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 near-universal 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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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
near-universal 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.
penetrance: COMPLETE
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."
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.
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
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
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
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.
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.
- 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
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 and Intellectual Disability
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: 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.
- 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: Global Developmental Delay and 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: PARTIAL
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.
phenotypes:
- category: Neurologic
name: Global Developmental Delay and Intellectual Disability
description: >-
Global developmental delay and intellectual disability are universal,
ranging from mild to severe. Level of intellectual disability correlates
with variant position, being more severe in late-truncating variants.
phenotype_term:
preferred_term: Intellectual disability
term:
id: HP:0001249
label: Intellectual disability
frequency: OBLIGATE
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 comprehensive cohort documents intellectual disability and
developmental delay as universal.
- 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.
- category: Neurodevelopmental
name: Expressive Speech Delay
description: >-
Marked expressive speech delay is universal and often described as a form of
verbal dyspraxia, with receptive language consistently more developed than
expressive language.
phenotype_term:
preferred_term: Delayed speech and language development
term:
id: HP:0000750
label: Delayed speech and language development
frequency: OBLIGATE
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 cohort documents marked expressive speech delay as universal.
- 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.
phenotype_term:
preferred_term: Craniofacial dysmorphism
term:
id: HP:0001999
label: Abnormal facial shape
frequency: VERY_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.
- 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.
- 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.
- 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. A minority have isolated neutropenia or other immune findings.
phenotype_term:
preferred_term: Recurrent infections
term:
id: HP:0002719
label: Recurrent infections
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: >-
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.
- reference: PMID:30245513
reference_title: "KAT6A Syndrome: genotype-phenotype correlation in 76 patients with pathogenic KAT6A variants."
supports: PARTIAL
evidence_source: HUMAN_CLINICAL
snippet: "three individuals report isolated moderate to severe neutropenia5,13."
explanation: >-
A minority have isolated neutropenia, a distinct immune finding that may
contribute to infection susceptibility in some patients.
- 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
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: >-
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
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: >-
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
frequency: VERY_RARE
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
frequency: VERY_RARE
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.
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 universal expressive speech delay and verbal dyspraxia.
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: >-
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.
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.
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)
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)
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:
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.
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)
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)
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)
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)
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)
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.
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)
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.
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)
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)
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)
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)
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)
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.
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)
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.
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.
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.
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)
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.
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.
There is no approved disease-modifying pharmacotherapy, gene therapy, RNA therapy, or cell therapy. Care is multidisciplinary and phenotype-directed:
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.
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.
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:
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.
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)
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.
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.
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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(urreizti2020fivenewcases pages 7-8): Roser Urreizti, Estrella Lopez-Martin, Antonio Martinez-Monseny, Montse Pujadas, Laura Castilla-Vallmanya, Luis Alberto Pérez-Jurado, Mercedes Serrano, Daniel Natera-de Benito, Beatriz Martínez-Delgado, Manuel Posada-de-la-Paz, Javier Alonso, Purificación Marin-Reina, Mar O’Callaghan, Daniel Grinberg, Eva Bermejo-Sánchez, and Susanna Balcells. Five new cases of syndromic intellectual disability due to kat6a mutations: widening the molecular and clinical spectrum. Orphanet Journal of Rare Diseases, Feb 2020. URL: https://doi.org/10.1186/s13023-020-1317-9, doi:10.1186/s13023-020-1317-9. This article has 48 citations and is from a peer-reviewed journal.
(kennedy2019kat6asyndromegenotype–phenotype pages 6-7): 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.
(bae2021identificationofa pages 5-6): Soyoung Bae, Aram Yang, Jinsup Kim, Hyun Ju Lee, and Hyun Kyung Park. Identification of a novel kat6a variant in an infant presenting with facial dysmorphism and developmental delay: a case report and literature review. BMC Medical Genomics, Dec 2021. URL: https://doi.org/10.1186/s12920-021-01148-x, doi:10.1186/s12920-021-01148-x. This article has 22 citations and is from a peer-reviewed journal.
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(weber2023thehistoneacetyltransferase pages 1-2): Lisa Marie Weber, Yulin Jia, Bastian Stielow, Stephen S Gisselbrecht, Yinghua Cao, Yanpeng Ren, Iris Rohner, Jessica King, Elisabeth Rothman, Sabrina Fischer, Clara Simon, Ignasi Forné, Andrea Nist, Thorsten Stiewe, Martha L Bulyk, Zhanxin Wang, and Robert Liefke. The histone acetyltransferase kat6a is recruited to unmethylated cpg islands via a dna binding winged helix domain. Nucleic Acids Research, 51:574-594, Dec 2023. URL: https://doi.org/10.1093/nar/gkac1188, doi:10.1093/nar/gkac1188. This article has 44 citations and is from a highest quality peer-reviewed journal.
(munueracabeza2022pantothenateandlcarnitine pages 15-16): Manuel Munuera-Cabeza, Mónica Álvarez-Córdoba, Juan Suárez-Rivero, Suleva Povea-Cabello, Irene Villalón-García, Marta Talaverón-Rey, Alejandra Suárez-Carrillo, Diana Reche-López, Paula Cilleros-Holgado, Rocío Piñero-Pérez, and José Sánchez-Alcázar. Pantothenate and l-carnitine supplementation improves pathological alterations in cellular models of kat6a syndrome. Genes, 13:2300, Dec 2022. URL: https://doi.org/10.3390/genes13122300, doi:10.3390/genes13122300. This article has 6 citations.
(lin2020diagnosisofarboledatham pages 1-3): Yung-Feng Lin, Tzu-Ching Lin, Ralph Kirby, Hui-Ying Weng, Yen-Ming Liu, Dau-Ming Niu, Shih-Feng Tsai, and Chia-Feng Yang. Diagnosis of arboleda-tham syndrome by whole genome sequencing in an asian boy with severe developmental delay. Molecular Genetics and Metabolism Reports, 25:100686, Dec 2020. URL: https://doi.org/10.1016/j.ymgmr.2020.100686, doi:10.1016/j.ymgmr.2020.100686. This article has 22 citations.
(bae2021identificationofa pages 6-7): Soyoung Bae, Aram Yang, Jinsup Kim, Hyun Ju Lee, and Hyun Kyung Park. Identification of a novel kat6a variant in an infant presenting with facial dysmorphism and developmental delay: a case report and literature review. BMC Medical Genomics, Dec 2021. URL: https://doi.org/10.1186/s12920-021-01148-x, doi:10.1186/s12920-021-01148-x. This article has 22 citations and is from a peer-reviewed journal.
(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.