craniosynostosis is reported in a total of 6 patients5."
The cohort reports craniosynostosis in a total of 6 patients.
Dental Anomalies FREQUENT Abnormality of the dentition HP:0000164 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dental anomalies, annotated with Abnormality of the dentition (HP:0000164). HP:0000164 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30245513 SUPPORT Human Clinical
"teeth abnormalities were common."
The cohort documents teeth abnormalities as common.
Immune 1
Recurrent Infections HP:0002719 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent infections (HP:0002719). HP:0002719 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30245513 SUPPORT Human Clinical
"those that did tended to report common childhood illnesses including otitis media and upper and lower respiratory tract infections"
The cohort documents recurrent common childhood infections in the subset of patients reporting frequent infections.
Musculoskeletal 1
Hypotonia FREQUENT HP:0001252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypotonia (HP:0001252). HP:0001252 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30245513 SUPPORT Human Clinical
"Hypotonia is common and contributes to motor delay."
The cohort documents hypotonia as common and a contributor to motor delay.
Nervous System 8
Intellectual Disability VERY_FREQUENT HP:0001249 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intellectual disability (HP:0001249). HP:0001249 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:30245513 SUPPORT Human Clinical
"Intellectual disability and developmental delay are universal."
The 2019 cohort found both features in all ascertained participants; the frequency is conservatively downgraded from obligate because later inherited cases include normal cognition.
PMID:38741077 SUPPORT Human Clinical
"Findings suggest global cognitive impairment with nonverbal cognition scores similar to those for receptive language"
A dedicated neuropsychological study characterizes the impairment as global, with nonverbal cognition tracking receptive language.
PMID:39740728 SUPPORT Human Clinical
"The description includes an affected first child with premature pubarche (the first individual to our knowledge), a mildly affected second child with normal cognitive performance assessment (the third reported individual with normal assessment of cognition and KAT6A syndrome), and a..."
This inherited family establishes rare exceptions to the earlier universal-intellectual-disability framing and supports variable expressivity.
Global Developmental Delay VERY_FREQUENT HP:0001263 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:30245513 SUPPORT Human Clinical
"Intellectual disability and developmental delay are universal."
The 76-person cohort provides the largest direct clinical anchor for developmental delay, while later inherited cases prevent an obligate syndrome-wide frequency assertion.
PMID:42040242 SUPPORT Human Clinical
"Global developmental delay was universal, with marked speech impairment; most patients remained minimally verbal beyond age 5."
The 2026 molecularly confirmed cohort found global developmental delay in all 14 participants; rare inherited cases prevent an obligate syndrome-wide assertion.
Expressive Speech Delay VERY_FREQUENT Delayed speech and language development HP:0000750 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Delayed speech and language development (HP:0000750). HP:0000750 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:30245513 SUPPORT Human Clinical
"Marked expressive speech delay is universal."
The 2019 cohort documents marked expressive speech delay as universal in that sample; the syndrome-wide band is kept conservative.
PMID:35892268 SUPPORT Human Clinical
"Seventy-three percent (36/49) were minimally-verbal, relying on nonverbal behaviors to communicate."
Standardized survey and telehealth assessment quantify the severe communication phenotype in a dedicated 49-person cohort.
Sleep Disturbance FREQUENT HP:0002360 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sleep disturbance (HP:0002360). HP:0002360 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30245513 SUPPORT Human Clinical
"Over 30% of patients in this cohort reported sleep disturbance."
The cohort reports sleep disturbance in over 30% of patients.
Autistic Behavior OCCASIONAL HP:0000729 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Autistic behavior (HP:0000729). HP:0000729 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:30245513 SUPPORT Human Clinical
"Autism and autistic features have been reported in approximately 25% of newly reported cases."
The cohort reports autism/autistic features in approximately 25% of newly reported cases.
PMID:38741077 SUPPORT Human Clinical
"Autism-related features, particularly restricted interests and repetitive behaviors, and broad adaptive deficits were common in our sample juxtaposed with a relatively strong social drive and low frequency of internalizing and externalizing behavioral problems."
A dedicated neuropsychological study characterizes the autism-related features and their relative sparing of social drive.
Chiari Malformation OCCASIONAL HP:0002308 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Chiari malformation (HP:0002308). HP:0002308 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:42040242 SUPPORT Human Clinical
"Brain imaging revealed type 1 Chiari malformation and white matter hyperintensities in 2 of the 10 assessed (20%), suggesting a broader neuroanatomic involvement."
The molecularly confirmed cohort quantifies the combined neuroimaging observations in the occasional frequency band.
PMID:30245513 SUPPORT Human Clinical
"hydrocephalus and a Chiari malformation in patient 33"
The earlier large cohort independently corroborates Chiari malformation.
Cerebral White Matter Hyperintensities OCCASIONAL Hyperintensity of cerebral white matter on MRI HP:0030890 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hyperintensity of cerebral white matter on MRI (HP:0030890). HP:0030890 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42040242 SUPPORT Human Clinical
"Brain imaging revealed type 1 Chiari malformation and white matter hyperintensities in 2 of the 10 assessed (20%), suggesting a broader neuroanatomic involvement."
This quantified imaging cohort supports an occasional band while the grouped wording prevents a phenotype-specific estimate.
Seizures OCCASIONAL HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30245513 SUPPORT Human Clinical
"Seizure activity has only been reported in seven patients and there is no consistency in seizure type"
The cohort reports seizures in only seven patients, an uncommon feature.
🧬

Genetic Associations

1
KAT6A Pathogenic Variants (Causative)
Gene: KAT6A hgnc:13013 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is KAT6A (hgnc:13013). hgnc:13013 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Autosomal dominant inheritance
Show evidence (2 references)
PMID:25728777 SUPPORT Human Clinical
"Finally, by detailed clinical characterization we provide evidence that heterozygous mutations in KAT6A cause a distinct intellectual disability syndrome."
Establishes KAT6A as the causative gene for a distinct intellectual disability syndrome.
PMID:30245513 SUPPORT Human Clinical
"Our analysis identifies hotspot nonsense mutations within the penultimate exons at amino acid positions 1019, 1024, and 1129 that account for 19.1% (13/68) of pathogenic variants in unrelated individuals."
Quantifies the recurrent truncating hotspots that make up a substantial fraction of pathogenic variants.
💊

Medical Actions

5
Multidisciplinary Supportive Care
Category: Therapeutic Action: supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Platform: Other
Management is symptomatic and individualized, coordinating developmental, nutritional, gastrointestinal, cardiac, ophthalmologic, and infectious-disease care. Early cardiology assessment with echocardiography is recommended given the high prevalence of cardiac lesions.
Target Phenotypes: Abnormal heart morphology HP:0001627 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Abnormal heart morphology (HP:0001627). HP:0001627 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30245513 SUPPORT Human Clinical
"The prevalence of cardiac lesions highlights the need for early cardiology assessment."
The cohort recommends early cardiology assessment as part of individualized multidisciplinary care.
Speech and Language Therapy
Category: Therapeutic Action: speech therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is speech therapy, annotated with Speech Language Therapy (NCIT:C159273). NCIT:C159273 is a clinical intervention from the NCI Thesaurus. Ontology label: Speech Language Therapy NCIT:C159273
Platform: Behavioral / lifestyle
Speech and language therapy, augmented by sign language and communication aids, addresses the very frequent expressive speech delay and speech-motor impairment.
Target Phenotypes: Delayed speech and language development HP:0000750 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Delayed speech and language development (HP:0000750). HP:0000750 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30245513 SUPPORT Human Clinical
"Use of sign language and communication aids are helpful."
The cohort supports communication-focused intervention for the characteristic expressive speech delay.
Cardiac Surgical or Catheter Intervention
Category: Therapeutic Action: septal defect repairNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is septal defect repair (NCIT:C148075). NCIT:C148075 is a clinical intervention from the NCI Thesaurus. Ontology label: Septal Defect Repair NCIT:C148075
Platform: Surgery
A substantial proportion of patients with cardiac malformations require intervention by open-heart surgery or cardiac catheterization.
Target Phenotypes: Atrial septal defect HP:0001631 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Atrial septal defect (HP:0001631). HP:0001631 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30245513 SUPPORT Human Clinical
"At least 45% of patients with cardiac malformations required intervention (open heart surgery or via cardiac catheterization)."
The cohort documents cardiac intervention in at least 45% of patients with cardiac malformations.
Pantothenate and L-Carnitine Supplementation
Category: Therapeutic Action: nutritional supplementationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is nutritional supplementation, annotated with Nutritional Support (NCIT:C15433). NCIT:C15433 is a clinical intervention from the NCI Thesaurus. Ontology label: Nutritional Support NCIT:C15433
Agent: pantothenate CHEBI:16454 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses pantothenate (CHEBI:16454). CHEBI:16454 is a therapeutic agent from Chemical Entities of Biological Interest. L-carnitine CHEBI:16347 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses L-carnitine, annotated with (R)-carnitine (CHEBI:16347). CHEBI:16347 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
An experimental, preclinical intervention. In patient-derived fibroblast models of KAT6A syndrome, pantothenate plus L-carnitine increased histone acetylation, partially corrected protein and transcriptomic expression patterns, and improved cell bioenergetics. This is in vitro evidence only and has not been evaluated as a clinical therapy.
Mechanism Target:
RESTORES Mitochondrial and Bioenergetic Dysfunction — Pantothenate (a CoA precursor) and L-carnitine act as mitochondrial boosting agents that improve the impaired cell bioenergetics of KAT6A-mutant fibroblasts in vitro; this is the mechanistic rationale for the intervention.
Show evidence (1 reference)
PMID:36553567 SUPPORT In Vitro
"the cell bioenergetics of mutant cells was significantly improved"
The patient-fibroblast experiment directly supports restoration of the nominated bioenergetic mechanism, but not clinical benefit.
Show evidence (1 reference)
PMID:36553567 SUPPORT In Vitro
"Pantothenate and L-carnitine treatment increased histone acetylation and partially corrected protein and transcriptomic expression patterns in mutant KAT6A cells."
Patient-derived fibroblast models show that pantothenate and L-carnitine partially correct KAT6A-associated cellular abnormalities, an experimental preclinical lead.
Acetyl-L-Carnitine
Category: Therapeutic Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: acetyl-L-carnitine CHEBI:57589 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses acetyl-L-carnitine, annotated with O-acetyl-L-carnitine (CHEBI:57589). CHEBI:57589 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
An experimental mouse intervention, not an established treatment for people with Arboleda-Tham syndrome. Acetyl-L-carnitine restored H3K23 acetylation and improved selected behavioral measures in Kat6a-haploinsufficient mice; efficacy, safety, dose, developmental timing, and variant dependence remain untested clinically.
Mechanism Target:
RESTORES Dysregulated Histone H3 Acetylation — Acetyl-L-carnitine serves as an acetyl donor and restored brain H3K23 acetylation in a Kat6a-haploinsufficient mouse model.
Show evidence (1 reference)
PMID:41702672 SUPPORT Model Organism
"Treatment with the acetyl-donor, acetyl-L-carnitine (ALCAR) resulted in the rescue of H3K23ac levels in mouse brain and amelioration of the hyperactivity and learning impairments."
The mouse experiment directly supports restoration of the nominated chromatin mark and selected behavioral outcomes, not human efficacy.
Show evidence (1 reference)
PMID:41702672 SUPPORT Model Organism
"Treatment with the acetyl-donor, acetyl-L-carnitine (ALCAR) resulted in the rescue of H3K23ac levels in mouse brain and amelioration of the hyperactivity and learning impairments."
This is preclinical rescue in Kat6a-haploinsufficient mice and is not evidence of efficacy in affected people.
🔬

Diagnosis

3
Exome or genome sequencing
Diagnosis is molecular. Because the clinical features overlap many developmental syndromes and there is no single pathognomonic feature, identification of a heterozygous pathogenic KAT6A variant by exome (or genome) sequencing, typically trio-based to establish de novo status, establishes the diagnosis.
molecular genetic testing NCIT:C19770 NCI Thesaurus (NCIT)
Results: A heterozygous pathogenic or likely pathogenic KAT6A variant confirms the diagnosis.
Show evidence (2 references)
PMID:25728775 SUPPORT Human Clinical
"identified by clinical exome sequencing (CES) in four independent families"
The founding series identified the disorder by clinical exome sequencing.
PMID:25728777 SUPPORT Human Clinical
"with mutations in KAT6A/MOZ detected by whole-exome sequencing"
An independent series likewise established the diagnosis by whole-exome sequencing.
Baseline cardiac evaluation
Given the high prevalence of cardiac lesions, baseline cardiology assessment with echocardiography is recommended at diagnosis.
clinical assessment NCIT:C124351 NCI Thesaurus (NCIT)
Results: Echocardiography identifies septal defects and persistence of fetal anatomy that may require intervention.
Show evidence (1 reference)
PMID:30245513 SUPPORT Human Clinical
"The prevalence of cardiac lesions highlights the need for early cardiology assessment."
The cohort recommends early cardiology assessment given the cardiac-lesion prevalence.
DNA methylation episignature analysis
Genome-wide DNA methylation analysis can provide an adjunctive molecular classifier when a KAT6A variant is uncertain or when KAT6A- and KAT6B-related disorders are difficult to distinguish. It does not replace sequence-based diagnosis and was validated as a biomarker rather than as a screening test.
DNA methylation analysis NCIT:C63328 NCI Thesaurus (NCIT)
Results: A KAT6A-associated episignature supports classification of the molecular finding and is distinct from the episignatures reported for KAT6B disorders.
Show evidence (1 reference)
PMID:37249002 SUPPORT Human Clinical
"In this study we describe distinct episignatures for KAT6A syndrome, caused by pathogenic variants in the lysine acetyltransferase A gene (KAT6A), and for the two neurodevelopmental disorders associated with lysine acetyl transferase B (KAT6B)."
The clinical methylome study establishes separable KAT6A and KAT6B episignatures as adjunctive diagnostic classifiers.
🔀

Differential Diagnoses

1

Conditions with similar clinical presentations that must be differentiated from Arboleda-Tham Syndrome:

📊

Related Datasets

3
DNA methylation profiling of Arboleda-Tham syndrome in primary human fibroblasts geo:GSE210484
Arboleda-Tham Syndrome is a rare disease caused by de novo mutations in the KAT6A gene. Epigenetic changes to the genome resulting from pathogenic mutations were investigated by DNAme profiling.
human METHYLATION n=25
PMID:36064314
Identified by GEO DataSets index search for Arboleda-Tham Syndrome (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.
KAT6A mutations in Arboleda-Tham syndrome affect regulation and expression of HOXC genes [RNA-seq] geo:GSE237022
Arboleda-Tham Syndrome (ARTHS) is a rare genetic disorder caused by heterozygous, de novo truncating mutations in the gene KAT6A (Lysine(K) acetyltransferase 6A). ARTHS is clinically heterogeneous but characterized by several common features including intellectual disability, developmental and speech delay, hypotonia, congenital heart defects and gastrointestinal problems. KAT6A mRNA is highly expressed throughout early development and the levels of expression are lower levels in differentiated tissues, suggesting a key role maintenance of the stem cell characteristics.
human BULK RNA SEQ n=15
Identified by GEO DataSets index search for Arboleda-Tham Syndrome (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.
KAT6A mutations in Arboleda-Tham syndrome affect regulation and expression of HOXC genes [ChIP-seq] geo:GSE237021
Arboleda-Tham Syndrome (ARTHS) is a rare genetic disorder caused by heterozygous, de novo truncating mutations in the gene KAT6A (Lysine(K) acetyltransferase 6A). ARTHS is clinically heterogeneous but characterized by several common features including intellectual disability, developmental and speech delay, hypotonia, congenital heart defects and gastrointestinal problems. KAT6A mRNA is highly expressed throughout early development and the levels of expression are lower levels in differentiated tissues, suggesting a key role maintenance of the stem cell characteristics.
human CHIP SEQ n=14
Identified by GEO DataSets index search for Arboleda-Tham Syndrome (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.
{ }

Source YAML

click to show 
name: Arboleda-Tham Syndrome
creation_date: "2026-07-30T00:00:00Z"
synonyms:
- KAT6A syndrome
- KAT6A-related intellectual disability
- Mental retardation, autosomal dominant 32
- MRD32
description: >-
  Arboleda-Tham syndrome (KAT6A syndrome) is an autosomal dominant
  neurodevelopmental disorder caused by heterozygous, usually de novo,
  pathogenic variants in KAT6A, a MYST-family lysine acetyltransferase that
  acetylates histone H3 (notably H3K9 and H3K18) within a multi-subunit complex
  with BRPF1/2/3, ING5, and hEAF6 to drive developmental transcriptional
  programs. The core phenotype comprises global developmental delay with
  usually co-occurring intellectual disability and marked expressive speech delay,
  neonatal hypotonia, early feeding and oromotor difficulties, recognizable
  craniofacial dysmorphism (broad nasal tip and thin, tented upper lip), and
  congenital cardiac defects, most often septal defects. Gastrointestinal
  dysmotility (reflux, constipation, and an increased risk of intestinal
  obstruction), microcephaly, ophthalmologic anomalies (notably strabismus),
  recurrent infections, and variable behavioral features complete the spectrum.
  A genotype-phenotype correlation is recognized: early-truncating variants
  (exons 1-15) are predicted to trigger nonsense-mediated decay and
  haploinsufficiency and are associated with milder disease, whereas
  late-truncating variants (exons 16-17) escape nonsense-mediated decay and are
  associated with more severe developmental delay and a higher frequency of
  several syndromic features.
category: Mendelian
disease_term:
  preferred_term: KAT6A syndrome
  term:
    id: MONDO:0014558
    label: autosomal dominant intellectual disability-craniofacial anomalies-cardiac defects syndrome
parents:
- autosomal dominant syndromic intellectual disability
- multiple congenital anomalies/dysmorphic syndrome-intellectual disability

inheritance:
- name: Autosomal dominant inheritance
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    Arboleda-Tham syndrome is autosomal dominant and is almost always caused by
    a de novo heterozygous pathogenic KAT6A variant.
  evidence:
  - reference: PMID:25728775
    reference_title: "De novo nonsense mutations in KAT6A, a lysine acetyl-transferase gene, cause a syndrome including microcephaly and global developmental delay."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we report a syndrome caused by de novo heterozygous nonsense
      mutations in KAT6A (a.k.a., MOZ, MYST3) identified by clinical exome
      sequencing (CES) in four independent families.
    explanation: >-
      The founding series establishes heterozygous, de novo KAT6A variants as
      the cause, consistent with autosomal dominant inheritance.
  - reference: PMID:39740728
    reference_title: Phenotypic variability in a family with an inherited KAT6A frameshift variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we report a Danish family, where an inherited KAT6A frameshift
      variant c.2710dup (p.(Glu904Glyfs∗12)) show clinical variability in
      disease phenotype expression among three family members.
    explanation: >-
      This family demonstrates that vertical transmission of a constitutional
      frameshift allele can occur and that expression is variable; de novo
      occurrence is usual rather than universal.
  expressivity: VARIABLE

references:
- reference: PMID:25728775
  title: "De novo nonsense mutations in KAT6A, a lysine acetyl-transferase gene, cause a syndrome including microcephaly and global developmental delay."
- reference: PMID:25728777
  title: "Dominant mutations in KAT6A cause intellectual disability with recognizable syndromic features."
- reference: PMID:30245513
  title: "KAT6A Syndrome: genotype-phenotype correlation in 76 patients with pathogenic KAT6A variants."
- reference: PMID:38741077
  title: "Neuropsychological profile associated with KAT6A syndrome: Emergent genotype-phenotype trends."
- reference: PMID:38758792
  title: "KAT6A deficiency impairs cognitive functions through suppressing RSPO2/Wnt signaling in hippocampal CA3."
- reference: PMID:36553567
  title: "Pantothenate and L-Carnitine Supplementation Improves Pathological Alterations in Cellular Models of KAT6A Syndrome."
- reference: PMID:35892268
  title: "Speech and language development and genotype-phenotype correlation in 49 individuals with KAT6A syndrome."
- reference: PMID:37249002
  title: DNA methylation episignatures are sensitive and specific biomarkers for detection of patients with KAT6A/KAT6B variants.
- reference: PMID:37861717
  title: KAT6A mutations in Arboleda-Tham syndrome drive epigenetic regulation of posterior HOXC cluster.
- reference: PMID:39740728
  title: Phenotypic variability in a family with an inherited KAT6A frameshift variant.
- reference: PMID:41702672
  title: Acetyl-carnitine improves hyperactivity and learning deficits in KAT6A haploinsufficient mice.
- reference: PMID:42040242
  title: "Expanding the Clinical Spectrum of Arboleda-Tham Syndrome: Neuroimaging Findings and Hematologic Manifestations."
- reference: PMID:42081590
  title: KAT6A is essential for developmental control gene expression in neural stem and progenitor cells.

