| 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” (pqac-00000001, pqac-00000020, pqac-00000000) | 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 (pqac-00000001, pqac-00000002, pqac-00000020) | 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 (pqac-00000001, pqac-00000003, pqac-00000012, pqac-00000020) | 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 (pqac-00000005, pqac-00000009, pqac-00000011) | 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 (pqac-00000005, pqac-00000006, pqac-00000011) | 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 (pqac-00000005, pqac-00000003) | 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 (pqac-00000005, pqac-00000006, pqac-00000008) | 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 (pqac-00000005, pqac-00000006, pqac-00000011) | 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 (pqac-00000005, pqac-00000020) | 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 (pqac-00000006, pqac-00000011, pqac-00000003) | 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 (pqac-00000005) | 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* (pqac-00000010, pqac-00000012, pqac-00000020) | 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 (pqac-00000001, pqac-00000006, pqac-00000009, pqac-00000018) | 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 (pqac-00000001, pqac-00000011, pqac-00000018, pqac-00000020) | 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 (pqac-00000014, pqac-00000016, pqac-00000018, pqac-00000019) | 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 (pqac-00000021, pqac-00000019) | 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** (pqac-00000016, pqac-00000018) | 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 (pqac-00000015, pqac-00000019) | 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 (pqac-00000001, pqac-00000003, pqac-00000004, pqac-00000020) | 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 (pqac-00000006, pqac-00000007, pqac-00000011) | 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 (pqac-00000014, pqac-00000015, pqac-00000016, pqac-00000018) | 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 (pqac-00000002, pqac-00000018, pqac-00000019) | 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 (pqac-00000010, pqac-00000006, pqac-00000020) | 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 (pqac-00000010, pqac-00000011, pqac-00000013) | 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.*