mechanistic_hypotheses:
- hypothesis_group_id: early_truncating_nmd_haploinsufficiency
  hypothesis_label: Early-Truncating NMD / Haploinsufficiency Branch
  status: CANONICAL
  description: >-
    Truncating variants in exons 1-15 are predicted to trigger
    nonsense-mediated decay of the mutant transcript, producing KAT6A
    haploinsufficiency. This branch is associated with a milder phenotype, with
    a majority of early-truncating cases rated as having mild intellectual
    disability.
  evidence:
  - reference: PMID:30245513
    reference_title: "KAT6A Syndrome: genotype-phenotype correlation in 76 patients with pathogenic KAT6A variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This suggests a potential role for nonsense mediated decay (NMD), where
      truncating mutations in the first 15 exons trigger NMD mechanisms and
      result in haploinsufficiency while mutations in exons 16 and 17 would not
      result in NMD, therefore the mRNA would result in a translated but
      dysfunctional protein that may have gain-of function or dominant negative
      effects.
    explanation: >-
      The genotype-phenotype study proposes NMD-mediated haploinsufficiency for
      early-truncating variants as the basis for milder disease.
- hypothesis_group_id: late_truncating_nmd_escape
  hypothesis_label: Late-Truncating NMD-Escape Branch
  status: ALTERNATIVE
  description: >-
    Truncating variants in the last two exons (16-17) escape nonsense-mediated
    decay and are predicted to yield a translated but dysfunctional protein with
    possible gain-of-function or dominant-negative effects. This branch is
    associated with more severe developmental delay and a higher frequency of
    several syndromic features. Direct demonstration of mutant protein and its
    mode of action in patient tissue remains an evidence gap. The two halves of
    this branch are not equally supported: the clinical severity gradient is
    reproduced across independent cohorts, while the molecular claim is unproven.
    KAT6A is among the most loss-of-function-intolerant genes in the genome and
    early decay-competent truncations are unambiguously pathogenic, so
    haploinsufficiency is the baseline mechanism and this branch is better read as
    a severity modifier layered on it than as a competing primary mechanism.
  evidence:
  - reference: PMID:30245513
    reference_title: "KAT6A Syndrome: genotype-phenotype correlation in 76 patients with pathogenic KAT6A variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      95% of late truncating cases (exon 16 and 17) were rated as moderate or
      severe, while 60% of early truncating cases (exons 1-15) were rated as
      mild
    explanation: >-
      The cohort documents the more severe developmental phenotype associated
      with the NMD-escaping late-truncating branch.
- hypothesis_group_id: kat6a_rspo2_wnt_hippocampal
  hypothesis_label: KAT6A-RSPO2-Wnt Hippocampal Signaling Branch
  status: EMERGING
  description: >-
    An emerging mechanism, so far demonstrated only in mice, links KAT6A
    deficiency to impaired cognition through a specific transcriptional target:
    KAT6A activates the CA3-enriched Wnt activator R-spondin 2 (RSPO2), and its
    loss reduces hippocampal CA3 synaptic structure, plasticity, and Wnt
    signaling. Restoring RSPO2 in CA3 neurons rescues Wnt signaling and
    learning behaviors in Kat6a mutant mice, nominating the KAT6A-RSPO2-Wnt axis
    as a candidate therapeutic target. Fidelity to human KAT6A-syndrome
    cognition is not yet established.
  evidence:
  - reference: PMID:38758792
    reference_title: "KAT6A deficiency impairs cognitive functions through suppressing RSPO2/Wnt signaling in hippocampal CA3."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Collectively, our results demonstrate that KAT6A-RSPO2-Wnt signaling plays
      a critical role in regulating hippocampal CA3 synaptic plasticity and
      cognitive function, providing potential therapeutic targets for KAT6A
      syndrome and related neurodevelopmental diseases.
    explanation: >-
      A mouse study defines the KAT6A-RSPO2-Wnt hippocampal axis as an emerging
      mechanism of the cognitive phenotype and a candidate therapeutic target.

pathophysiology:
- name: Heterozygous KAT6A Pathogenic Variation
  description: >-
    The initiating lesion is a heterozygous, usually de novo, pathogenic KAT6A
    variant. Most established alleles are protein-truncating (nonsense or
    frameshift), with recurrent hotspots in the arginine-rich acidic domain, and
    are distributed across the gene with a bias toward the last two exons.
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  genes:
  - preferred_term: KAT6A
    term:
      id: hgnc:13013
      label: KAT6A
  genetic_context:
    gene:
      preferred_term: KAT6A
      term:
        id: hgnc:13013
        label: KAT6A
    variant_origin: DE_NOVO
    zygosity: HETEROZYGOUS
    functional_impact_category: UNKNOWN
    description: >-
      De novo heterozygous protein-truncating KAT6A alleles. Recorded as UNKNOWN because
      the mechanism depends on truncation position and neither branch has been
      demonstrated at the protein level: early truncations (exons 1-15) are expected to
      trigger nonsense-mediated decay and act by haploinsufficiency
      (mechanistic_hypotheses#early_truncating_nmd_haploinsufficiency), while late
      truncations (exons 16-17) escape decay and may act through a dysfunctional,
      possibly gain-of-function or dominant-negative, protein
      (mechanistic_hypotheses#late_truncating_nmd_escape). Once demonstrated, the two
      branches warrant separate contexts rather than one category.
  evidence:
  - reference: PMID:25728777
    reference_title: "Dominant mutations in KAT6A cause intellectual disability with recognizable syndromic features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All five different de novo heterozygous truncating mutations were located
      in the C-terminal transactivation domain of KAT6A
    explanation: >-
      The founding series establishes heterozygous, de novo truncating KAT6A
      variants clustered in the C-terminal domain.
  downstream:
  - target: Mitochondrial and Bioenergetic Dysfunction
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:36553567
      reference_title: "Pantothenate and L-Carnitine Supplementation Improves Pathological Alterations in Cellular Models of KAT6A Syndrome."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        we examined the pathophysiological alterations in fibroblasts derived
        from three patients harboring KAT6A mutations
      explanation: >-
        Patient fibroblasts harboring KAT6A mutations exhibit the
        pathophysiological alterations, including the bioenergetic deficit; the
        intervening steps are unresolved.
  - target: NMD-Mediated KAT6A Haploinsufficiency
    causal_link_type: DIRECT
    hypothesis_groups:
    - early_truncating_nmd_haploinsufficiency
    evidence:
    - reference: PMID:30245513
      reference_title: "KAT6A Syndrome: genotype-phenotype correlation in 76 patients with pathogenic KAT6A variants."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        This suggests a potential role for nonsense mediated decay (NMD), where
        truncating mutations in the first 15 exons trigger NMD mechanisms and
        result in haploinsufficiency while mutations in exons 16 and 17 would not
        result in NMD, therefore the mRNA would result in a translated but
        dysfunctional protein that may have gain-of function or dominant negative
        effects.
      explanation: >-
        For early-truncating (exon 1-15) variants, NMD of the mutant transcript
        is proposed to produce KAT6A haploinsufficiency.
  - target: NMD-Escaping Dysfunctional KAT6A Protein
    causal_link_type: DIRECT
    hypothesis_groups:
    - late_truncating_nmd_escape
    evidence:
    - reference: PMID:30245513
      reference_title: "KAT6A Syndrome: genotype-phenotype correlation in 76 patients with pathogenic KAT6A variants."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        This suggests a potential role for nonsense mediated decay (NMD), where
        truncating mutations in the first 15 exons trigger NMD mechanisms and
        result in haploinsufficiency while mutations in exons 16 and 17 would not
        result in NMD, therefore the mRNA would result in a translated but
        dysfunctional protein that may have gain-of function or dominant negative
        effects.
      explanation: >-
        For late-truncating (exon 16-17) variants, escape from NMD is proposed to
        yield a translated but dysfunctional protein with possible
        gain-of-function or dominant-negative activity.

- name: NMD-Mediated KAT6A Haploinsufficiency
  conforms_to: "epigenetic_machinery_neurodevelopmental_dysregulation#Epigenetic Machinery Component Haploinsufficiency"
  description: >-
    Early-truncating variants (exons 1-15) are predicted to trigger
    nonsense-mediated decay of the mutant transcript, reducing functional KAT6A
    dosage (haploinsufficiency). This is the canonical route and is associated
    with milder disease.
  biological_scale: MOLECULAR
  mechanism_confidence: PROVISIONAL
  downstream:
  - target: Dysregulated Histone H3 Acetylation
    causal_link_type: DIRECT
    hypothesis_groups:
    - early_truncating_nmd_haploinsufficiency
    evidence:
    - reference: PMID:25728775
      reference_title: "De novo nonsense mutations in KAT6A, a lysine acetyl-transferase gene, cause a syndrome including microcephaly and global developmental delay."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        We further demonstrate that KAT6A mutations result in dysregulation of
        H3K9 and H3K18 acetylation and altered P53 signaling.
      explanation: >-
        Reduced KAT6A dosage converges on dysregulated histone H3 acetylation.

- name: NMD-Escaping Dysfunctional KAT6A Protein
  description: >-
    Late-truncating variants (exons 16-17) escape nonsense-mediated decay and
    are predicted to produce a translated but dysfunctional protein that may act
    by gain-of-function or dominant-negative mechanisms. This is the alternative
    route and is associated with more severe disease. Direct demonstration of
    mutant protein and its mode of action in patient tissue remains an evidence
    gap.
  biological_scale: MOLECULAR
  mechanism_confidence: PROVISIONAL
  downstream:
  - target: Dysregulated Histone H3 Acetylation
    causal_link_type: DIRECT
    hypothesis_groups:
    - late_truncating_nmd_escape
    evidence:
    - reference: PMID:25728775
      reference_title: "De novo nonsense mutations in KAT6A, a lysine acetyl-transferase gene, cause a syndrome including microcephaly and global developmental delay."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        We further demonstrate that KAT6A mutations result in dysregulation of
        H3K9 and H3K18 acetylation and altered P53 signaling.
      explanation: >-
        A dysfunctional protein likewise converges on dysregulated histone H3
        acetylation.

- name: Dysregulated Histone H3 Acetylation
  conforms_to: "epigenetic_machinery_neurodevelopmental_dysregulation#Permissive-Repressive Chromatin State Imbalance"
  description: >-
    KAT6A (MOZ/MYST3) is a MYST-family histone acetyltransferase that, within a
    complex containing BRPF1/2/3, ING5, and hEAF6, acetylates lysine residues on
    histone H3 tails (notably H3K9 and H3K18). Pathogenic variants dysregulate
    H3K9 and H3K18 acetylation, altering the chromatin state that governs
    developmental gene expression. (GO lacks a current, non-obsolete
    histone-H3-specific acetylation biological-process term; the H3 specificity
    is carried by the H3K9 and H3K18 molecular-function annotations.)
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  molecular_functions:
  - preferred_term: histone acetyltransferase activity
    term:
      id: GO:0004402
      label: histone acetyltransferase activity
  - preferred_term: histone H3K9 acetyltransferase activity
    term:
      id: GO:0043992
      label: histone H3K9 acetyltransferase activity
    modifier: DYSREGULATED
  - preferred_term: histone H3K18 acetyltransferase activity
    term:
      id: GO:0043993
      label: histone H3K18 acetyltransferase activity
    modifier: DYSREGULATED
  biological_processes:
  - preferred_term: chromatin organization
    term:
      id: GO:0006325
      label: chromatin organization
    modifier: ABNORMAL
  evidence:
  - reference: PMID:25728775
    reference_title: "De novo nonsense mutations in KAT6A, a lysine acetyl-transferase gene, cause a syndrome including microcephaly and global developmental delay."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We further demonstrate that KAT6A mutations result in dysregulation of
      H3K9 and H3K18 acetylation and altered P53 signaling.
    explanation: >-
      Directly supports dysregulated H3K9/H3K18 acetylation as the molecular
      consequence of KAT6A mutation.
  - reference: PMID:30245513
    reference_title: "KAT6A Syndrome: genotype-phenotype correlation in 76 patients with pathogenic KAT6A variants."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      KAT6A and KAT6B each function in a multi-subunit complex with three other
      proteins: BRPF1/2/3, ING5 and hEAF6
    explanation: >-
      Establishes the KAT6A histone-acetyltransferase complex through which the
      enzyme acts on histone H3.
  - reference: PMID:37861717
    reference_title: KAT6A mutations in Arboleda-Tham syndrome drive epigenetic regulation of posterior HOXC cluster.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Finally, we used unbiased proteomic mass spectrometry and identified two
      new histone post-translational modifications (PTMs) that are disrupted in
      ARTHS: H2A and H3K56 acetylation.
    explanation: >-
      Patient-derived fibroblast multi-omics extends the established
      acetylation defect beyond H3K9/H3K18 to H2A and H3K56 marks.
  downstream:
  - target: Altered p53 Signaling
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:25728775
      reference_title: "De novo nonsense mutations in KAT6A, a lysine acetyl-transferase gene, cause a syndrome including microcephaly and global developmental delay."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        We further demonstrate that KAT6A mutations result in dysregulation of
        H3K9 and H3K18 acetylation and altered P53 signaling.
      explanation: >-
        Dysregulated acetylation is accompanied by altered p53 signaling in the
        same functional study.
  - target: Altered Developmental Transcriptional Programs
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:30245513
      reference_title: "KAT6A Syndrome: genotype-phenotype correlation in 76 patients with pathogenic KAT6A variants."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        These proteins form a complex to acetylate lysine residues on histone H3
        tails, thereby promoting a wide range of developmental programs.
      explanation: >-
        Links KAT6A-mediated histone H3 acetylation to the developmental
        transcriptional programs disrupted in the disorder.
  - target: Posterior HOXC Cluster Overexpression
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:37861717
      reference_title: KAT6A mutations in Arboleda-Tham syndrome drive epigenetic regulation of posterior HOXC cluster.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Within fibroblasts, we show a distinct set of genes from the posterior
        HOXC gene cluster (HOXC10, HOXC11, HOXC-AS3, HOXC-AS2, and HOTAIR) that
        are overexpressed in ARTHS and are transcription factors critical for
        early development body segment patterning.
      explanation: >-
        Patient-fibroblast epigenome and transcriptome profiling directly links
        KAT6A-associated chromatin dysregulation to posterior HOXC overexpression.
  - target: Impaired Neural Progenitor Proliferation and Differentiation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:42081590
      reference_title: KAT6A is essential for developmental control gene expression in neural stem and progenitor cells.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Together, these two functions appear to be required for normal gene
        expression in neural progenitors and essential for proliferation and
        neuronal differentiation.
      explanation: >-
        Mouse neural-system and progenitor-cell experiments connect KAT6A's
        chromatin functions to progenitor proliferation and neuronal differentiation.

- name: Posterior HOXC Cluster Overexpression
  description: >-
    Multi-omic profiling of eight patient-derived dermal fibroblast lines found
    increased chromatin accessibility, H3K23 acetylation, gene-body DNA
    methylation, and overexpression across a posterior HOXC gene cluster. This
    is a reproducible human-cell molecular readout; fibroblasts do not establish
    which developmental tissues carry the same signature or whether HOXC
    overexpression causes particular clinical features.
  biological_scale: MOLECULAR
  mechanism_confidence: PROVISIONAL
  biological_processes:
  - preferred_term: gene expression
    term:
      id: GO:0010467
      label: gene expression
    modifier: INCREASED
  evidence:
  - reference: PMID:37861717
    reference_title: KAT6A mutations in Arboleda-Tham syndrome drive epigenetic regulation of posterior HOXC cluster.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The genomic loci harboring HOXC genes are epigenetically regulated with
      increased chromatin accessibility, high levels of H3K23ac, and increased
      gene-body DNA methylation compared to controls, all of which are
      consistent with transcriptomic overexpression.
    explanation: >-
      This directly supports the coupled chromatin and transcriptional HOXC
      phenotype in patient fibroblasts while not assigning an unproven organ-level consequence.

- name: Impaired Neural Progenitor Proliferation and Differentiation
  conforms_to: "epigenetic_machinery_neurodevelopmental_dysregulation#Impaired Neuronal Maturation, Plasticity, and Postnatal Neurogenesis"
  description: >-
    In mouse neural stem and progenitor cells, loss of one or both Kat6a alleles
    disrupts H3K23 acetylation and MLL1 recruitment at developmental genes,
    impairing normal proliferation and neuronal differentiation. The result
    strengthens the developmental-neurobiology bridge but has not yet been
    demonstrated in patient-derived neural progenitors or human brain tissue.
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  cell_types:
  - preferred_term: neural stem cell
    term:
      id: CL:0000047
      label: neural stem cell
  biological_processes:
  - preferred_term: neural precursor cell proliferation
    term:
      id: GO:0061351
      label: neural precursor cell proliferation
    modifier: DECREASED
  - preferred_term: neuron differentiation
    term:
      id: GO:0030182
      label: neuron differentiation
    modifier: DECREASED
  evidence:
  - reference: PMID:42081590
    reference_title: KAT6A is essential for developmental control gene expression in neural stem and progenitor cells.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Our data suggests two modes of action for KAT6A: (1) acetylation of
      histone H3 on lysine 23 at promoters and enhancers and (2) recruitment of
      the trithorax group protein MLL1 (KMT2A) to promote the expression of
      developmental genes, including SOX and homeodomain genes.
    explanation: >-
      The mouse study identifies the two chromatin functions upstream of the
      neural-progenitor proliferation and differentiation defect.
  downstream:
  - target: Global Developmental Delay
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:42081590
      reference_title: KAT6A is essential for developmental control gene expression in neural stem and progenitor cells.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Together, these two functions appear to be required for normal gene
        expression in neural progenitors and essential for proliferation and
        neuronal differentiation.
      explanation: >-
        The model supplies a plausible developmental bridge to human delay, but
        the clinical endpoint is an extrapolation and is therefore only partially supported.

- name: Altered p53 Signaling
  description: >-
    Beyond its direct catalytic effect on histone H3, KAT6A dysfunction perturbs
    p53-associated transcriptional programs. Patient-derived fibroblasts show
    altered expression of p53-associated genes, a downstream transcriptional
    consequence distinct from the direct loss of histone acetylation. The
    specific disease-level consequences downstream of altered p53 signaling in
    KAT6A syndrome are not established, so this node is intentionally left as a
    terminal molecular readout.
  biological_scale: MOLECULAR
  mechanism_confidence: PROVISIONAL
  biological_processes:
  - preferred_term: signal transduction by p53 class mediator
    term:
      id: GO:0072331
      label: signal transduction by p53 class mediator
    modifier: ABNORMAL
  evidence:
  - reference: PMID:30245513
    reference_title: "KAT6A Syndrome: genotype-phenotype correlation in 76 patients with pathogenic KAT6A variants."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      demonstrated altered expression of p53- associated genes
    explanation: >-
      Patient fibroblast transcriptomics show altered p53-associated gene
      expression downstream of KAT6A dysfunction.

- name: Altered Developmental Transcriptional Programs
  conforms_to: "epigenetic_machinery_neurodevelopmental_dysregulation#Dysregulated Neurodevelopmental Transcriptional Program"
  description: >-
    Disrupted KAT6A-dependent histone acetylation alters the transcriptional
    programs that pattern the developing brain, craniofacial skeleton, heart, and
    other organs, producing the multisystem congenital and neurodevelopmental
    phenotype. The intervening steps from chromatin dysregulation to each
    organ-level endpoint are not individually resolved in humans.
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  biological_processes:
  - preferred_term: regulation of transcription by RNA polymerase II
    term:
      id: GO:0006357
      label: regulation of transcription by RNA polymerase II
    modifier: ABNORMAL
  - preferred_term: nervous system development
    term:
      id: GO:0007399
      label: nervous system development
    modifier: ABNORMAL
  evidence:
  - reference: PMID:30245513
    reference_title: "KAT6A Syndrome: genotype-phenotype correlation in 76 patients with pathogenic KAT6A variants."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      These proteins form a complex to acetylate lysine residues on histone H3
      tails, thereby promoting a wide range of developmental programs.
    explanation: >-
      Supports the link between the KAT6A acetyltransferase complex and broad
      developmental transcriptional programs.
  downstream:
  - target: Global Developmental Delay
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:25728775
      reference_title: "De novo nonsense mutations in KAT6A, a lysine acetyl-transferase gene, cause a syndrome including microcephaly and global developmental delay."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Common features among all four probands include primary microcephaly,
        global developmental delay including profound speech delay, and
        craniofacial dysmorphism, as well as more varied features such as
        feeding difficulties, cardiac defects, and ocular anomalies.
      explanation: >-
        Links KAT6A dysfunction to the core neurodevelopmental phenotype.
  - target: Intellectual Disability
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:30245513
      reference_title: "KAT6A Syndrome: genotype-phenotype correlation in 76 patients with pathogenic KAT6A variants."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Intellectual disability and developmental delay are universal."
      explanation: >-
        The large clinical cohort links KAT6A syndrome to intellectual disability;
        later inherited cases show that the association is not obligate.
  - target: Expressive Speech Delay
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:25728775
      reference_title: "De novo nonsense mutations in KAT6A, a lysine acetyl-transferase gene, cause a syndrome including microcephaly and global developmental delay."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Common features among all four probands include primary microcephaly,
        global developmental delay including profound speech delay, and
        craniofacial dysmorphism
      explanation: >-
        Profound speech delay is part of the core developmental phenotype; the
        intervening mechanism is unresolved.
  - target: Craniofacial Dysmorphism
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:25728775
      reference_title: "De novo nonsense mutations in KAT6A, a lysine acetyl-transferase gene, cause a syndrome including microcephaly and global developmental delay."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Common features among all four probands include primary microcephaly,
        global developmental delay including profound speech delay, and
        craniofacial dysmorphism
      explanation: >-
        Links KAT6A dysfunction to craniofacial dysmorphism.
  - target: Congenital Cardiac Defects
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:25728775
      reference_title: "De novo nonsense mutations in KAT6A, a lysine acetyl-transferase gene, cause a syndrome including microcephaly and global developmental delay."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        more varied features such as feeding difficulties, cardiac defects, and
        ocular anomalies.
      explanation: >-
        Links KAT6A dysfunction to congenital cardiac defects among the varied
        multisystem features.
  - target: Hypotonia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:25728777
      reference_title: "Dominant mutations in KAT6A cause intellectual disability with recognizable syndromic features."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The common phenotype includes hypotonia, intellectual disability, early
        feeding and oromotor difficulties, microcephaly and/or craniosynostosis,
        and cardiac defects in combination with subtle facial features such as
        bitemporal narrowing, broad nasal tip, thin upper lip
      explanation: >-
        The common phenotype includes hypotonia; the intervening developmental
        mechanism is unresolved.
  - target: Feeding Difficulties
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:25728777
      reference_title: "Dominant mutations in KAT6A cause intellectual disability with recognizable syndromic features."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The common phenotype includes hypotonia, intellectual disability, early
        feeding and oromotor difficulties, microcephaly and/or craniosynostosis,
        and cardiac defects in combination with subtle facial features such as
        bitemporal narrowing, broad nasal tip, thin upper lip
      explanation: >-
        Early feeding and oromotor difficulties are part of the common
        developmental phenotype.
  - target: Microcephaly
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:25728775
      reference_title: "De novo nonsense mutations in KAT6A, a lysine acetyl-transferase gene, cause a syndrome including microcephaly and global developmental delay."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Common features among all four probands include primary microcephaly,
        global developmental delay including profound speech delay, and
        craniofacial dysmorphism
      explanation: >-
        Primary microcephaly is a common feature of the disorder; the
        developmental bridge is unresolved.
  - target: Gastroesophageal Reflux
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:30245513
      reference_title: "KAT6A Syndrome: genotype-phenotype correlation in 76 patients with pathogenic KAT6A variants."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The high prevalence of reflux and constipation is suggestive of
        dysfunctional intestinal motility.
      explanation: >-
        Reflux is linked to dysfunctional intestinal motility, plausibly a
        developmental consequence of KAT6A dysfunction.
  - target: Constipation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:30245513
      reference_title: "KAT6A Syndrome: genotype-phenotype correlation in 76 patients with pathogenic KAT6A variants."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The high prevalence of reflux and constipation is suggestive of
        dysfunctional intestinal motility.
      explanation: >-
        Constipation is linked to dysfunctional intestinal motility, plausibly a
        developmental consequence of KAT6A dysfunction.
  - target: KAT6A-RSPO2-Wnt Hippocampal Signaling Deficit
    causal_link_type: DIRECT
    hypothesis_groups:
    - kat6a_rspo2_wnt_hippocampal
    evidence:
    - reference: PMID:38758792
      reference_title: "KAT6A deficiency impairs cognitive functions through suppressing RSPO2/Wnt signaling in hippocampal CA3."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        We further identify a CA3-enriched gene Rspo2, encoding Wnt activator
        R-spondin 2, as a key transcriptional target of KAT6A.
      explanation: >-
        In mice, RSPO2 is a direct transcriptional target of KAT6A, linking the
        acetyltransferase to a specific hippocampal signaling program.
  - target: Atrial Septal Defect
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Specific cardiac lesion within the congenital cardiac phenotype already
      attributed to disrupted developmental transcription; the intervening
      cardiogenic steps are unresolved.
    evidence:
    - reference: PMID:30245513
      reference_title: "KAT6A Syndrome: genotype-phenotype correlation in 76 patients with pathogenic KAT6A variants."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Most frequent are septal defects including atrial septal defects (34%),
        ventricular septal defects in (8%), and persistence of the fetal anatomy
        (19%) (patent foreman ovale, and persistent ductus arteriosus).
      explanation: >-
        Atrial septal defect is the most frequent specific cardiac lesion in the
        cohort; the developmental bridge from KAT6A-dependent transcription is
        unresolved.
  - target: Ventricular Septal Defect
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Specific cardiac lesion within the congenital cardiac phenotype already
      attributed to disrupted developmental transcription; the intervening
      cardiogenic steps are unresolved.
    evidence:
    - reference: PMID:30245513
      reference_title: "KAT6A Syndrome: genotype-phenotype correlation in 76 patients with pathogenic KAT6A variants."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Most frequent are septal defects including atrial septal defects (34%),
        ventricular septal defects in (8%), and persistence of the fetal anatomy
        (19%) (patent foreman ovale, and persistent ductus arteriosus).
      explanation: >-
        Ventricular septal defects occur in 8% of the cohort as part of the
        septal-defect spectrum.
  - target: Patent Ductus Arteriosus
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Persistence of fetal cardiovascular anatomy within the congenital cardiac
      phenotype attributed to disrupted developmental transcription.
    evidence:
    - reference: PMID:30245513
      reference_title: "KAT6A Syndrome: genotype-phenotype correlation in 76 patients with pathogenic KAT6A variants."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Most frequent are septal defects including atrial septal defects (34%),
        ventricular septal defects in (8%), and persistence of the fetal anatomy
        (19%) (patent foreman ovale, and persistent ductus arteriosus).
      explanation: >-
        Persistent ductus arteriosus is part of the persistence-of-fetal-anatomy
        category reported in 19% of the cohort.
  - target: Patent Foramen Ovale
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Persistence of fetal cardiovascular anatomy within the congenital cardiac
      phenotype attributed to disrupted developmental transcription.
    evidence:
    - reference: PMID:30245513
      reference_title: "KAT6A Syndrome: genotype-phenotype correlation in 76 patients with pathogenic KAT6A variants."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Most frequent are septal defects including atrial septal defects (34%),
        ventricular septal defects in (8%), and persistence of the fetal anatomy
        (19%) (patent foreman ovale, and persistent ductus arteriosus).
      explanation: >-
        Patent foramen ovale is part of the persistence-of-fetal-anatomy
        category reported in 19% of the cohort.
  - target: Broad Nasal Tip
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Specific facial feature within the craniofacial dysmorphism already
      attributed to disrupted developmental transcription.
    evidence:
    - reference: PMID:30245513
      reference_title: "KAT6A Syndrome: genotype-phenotype correlation in 76 patients with pathogenic KAT6A variants."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        A broad nasal tip, which may become more obvious with age, and a thin,
        tented upper lip, are the most consistent facial features in patients with
        KAT6A syndrome.
      explanation: >-
        Broad nasal tip is one of the two most consistent facial features; the
        craniofacial developmental bridge is unresolved.
  - target: Thin, Tented Upper Lip
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Specific facial feature within the craniofacial dysmorphism already
      attributed to disrupted developmental transcription.
    evidence:
    - reference: PMID:30245513
      reference_title: "KAT6A Syndrome: genotype-phenotype correlation in 76 patients with pathogenic KAT6A variants."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        A broad nasal tip, which may become more obvious with age, and a thin,
        tented upper lip, are the most consistent facial features in patients with
        KAT6A syndrome.
      explanation: >-
        A thin, tented upper lip is one of the two most consistent facial
        features; the craniofacial developmental bridge is unresolved.
  - target: Low-Set, Posteriorly Rotated Ears
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Specific facial feature within the craniofacial dysmorphism already
      attributed to disrupted developmental transcription.
    evidence:
    - reference: PMID:30245513
      reference_title: "KAT6A Syndrome: genotype-phenotype correlation in 76 patients with pathogenic KAT6A variants."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Notable features present in a significant minority are epicanthic folds
        and low set and posteriorly rotated ears, which are occasionally folded
      explanation: >-
        Ear position anomalies are part of the recognizable craniofacial
        phenotype produced by disrupted developmental programs.
  - target: Craniosynostosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Skull development anomaly within the craniofacial spectrum attributed to
      disrupted developmental transcription.
    evidence:
    - reference: PMID:25728777
      reference_title: "Dominant mutations in KAT6A cause intellectual disability with recognizable syndromic features."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The common phenotype includes hypotonia, intellectual disability, early
        feeding and oromotor difficulties, microcephaly and/or craniosynostosis,
        and cardiac defects in combination with subtle facial features such as
        bitemporal narrowing, broad nasal tip, thin upper lip
      explanation: >-
        Craniosynostosis is listed within the common developmental phenotype of
        the founding series; the skull-suture bridge is unresolved.
  - target: Dental Anomalies
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Dentition anomalies within the craniofacial spectrum attributed to
      disrupted developmental transcription.
    evidence:
    - reference: PMID:30245513
      reference_title: "KAT6A Syndrome: genotype-phenotype correlation in 76 patients with pathogenic KAT6A variants."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Within the mouth a high arched narrow palate was noted in a few patients
        and teeth abnormalities were common.
      explanation: >-
        Common teeth abnormalities are part of the craniofacial developmental
        phenotype; the odontogenic bridge is unresolved.
  - target: Hearing Impairment
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Congenital hearing defects are a developmental anomaly within the
      multisystem congenital phenotype; the otologic developmental bridge is
      unresolved.
    evidence:
    - reference: PMID:30245513
      reference_title: "KAT6A Syndrome: genotype-phenotype correlation in 76 patients with pathogenic KAT6A variants."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        These included microcephaly, neonatal hypotonia, feeding difficulties,
        reflux, constipation, congenital hearing defects, and frequent infections.
      explanation: >-
        Congenital hearing defects segregate with the more severe late-truncating
        genotype, consistent with a developmental origin.
  - target: Strabismus
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Ocular anomaly within the multisystem congenital and neurodevelopmental
      phenotype; whether the defect is primarily oculomotor-neural or muscular
      is unresolved.
    evidence:
    - reference: PMID:30245513
      reference_title: "KAT6A Syndrome: genotype-phenotype correlation in 76 patients with pathogenic KAT6A variants."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Strabismus is reported in 54% of patients."
      explanation: >-
        Strabismus affects over half of patients as part of the syndromic ocular
        phenotype; the intervening mechanism is unresolved.
    - reference: PMID:25728775
      reference_title: "De novo nonsense mutations in KAT6A, a lysine acetyl-transferase gene, cause a syndrome including microcephaly and global developmental delay."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        more varied features such as feeding difficulties, cardiac defects, and
        ocular anomalies.
      explanation: >-
        The founding series lists ocular anomalies among the varied congenital
        features of the syndrome.
  - target: Cryptorchidism
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Congenital genitourinary anomaly within the multisystem congenital
      phenotype; the developmental bridge is unresolved.
    evidence:
    - reference: PMID:30245513
      reference_title: "KAT6A Syndrome: genotype-phenotype correlation in 76 patients with pathogenic KAT6A variants."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        we found a small number of patients had undescended testes (boys),
        clinodactyly and/or brachydactyly.
      explanation: >-
        Undescended testes in a small number of male patients are a congenital
        anomaly within the syndromic developmental spectrum.
  - target: Intestinal Obstruction
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Structural gastrointestinal malformations (malrotation, duodenal web)
      underlie several obstruction cases, indicating a developmental origin;
      dysmotility may contribute in others.
    evidence:
    - reference: PMID:30245513
      reference_title: "KAT6A Syndrome: genotype-phenotype correlation in 76 patients with pathogenic KAT6A variants."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        One required surgery for a duodenal web and malrotation, the second also
        required surgery for a malrotation
      explanation: >-
        Documented malrotation and duodenal web place several obstructions on a
        congenital-malformation footing rather than acquired disease.
  - target: Autistic Behavior
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Neurobehavioral manifestation of the neurodevelopmental phenotype, at the
      same epistemic level as the wired intellectual-disability and
      developmental-delay edges.
    evidence:
    - reference: PMID:30245513
      reference_title: "KAT6A Syndrome: genotype-phenotype correlation in 76 patients with pathogenic KAT6A variants."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Autism and autistic features have been reported in approximately 25% of
        newly reported cases.
      explanation: >-
        Autistic features are part of the neurobehavioral phenotype; the circuit
        mechanism is unresolved.
  - target: Sleep Disturbance
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Neurobehavioral manifestation of the neurodevelopmental phenotype; no
      sleep-specific mechanism has been studied.
    evidence:
    - reference: PMID:30245513
      reference_title: "KAT6A Syndrome: genotype-phenotype correlation in 76 patients with pathogenic KAT6A variants."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Over 30% of patients in this cohort reported sleep disturbance."
      explanation: >-
        Sleep disturbance is a recurrent feature of the neurodevelopmental
        phenotype; the intervening mechanism is unresolved.
  - target: Seizures
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Uncommon neurologic manifestation of abnormal brain development; no
      consistent seizure type or epileptogenic mechanism has been identified.
    evidence:
    - reference: PMID:30245513
      reference_title: "KAT6A Syndrome: genotype-phenotype correlation in 76 patients with pathogenic KAT6A variants."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Seizure activity has only been reported in seven patients and there is no
        consistency in seizure type
      explanation: >-
        Seizures are an uncommon, heterogeneous manifestation of the
        neurodevelopmental phenotype; the epileptogenic bridge is unresolved.
  - target: Impaired Hematopoietic Stem Cell Function
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:30245513
      reference_title: "KAT6A Syndrome: genotype-phenotype correlation in 76 patients with pathogenic KAT6A variants."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Tissue- or cell-specific knockout have shown that KAT6A regulates
        transcriptional programs important for skeletogenesis, hematopoeisis, and
        splenic and thymic function
      explanation: >-
        Mouse knockouts show KAT6A-dependent transcriptional programs are
        required for hematopoiesis, connecting the transcriptional mechanism to
        the hematopoietic compartment.

- name: KAT6A-RSPO2-Wnt Hippocampal Signaling Deficit
  description: >-
    In a mouse model, KAT6A deficiency lowers transcription of the CA3-enriched
    Wnt activator R-spondin 2 (RSPO2), impairing canonical Wnt signaling and
    synaptic structure and plasticity in hippocampal CA3 pyramidal neurons and
    producing memory deficits. Restoring RSPO2 in CA3 neurons rescues Wnt
    signaling and learning behaviors, nominating this axis as a candidate
    therapeutic target. This mechanism is currently established only in mice; its
    fidelity to human KAT6A-syndrome cognition is unproven.
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  cell_types:
  - preferred_term: hippocampal CA3 pyramidal neuron
    term:
      id: CL:1001571
      label: hippocampal pyramidal neuron
  biological_processes:
  - preferred_term: canonical Wnt signaling pathway
    term:
      id: GO:0060070
      label: canonical Wnt signaling pathway
    modifier: DECREASED
  - preferred_term: regulation of synaptic plasticity
    term:
      id: GO:0048167
      label: regulation of synaptic plasticity
    modifier: ABNORMAL
  - preferred_term: learning or memory
    term:
      id: GO:0007611
      label: learning or memory
    modifier: ABNORMAL
  evidence:
  - reference: PMID:38758792
    reference_title: "KAT6A deficiency impairs cognitive functions through suppressing RSPO2/Wnt signaling in hippocampal CA3."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Here, we find that KAT6A deficiency impairs synaptic structure and
      plasticity in hippocampal CA3, but not in CA1 region, resulting in memory
      deficits in mice.
    explanation: >-
      The mouse model localizes the KAT6A cognitive mechanism to CA3 synaptic
      structure and plasticity.
  downstream:
  - target: Intellectual Disability
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - kat6a_rspo2_wnt_hippocampal
    evidence:
    - reference: PMID:38758792
      reference_title: "KAT6A deficiency impairs cognitive functions through suppressing RSPO2/Wnt signaling in hippocampal CA3."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        restoring RSPO2 expression in CA3 neurons rescues the deficits in Wnt
        signaling and learning-associated behaviors in Kat6a mutant mice.
      explanation: >-
        Rescue of learning behaviors in mice links the RSPO2-Wnt deficit to the
        cognitive phenotype, though human relevance is not yet established.

- name: Mitochondrial and Bioenergetic Dysfunction
  description: >-
    Patient-derived fibroblasts carrying KAT6A mutations show impaired cellular
    bioenergetics alongside the histone-acetylation defect. This cellular
    bioenergetic deficit is the mechanistic rationale for the experimental
    pantothenate and L-carnitine intervention, which corrects it in vitro. The
    finding is from patient fibroblast models; its contribution to the clinical
    phenotype in vivo is not established.
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  evidence:
  - reference: PMID:36553567
    reference_title: "Pantothenate and L-Carnitine Supplementation Improves Pathological Alterations in Cellular Models of KAT6A Syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "the cell bioenergetics of mutant cells was significantly improved"
    explanation: >-
      That bioenergetics of mutant cells could be significantly improved by
      treatment establishes a baseline bioenergetic deficit in KAT6A-mutant
      fibroblasts.

- name: Impaired Hematopoietic Stem Cell Function
  description: >-
    KAT6A (MOZ) was originally characterized as a master regulator of
    hematopoiesis: complete-knockout mice die in embryogenesis from a failure of
    hematopoiesis, and tissue-specific knockouts show KAT6A-dependent
    transcriptional programs in blood lineages. In heterozygous patients an
    emerging hematologic spectrum (transient neonatal neutropenia through severe
    aplastic anemia) is consistent with impaired hematopoietic stem cell
    function, but the causal bridge from heterozygous KAT6A variation to human
    cytopenias and marrow failure has not been directly demonstrated, so this
    node and its outgoing edges are provisional.
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  cell_types:
  - preferred_term: hematopoietic stem cell
    term:
      id: CL:0000037
      label: hematopoietic stem cell
  biological_processes:
  - preferred_term: hemopoiesis
    term:
      id: GO:0030097
      label: hemopoiesis
    modifier: ABNORMAL
  evidence:
  - reference: PMID:30245513
    reference_title: "KAT6A Syndrome: genotype-phenotype correlation in 76 patients with pathogenic KAT6A variants."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Complete knockout mouse models result in embryonic lethality, due to a
      failure of hematopoiesis.
    explanation: >-
      Mouse knockouts establish KAT6A as essential for hematopoiesis; the human
      heterozygous state is a partial, not complete, loss of function.
  - reference: PMID:30245513
    reference_title: "KAT6A Syndrome: genotype-phenotype correlation in 76 patients with pathogenic KAT6A variants."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      One hypothesis is that KAT6A syndrome may result in a variety of
      abnormalities of blood cell lines.
    explanation: >-
      The clinical cohort explicitly frames blood-lineage abnormalities as a
      hypothesis rather than an established mechanism, which is why this node is
      provisional.
  downstream:
  - target: Neutropenia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:42040242
      reference_title: "Expanding the Clinical Spectrum of Arboleda-Tham Syndrome: Neuroimaging Findings and Hematologic Manifestations."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Notably, 3 of 11 patients (27%) exhibited hematologic abnormalities,
        ranging from transient neonatal neutropenia to severe aplastic anemia
        requiring hematopoietic stem cell transplantation.
      explanation: >-
        Neonatal neutropenia sits within the hematologic spectrum plausibly
        produced by impaired KAT6A-dependent hematopoiesis; the human bridge is
        not directly demonstrated.
  - target: Aplastic Anemia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:42040242
      reference_title: "Expanding the Clinical Spectrum of Arboleda-Tham Syndrome: Neuroimaging Findings and Hematologic Manifestations."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Notably, 3 of 11 patients (27%) exhibited hematologic abnormalities,
        ranging from transient neonatal neutropenia to severe aplastic anemia
        requiring hematopoietic stem cell transplantation.
      explanation: >-
        Severe aplastic anemia is the most severe observed manifestation of the
        hematologic spectrum plausibly produced by impaired KAT6A-dependent
        hematopoiesis; the human bridge is not directly demonstrated.

phenotypes:
- category: Neurodevelopmental
  name: Intellectual Disability
  description: >-
    Intellectual disability is very common and ranges from mild to severe, with
    greater group-level severity among late-truncating variants. It is not
    universal: normally assessed cognition has now been reported in rare
    inherited-variant cases.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:30245513
    reference_title: "KAT6A Syndrome: genotype-phenotype correlation in 76 patients with pathogenic KAT6A variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Intellectual disability and developmental delay are universal."
    explanation: >-
      The 2019 cohort found both features in all ascertained participants; the
      frequency is conservatively downgraded from obligate because later inherited cases include normal cognition.
  - reference: PMID:38741077
    reference_title: "Neuropsychological profile associated with KAT6A syndrome: Emergent genotype-phenotype trends."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Findings suggest global cognitive impairment with nonverbal cognition
      scores similar to those for receptive language
    explanation: >-
      A dedicated neuropsychological study characterizes the impairment as
      global, with nonverbal cognition tracking receptive language.
  - reference: PMID:39740728
    reference_title: Phenotypic variability in a family with an inherited KAT6A frameshift variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The description includes an affected first child with premature pubarche
      (the first individual to our knowledge), a mildly affected second child
      with normal cognitive performance assessment (the third reported
      individual with normal assessment of cognition and KAT6A syndrome), and a
      self-sufficient adult family member.
    explanation: >-
      This inherited family establishes rare exceptions to the earlier
      universal-intellectual-disability framing and supports variable expressivity.
- category: Neurodevelopmental
  name: Global Developmental Delay
  description: >-
    Global developmental delay is a defining early-life feature in clinically
    ascertained cohorts, affecting motor, language, and adaptive development.
    Rare inherited-variant relatives may have normal standardized development,
    so the association is very frequent rather than obligate.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:30245513
    reference_title: "KAT6A Syndrome: genotype-phenotype correlation in 76 patients with pathogenic KAT6A variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Intellectual disability and developmental delay are universal."
    explanation: >-
      The 76-person cohort provides the largest direct clinical anchor for
      developmental delay, while later inherited cases prevent an obligate
      syndrome-wide frequency assertion.
  - reference: PMID:42040242
    reference_title: "Expanding the Clinical Spectrum of Arboleda-Tham Syndrome: Neuroimaging Findings and Hematologic Manifestations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Global developmental delay was universal, with marked speech impairment;
      most patients remained minimally verbal beyond age 5.
    explanation: >-
      The 2026 molecularly confirmed cohort found global developmental delay in
      all 14 participants; rare inherited cases prevent an obligate syndrome-wide assertion.
- category: Neurodevelopmental
  name: Expressive Speech Delay
  description: >-
    Marked expressive speech delay is very frequent. Many affected people are
    minimally verbal into adulthood, and verbal participants may have both
    phonological impairment and speech apraxia; receptive and expressive
    language are variably but substantially affected.
  phenotype_term:
    preferred_term: Delayed speech and language development
    term:
      id: HP:0000750
      label: Delayed speech and language development
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:30245513
    reference_title: "KAT6A Syndrome: genotype-phenotype correlation in 76 patients with pathogenic KAT6A variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Marked expressive speech delay is universal."
    explanation: >-
      The 2019 cohort documents marked expressive speech delay as universal in
      that sample; the syndrome-wide band is kept conservative.
  - reference: PMID:35892268
    reference_title: "Speech and language development and genotype-phenotype correlation in 49 individuals with KAT6A syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Seventy-three percent (36/49) were minimally-verbal, relying on nonverbal
      behaviors to communicate.
    explanation: >-
      Standardized survey and telehealth assessment quantify the severe
      communication phenotype in a dedicated 49-person cohort.
- category: Neurologic
  name: Hypotonia
  description: >-
    Hypotonia is common, frequently with neonatal onset, and contributes to
    motor delay; truncal hypotonia is often combined with limb hypertonia in the
    neonatal period. Neonatal hypotonia is one of the features significantly
    more common in late-truncating variants.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  frequency: FREQUENT
  evidence:
  - reference: PMID:30245513
    reference_title: "KAT6A Syndrome: genotype-phenotype correlation in 76 patients with pathogenic KAT6A variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hypotonia is common and contributes to motor delay."
    explanation: >-
      The cohort documents hypotonia as common and a contributor to motor delay.
- category: Gastrointestinal
  name: Feeding Difficulties
  description: >-
    Feeding difficulties are common, frequently with oromotor dysfunction and
    difficulty establishing feeding at birth; nasogastric feeding is often
    required and some patients need gastrostomy.
  phenotype_term:
    preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
  frequency: FREQUENT
  evidence:
  - reference: PMID:30245513
    reference_title: "KAT6A Syndrome: genotype-phenotype correlation in 76 patients with pathogenic KAT6A variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "78% of patients experienced feeding difficulties."
    explanation: >-
      The cohort reports feeding difficulties in 78% of patients, within the
      frequent band.
- category: Cardiovascular
  name: Congenital Cardiac Defects
  description: >-
    Cardiac malformations, most often septal defects, are present in about half
    of patients; atrial septal defects are the most frequent, followed by
    ventricular septal defects and persistence of fetal anatomy (patent foramen
    ovale, patent ductus arteriosus). Many require intervention.
  phenotype_term:
    preferred_term: Abnormal heart morphology
    term:
      id: HP:0001627
      label: Abnormal heart morphology
  frequency: FREQUENT
  evidence:
  - reference: PMID:30245513
    reference_title: "KAT6A Syndrome: genotype-phenotype correlation in 76 patients with pathogenic KAT6A variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cardiac malformations are present in half (51%) of our cohort."
    explanation: >-
      The cohort documents cardiac malformations in 51% of patients.
- category: Cardiovascular
  name: Atrial Septal Defect
  description: >-
    Atrial septal defect is the most frequent cardiac lesion in KAT6A syndrome.
  phenotype_term:
    preferred_term: Atrial septal defect
    term:
      id: HP:0001631
      label: Atrial septal defect
  frequency: FREQUENT
  evidence:
  - reference: PMID:30245513
    reference_title: "KAT6A Syndrome: genotype-phenotype correlation in 76 patients with pathogenic KAT6A variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Most frequent are septal defects including atrial septal defects (34%),
      ventricular septal defects in (8%), and persistence of the fetal anatomy
      (19%) (patent foreman ovale, and persistent ductus arteriosus).
    explanation: >-
      The cohort reports atrial septal defects in 34% of patients, the most
      frequent cardiac lesion.
- category: Cardiovascular
  name: Ventricular Septal Defect
  description: >-
    Ventricular septal defect occurs in a minority of patients with cardiac
    involvement.
  phenotype_term:
    preferred_term: Ventricular septal defect
    term:
      id: HP:0001629
      label: Ventricular septal defect
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:30245513
    reference_title: "KAT6A Syndrome: genotype-phenotype correlation in 76 patients with pathogenic KAT6A variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Most frequent are septal defects including atrial septal defects (34%),
      ventricular septal defects in (8%), and persistence of the fetal anatomy
      (19%) (patent foreman ovale, and persistent ductus arteriosus).
    explanation: >-
      The cohort reports ventricular septal defects in 8% of patients.
- category: Craniofacial
  name: Craniofacial Dysmorphism
  description: >-
    Recognizable craniofacial dysmorphism is a core feature, most consistently a
    broad nasal tip and a thin, tented upper lip, with additional features
    including bitemporal narrowing, prominent nasal bridge, and a short, flat
    philtrum. A 2026 cohort enriched for late-truncating variants (13 of 14)
    nevertheless documented dysmorphism in 79%, supporting a frequent rather
    than very-frequent syndrome-wide band.
  phenotype_term:
    preferred_term: Craniofacial dysmorphism
    term:
      id: HP:0001999
      label: Abnormal facial shape
  frequency: FREQUENT
  evidence:
  - reference: PMID:25728775
    reference_title: "De novo nonsense mutations in KAT6A, a lysine acetyl-transferase gene, cause a syndrome including microcephaly and global developmental delay."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Common features among all four probands include primary microcephaly,
      global developmental delay including profound speech delay, and
      craniofacial dysmorphism
    explanation: >-
      The founding series lists craniofacial dysmorphism among the common
      features shared by all probands.
  - reference: PMID:42040242
    reference_title: "Expanding the Clinical Spectrum of Arboleda-Tham Syndrome: Neuroimaging Findings and Hematologic Manifestations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Craniofacial dysmorphisms were observed in 11 patients (79%)"
    explanation: >-
      The 2026 cohort quantifies craniofacial dysmorphism at 79%, within the
      frequent band and below the threshold for a very-frequent assertion.
- category: Craniofacial
  name: Broad Nasal Tip
  description: >-
    A broad nasal tip, which may become more obvious with age, is one of the two
    most consistent facial features of KAT6A syndrome.
  phenotype_term:
    preferred_term: Broad nasal tip
    term:
      id: HP:0000455
      label: Broad nasal tip
  frequency: FREQUENT
  evidence:
  - reference: PMID:30245513
    reference_title: "KAT6A Syndrome: genotype-phenotype correlation in 76 patients with pathogenic KAT6A variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A broad nasal tip, which may become more obvious with age, and a thin,
      tented upper lip, are the most consistent facial features in patients with
      KAT6A syndrome.
    explanation: >-
      The cohort identifies broad nasal tip as one of the two most consistent
      facial features.
- category: Craniofacial
  name: Thin, Tented Upper Lip
  description: >-
    A thin, tented upper lip is one of the two most consistent facial features
    of KAT6A syndrome.
  phenotype_term:
    preferred_term: Thin, tented upper lip vermilion
    term:
      id: HP:0000219
      label: Thin upper lip vermilion
  frequency: FREQUENT
  evidence:
  - reference: PMID:30245513
    reference_title: "KAT6A Syndrome: genotype-phenotype correlation in 76 patients with pathogenic KAT6A variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A broad nasal tip, which may become more obvious with age, and a thin,
      tented upper lip, are the most consistent facial features in patients with
      KAT6A syndrome.
    explanation: >-
      The cohort identifies a thin, tented upper lip as one of the two most
      consistent facial features.
- category: Neurologic
  name: Microcephaly
  description: >-
    Microcephaly is present in roughly a quarter of patients and is not always
    present at birth; earlier smaller series reported a higher rate.
    Microcephaly is one of the features significantly more common in
    late-truncating variants.
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:30245513
    reference_title: "KAT6A Syndrome: genotype-phenotype correlation in 76 patients with pathogenic KAT6A variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      in our larger cohort, only 25% individuals had microcephaly, which was not
      always present at birth.
    explanation: >-
      The larger cohort reports microcephaly in 25% of patients, within the
      occasional band.
- category: Ophthalmologic
  name: Strabismus
  description: >-
    Strabismus is a common ophthalmologic finding, can be intermittent, and may
    lead to amblyopia if unrecognized and untreated.
  phenotype_term:
    preferred_term: Strabismus
    term:
      id: HP:0000486
      label: Strabismus
  frequency: FREQUENT
  evidence:
  - reference: PMID:30245513
    reference_title: "KAT6A Syndrome: genotype-phenotype correlation in 76 patients with pathogenic KAT6A variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Strabismus is reported in 54% of patients."
    explanation: >-
      The cohort reports strabismus in 54% of patients.
  sequelae:
  - target: Amblyopia
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:30245513
      reference_title: "KAT6A Syndrome: genotype-phenotype correlation in 76 patients with pathogenic KAT6A variants."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Strabismus can result in amblyopia and this is more likely to occur if
        it is unrecognized and untreated.
      explanation: >-
        The cohort explicitly attributes amblyopia risk to unrecognized,
        untreated strabismus, a standard clinical causal sequence.
- category: Gastrointestinal
  name: Constipation
  description: >-
    Constipation affects over half of patients, many requiring long-term
    laxatives, and is one of the features significantly more common in
    late-truncating variants.
  phenotype_term:
    preferred_term: Constipation
    term:
      id: HP:0002019
      label: Constipation
  frequency: FREQUENT
  evidence:
  - reference: PMID:30245513
    reference_title: "KAT6A Syndrome: genotype-phenotype correlation in 76 patients with pathogenic KAT6A variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Constipation is a significant issue for over half of our patients and many
      are on long term laxatives.
    explanation: >-
      The cohort documents constipation in over half of patients.
- category: Gastrointestinal
  name: Gastroesophageal Reflux
  description: >-
    Gastroesophageal reflux is a significant and prevalent issue, suggestive of
    dysfunctional intestinal motility, and some patients require fundoplication.
  phenotype_term:
    preferred_term: Gastroesophageal reflux
    term:
      id: HP:0002020
      label: Gastroesophageal reflux
  frequency: FREQUENT
  evidence:
  - reference: PMID:30245513
    reference_title: "KAT6A Syndrome: genotype-phenotype correlation in 76 patients with pathogenic KAT6A variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The high prevalence of reflux and constipation is suggestive of
      dysfunctional intestinal motility.
    explanation: >-
      The cohort notes a high prevalence of reflux alongside constipation.
- category: Gastrointestinal
  name: Intestinal Obstruction
  description: >-
    An increased risk of gastrointestinal obstruction is a novel association;
    several patients had bowel obstruction, in some cases from malrotation or a
    duodenal web, requiring surgery.
  phenotype_term:
    preferred_term: Intestinal obstruction
    term:
      id: HP:0005214
      label: Intestinal obstruction
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:30245513
    reference_title: "KAT6A Syndrome: genotype-phenotype correlation in 76 patients with pathogenic KAT6A variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "novel associations, including an increased risk of gastrointestinal obstruction."
    explanation: >-
      The cohort identifies an increased risk of gastrointestinal obstruction as
      a novel association.
  - reference: PMID:30245513
    reference_title: "KAT6A Syndrome: genotype-phenotype correlation in 76 patients with pathogenic KAT6A variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      four patients in this study (patients 6, 22, 42 and 46) had bowel
      obstruction.
    explanation: >-
      Four of 76 participants (5.3%) had bowel obstruction, supporting the
      occasional frequency band.
- category: Neurologic
  name: Sleep Disturbance
  description: >-
    Over 30% of patients report sleep disturbance, including difficulty
    initiating and maintaining sleep, and some have central or obstructive sleep
    apnea.
  phenotype_term:
    preferred_term: Sleep disturbance
    term:
      id: HP:0002360
      label: Sleep disturbance
  frequency: FREQUENT
  evidence:
  - reference: PMID:30245513
    reference_title: "KAT6A Syndrome: genotype-phenotype correlation in 76 patients with pathogenic KAT6A variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Over 30% of patients in this cohort reported sleep disturbance."
    explanation: >-
      The cohort reports sleep disturbance in over 30% of patients.
- category: Psychiatric
  name: Autistic Behavior
  description: >-
    Autism and autistic features, particularly restricted interests and
    repetitive behaviors, are reported in roughly a quarter of newly reported
    cases, often juxtaposed with a relatively strong social drive.
  phenotype_term:
    preferred_term: Autistic behavior
    term:
      id: HP:0000729
      label: Autistic behavior
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:30245513
    reference_title: "KAT6A Syndrome: genotype-phenotype correlation in 76 patients with pathogenic KAT6A variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Autism and autistic features have been reported in approximately 25% of
      newly reported cases.
    explanation: >-
      The cohort reports autism/autistic features in approximately 25% of newly
      reported cases.
  - reference: PMID:38741077
    reference_title: "Neuropsychological profile associated with KAT6A syndrome: Emergent genotype-phenotype trends."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Autism-related features, particularly restricted interests and repetitive
      behaviors, and broad adaptive deficits were common in our sample
      juxtaposed with a relatively strong social drive and low frequency of
      internalizing and externalizing behavioral problems.
    explanation: >-
      A dedicated neuropsychological study characterizes the autism-related
      features and their relative sparing of social drive.
- category: Immunologic
  name: Recurrent Infections
  description: >-
    Frequent infections are reported in a subset of patients, most commonly
    common childhood illnesses (otitis media, respiratory tract infections);
    frequent infections are significantly more common in late-truncating
    variants. Neutropenia is represented separately because it is a distinct
    hematologic phenotype and is not established as the cause of infections.
  phenotype_term:
    preferred_term: Recurrent infections
    term:
      id: HP:0002719
      label: Recurrent infections
  evidence:
  - reference: PMID:30245513
    reference_title: "KAT6A Syndrome: genotype-phenotype correlation in 76 patients with pathogenic KAT6A variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      those that did tended to report common childhood illnesses including
      otitis media and upper and lower respiratory tract infections
    explanation: >-
      The cohort documents recurrent common childhood infections in the subset
      of patients reporting frequent infections.
- category: Hematologic
  name: Neutropenia
  description: >-
    Transient neonatal and isolated moderate-to-severe neutropenia have been
    reported across independent cohorts. The 2026 retrospective cohort grouped
    neutropenia with other hematologic abnormalities in 3 of 11 assessed
    patients, so phenotype-specific prevalence, natural history, and surveillance
    thresholds remain unresolved.
  phenotype_term:
    preferred_term: Neutropenia
    term:
      id: HP:0001875
      label: Decreased total neutrophil count
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:30245513
    reference_title: "KAT6A Syndrome: genotype-phenotype correlation in 76 patients with pathogenic KAT6A variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "three individuals report isolated moderate to severe neutropenia5,13."
    explanation: >-
      The 76-person cohort consolidates three reports of isolated
      moderate-to-severe neutropenia, supporting an occasional frequency band.
  - reference: PMID:42040242
    reference_title: "Expanding the Clinical Spectrum of Arboleda-Tham Syndrome: Neuroimaging Findings and Hematologic Manifestations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Notably, 3 of 11 patients (27%) exhibited hematologic abnormalities,
      ranging from transient neonatal neutropenia to severe aplastic anemia
      requiring hematopoietic stem cell transplantation.
    explanation: >-
      The molecularly confirmed cohort independently includes transient neonatal
      neutropenia within an emerging hematologic spectrum. The pathograph link
      through impaired hematopoietic stem cell function is provisional, resting
      on mouse hematopoiesis data rather than a demonstrated human bridge.
- category: Hematologic
  name: Aplastic Anemia
  description: >-
    Severe aplastic anemia requiring hematopoietic stem cell transplantation was
    reported within the emerging hematologic spectrum in a 2026 retrospective
    cohort. The combined hematologic denominator was 3 of 11, but the
    phenotype-specific frequency and surveillance implications require replication.
  phenotype_term:
    preferred_term: Aplastic anemia
    term:
      id: HP:0001915
      label: Aplastic anemia
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:42040242
    reference_title: "Expanding the Clinical Spectrum of Arboleda-Tham Syndrome: Neuroimaging Findings and Hematologic Manifestations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Notably, 3 of 11 patients (27%) exhibited hematologic abnormalities,
      ranging from transient neonatal neutropenia to severe aplastic anemia
      requiring hematopoietic stem cell transplantation.
    explanation: >-
      This establishes aplastic anemia as a specifically observed severe
      manifestation while leaving its individual prevalence unresolved.
- category: Neurologic
  name: Chiari Malformation
  description: >-
    Type 1 Chiari malformation is an uncommon neuroimaging finding, observed in
    a 2026 cohort and independently reported in the earlier 76-person series.
    The newer study grouped Chiari malformation and white-matter
    hyperintensities in 2 of 10 imaged participants.
  phenotype_term:
    preferred_term: Chiari malformation
    term:
      id: HP:0002308
      label: Chiari malformation
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:42040242
    reference_title: "Expanding the Clinical Spectrum of Arboleda-Tham Syndrome: Neuroimaging Findings and Hematologic Manifestations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Brain imaging revealed type 1 Chiari malformation and white matter
      hyperintensities in 2 of the 10 assessed (20%), suggesting a broader
      neuroanatomic involvement.
    explanation: >-
      The molecularly confirmed cohort quantifies the combined neuroimaging
      observations in the occasional frequency band.
  - reference: PMID:30245513
    reference_title: "KAT6A Syndrome: genotype-phenotype correlation in 76 patients with pathogenic KAT6A variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "hydrocephalus and a Chiari malformation in patient 33"
    explanation: >-
      The earlier large cohort independently corroborates Chiari malformation.
- category: Neurologic
  name: Cerebral White Matter Hyperintensities
  description: >-
    Cerebral white-matter hyperintensities are an emerging neuroimaging finding.
    They were grouped with type 1 Chiari malformation in 2 of 10 imaged
    participants in a 2026 retrospective cohort, and replication is needed.
  phenotype_term:
    preferred_term: Hyperintensity of cerebral white matter on MRI
    term:
      id: HP:0030890
      label: Hyperintensity of cerebral white matter on MRI
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:42040242
    reference_title: "Expanding the Clinical Spectrum of Arboleda-Tham Syndrome: Neuroimaging Findings and Hematologic Manifestations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Brain imaging revealed type 1 Chiari malformation and white matter
      hyperintensities in 2 of the 10 assessed (20%), suggesting a broader
      neuroanatomic involvement.
    explanation: >-
      This quantified imaging cohort supports an occasional band while the
      grouped wording prevents a phenotype-specific estimate.
- category: Neurologic
  name: Seizures
  description: >-
    Seizures are uncommon and reported in only a few patients, with no
    consistent seizure type.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:30245513
    reference_title: "KAT6A Syndrome: genotype-phenotype correlation in 76 patients with pathogenic KAT6A variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Seizure activity has only been reported in seven patients and there is no
      consistency in seizure type
    explanation: >-
      The cohort reports seizures in only seven patients, an uncommon feature.
- category: Craniofacial
  name: Craniosynostosis
  description: >-
    Craniosynostosis is an uncommon feature, reported in a small number of
    patients.
  phenotype_term:
    preferred_term: Craniosynostosis
    term:
      id: HP:0001363
      label: Craniosynostosis
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:30245513
    reference_title: "KAT6A Syndrome: genotype-phenotype correlation in 76 patients with pathogenic KAT6A variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Craniosynostosis is reported in a total of 6 patients5."
    explanation: >-
      The cohort reports craniosynostosis in a total of 6 patients.
- category: Craniofacial
  name: Low-Set, Posteriorly Rotated Ears
  description: >-
    Low-set and posteriorly rotated ears, occasionally folded, are present in a
    significant minority, alongside epicanthic folds.
  phenotype_term:
    preferred_term: Low-set, posteriorly rotated ears
    term:
      id: HP:0000377
      label: Abnormal pinna morphology
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:30245513
    reference_title: "KAT6A Syndrome: genotype-phenotype correlation in 76 patients with pathogenic KAT6A variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Notable features present in a significant minority are epicanthic folds
      and low set and posteriorly rotated ears, which are occasionally folded
    explanation: >-
      The cohort documents low-set, posteriorly rotated ears in a significant
      minority of patients.
- category: Otologic
  name: Hearing Impairment
  description: >-
    Congenital hearing defects occur in KAT6A syndrome and are one of the
    features significantly enriched in patients with late-truncating variants.
  phenotype_term:
    preferred_term: Hearing impairment
    term:
      id: HP:0000365
      label: Hearing impairment
  evidence:
  - reference: PMID:30245513
    reference_title: "KAT6A Syndrome: genotype-phenotype correlation in 76 patients with pathogenic KAT6A variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These included microcephaly, neonatal hypotonia, feeding difficulties,
      reflux, constipation, congenital hearing defects, and frequent infections.
    explanation: >-
      Congenital hearing defects are among the subphenotypes significantly more
      common in late-truncating variants; an overall cohort frequency is not
      given, so no frequency band is assigned.
- category: Craniofacial
  name: Dental Anomalies
  description: >-
    Teeth abnormalities are common, including previously reported abnormal
    peg-shaped teeth.
  phenotype_term:
    preferred_term: Dental anomalies
    term:
      id: HP:0000164
      label: Abnormality of the dentition
  frequency: FREQUENT
  evidence:
  - reference: PMID:30245513
    reference_title: "KAT6A Syndrome: genotype-phenotype correlation in 76 patients with pathogenic KAT6A variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "teeth abnormalities were common."
    explanation: >-
      The cohort documents teeth abnormalities as common.
- category: Cardiovascular
  name: Patent Ductus Arteriosus
  description: >-
    Patent ductus arteriosus, together with patent foramen ovale, constitutes
    the "persistence of fetal anatomy" cardiac category reported in 19% of the
    cohort.
  phenotype_term:
    preferred_term: Patent ductus arteriosus
    term:
      id: HP:0001643
      label: Patent ductus arteriosus
  evidence:
  - reference: PMID:30245513
    reference_title: "KAT6A Syndrome: genotype-phenotype correlation in 76 patients with pathogenic KAT6A variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Most frequent are septal defects including atrial septal defects (34%),
      ventricular septal defects in (8%), and persistence of the fetal anatomy
      (19%) (patent foreman ovale, and persistent ductus arteriosus).
    explanation: >-
      Persistent ductus arteriosus is part of the persistence-of-fetal-anatomy
      category reported in 19% of the cohort (combined with patent foramen ovale).
- category: Cardiovascular
  name: Patent Foramen Ovale
  description: >-
    Patent foramen ovale, together with patent ductus arteriosus, constitutes
    the "persistence of fetal anatomy" cardiac category reported in 19% of the
    cohort.
  phenotype_term:
    preferred_term: Patent foramen ovale
    term:
      id: HP:0001655
      label: Patent foramen ovale
  evidence:
  - reference: PMID:30245513
    reference_title: "KAT6A Syndrome: genotype-phenotype correlation in 76 patients with pathogenic KAT6A variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Most frequent are septal defects including atrial septal defects (34%),
      ventricular septal defects in (8%), and persistence of the fetal anatomy
      (19%) (patent foreman ovale, and persistent ductus arteriosus).
    explanation: >-
      Patent foramen ovale is part of the persistence-of-fetal-anatomy category
      reported in 19% of the cohort (combined with patent ductus arteriosus).
- category: Ophthalmologic
  name: Amblyopia
  description: >-
    Amblyopia is reported in several patients, and is more likely when
    strabismus is unrecognized and untreated.
  phenotype_term:
    preferred_term: Amblyopia
    term:
      id: HP:0000646
      label: Amblyopia
  evidence:
  - reference: PMID:30245513
    reference_title: "KAT6A Syndrome: genotype-phenotype correlation in 76 patients with pathogenic KAT6A variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Amblyopia is reported in several patients."
    explanation: >-
      The cohort documents amblyopia in several patients, an uncommon secondary
      complication of strabismus.
- category: Genitourinary
  name: Cryptorchidism
  description: >-
    Undescended testes are reported in a small number of male patients.
  phenotype_term:
    preferred_term: Cryptorchidism
    term:
      id: HP:0000028
      label: Cryptorchidism
  evidence:
  - reference: PMID:30245513
    reference_title: "KAT6A Syndrome: genotype-phenotype correlation in 76 patients with pathogenic KAT6A variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we found a small number of patients had undescended testes (boys),
      clinodactyly and/or brachydactyly.
    explanation: >-
      The cohort documents undescended testes in a small number of male patients.

genetic:
- name: KAT6A Pathogenic Variants
  gene_term:
    preferred_term: KAT6A
    term:
      id: hgnc:13013
      label: KAT6A
  association: Causative
  presence: Positive
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  notes: >-
    Heterozygous pathogenic KAT6A variants are usually de novo and predominantly
    protein-truncating (nonsense or frameshift), with recurrent hotspots in the
    arginine-rich acidic domain (amino acid positions 1019, 1024, 1129). Variant
    position drives an allele-dependent molecular consequence: early-truncating
    variants (exons 1-15) are predicted to trigger NMD and haploinsufficiency
    and are associated with milder disease, whereas late-truncating variants
    (exons 16-17) escape NMD and are associated with more severe disease.
    Missense variants are reported but require variant-specific functional
    evidence.
  inheritance:
  - name: Autosomal dominant inheritance
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
    description: >-
      Arboleda-Tham syndrome is autosomal dominant and almost always caused by a
      de novo KAT6A variant.
    evidence:
    - reference: PMID:25728775
      reference_title: "De novo nonsense mutations in KAT6A, a lysine acetyl-transferase gene, cause a syndrome including microcephaly and global developmental delay."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Here, we report a syndrome caused by de novo heterozygous nonsense
        mutations in KAT6A (a.k.a., MOZ, MYST3) identified by clinical exome
        sequencing (CES) in four independent families.
      explanation: >-
        The founding series establishes de novo heterozygous KAT6A variants as
        causal.
  evidence:
  - reference: PMID:25728777
    reference_title: "Dominant mutations in KAT6A cause intellectual disability with recognizable syndromic features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Finally, by detailed clinical characterization we provide evidence that
      heterozygous mutations in KAT6A cause a distinct intellectual disability
      syndrome.
    explanation: >-
      Establishes KAT6A as the causative gene for a distinct intellectual
      disability syndrome.
  - reference: PMID:30245513
    reference_title: "KAT6A Syndrome: genotype-phenotype correlation in 76 patients with pathogenic KAT6A variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our analysis identifies hotspot nonsense mutations within the penultimate
      exons at amino acid positions 1019, 1024, and 1129 that account for 19.1%
      (13/68) of pathogenic variants in unrelated individuals.
    explanation: >-
      Quantifies the recurrent truncating hotspots that make up a substantial
      fraction of pathogenic variants.

diagnosis:
- name: Exome or genome sequencing
  description: >-
    Diagnosis is molecular. Because the clinical features overlap many
    developmental syndromes and there is no single pathognomonic feature,
    identification of a heterozygous pathogenic KAT6A variant by exome (or
    genome) sequencing, typically trio-based to establish de novo status,
    establishes the diagnosis.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: NCIT:C19770
      label: Molecular Analysis
  results: >-
    A heterozygous pathogenic or likely pathogenic KAT6A variant confirms the
    diagnosis.
  evidence:
  - reference: PMID:25728775
    reference_title: "De novo nonsense mutations in KAT6A, a lysine acetyl-transferase gene, cause a syndrome including microcephaly and global developmental delay."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "identified by clinical exome sequencing (CES) in four independent families"
    explanation: >-
      The founding series identified the disorder by clinical exome sequencing.
  - reference: PMID:25728777
    reference_title: "Dominant mutations in KAT6A cause intellectual disability with recognizable syndromic features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "with mutations in KAT6A/MOZ detected by whole-exome sequencing"
    explanation: >-
      An independent series likewise established the diagnosis by whole-exome
      sequencing.
- name: Baseline cardiac evaluation
  description: >-
    Given the high prevalence of cardiac lesions, baseline cardiology assessment
    with echocardiography is recommended at diagnosis.
  diagnosis_term:
    preferred_term: clinical assessment
    term:
      id: NCIT:C124351
      label: Clinical Evaluation
  results: >-
    Echocardiography identifies septal defects and persistence of fetal anatomy
    that may require intervention.
  evidence:
  - reference: PMID:30245513
    reference_title: "KAT6A Syndrome: genotype-phenotype correlation in 76 patients with pathogenic KAT6A variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The prevalence of cardiac lesions highlights the need for early cardiology
      assessment.
    explanation: >-
      The cohort recommends early cardiology assessment given the cardiac-lesion
      prevalence.
- name: DNA methylation episignature analysis
  description: >-
    Genome-wide DNA methylation analysis can provide an adjunctive molecular
    classifier when a KAT6A variant is uncertain or when KAT6A- and KAT6B-related
    disorders are difficult to distinguish. It does not replace sequence-based
    diagnosis and was validated as a biomarker rather than as a screening test.
  diagnosis_term:
    preferred_term: DNA methylation analysis
    term:
      id: NCIT:C63328
      label: DNA Methylation Analysis
  results: >-
    A KAT6A-associated episignature supports classification of the molecular
    finding and is distinct from the episignatures reported for KAT6B disorders.
  evidence:
  - reference: PMID:37249002
    reference_title: DNA methylation episignatures are sensitive and specific biomarkers for detection of patients with KAT6A/KAT6B variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In this study we describe distinct episignatures for KAT6A syndrome,
      caused by pathogenic variants in the lysine acetyltransferase A gene
      (KAT6A), and for the two neurodevelopmental disorders associated with
      lysine acetyl transferase B (KAT6B).
    explanation: >-
      The clinical methylome study establishes separable KAT6A and KAT6B
      episignatures as adjunctive diagnostic classifiers.

differential_diagnoses:
- name: KAT6B-related neurodevelopmental disorders
  description: >-
    Genitopatellar and Say-Barber-Biesecker-Young-Simpson syndromes can overlap
    in developmental delay, hypotonia, feeding difficulty, craniofacial
    dysmorphism, and congenital anomalies. Gene-specific sequencing identifies
    KAT6A versus KAT6B variants, and their distinct DNA methylation
    episignatures can assist classification when molecular findings are ambiguous.
  evidence:
  - reference: PMID:37249002
    reference_title: DNA methylation episignatures are sensitive and specific biomarkers for detection of patients with KAT6A/KAT6B variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In this study we describe distinct episignatures for KAT6A syndrome,
      caused by pathogenic variants in the lysine acetyltransferase A gene
      (KAT6A), and for the two neurodevelopmental disorders associated with
      lysine acetyl transferase B (KAT6B).
    explanation: >-
      Distinct molecular signatures support KAT6B-related disorders as a
      relevant but separable differential diagnosis.

treatments:
- name: Multidisciplinary Supportive Care
  description: >-
    Management is symptomatic and individualized, coordinating developmental,
    nutritional, gastrointestinal, cardiac, ophthalmologic, and
    infectious-disease care. Early cardiology assessment with echocardiography is
    recommended given the high prevalence of cardiac lesions.
  action_category: THERAPEUTIC
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  therapeutic_modality: OTHER
  evidence:
  - reference: PMID:30245513
    reference_title: "KAT6A Syndrome: genotype-phenotype correlation in 76 patients with pathogenic KAT6A variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The prevalence of cardiac lesions highlights the need for early cardiology
      assessment.
    explanation: >-
      The cohort recommends early cardiology assessment as part of
      individualized multidisciplinary care.
  target_phenotypes:
  - preferred_term: Abnormal heart morphology
    term:
      id: HP:0001627
      label: Abnormal heart morphology
- name: Speech and Language Therapy
  description: >-
    Speech and language therapy, augmented by sign language and communication
    aids, addresses the very frequent expressive speech delay and speech-motor
    impairment.
  action_category: THERAPEUTIC
  treatment_term:
    preferred_term: speech therapy
    term:
      id: NCIT:C159273
      label: Speech Language Therapy
  therapeutic_modality: BEHAVIORAL
  evidence:
  - reference: PMID:30245513
    reference_title: "KAT6A Syndrome: genotype-phenotype correlation in 76 patients with pathogenic KAT6A variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Use of sign language and communication aids are helpful."
    explanation: >-
      The cohort supports communication-focused intervention for the
      characteristic expressive speech delay.
  target_phenotypes:
  - preferred_term: Delayed speech and language development
    term:
      id: HP:0000750
      label: Delayed speech and language development
- name: Cardiac Surgical or Catheter Intervention
  description: >-
    A substantial proportion of patients with cardiac malformations require
    intervention by open-heart surgery or cardiac catheterization.
  action_category: THERAPEUTIC
  treatment_term:
    preferred_term: septal defect repair
    term:
      id: NCIT:C148075
      label: Septal Defect Repair
  therapeutic_modality: SURGERY
  evidence:
  - reference: PMID:30245513
    reference_title: "KAT6A Syndrome: genotype-phenotype correlation in 76 patients with pathogenic KAT6A variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      At least 45% of patients with cardiac malformations required intervention
      (open heart surgery or via cardiac catheterization).
    explanation: >-
      The cohort documents cardiac intervention in at least 45% of patients with
      cardiac malformations.
  target_phenotypes:
  - preferred_term: Atrial septal defect
    term:
      id: HP:0001631
      label: Atrial septal defect
- name: Pantothenate and L-Carnitine Supplementation
  description: >-
    An experimental, preclinical intervention. In patient-derived fibroblast
    models of KAT6A syndrome, pantothenate plus L-carnitine increased histone
    acetylation, partially corrected protein and transcriptomic expression
    patterns, and improved cell bioenergetics. This is in vitro evidence only
    and has not been evaluated as a clinical therapy.
  action_category: THERAPEUTIC
  treatment_term:
    preferred_term: nutritional supplementation
    term:
      id: NCIT:C15433
      label: Nutritional Support
    therapeutic_agent:
    - preferred_term: pantothenate
      term:
        id: CHEBI:16454
        label: pantothenate
    - preferred_term: L-carnitine
      term:
        id: CHEBI:16347
        label: (R)-carnitine
  therapeutic_modality: SMALL_MOLECULE
  target_mechanisms:
  - target: Mitochondrial and Bioenergetic Dysfunction
    treatment_effect: RESTORES
    description: >-
      Pantothenate (a CoA precursor) and L-carnitine act as mitochondrial
      boosting agents that improve the impaired cell bioenergetics of
      KAT6A-mutant fibroblasts in vitro; this is the mechanistic rationale for
      the intervention.
    evidence:
    - reference: PMID:36553567
      reference_title: "Pantothenate and L-Carnitine Supplementation Improves Pathological Alterations in Cellular Models of KAT6A Syndrome."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "the cell bioenergetics of mutant cells was significantly improved"
      explanation: >-
        The patient-fibroblast experiment directly supports restoration of the
        nominated bioenergetic mechanism, but not clinical benefit.
  evidence:
  - reference: PMID:36553567
    reference_title: "Pantothenate and L-Carnitine Supplementation Improves Pathological Alterations in Cellular Models of KAT6A Syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Pantothenate and L-carnitine treatment increased histone acetylation and
      partially corrected protein and transcriptomic expression patterns in
      mutant KAT6A cells.
    explanation: >-
      Patient-derived fibroblast models show that pantothenate and L-carnitine
      partially correct KAT6A-associated cellular abnormalities, an experimental
      preclinical lead.
- name: Acetyl-L-Carnitine
  description: >-
    An experimental mouse intervention, not an established treatment for people
    with Arboleda-Tham syndrome. Acetyl-L-carnitine restored H3K23 acetylation
    and improved selected behavioral measures in Kat6a-haploinsufficient mice;
    efficacy, safety, dose, developmental timing, and variant dependence remain
    untested clinically.
  action_category: THERAPEUTIC
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: acetyl-L-carnitine
      term:
        id: CHEBI:57589
        label: O-acetyl-L-carnitine
  therapeutic_modality: SMALL_MOLECULE
  target_mechanisms:
  - target: Dysregulated Histone H3 Acetylation
    treatment_effect: RESTORES
    description: >-
      Acetyl-L-carnitine serves as an acetyl donor and restored brain H3K23
      acetylation in a Kat6a-haploinsufficient mouse model.
    evidence:
    - reference: PMID:41702672
      reference_title: Acetyl-carnitine improves hyperactivity and learning deficits in KAT6A haploinsufficient mice.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Treatment with the acetyl-donor, acetyl-L-carnitine (ALCAR) resulted in
        the rescue of H3K23ac levels in mouse brain and amelioration of the
        hyperactivity and learning impairments.
      explanation: >-
        The mouse experiment directly supports restoration of the nominated
        chromatin mark and selected behavioral outcomes, not human efficacy.
  evidence:
  - reference: PMID:41702672
    reference_title: Acetyl-carnitine improves hyperactivity and learning deficits in KAT6A haploinsufficient mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Treatment with the acetyl-donor, acetyl-L-carnitine (ALCAR) resulted in
      the rescue of H3K23ac levels in mouse brain and amelioration of the
      hyperactivity and learning impairments.
    explanation: >-
      This is preclinical rescue in Kat6a-haploinsufficient mice and is not
      evidence of efficacy in affected people.

discussions:
- discussion_id: gap_kat6a_preclinical_translation
  prompt: >-
    Do the neural-progenitor, hippocampal RSPO2-Wnt, and histone-acetylation
    abnormalities found in Kat6a mouse models reproduce human neural pathology,
    and can acetyl-L-carnitine safely improve clinically meaningful outcomes?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Impaired Neural Progenitor Proliferation and Differentiation
  - pathophysiology#KAT6A-RSPO2-Wnt Hippocampal Signaling Deficit
  - treatments#Acetyl-L-Carnitine
  rationale: >-
    The mechanistic and intervention results are from mouse neural cells or
    whole animals. Patient fibroblasts establish chromatin abnormalities but do
    not validate the neural circuit mechanisms, clinical endpoints, dose, or
    variant-specific treatment response in people.
  evidence:
  - reference: PMID:41702672
    reference_title: Acetyl-carnitine improves hyperactivity and learning deficits in KAT6A haploinsufficient mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Treatment with the acetyl-donor, acetyl-L-carnitine (ALCAR) resulted in
      the rescue of H3K23ac levels in mouse brain and amelioration of the
      hyperactivity and learning impairments.
    explanation: >-
      Mouse rescue motivates translation but cannot establish human benefit.
- discussion_id: gap_kat6a_hematologic_natural_history
  prompt: >-
    What are the incidence, age-specific natural history, predictors, and
    evidence-based surveillance thresholds for neutropenia, marrow failure, and
    other hematologic abnormalities in Arboleda-Tham syndrome?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - phenotypes#Neutropenia
  - phenotypes#Aplastic Anemia
  rationale: >-
    The first quantified cohort reports a broad severity range in only three
    affected participants. It does not define longitudinal risk or justify a
    uniform blood-count schedule or intervention threshold.
  evidence:
  - reference: PMID:42040242
    reference_title: "Expanding the Clinical Spectrum of Arboleda-Tham Syndrome: Neuroimaging Findings and Hematologic Manifestations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Notably, 3 of 11 patients (27%) exhibited hematologic abnormalities,
      ranging from transient neonatal neutropenia to severe aplastic anemia
      requiring hematopoietic stem cell transplantation.
    explanation: >-
      This small retrospective denominator establishes the signal while leaving
      prevalence, trajectory, predictors, and surveillance unresolved.
- discussion_id: gap_kat6a_recurrent_infection_mechanism
  prompt: >-
    Do recurrent infections in Arboleda-Tham syndrome reflect a primary
    KAT6A-dependent immune defect, secondary or structural factors, or ordinary
    childhood infection rates?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - phenotypes#Recurrent Infections
  rationale: >-
    The largest cohort explicitly cautions that the common childhood infections
    reported by a subset of patients are not necessarily indicative of
    immunodysfunction, while isolated patients had hypogammaglobulinemia,
    unusual infections, or structural predispositions. Mouse studies show
    KAT6A-dependent memory B-cell formation and CD8 T-cell responses, but no
    human immunophenotyping study has tested that bridge, so no causal edge is
    asserted for this phenotype.
  evidence:
  - reference: PMID:30245513
    reference_title: "KAT6A Syndrome: genotype-phenotype correlation in 76 patients with pathogenic KAT6A variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Many children experience recurrent infections of these types, so this is
      not necessarily indicative of immunodysfunction.
    explanation: >-
      The cohort's own caution is the reason the infection phenotype is left
      without a mechanistic edge.
  - reference: PMID:30245513
    reference_title: "KAT6A Syndrome: genotype-phenotype correlation in 76 patients with pathogenic KAT6A variants."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Further studies demonstrated that KAT6A-mediated acetylation promotes
      memory B-cell formation and the CD8 T-cell response to viral infection
    explanation: >-
      Mouse immunology supplies a candidate mechanism that human studies have
      not yet tested.
- discussion_id: gap_kat6a_neuroanatomic_findings_mechanism
  prompt: >-
    What developmental mechanism produces type 1 Chiari malformation and
    cerebral white-matter hyperintensities in Arboleda-Tham syndrome, and are
    these neuroimaging findings KAT6A-specific or coincidental?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - phenotypes#Chiari Malformation
  - phenotypes#Cerebral White Matter Hyperintensities
  rationale: >-
    Both findings come from a small retrospective imaging denominator (2 of 10
    imaged patients, reported jointly) with a single corroborating Chiari case
    in the earlier 76-person cohort, where major structural brain anomalies were
    described as rare. No study links these findings to KAT6A-dependent
    skull-base, hindbrain, or white-matter development, so no causal edge is
    asserted for either phenotype.
  evidence:
  - reference: PMID:42040242
    reference_title: "Expanding the Clinical Spectrum of Arboleda-Tham Syndrome: Neuroimaging Findings and Hematologic Manifestations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Brain imaging revealed type 1 Chiari malformation and white matter
      hyperintensities in 2 of the 10 assessed (20%), suggesting a broader
      neuroanatomic involvement.
    explanation: >-
      The observation is quantified but mechanistically unexplained, so it is
      recorded as a knowledge gap rather than a manufactured causal edge.

- discussion_id: kat6a_truncation_position_mechanism_controversy
  prompt: >-
    Do late-truncating KAT6A alleles that escape nonsense-mediated decay act through a
    dysfunctional protein with gain-of-function or dominant-negative activity, or is
    Arboleda-Tham syndrome a haploinsufficiency disorder across the whole allelic series
    with position effects explained by residual dosage?
  kind: CONTROVERSY
  status: OPEN
  attaches_to:
  - pathophysiology#Heterozygous KAT6A Pathogenic Variation
  - pathophysiology#NMD-Mediated KAT6A Haploinsufficiency
  - pathophysiology#NMD-Escaping Dysfunctional KAT6A Protein
  - mechanistic_hypotheses#early_truncating_nmd_haploinsufficiency
  - mechanistic_hypotheses#late_truncating_nmd_escape
  posed_by: claude-code
  posed_date: "2026-09-05T00:00:00Z"
  rationale: >-
    The genotype-phenotype correlation (late truncations more severe) and patient-cell
    multi-omics showing HOXC derepression point toward an active truncated protein,
    while the earliest truncations behave as nulls and a heterozygous Kat6a null mouse
    reproduces core behavioural features. Neither truncated protein in patient cells nor
    a same-background comparison of early, late and null alleles has been published, so
    the variant's functional_impact_category is UNKNOWN and the two hypotheses are kept
    as separate branches.
  evidence:
  - reference: PMID:41702672
    reference_title: "Acetyl-carnitine improves hyperactivity and learning deficits in KAT6A haploinsufficient mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "very early truncations, which are likely to represent complete loss of function of one allele"
    explanation: >-
      The haploinsufficient-mouse study assigns the earliest human truncations to a
      null-like class, the loss-of-function pole of the controversy.
  - reference: PMID:37861717
    reference_title: "KAT6A mutations in Arboleda-Tham syndrome drive epigenetic regulation of posterior HOXC cluster."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "our study suggests that KAT6A truncating mutations may have some abnormal, potentially gain-of-function effects causing upregulation of specific HOX genes and clusters."
    explanation: >-
      Patient-cell multi-omics raises a gain-of-function reading for truncating alleles,
      the opposite pole.
  - reference: PMID:37861717
    reference_title: "KAT6A mutations in Arboleda-Tham syndrome drive epigenetic regulation of posterior HOXC cluster."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "However, this molecular role requires additional study to demonstrate definitive proof of the gain-of-function effects in model systems."
    explanation: >-
      The same authors mark the gain-of-function reading as undemonstrated, which is why
      the category stays UNKNOWN.
  proposed_experiments:
  - experiment_id: exp_arths_truncation_position_isogenic_panel
    name: Truncated-KAT6A protein detection and early- versus late-truncation isogenic comparison
    description: >-
      Test for truncated KAT6A protein in patient lymphoblastoid or fibroblast lines
      carrying early (exon 1-15) and late (exon 16-17) truncations by N-terminal
      immunoblot and targeted proteomics, with and without nonsense-mediated-decay
      inhibition. Then derive isogenic human iPSC lines carrying a representative early
      truncation, a representative late truncation, a heterozygous KAT6A null, and a
      corrected control; differentiate to neural progenitors; and compare H3K9/H3K23
      acetylation, posterior HOXC cluster expression, and neural-progenitor
      proliferation, with wild-type add-back and mutant-selective knockdown arms.
    experiment_type:
      preferred_term: Patient-cell proteomics plus isogenic iPSC allelic series stratified by truncation position
    decision_criterion: >-
      The late-truncation branch is dominant or gain of function if truncated protein is
      detected for late but not early alleles and the late knock-in line diverges from
      the null on HOXC and acetylation readouts in a way that mutant-selective knockdown
      corrects; both branches are loss of function if early, late and null lines match
      and wild-type add-back rescues each.
    would_support:
    - mechanistic_hypotheses#late_truncating_nmd_escape
    - mechanistic_hypotheses#early_truncating_nmd_haploinsufficiency
    would_refute:
    - mechanistic_hypotheses#early_truncating_nmd_haploinsufficiency
    - mechanistic_hypotheses#late_truncating_nmd_escape
    supporting_outcome:
    - >-
      Late alleles express truncated protein and behave differently from the null with
      mutant-selective rescue: the entry should carry two contexts, LOSS_OF_FUNCTION for
      early and GAIN_OF_FUNCTION or DOMINANT_NEGATIVE for late truncations.
    refuting_outcome:
    - >-
      No truncated protein for either class and all mutant lines match the null: a
      single LOSS_OF_FUNCTION context covers the allelic series.
review_notes: >-
  Publication-readiness review completed through 2026-08-05. No population-based
  prevalence or incidence estimate, disease-specific clinical trial, controlled
  treatment study, formal practice guideline, or established disease-modifying
  therapy was found. Adult natural history, life expectancy, quality of life,
  hematologic surveillance, and variant-specific prognosis remain sparse. The
  quantified Chiari-malformation and cerebral-white-matter observations are
  represented as emerging phenotypes; the single radioulnar-synostosis
  observation was not promoted. The D2P audit produced 117 suggestions/issues;
  high-value current evidence was incorporated, while small-series source-only
  dysmorphology, narrow duplicates of represented phenotypes, and unsupported
  causal links were explicitly deferred. Unlinked phenotypes were not given
  speculative pathograph edges merely to raise connectivity. ClinicalTrials.gov
  returned no disease-specific study for the exact disorder query, and no
  KAT6A-specific GeneReviews chapter was found.
datasets:
- accession: geo:GSE210484
  title: DNA methylation profiling of Arboleda-Tham syndrome in primary human fibroblasts
  description: Arboleda-Tham Syndrome is a rare disease caused by de novo mutations in the KAT6A gene. Epigenetic changes to the genome resulting from pathogenic mutations were investigated by DNAme profiling.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: METHYLATION
  sample_count: 25
  publication: PMID:36064314
  notes: Identified by GEO DataSets index search for Arboleda-Tham Syndrome (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.
- accession: geo:GSE237022
  title: KAT6A mutations in Arboleda-Tham syndrome affect regulation and expression of HOXC genes [RNA-seq]
  description: Arboleda-Tham Syndrome (ARTHS) is a rare genetic disorder caused by heterozygous, de novo truncating mutations in the gene KAT6A (Lysine(K) acetyltransferase 6A). ARTHS is clinically heterogeneous but characterized by several common features including intellectual disability, developmental and speech delay, hypotonia, congenital heart defects and gastrointestinal problems. KAT6A mRNA is highly expressed throughout early development and the levels of expression are lower levels in differentiated tissues, suggesting a key role maintenance of the stem cell characteristics.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: BULK_RNA_SEQ
  sample_count: 15
  notes: Identified by GEO DataSets index search for Arboleda-Tham Syndrome (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.
- accession: geo:GSE237021
  title: KAT6A mutations in Arboleda-Tham syndrome affect regulation and expression of HOXC genes [ChIP-seq]
  description: Arboleda-Tham Syndrome (ARTHS) is a rare genetic disorder caused by heterozygous, de novo truncating mutations in the gene KAT6A (Lysine(K) acetyltransferase 6A). ARTHS is clinically heterogeneous but characterized by several common features including intellectual disability, developmental and speech delay, hypotonia, congenital heart defects and gastrointestinal problems. KAT6A mRNA is highly expressed throughout early development and the levels of expression are lower levels in differentiated tissues, suggesting a key role maintenance of the stem cell characteristics.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: CHIP_SEQ
  sample_count: 14
  notes: Identified by GEO DataSets index search for Arboleda-Tham Syndrome (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.
📚

References & Deep Research

References

13
PMID:25728775
De novo nonsense mutations in KAT6A, a lysine acetyl-transferase gene, cause a syndrome including microcephaly and global developmental delay.
No top-level findings curated for this source.
PMID:25728777
Dominant mutations in KAT6A cause intellectual disability with recognizable syndromic features.
No top-level findings curated for this source.
PMID:30245513
KAT6A Syndrome: genotype-phenotype correlation in 76 patients with pathogenic KAT6A variants.
No top-level findings curated for this source.
PMID:38741077
Neuropsychological profile associated with KAT6A syndrome: Emergent genotype-phenotype trends.
No top-level findings curated for this source.
PMID:38758792
KAT6A deficiency impairs cognitive functions through suppressing RSPO2/Wnt signaling in hippocampal CA3.
No top-level findings curated for this source.
PMID:36553567
Pantothenate and L-Carnitine Supplementation Improves Pathological Alterations in Cellular Models of KAT6A Syndrome.
No top-level findings curated for this source.
PMID:35892268
Speech and language development and genotype-phenotype correlation in 49 individuals with KAT6A syndrome.
No top-level findings curated for this source.
PMID:37249002
DNA methylation episignatures are sensitive and specific biomarkers for detection of patients with KAT6A/KAT6B variants.
No top-level findings curated for this source.
PMID:37861717
KAT6A mutations in Arboleda-Tham syndrome drive epigenetic regulation of posterior HOXC cluster.
No top-level findings curated for this source.
PMID:39740728
Phenotypic variability in a family with an inherited KAT6A frameshift variant.
No top-level findings curated for this source.
PMID:41702672
Acetyl-carnitine improves hyperactivity and learning deficits in KAT6A haploinsufficient mice.
No top-level findings curated for this source.
PMID:42040242
Expanding the Clinical Spectrum of Arboleda-Tham Syndrome: Neuroimaging Findings and Hematologic Manifestations.
No top-level findings curated for this source.
PMID:42081590
KAT6A is essential for developmental control gene expression in neural stem and progenitor cells.
No top-level findings curated for this source.

Deep Research

1

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

Evaluations and curation notes (3)

Edit: Arboleda-Tham Syndrome - promote assessed provider findings · 2026-09-07T18:57:30Z · View source

Screened the entry's contested-mechanism hypothesis with the OpenScientist hypothesis deep-research runner, assessed the report into kb/hypotheses/<disease>/<hypothesis_id>/assessments/, and promoted only claims that survived that review. Bohring-Opitz gained three references: direct protein-level detection of truncated ASXL1 and sufficiency of a truncated fragment for neural-crest defects on the dominant/gain side, and constitutive Asxl1 deletion reproducing BOS-like malformations on the loss side, with the controversy rationale widened accordingly. Arboleda-Tham gained no new evidence; its late-truncating hypothesis was reframed as a severity modifier layered on a haploinsufficiency baseline rather than a competing primary mechanism. ADNP gained two items from one paper, mutant mRNA detected in patient blood supporting the branch premise and a systematic failure to detect mutant protein in patient material recorded as REFUTE, with the hypothesis description amended so it no longer implies the question is merely unexamined. The variant functional_impact_category stays UNKNOWN in all three: no run performed the comparison that would settle it, and nothing from any provider computational analysis was promoted because every bundle omitted the manifest and code it claimed. Validated with linkml-validate, the reference snippet audit, term validation, and the snippet-grading, enum, duplicate-key, entity-ref, title-snippet and reference-title checks.

Enhance Arboleda-Tham Syndrome from falcon and red-team review · 2026-07-31T00:03:13Z · View source

Same-session enhancement after falcon (Edison) deep-research completed and a red-team pre-PR review. Falcon corroborated the primary-literature entry and added two verified leads: the KAT6A-RSPO2-Wnt hippocampal-CA3 cognitive mechanism (PMID:38758792 Liu 2024, mouse, added as an EMERGING mechanistic hypothesis plus a MODEL_ORGANISM pathophysiology node) and pantothenate + L-carnitine supplementation correcting cellular abnormalities in patient fibroblasts (PMID:36553567 Munuera-Cabeza 2022, added as an experimental IN_VITRO treatment). Red-team review fixes: replaced the Recurrent Infections evidence snippet with one that actually supports recurrent infections (kept neutropenia as PARTIAL secondary evidence); recalibrated Seizures and Craniosynostosis frequency from VERY_RARE to OCCASIONAL to match ~9 and ~8 percent of the 76-patient cohort. All new snippets verified as exact substrings of freshly fetched cached abstracts; DOIs resolved to real PMIDs via PubMed. just validate passes; compliance 99.2 percent.

Create Arboleda-Tham Syndrome (KAT6A) · 2026-07-30T23:53:39Z · View source

New KB entry for Arboleda-Tham syndrome / KAT6A syndrome (MONDO:0014558, gene KAT6A hgnc:13013). NEC preflight confirmed MONDO:0014558 maps to KAT6A/Arboleda-Tham (OMIM:616268), not CDK13. Deep research via falcon (Edison). Primary-literature baseline: the two founding AJHG 2015 papers (PMID:25728775 Arboleda, PMID:25728777 Tham), the 76-patient genotype-phenotype cohort (PMID:30245513 Kennedy 2019), and the KAT6A neuropsychological profile (PMID:38741077 Ng 2024). No dedicated KAT6A GeneReviews chapter exists. Curated a four-node pathophysiology chain (heterozygous KAT6A variant -> allele-dependent NMD -> dysregulated H3K9/H3K18 acetylation and altered p53 signaling -> altered developmental transcriptional programs) with early/late-truncating NMD hypothesis groups; 18 phenotypes with frequency bands and exact-quote evidence; KAT6A causative genetic block; supportive-care, speech-therapy, and cardiac-intervention treatments. All snippets verified as exact substrings of cached abstracts. Validated with just validate (schema+terms+references pass); compliance 99.1%.

Falcon ▸
Arboleda–Tham Syndrome (KAT6A Syndrome): Comprehensive Disease-Characteristics Report
Edison Scientific Literature 35 citations 2026-07-30T23:55:35.801042

Arboleda–Tham Syndrome (KAT6A Syndrome): Comprehensive Disease-Characteristics Report

Executive summary

Arboleda–Tham syndrome (ARTHS), more commonly called KAT6A syndrome, is a rare autosomal-dominant Mendelian chromatinopathy caused by heterozygous pathogenic variants in KAT6A, a lysine acetyltransferase and transcriptional regulator. The defining phenotype is congenital or early-childhood neurodevelopmental impairment—particularly severe expressive speech delay—with variable hypotonia, feeding and gastrointestinal dysfunction, characteristic craniofacial features, eye abnormalities, congenital heart disease, microcephaly, growth impairment, sleep disturbance, behavioral differences, and occasional seizures. Most affected individuals have a de novo protein-truncating variant; late truncations in exons 16–17 tend to produce a more severe phenotype than earlier truncations. The best available cohort contained 76 individuals aged 1–32 years, so population prevalence, adult natural history, life expectancy, and formal quality-of-life outcomes remain poorly defined. (kennedy2019kat6asyndromegenotype–phenotype pages 8-9, kennedy2019kat6asyndromegenotype–phenotype pages 1-2)

The strongest recent mechanistic advance is a 2024 mouse study identifying a KAT6A→RSPO2→Wnt/β-catenin pathway in hippocampal CA3 pyramidal neurons. Kat6a deficiency reduced CA3 synaptic structure and plasticity and impaired memory; AAV-mediated restoration of RSPO2 substantially rescued the molecular, synaptic, and behavioral deficits. This is important proof of biological reversibility but not yet a human treatment. (liu2024kat6adeficiencyimpairs pages 8-9, liu2024kat6adeficiencyimpairs pages 1-2)

The following compact table summarizes high-yield knowledge-base annotations; ontology mappings are suggestions and should be validated against the release used by the target database.

domain evidence-backed finding suggested ontology identifiers/terms evidence type/strength
disease entity Arboleda-Tham syndrome / KAT6A syndrome; Mendelian chromatinopathy / neurodevelopmental disorder caused by pathogenic KAT6A variants; disease-level resource also represented as “autosomal dominant intellectual disability-craniofacial anomalies-cardiac defects syndrome” (bae2021identificationofa pages 1-2, arboleda2015denovononsense pages 1-2, OpenTargets Search: Arboleda-Tham syndrome-KAT6A) Suggested: MONDO:0014558; OMIM/MIM: 616268; category: Mendelian disorder Strong: discovery paper + curated disease-target resource + later case series/cohort
causal gene Causal gene is KAT6A (aka MOZ, MYST3), encoding lysine acetyltransferase 6A; gene MIM 601408 (bae2021identificationofa pages 1-2, munueracabeza2022pantothenateandlcarnitine pages 1-2, arboleda2015denovononsense pages 1-2) Suggested: HGNC gene KAT6A; OMIM/MIM: 601408 Strong: multiple human genetic studies
inheritance Predominantly autosomal dominant, usually de novo heterozygous variants; one maternally inherited missense/VUS-like situation reported in cohort work, supporting variable expressivity for some missense alleles (bae2021identificationofa pages 1-2, lin2020diagnosisofarboledatham pages 3-4, kennedy2019kat6asyndromegenotype–phenotype pages 2-3, arboleda2015denovononsense pages 1-2) Suggested: HP:0000006 Autosomal dominant inheritance; HP:0025352 De novo constitutional mutation Strong for AD/de novo; moderate for broader penetrance/expressivity nuances
core neurodevelopment Global developmental delay / intellectual disability is essentially universal in compiled cohorts (100%); speech delay is especially prominent (99%) and often the most severe developmental domain (urreizti2020fivenewcases pages 7-8, kennedy2019kat6asyndromegenotype–phenotype pages 8-9, kennedy2019kat6asyndromegenotype–phenotype pages 6-7) Suggested: HP:0001263 Global developmental delay; HP:0001249 Intellectual disability; HP:0002463 Global developmental delay/variable severity; HP:0000750 Delayed speech and language development Strong: largest cohort + case series
feeding / GI phenotype Feeding difficulties in infancy are common (79%), often with reflux, constipation, and oromotor dysfunction; bowel malrotation/obstruction risk highlighted in management recommendations (urreizti2020fivenewcases pages 7-8, bae2021identificationofa pages 5-6, kennedy2019kat6asyndromegenotype–phenotype pages 6-7) Suggested: HP:0011968 Feeding difficulties; HP:0002020 Gastroesophageal reflux; HP:0002019 Constipation; MAXO suggested: feeding support / laxative therapy / GI surveillance Strong for feeding/constipation; moderate for obstruction risk
hypotonia Neonatal hypotonia reported in 74% and contributes to early motor delay and feeding issues (urreizti2020fivenewcases pages 7-8, lin2020diagnosisofarboledatham pages 3-4) Suggested: HP:0001290 Generalized hypotonia; HP:0008947 Infantile muscular hypotonia Strong: cohort-supported
craniofacial / ear phenotype Ear anomalies are frequent (83%); characteristic dysmorphism includes bulbous/prominent nose, thin upper lip, low-set ears, epicanthal folds, frontal bossing, long face/midface retrusion in some patients (urreizti2020fivenewcases pages 7-8, bae2021identificationofa pages 5-6, urreizti2020fivenewcases pages 6-7) Suggested: HP:0000357 Abnormality of the external ear; HP:0000369 Low-set ears; HP:0000426 Prominent nasal bridge; HP:0000219 Thin upper lip vermilion Moderate-strong: cohort + repeated case reports
ophthalmic phenotype Eye anomalies occur in 72%; strabismus/visual issues affect over half of the cohort and may risk amblyopia if untreated (urreizti2020fivenewcases pages 7-8, bae2021identificationofa pages 5-6, kennedy2019kat6asyndromegenotype–phenotype pages 6-7) Suggested: HP:0000478 Abnormality of the eye; HP:0000486 Strabismus; HP:0000505 Visual impairment; MAXO suggested: ophthalmology surveillance Strong for broad eye involvement; moderate for specific subfeatures
microcephaly Microcephaly reported in 36% overall; was a prominent feature in the original discovery series (urreizti2020fivenewcases pages 7-8, arboleda2015denovononsense pages 1-2) Suggested: HP:0000252 Microcephaly Strong
cardiac phenotype Congenital heart disease occurs in about 50%, commonly septal defects/PDA/PFO; about half of affected cardiac cases required surgical intervention in the large cohort (bae2021identificationofa pages 5-6, kennedy2019kat6asyndromegenotype–phenotype pages 6-7, lin2020diagnosisofarboledatham pages 3-4) Suggested: HP:0001627 Abnormality of the cardiovascular system; HP:0001631 Atrial septal defect; HP:0001643 Patent ductus arteriosus; MAXO suggested: echocardiography / cardiology evaluation / cardiac surgery Strong for frequency and need for baseline cardiac workup
seizures / sleep Seizures reported in 13% and sleep disturbance in 42% in compiled cohort data (urreizti2020fivenewcases pages 7-8) Suggested: HP:0001250 Seizure; HP:0002360 Sleep disturbance Moderate: cohort-supported but less deeply characterized
genotype spectrum Most variants are truncating; in 52 novel cases, 88% (39/44) were predicted truncating. Recurrent hotspot truncations occur at aa 1019, 1024, 1129; recurrent nonsense variants include p.Arg1024 and p.Arg1129 (kennedy2019kat6asyndromegenotype–phenotype pages 1-2, kennedy2019kat6asyndromegenotype–phenotype pages 2-3, arboleda2015denovononsense pages 1-2) Suggested: SO terms—nonsense_variant, frameshift_variant, splice_donor/acceptor_variant, missense_variant Strong
genotype-phenotype correlation Late-truncating variants in exons 16–17 associate with more severe ID/speech problems and more microcephaly, hypotonia, cardiac and GI complications; early truncating variants likely undergo NMD and may have fewer GI symptoms (bae2021identificationofa pages 1-2, bae2021identificationofa pages 5-6, kennedy2019kat6asyndromegenotype–phenotype pages 8-9, liu2024kat6adeficiencyimpairs pages 1-2) Suggested: exon 16/17 late-truncating subgroup annotation; mechanism note: escape from NMD vs haploinsufficiency Moderate-strong: cohort-based correlation, still mechanistically incomplete
primary anatomy Main affected systems are central nervous system, heart, gastrointestinal tract, eye, craniofacial structures, and growth pathways (bae2021identificationofa pages 1-2, kennedy2019kat6asyndromegenotype–phenotype pages 6-7, liu2024kat6adeficiencyimpairs pages 1-2, arboleda2015denovononsense pages 1-2) Suggested UBERON: brain, hippocampus, heart, gastrointestinal tract, eye, craniofacial skeleton Strong at organ-system level
cell types Experimental evidence points especially to hippocampal CA3 pyramidal excitatory neurons for cognitive mechanism; patient-derived dermal fibroblasts are established disease cell models (munueracabeza2022pantothenateandlcarnitine pages 1-2, liu2024kat6adeficiencyimpairs pages 8-9, liu2024kat6adeficiencyimpairs pages 1-2, arboleda2015denovononsense pages 6-7) Suggested CL terms: excitatory neuron, pyramidal neuron, fibroblast Strong for model systems; moderate for direct human tissue causality
subcellular / chromatin localization KAT6A is a chromatin-associated lysine acetyltransferase recruited to unmethylated CpG islands via an N-terminal winged-helix DNA-binding domain; affects histone acetylation including H3K9 and H3K23 contexts (weber2023thehistoneacetyltransferase pages 1-2, arboleda2015denovononsense pages 6-7) Suggested GO CC/BP: nucleus, chromatin, histone acetyltransferase complex, regulation of transcription by RNA polymerase II; histone marks: H3K9ac, H3K23ac/propionylation context Strong biochemistry/mechanism
core mechanism Best current mechanistic chain: KAT6A deficiency → reduced transcription of CA3-enriched RSPO2 → impaired Wnt/β-catenin signaling in hippocampal CA3 → reduced dendritic spine density / synaptic plasticity → hippocampus-dependent memory deficits (liu2024kat6adeficiencyimpairs pages 8-9, liu2024kat6adeficiencyimpairs pages 1-2) Suggested GO/BP: histone acetylation; positive regulation of Wnt signaling pathway; synaptic plasticity; learning or memory. Suggested pathway label: KAT6A–RSPO2–Wnt axis Strong preclinical evidence; not yet fully validated in humans
additional molecular abnormalities Patient fibroblasts show altered histone acetylation (decreased H3K9ac, increased H3K18ac in original work), altered p53-related expression, transcriptomic disruption, and mitochondrial/bioenergetic defects with reduced acetylation/deacetylation, CoA-metabolism and antioxidant proteins (munueracabeza2022pantothenateandlcarnitine pages 15-16, arboleda2015denovononsense pages 6-7) Suggested GO/BP: regulation of apoptotic process, cellular metabolism, mitochondrial function, oxidative stress response Moderate: human in vitro evidence from small numbers
diagnostics Diagnosis is primarily by WES/WGS, especially trio-based testing for de novo variants; WGS and WES both successfully diagnosed infants/children with syndromic developmental delay and dysmorphism (bae2021identificationofa pages 1-2, lin2020diagnosisofarboledatham pages 3-4, lin2020diagnosisofarboledatham pages 1-3, arboleda2015denovononsense pages 1-2) Suggested testing annotations: trio WES, trio WGS, Sanger confirmation; phenotype-driven genomic testing Strong
supportive management Current management is supportive and surveillance-based: early developmental assessment/intervention, speech-language therapy and communication aids/sign language, cardiology evaluation with ECG/echocardiogram, GI management for reflux/constipation/feeding issues, ophthalmology review, rehabilitation and serial developmental follow-up (bae2021identificationofa pages 5-6, bae2021identificationofa pages 6-7, kennedy2019kat6asyndromegenotype–phenotype pages 6-7) Suggested MAXO: developmental therapy, speech therapy, augmentative communication, cardiology assessment, ophthalmologic monitoring, GI symptom management, rehabilitation Moderate-strong: expert cohort recommendations rather than trials
experimental interventions No established disease-specific therapy retrieved. Preclinical/cellular candidates: pantothenate + L-carnitine improved histone acetylation, transcriptomic/protein abnormalities and bioenergetics in three patient fibroblast lines; RSPO2 restoration / Wnt enhancement rescued synaptic and behavioral phenotypes in mouse CA3 (munueracabeza2022pantothenateandlcarnitine pages 1-2, munueracabeza2022pantothenateandlcarnitine pages 15-16, liu2024kat6adeficiencyimpairs pages 8-9, liu2024kat6adeficiencyimpairs pages 1-2) Suggested CHEBI/MAXO notes: pantothenate supplementation, L-carnitine supplementation, AAV-mediated RSPO2 restoration, Wnt-pathway enhancement Weak-moderate for translation: preclinical only
model organisms Kat6a homozygous knockout mice are embryonic lethal with developmental/vascular-cardiac and hematopoietic defects; haploinsufficient and neuron-specific mouse models reproduce growth and cognitive phenotypes; AAV rescue supports reversibility of some neural deficits (munueracabeza2022pantothenateandlcarnitine pages 1-2, liu2024kat6adeficiencyimpairs pages 1-2, arboleda2015denovononsense pages 6-7) Suggested model annotations: mouse knockout, conditional neuronal knockout, AAV rescue model Strong for disease-mechanism modeling
epidemiology / demographics Largest cohort included 76 patients, age 1–32 years, sex roughly balanced (49% female, 51% male). True population prevalence/incidence remain undefined; one report estimated pathogenic KAT6A variants in ~1% of undiagnosed syndromic developmental delay referrals, which is not a population prevalence estimate (kennedy2019kat6asyndromegenotype–phenotype pages 1-2, bae2021identificationofa pages 5-6, arboleda2015denovononsense pages 1-2) Suggested epidemiology note: prevalence unknown; ascertainment from case reports/cohorts, not population registry Moderate for cohort demographics; weak for prevalence
evidence gaps Major gaps: no robust population prevalence/incidence, no disease-specific survival/life-expectancy data, sparse formal QoL studies, limited penetrance estimates, no validated biomarkers for monitoring, no established episignature data in retrieved full texts, no controlled treatment trials, and little evidence for environmental/protective factors or gene-environment interaction (kennedy2019kat6asyndromegenotype–phenotype pages 1-2, kennedy2019kat6asyndromegenotype–phenotype pages 6-7, kennedy2019kat6asyndromegenotype–phenotype pages 9-10) Suggested annotation: evidence gap / not established / not retrieved Strong confidence that these are current knowledge gaps based on gathered evidence

Table: This table compiles the highest-yield, evidence-backed annotations for Arboleda-Tham/KAT6A syndrome using only the information gathered in the preceding search. It is useful as a compact knowledge-base scaffold spanning identifiers, phenotype frequencies, mechanism, diagnostics, management, and evidence gaps.

1. Disease information

Definition and identifiers

  • Preferred names: Arboleda–Tham syndrome; KAT6A syndrome.
  • Alternative names: autosomal dominant intellectual disability–craniofacial anomalies–cardiac defects syndrome; autosomal dominant mental retardation 32; KAT6A-related neurodevelopmental disorder.
  • MONDO: MONDO:0014558, represented as autosomal dominant intellectual disability–craniofacial anomalies–cardiac defects syndrome.
  • OMIM phenotype: 616268.
  • Causal gene: KAT6A, OMIM gene 601408, also known as MOZ and MYST3; Ensembl target ENSG00000083168.
  • Chromosomal location: 8p11.21/8p11 region.
  • ICD-10/ICD-11 and MeSH: no syndrome-specific code or descriptor was established in the retrieved evidence. Coding generally must use broader congenital-malformation, intellectual-disability, or genetic-syndrome categories. (OpenTargets Search: Arboleda-Tham syndrome-KAT6A, bae2021identificationofa pages 1-2, lin2020diagnosisofarboledatham pages 3-4)

The syndrome was delineated in 2015 after clinical trio-exome sequencing identified de novo heterozygous nonsense variants in four unrelated families. The discovery abstract states: “Common features among all four probands include primary microcephaly, global developmental delay including profound speech delay, and craniofacial dysmorphism.” [Arboleda et al., published March 5, 2015; DOI: https://doi.org/10.1016/j.ajhg.2015.01.017]. (arboleda2015denovononsense pages 1-2)

Evidence provenance

The evidence is principally aggregated disease-level information derived from individually ascertained patients, including clinician reports, family surveys, case reports, exome/genome cohorts, and literature review. It is not based on a population registry or systematic extraction from longitudinal electronic health records. The largest study combined 52 new cases with previously published individuals for a total of 76. (kennedy2019kat6asyndromegenotype–phenotype pages 1-2)

2. Etiology

Causal and genetic risk factors

ARTHS is caused by a heterozygous constitutional pathogenic variant in KAT6A. Most reported variants are nonsense or frameshift alleles, although splice-site and selected missense variants have also been described. In the 2019 cohort, 39/44 novel variants (88%) were predicted truncating. Recurrent nonsense hotspots at amino-acid positions 1019, 1024, and 1129 accounted for 13/68 (19.1%) pathogenic variants among unrelated individuals. (kennedy2019kat6asyndromegenotype–phenotype pages 8-9, kennedy2019kat6asyndromegenotype–phenotype pages 2-3)

Examples include:

  • NM_006766.5:c.3385C>T, p.Arg1129Ter, recurrent in the discovery series;
  • c.3070C>T, p.Arg1024Ter;
  • NM_006766.5:c.3411del, p.Glu1139SerfsTer41, a de novo exon-17 variant associated with severe delay;
  • c.1312C>T, p.Arg438Ter, an early truncating variant expected to undergo nonsense-mediated decay;
  • c.3427_3428insTA, p.Ser1143LeufsTer5;
  • c.1075G>A, p.Gly359Ser, which experimentally altered splicing rather than acting solely as a missense allele. (bae2021identificationofa pages 1-2, lin2020diagnosisofarboledatham pages 3-4, urreizti2020fivenewcases pages 7-8, arboleda2015denovononsense pages 1-2)

Pathogenic constitutional variants are expected to be absent or extremely rare from population databases because of strong functional constraint and severe early-onset effects. Exact gnomAD/TOPMed frequencies were not available in the retrieved texts and should be obtained variant-by-variant rather than inferred.

Environmental, infectious, and lifestyle risk factors

No toxin, infection, radiation, diet, smoking, alcohol, occupation, or other lifestyle exposure is known to cause ARTHS. It is not infectious or environmentally acquired. Phenotypic variability may reflect genetic background, epigenetic state, development, clinical ascertainment, and possibly environment, but no reproducible gene–environment interaction has been demonstrated. The 2019 cohort explicitly considered background genetic variation and environmental factors plausible contributors to expressivity, not established causal exposures. (kennedy2019kat6asyndromegenotype–phenotype pages 9-10, arboleda2015denovononsense pages 6-7)

Protective factors and modifiers

No validated protective allele, modifier gene, diet, or exposure is known. KAT6B may provide partial biochemical redundancy in some tissues, but this is mechanistic inference rather than a clinically established modifier. Pantothenate and L-carnitine improved cellular abnormalities in vitro; they have not been shown to prevent disease or improve outcomes in patients. (munueracabeza2022pantothenateandlcarnitine pages 1-2, liu2024kat6adeficiencyimpairs pages 8-9)

3. Phenotypes

The most reusable frequencies come from the 76-person cohort and the subsequent synthesis of approximately 80 reported cases. Denominators vary because not every feature was assessed in every patient; percentages should therefore be stored with study provenance rather than treated as population penetrance. (urreizti2020fivenewcases pages 7-8, kennedy2019kat6asyndromegenotype–phenotype pages 1-2)

Phenotype Frequency/current characterization Onset/course and functional impact Suggested HPO term
Global developmental delay/intellectual disability Approximately 100%; severity variable Infancy/early childhood; chronic and lifelong; affects learning, independence, and adaptive function HP:0001263; HP:0001249
Speech/language delay Approximately 99%; expressive speech disproportionately severe May become clearer after infancy; often persistent and a major participation barrier HP:0000750; consider childhood apraxia/motor-speech annotation when formally diagnosed
Neonatal/infantile hypotonia Approximately 74% Early onset; may worsen feeding and motor milestone acquisition HP:0001290 / HP:0008947
Feeding difficulty Approximately 79% Usually infancy; oromotor dysfunction, reflux, and poor growth may require tube feeding HP:0011968
Gastroesophageal reflux/constipation Common, exact denominator variable Usually chronic or recurrent; constipation may require long-term treatment HP:0002020; HP:0002019
Congenital heart disease About 50%; septal defects and PDA/PFO common Congenital and generally structurally stable after treatment; about half of cardiac cases required surgery HP:0001627; HP:0001631; HP:0001643
Eye abnormalities About 72%; strabismus/visual problems in over half Childhood; untreated strabismus can lead to permanent amblyopia HP:0000478; HP:0000486; HP:0000505
External-ear anomalies About 83% Congenital, usually nonprogressive HP:0000357; HP:0000369
Microcephaly About 36% overall Congenital or postnatal; severity variable HP:0000252
Characteristic face Broad/bulbous nasal tip or prominent bridge, thin/tented upper lip, low-set ears, epicanthi, short philtrum, frontal bossing or midface retrusion Congenital; facial gestalt may evolve with age HP:0000426; HP:0000219; HP:0000286
Sleep disturbance About 42% Childhood; potentially chronic/fluctuating and burdensome to families HP:0002360
Seizures About 13% Variable onset and type; not a universal defining feature HP:0001250
Behavioral/autistic features Autism reported at approximately 25% in one synthesis; stereotypies and other behavioral differences vary Childhood; effects on education and social function vary HP:0000729; HP:0000717
Skeletal abnormalities Scoliosis, kyphosis, torticollis, syndactyly, pes planus, genu valgum; craniosynostosis around 10% in one synthesis Congenital or developing with growth; may affect mobility or require surgery Feature-specific HPO terms
Genitourinary findings Cryptorchidism in some males; inguinal hernia reported Congenital HP:0000028; HP:0000023
Recurrent infections Reported in case series, frequency uncertain Episodic; immune mechanism not established HP:0002719

These estimates are supported by the five-case/literature synthesis reporting developmental delay/ID 100%, speech delay 99%, feeding difficulty 79%, neonatal hypotonia 74%, ear anomalies 83%, eye anomalies 72%, microcephaly 36%, seizures 13%, and sleep disturbance 42%. (urreizti2020fivenewcases pages 7-8) Congenital heart disease occurs in approximately half, and feeding difficulties were estimated at 78.7% in another review. (bae2021identificationofa pages 5-6, kennedy2019kat6asyndromegenotype–phenotype pages 6-7)

Quality of life

No validated ARTHS-specific EQ-5D, SF-36, PROMIS, or caregiver-burden dataset was identified. The major inferred burdens are impaired communication, intellectual and adaptive limitations, feeding support, constipation, visual disability, sleep disruption, mobility problems, and repeated specialty care. Communication aids and early speech therapy are therefore clinically important even in the absence of controlled quality-of-life trials. (bae2021identificationofa pages 6-7, kennedy2019kat6asyndromegenotype–phenotype pages 6-7)

4. Genetic and molecular information

Gene and protein

KAT6A encodes a roughly 250-kDa MYST-family lysine acetyltransferase. Important regions include an N-terminal NEMM/winged-helix region, a double PHD finger, the catalytic histone-acetyltransferase domain, and long acidic and serine/methionine-rich C-terminal regions. KAT6A operates in multiprotein chromatin complexes with BRPF-family scaffolds, ING4/ING5, and MEAF6/EAF6-associated components. It modifies histone and non-histone substrates, including p53. (arboleda2015denovononsense pages 6-7, weber2023thehistoneacetyltransferase pages 1-2)

Variant classes and consequences

  • Early truncating variants, exons 1–15: commonly expected to trigger nonsense-mediated mRNA decay and produce haploinsufficiency.
  • Late truncating variants, exons 16–17: may escape nonsense-mediated decay, leaving truncated proteins with altered C-terminal regulatory functions. The cohort association with greater severity raises dominant-negative or altered-function possibilities, but these mechanisms are not fully proven in patients.
  • Canonical splice variants: pathogenic when demonstrated to disrupt splicing.
  • Missense variants: require cautious evaluation. De novo status, absence from population databases, domain/residue conservation, phenotype concordance, functional evidence, and an ARTHS-compatible methylation signature can strengthen classification. A maternally inherited p.Ser371Tyr allele was classified as a VUS in the 2019 study. (kennedy2019kat6asyndromegenotype–phenotype pages 8-9, kennedy2019kat6asyndromegenotype–phenotype pages 2-3, liu2024kat6adeficiencyimpairs pages 1-2)

Variants causing the developmental syndrome are germline/constitutional, not somatic. Somatic KAT6A rearrangements or fusions are relevant to leukemia but are a separate disease mechanism and should not be conflated with ARTHS.

Genotype–phenotype relationship

Late truncations in exons 16–17 correlate with more severe intellectual disability, speech impairment, microcephaly, neonatal hypotonia, cardiac anomalies, and gastrointestinal complications. Early truncations may have fewer gastrointestinal manifestations. This is a group-level association, not a deterministic prognostic rule. (bae2021identificationofa pages 1-2, bae2021identificationofa pages 5-6, kennedy2019kat6asyndromegenotype–phenotype pages 8-9)

Epigenetics and chromosomal abnormalities

The syndrome is itself an epigenetic-regulator disorder. Patient fibroblasts showed reduced H3K9 acetylation and increased H3K18 acetylation in the original study, with altered p53-pathway expression. A later cellular study also found reduced histone-H3 acetylation, broad transcriptomic disturbance, and mitochondrial/bioenergetic abnormalities. (munueracabeza2022pantothenateandlcarnitine pages 15-16, arboleda2015denovononsense pages 6-7)

A 2023 publication reported sensitive and specific blood DNA-methylation episignatures for KAT6A/KAT6B variants, suggesting a future adjunct for VUS interpretation; however, the full study was not retrievable in this search, so assay performance should be verified directly before database entry or clinical use [Vos et al., Epigenomics, May 2023; DOI: https://doi.org/10.2217/epi-2023-0079].

No recurrent pathogenic aneuploidy, translocation, inversion, or syndrome-defining copy-number alteration is established as the usual cause. Deletions disrupting KAT6A could theoretically cause haploinsufficiency, but larger 8p alterations may produce blended phenotypes.

5. Environmental information

No environmental toxin, radiation exposure, pollutant, occupational factor, lifestyle behavior, or infectious agent is known to initiate ARTHS. Standard healthy diet, activity, vaccination, and avoidance of tobacco exposure remain appropriate general health measures but are not disease-specific prevention. Nutrient-dependent acetyl-CoA and mitochondrial biology may influence cellular acetylation, yet no clinical evidence establishes diet as a modifier of penetrance or severity. (munueracabeza2022pantothenateandlcarnitine pages 1-2, munueracabeza2022pantothenateandlcarnitine pages 15-16)

6. Mechanism and pathophysiology

Upstream molecular lesion

A pathogenic KAT6A allele reduces the amount of functional enzyme or yields a C-terminally truncated dysfunctional protein. KAT6A normally binds chromatin and catalyzes lysine acetylation, helping establish transcriptionally competent chromatin. A 2023 biochemical study showed that an N-terminal winged-helix domain directly recognizes unmethylated CpG motifs and recruits KAT6A to CpG islands genome-wide. Mutating essential DNA-binding residues abolished CpG-island enrichment; a winged-helix mutant also exerted a dominant-negative effect on H3K9 acetylation. (weber2023thehistoneacetyltransferase pages 1-2)

Downstream chromatin and cellular effects

The original patient-fibroblast study found altered H3K9/H3K18 acetylation and differential expression of 30 p53-pathway genes, enriched for apoptosis, transcriptional regulation, and metabolism. The authors concluded that KAT6A variants alter global acetylation and p53-mediated pathways. (arboleda2015denovononsense pages 6-7)

Fibroblasts from three patients subsequently showed reduced H3 acetylation and reduced proteins involved in acetylation/deacetylation, CoA metabolism, mitochondrial function, and antioxidant defense, including SIRT1, SIRT3, NAMPT, PANK2, mitochondrial respiratory-chain proteins, SOD1/SOD2, and GPX4. These findings support secondary mitochondrial and redox dysfunction, but fibroblasts are a surrogate model and do not establish that every abnormality occurs in human neurons or heart tissue. (munueracabeza2022pantothenateandlcarnitine pages 1-2, munueracabeza2022pantothenateandlcarnitine pages 15-16)

KAT6A–RSPO2–Wnt causal chain in the brain

The best-defined neural mechanism is:

KAT6A haploinsufficiency → reduced H3K23 acetylation at the Rspo2 promoter and reduced Rspo2 transcription → diminished RSPO2-dependent canonical Wnt/β-catenin signaling → reduced dendritic-spine density, excitatory transmission, and long-term potentiation in CA3 pyramidal neurons → impaired hippocampus-dependent learning and memory.

Single-nucleus RNA sequencing and chromatin analysis identified Rspo2 as the robust CA3-enriched transcriptional target. Excitatory-neuron Rspo2 deletion phenocopied Kat6a loss, whereas AAV-RSPO2 delivery restored β-catenin, synaptic physiology, dendritic spines, and much of the learning/memory phenotype. CA1 synaptic function was comparatively spared. (liu2024kat6adeficiencyimpairs pages 8-9, liu2024kat6adeficiencyimpairs pages 1-2)

Direct abstract quote: “Deletion of Rspo2 in excitatory neurons impairs memory formation, and restoring RSPO2 expression in CA3 neurons rescues the deficits in Wnt signaling and learning-associated behaviors in Kat6a mutant mice.” [Liu et al., Science Advances, May 17, 2024; DOI: https://doi.org/10.1126/sciadv.adm9326]. (liu2024kat6adeficiencyimpairs pages 1-2)

Suggested ontologies

  • GO biological process: histone acetylation; chromatin organization; regulation of transcription by RNA polymerase II; canonical Wnt signaling; synaptic plasticity; learning or memory; stem-cell maintenance; embryonic organ development.
  • GO cellular component: nucleus; chromatin; histone acetyltransferase complex; neuronal dendrite; excitatory synapse.
  • Cell Ontology: fibroblast; excitatory neuron; pyramidal neuron; hippocampal CA3 pyramidal neuron where an exact release-specific term exists; hematopoietic stem cell; neural-crest-derived craniofacial cell as a proposed developmental annotation.

Omics and advanced technologies

Human fibroblast RNA-seq demonstrated transcriptomic disturbance; the 2024 mouse study integrated single-nucleus RNA-seq with chromatin analysis. No validated human disease-specific proteomic, metabolomic, lipidomic, spatial-transcriptomic, organoid, or large iPSC atlas was identified. No published therapeutic CRISPR screen was retrieved. (munueracabeza2022pantothenateandlcarnitine pages 1-2, liu2024kat6adeficiencyimpairs pages 1-2, arboleda2015denovononsense pages 6-7)

7. Anatomical structures affected

  • Primary nervous-system involvement: developing brain and neural circuits governing cognition, speech, language, motor planning, tone, sleep, and behavior. The strongest mechanistic localization is hippocampal CA3, not evidence that disease is restricted to CA3.
  • Cardiovascular: atrial/ventricular septa, ductus arteriosus, and other congenital cardiac structures.
  • Gastrointestinal/oromotor: oral and pharyngeal feeding apparatus, esophagus, bowel motility, and occasionally intestinal rotation/obstruction.
  • Craniofacial: skull, palate, midface, nose, lips, jaw, and external ears.
  • Eye: extraocular alignment and visual system; ptosis and structural ocular abnormalities occur variably.
  • Musculoskeletal: spine, feet, joints, and cranial sutures in a subset.
  • Genitourinary: testes/inguinal region in some males.
  • Hematopoietic/immune system: major defects occur in complete mouse knockouts; recurrent infection and an isolated 2023 marrow-failure report warrant awareness, but routine human hematopoietic failure is not established. (lin2020diagnosisofarboledatham pages 3-4, urreizti2020fivenewcases pages 7-8, kennedy2019kat6asyndromegenotype–phenotype pages 6-7, arboleda2015denovononsense pages 6-7)

Suggested UBERON annotations include brain, hippocampus, CA3 field of hippocampus, heart, gastrointestinal tract, eye, palate, craniofacial skeleton, spinal column, and testis. Relevant subcellular annotations are nucleus, chromatin, nucleosome, and histone-acetyltransferase complex. No consistent lateralization is known.

8. Temporal development

ARTHS begins prenatally through disturbed embryonic gene regulation, although the neurodevelopmental phenotype often becomes clinically apparent in infancy. Congenital manifestations can include craniofacial differences, heart defects, palate abnormalities, hypotonia, feeding difficulty, growth restriction, and microcephaly. Developmental and especially expressive-language delays become clearer over the first years; an infant diagnosed at two months developed evident expressive-language delay by eight months. (bae2021identificationofa pages 1-2, bae2021identificationofa pages 6-7)

The disorder is chronic and lifelong. It has no accepted staging system, relapsing-remitting pattern, or spontaneous remission phenotype. Congenital structural abnormalities are generally stable or surgically corrected, while development continues slowly with variable gains. Constipation, sleep problems, orthopedic abnormalities, and communication disability may remain chronic. One individual had progressive cerebellar atrophy, but progressive neurodegeneration is not established as the typical course. (urreizti2020fivenewcases pages 7-8)

Early childhood is the principal intervention window for feeding safety, communication, motor development, vision, and cardiac assessment. Early genomic diagnosis therefore has practical value even without disease-modifying therapy. (bae2021identificationofa pages 6-7, kennedy2019kat6asyndromegenotype–phenotype pages 6-7)

9. Inheritance and population

Inheritance is autosomal dominant and usually de novo. For an affected individual with a constitutional pathogenic variant, the theoretical transmission risk is 50% per pregnancy, although reproductive fitness and individual circumstances vary. Parents testing negative in blood usually have a low recurrence risk, but parental germline or low-level somatic mosaicism cannot be excluded; no syndrome-specific mosaic recurrence rate is available.

Penetrance appears high for truncating pathogenic variants ascertained clinically, while expressivity is markedly variable. Missense alleles require greater caution because incomplete penetrance, alternate molecular effects, or misclassification may occur. Genetic anticipation is not expected because ARTHS is not a repeat-expansion disorder. Consanguinity is not etiologically relevant to a predominantly de novo dominant condition. No founder variant, carrier frequency, or population-specific enrichment is established. (kennedy2019kat6asyndromegenotype–phenotype pages 8-9, kennedy2019kat6asyndromegenotype–phenotype pages 2-3, kennedy2019kat6asyndromegenotype–phenotype pages 9-10)

The largest cohort included 76 individuals aged 1–32 years and was sex-balanced: 49% female and 51% male. Cases have been reported across multiple ancestries and regions; no geographic or ethnic predilection is established. Approximately 400–500 diagnosed patients had been cited by 2023–2024 mechanistic publications, but this is a reported-case count, not prevalence. A discovery-center estimate of 3/298, approximately 1%, among developmental-delay exomes reflects highly selected referral ascertainment and must not be interpreted as population prevalence. (kennedy2019kat6asyndromegenotype–phenotype pages 1-2, liu2024kat6adeficiencyimpairs pages 1-2, arboleda2015denovononsense pages 6-7, weber2023thehistoneacetyltransferase pages 1-2)

Population prevalence, birth incidence, and carrier frequency remain unknown.

10. Diagnostics

Clinical recognition

Clinical suspicion should arise with global developmental delay—especially profound expressive speech delay—plus hypotonia, feeding/GI problems, a broad or bulbous nose with thin upper lip, low-set ears, eye findings, microcephaly, or congenital heart disease. No purely clinical diagnostic criteria are sufficiently specific; molecular confirmation is required.

Recommended genetic approach

  1. Trio WES or WGS is the preferred broad approach for an undiagnosed syndromic neurodevelopmental disorder. WES identified the original de novo variants; WGS diagnosed a severe case within four weeks and may detect structural, noncoding, or coverage-limited variants missed by exome sequencing. (lin2020diagnosisofarboledatham pages 1-3, arboleda2015denovononsense pages 1-2)
  2. Neurodevelopmental/intellectual-disability or congenital-anomaly panels should include KAT6A and detect single-nucleotide variants and indels, with validated exon-level copy-number analysis.
  3. Single-gene sequencing is suitable when the phenotype is strongly suggestive or for familial testing.
  4. Confirm the variant and parental status by an orthogonal method such as Sanger sequencing where appropriate.
  5. Interpret variants using ACMG/AMP criteria, population frequency, predicted loss of function, exon position/NMD, de novo status, phenotype, splicing assays, and functional or methylation evidence.
  6. CMA remains useful when a copy-number disorder is suspected or sequencing is nondiagnostic. Routine karyotype/FISH, mitochondrial DNA testing, and repeat-expansion testing are not first-line ARTHS tests.

RNA sequencing can resolve suspected splice variants, while blood DNA-methylation profiling may support classification of uncertain KAT6A/KAT6B variants. Neither replaces primary DNA testing.

Baseline and surveillance evaluations

Recommended evaluations include developmental and speech-language assessment; feeding/swallowing and nutrition review; growth and head circumference; ECG and echocardiogram; ophthalmology; hearing; neurologic assessment with EEG when seizures are suspected; GI review for reflux, constipation, malrotation, or obstruction; musculoskeletal examination; and renal/genitourinary assessment guided by findings. Brain MRI is clinically indicated for seizures, abnormal neurologic progression, unusual head growth, or focal findings, not as a diagnostic biomarker. (bae2021identificationofa pages 5-6, kennedy2019kat6asyndromegenotype–phenotype pages 6-7)

Differential diagnosis

Important differentials include KAT6B-related Say–Barber–Biesecker–Young–Simpson/genitopatellar syndromes, BRPF1-related intellectual developmental disorder with dysmorphic facies and ptosis, Wiedemann–Steiner syndrome, Kabuki syndrome, Coffin–Siris spectrum, Cornelia de Lange spectrum, Rubinstein–Taybi syndrome, CDK13-related disorder, and other monogenic chromatinopathies. Distinction generally requires genomic testing because ID, speech delay, hypotonia, feeding problems, heart defects, and dysmorphism overlap.

Population newborn screening is unavailable. Cascade testing is appropriate after a molecular diagnosis; prenatal diagnosis and preimplantation genetic testing are technically possible when the familial variant is known.

11. Outcome and prognosis

No reliable 5- or 10-year survival rate, disease-specific mortality rate, or life-expectancy estimate exists. The 2019 cohort included adults up to age 32, showing survival into adulthood, but adult ascertainment is limited. (kennedy2019kat6asyndromegenotype–phenotype pages 1-2)

Morbidity is dominated by communication and intellectual disability, delayed motor and adaptive skills, feeding/GI problems, visual impairment, sleep disturbance, and congenital anomalies. Developmental skills may improve with therapy, but full recovery from the underlying neurodevelopmental disorder is not expected. Prognostic factors supported at group level include variant position—late truncations generally confer greater severity—and the burden of congenital heart, GI, feeding, neurologic, or orthopedic complications. Individual prediction remains imprecise because expressivity varies even among people with the same variant. (kennedy2019kat6asyndromegenotype–phenotype pages 8-9, arboleda2015denovononsense pages 6-7)

There is no validated circulating, imaging, electrophysiologic, or molecular prognostic biomarker. DNA methylation signatures are diagnostic/classification candidates rather than proven outcome biomarkers.

12. Treatment

Current clinical management

There is no approved disease-modifying pharmacotherapy, gene therapy, RNA therapy, or cell therapy. Care is multidisciplinary and phenotype-directed:

  • early intervention, special education, neuropsychology, and behavioral support;
  • intensive speech-language therapy, with sign language, picture systems, or speech-generating devices introduced early rather than waiting for speech to emerge;
  • physical and occupational therapy for hypotonia, coordination, mobility, and adaptive skills;
  • swallow/feeding therapy, nutritional support, reflux treatment, and enteral feeding when required;
  • constipation therapy and urgent evaluation of bilious vomiting or obstructive symptoms;
  • standard cardiology and cardiac-surgical care;
  • ophthalmologic treatment of strabismus, refractive error, ptosis, and amblyopia risk;
  • standard antiseizure therapy when epilepsy is confirmed;
  • sleep assessment and treatment of specific contributors;
  • orthopedic, craniofacial, dental, hearing, and genitourinary care as indicated. (bae2021identificationofa pages 5-6, bae2021identificationofa pages 6-7, kennedy2019kat6asyndromegenotype–phenotype pages 6-7)

Suggested MAXO annotations include genetic counseling, exome/genome sequencing, echocardiography, electrocardiography, ophthalmologic examination, developmental assessment, speech therapy, augmentative and alternative communication, physical therapy, occupational therapy, feeding therapy, enteral nutrition, laxative therapy, antiseizure pharmacotherapy, and corrective cardiac or craniofacial surgery.

Experimental strategies

Patient fibroblasts treated with pantothenate and L-carnitine showed increased histone acetylation, partial normalization of protein and transcriptomic patterns, and significantly improved bioenergetics. Direct abstract quote: “Pantothenate and L-carnitine treatment increased histone acetylation and partially corrected protein and transcriptomic expression patterns in mutant KAT6A cells.” [Munuera-Cabeza et al., published December 2022; DOI: https://doi.org/10.3390/genes13122300]. This was an in-vitro study of three patient cell lines, not a clinical trial; efficacy, dosing, safety, and developmental benefit in patients are unknown. (munueracabeza2022pantothenateandlcarnitine pages 1-2, munueracabeza2022pantothenateandlcarnitine pages 15-16)

Enhancing RSPO2/Wnt signaling rescued cognitive and synaptic deficits in mice, identifying a target rather than a ready treatment. Systemic Wnt activation has substantial developmental and oncogenic risks, and human translation will require tissue-specific delivery and extensive safety work. (liu2024kat6adeficiencyimpairs pages 8-9)

No disease-specific interventional ClinicalTrials.gov study was retrieved. There are therefore no evidence-based response rates, adverse-event profiles, combination regimens, or pharmacogenomic prescribing recommendations for ARTHS.

13. Prevention

Primary prevention by lifestyle modification or vaccination is not possible for a usually de novo genetic disorder. The principal preventive actions are reproductive and complication-focused:

  • preconception and postdiagnostic genetic counseling;
  • parental testing, with discussion of residual germline-mosaicism risk;
  • prenatal diagnosis or PGT-M when a pathogenic familial variant is known;
  • early molecular diagnosis and developmental intervention;
  • baseline cardiac and eye assessment to prevent avoidable cardiac morbidity and amblyopia;
  • feeding/swallowing assessment to reduce malnutrition and aspiration risk;
  • proactive constipation treatment and recognition of bowel obstruction;
  • seizure, sleep, orthopedic, and hearing surveillance according to symptoms.

No population carrier-screening or newborn-screening program is indicated by current evidence. Public-health sanitation, vector control, environmental remediation, vaccines, and antimicrobial prophylaxis are not disease-specific measures.

14. Other species and natural disease

No naturally occurring veterinary syndrome clearly orthologous to human ARTHS was identified, and there is no zoonotic or cross-species transmission. Relevant orthologues include mouse Kat6a and zebrafish kat6a; exact NCBI Gene and Taxon identifiers should be populated from current NCBI records. Standard taxonomy identifiers are Homo sapiens Taxon 9606, Mus musculus Taxon 10090, and Danio rerio Taxon 7955.

KAT6A’s chromatin, embryonic-development, hematopoietic, cardiac, craniofacial, and neural functions are evolutionarily conserved. Animal phenotypes are experimental genetic models rather than evidence of a recognized spontaneous livestock, companion-animal, or wildlife disease. (arboleda2015denovononsense pages 6-7, weber2023thehistoneacetyltransferase pages 1-2)

15. Model organisms and experimental systems

Mouse models

  • Constitutive homozygous Kat6a loss: embryonic or perinatal lethal, with vascular/cardiac, gastrointestinal, skeletal, thymic/splenic, neural-stem-cell, and hematopoietic defects. This model demonstrates essential developmental functions but is more severe than the usual human heterozygous syndrome. (arboleda2015denovononsense pages 6-7)
  • Kat6a+/− early-truncation model: approximately 50% hippocampal Kat6a expression, reduced body weight, and learning/memory abnormalities, modeling human haploinsufficiency.
  • Excitatory-neuron conditional knockout: reproduces CA3-specific synaptic and memory deficits without requiring whole-organism loss.
  • Rspo2 conditional knockout and AAV-RSPO2 rescue: establish pathway causality and demonstrate that selected postnatal neural deficits can be reversed in mice. (liu2024kat6adeficiencyimpairs pages 8-9, liu2024kat6adeficiencyimpairs pages 1-2)

Limitations include species differences, simplified alleles, incomplete modeling of late-truncating human variants, and inability of behavioral assays to reproduce human speech, language, congenital anomalies, and psychosocial outcomes.

Cellular and biochemical models

Patient dermal fibroblasts reproduce altered histone acetylation, p53-related transcription, mitochondrial dysfunction, and treatment-responsive molecular phenotypes. Their accessibility is an advantage, but they do not fully model developing neurons, cardiomyocytes, cranial neural crest, or gastrointestinal tissues. Recombinant-domain, DNA-binding, chromatin-immunoprecipitation, and genome-wide occupancy assays established direct KAT6A recruitment to unmethylated CpG islands. (munueracabeza2022pantothenateandlcarnitine pages 1-2, arboleda2015denovononsense pages 6-7, weber2023thehistoneacetyltransferase pages 1-2)

No mature ARTHS-specific iPSC-neuron, cerebral-organoid, or patient-derived cardiac-organoid platform was identified in the retrieved literature; these are logical priorities for variant-specific therapeutic testing.

Recent developments, 2023–2024

  1. Chromatin targeting: KAT6A was shown to bind unmethylated CpG islands directly through an N-terminal winged-helix domain, clarifying how the enzyme reaches genomic targets [published online December 20, 2022; journal issue 2023; DOI: https://doi.org/10.1093/nar/gkac1188]. (weber2023thehistoneacetyltransferase pages 1-2)
  2. DNA-methylation diagnostics: a 2023 study reported KAT6A/KAT6B episignatures as sensitive and specific biomarkers for variant detection/classification; direct review is needed for exact validation metrics [DOI: https://doi.org/10.2217/epi-2023-0079].
  3. Brain mechanism and rescue: the 2024 Science Advances study localized a major cognitive mechanism to CA3 KAT6A–RSPO2–Wnt signaling and achieved AAV-RSPO2 rescue [DOI: https://doi.org/10.1126/sciadv.adm9326]. (liu2024kat6adeficiencyimpairs pages 8-9, liu2024kat6adeficiencyimpairs pages 1-2)
  4. Phenotypic expansion: 2024 reports added prenatal/fetal observations, including fetal hepatic calcification, and additional Asian cases, but these remain isolated observations rather than established screening markers [DOIs: https://doi.org/10.1016/j.ejmg.2023.104906 and https://doi.org/10.1002/mgg3.2420].
  5. Clinical implementation: multidisciplinary chromatinopathy clinics increasingly integrate genomic sequencing, DNA-methylation profiling, anticipatory surveillance, and structured neurodevelopmental care; however, controlled ARTHS treatment trials remain absent.

Evidence assessment and major gaps

The gene–disease relationship and core phenotype are strongly supported by repeated de novo variants, recurrence, variant enrichment, and consistent human phenotypes. Genotype–phenotype correlation is moderately strong but subject to ascertainment and incomplete standardized testing. Cellular acetylation and metabolic abnormalities have direct human in-vitro support but small sample sizes. The CA3 RSPO2/Wnt mechanism has unusually strong preclinical causal evidence—including conditional genetics and rescue—but has not been demonstrated in human brain tissue or clinical intervention.

Priority gaps are population prevalence, adult natural history, formal adaptive and quality-of-life trajectories, penetrance of nontruncating variants, systematic immune/hematologic surveillance data, human neuronal and organoid models, validated longitudinal biomarkers, and controlled therapeutic trials. Consequently, experimental supplements or pathway-directed interventions should not be represented as established therapy.

References

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  20. (kennedy2019kat6asyndromegenotype–phenotype pages 9-10): Joanna Kennedy, David Goudie, Edward Blair, Kate Chandler, Shelagh Joss, Victoria McKay, Andrew Green, Ruth Armstrong, Melissa Lees, Benjamin Kamien, Bruce Hopper, Tiong Yang Tan, Patrick Yap, Zornitza Stark, Nobuhiko Okamoto, Noriko Miyake, Naomichi Matsumoto, Ellen Macnamara, Jennifer L. Murphy, Elizabeth McCormick, Hakon Hakonarson, Marni J. Falk, Dong Li, Patrick Blackburn, Eric Klee, Dusica Babovic-Vuksanovic, Susan Schelley, Louanne Hudgins, Sarina Kant, Bertrand Isidor, Benjamin Cogne, Kimberley Bradbury, Mark Williams, Chirag Patel, Helen Heussler, Celia Duff-Farrier, Phillis Lakeman, Ingrid Scurr, Usha Kini, Mariet Elting, Margot Reijnders, Janneke Schuurs-Hoeijmakers, Mohamed Wafik, Anne Blomhoff, Claudia A.L. Ruivenkamp, Esther Nibbeling, Alexander J.M. Dingemans, Emilie D. Douine, Stanley F. Nelson, Maja Hempel, Tatjana Bierhals, Davor Lessel, Jessika Johannsen, Valerie A. Arboleda, and Ruth Newbury-Ecob. Kat6a syndrome: genotype–phenotype correlation in 76 patients with pathogenic kat6a variants. Genetics in Medicine, 21:850-860, Apr 2019. URL: https://doi.org/10.1038/s41436-018-0259-2, doi:10.1038/s41436-018-0259-2. This article has 134 citations and is from a highest quality peer-reviewed journal.

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