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Inheritance

2

Autosomal dominant (de novo) HP:0000006

The majority of reported individuals carry de novo heterozygous KAT8 variants. KAT8 is predicted to be highly intolerant of loss-of-function change, which is consistent with dominant disease from a single altered allele.

Autosomal dominant inheritance

Show evidence (2 references)

PMID:31794431 SUPPORT Human Clinical

"All except individual T9 carry heterozygous de novo variants."

The direct statement that eight of nine individuals carry heterozygous de novo variants, which is what supports dominant inheritance.

PMID:31794431 SUPPORT Human Clinical

"the 2 variants from individual T9 and her family act differently from the de novo variants from individuals T1–T8"

Graded PARTIAL and kept as the boundary of the dominant claim, not as its support. It documents the one individual whose variants are not de novo, and is quoted here so the exception travels with the rule rather than being discovered later.

Autosomal recessive HP:0000007

A separate, biallelic form. A consanguineous Pakistani family segregated a homozygous KAT8 missense variant with the disorder, which the reporting authors identify as the first autosomal recessive inheritance pattern described for a KAT8-related disorder. The founding study had already anticipated a dual-inheritance locus, comparing KAT8 to genes such as EMC1 where both monoallelic and biallelic variants cause developmental disease.

Autosomal recessive inheritance

Show evidence (3 references)

PMID:41347281 SUPPORT Human Clinical

"This study reports, for the first time, an autosomal recessive inheritance pattern for a KAT8-related disorder, providing new insights into its genetic architecture."

Establishes the recessive form as a distinct inheritance mode for this locus.

PMID:41347281 SUPPORT Human Clinical

"In Family-2 with LIGOWS, a novel homozygous missense variant ((NM_182958.4): c.649A > C; (NP_892003.2): p.Met217Leu) was found in KAT8."

The specific homozygous allele underpinning the recessive report.

PMID:31794431 SUPPORT Human Clinical

"dual-mode inheritance has been reported for some genes. For example, both monoallelic and biallelic EMC1 (and several other genes) variants cause develop"

Graded PARTIAL - the founding study raises dual-mode inheritance as a hypothesis by analogy to EMC1, before the recessive family was reported. It anticipates the finding rather than establishing it.

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Discussions and Knowledge Gaps

2

Does valproate work in KAT8-related epilepsy by restoring histone acetylation, or simply as a broad-spectrum anticonvulsant? Nobody has measured the mark in a treated patient.

KNOWLEDGE GAP kat8_valproate_mechanism_untested

Attached to

treatments#Valproate for Epilepsy pathophysiology#Loss of Nucleosomal H4K16 Acetylation

The reasoning is attractive: KAT8 writes an acetylation mark, valproate inhibits the deacetylases that erase acetylation marks, and both treated individuals responded. But two patients cannot distinguish a mechanism-directed effect from valproate simply working as it does in many epilepsies, and the founding authors themselves phrase it as "may ameliorate". The question is answerable with existing technology - measure H4K16ac in patient-derived cells or accessible tissue before and after treatment, or compare response rates against a non-HDAC-inhibiting anticonvulsant in a larger cohort. It matters beyond this disorder: if the logic holds, HDAC inhibition becomes a rational strategy across the writer chromatinopathies, and if it does not, a plausible-sounding rationale is steering drug choice on no evidence.

Show evidence (2 references)

PMID:31794431 SUPPORT Human Clinical

"Valproate is a known deacetylase inhibitor and promotes histone acetylation (42), so it may ameliorate potential acetylation deficiency result"

The hypothesis as stated by its authors, in explicitly conditional terms.

PMID:31794431 SUPPORT Human Clinical

"Valproate was effective for treating epilepsy in at least 2 of the individuals."

The entire clinical evidence base - two individuals - which is why this is a gap rather than an established mechanism.

How do monoallelic de novo and biallelic KAT8 variants produce the same syndrome, and do the two forms differ in severity or in which domains are affected?

KNOWLEDGE GAP kat8_dual_inheritance

Attached to

inheritance#Autosomal recessive pathophysiology#KAT8 Loss of Function

KAT8 is highly intolerant of loss-of-function change, which fits dominant disease from a single de novo allele. Yet a homozygous missense variant segregates recessively in a consanguineous family, and the founding study had already flagged one individual whose variants behaved differently from the de novo cases. The most economical explanation is a dose-and-severity gradient - severe alleles causing dominant disease, milder hypomorphic alleles needing two copies - which would predict that the recessive alleles retain more residual acetyltransferase activity than the dominant ones. That is directly testable with the same nucleosomal H4K16 acetylation assay the founding study already used on the de novo variants, and has not been done for the recessive allele.

Show evidence (2 references)

PMID:41347281 SUPPORT Human Clinical

"This study reports, for the first time, an autosomal recessive inheritance pattern for a KAT8-related disorder, providing new insights into its genetic architecture."

Establishes that both inheritance modes occur at this locus.

PMID:41347281 SUPPORT Computational

"The functional consequences of the ADGRG1 and KAT8 missense variants were revealed as deleterious using bioinformatic prediction tools."

Graded PARTIAL and COMPUTATIONAL - the recessive allele's effect was assessed by in-silico prediction, not by the enzymatic assay that would settle the residual-activity question.

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Pathophysiology

5

KAT8 Loss of Function

Pathogenic KAT8 variants alter either the chromobarrel domain or the acetyltransferase core. The acetyltransferase domain comprises a KAT8/Mof-specific region absent from other MYST family members plus the MYST domain itself. Of the characterised missense variants, three alter the chromobarrel domain and four the acetyltransferase domain, so the disease can arise either by disrupting catalysis directly or by disrupting the reader module that positions the enzyme. KAT8 is highly intolerant of loss-of-function change and moderately intolerant of missense change.

KAT8 hgnc:17933

histone H4K16 acetyltransferase activity GO:0046972 ⇓ LOSS OF FUNCTION

Downstream

Loss of Nucleosomal H4K16 Acetylation

Show evidence (2 references)

PMID:31794431 SUPPORT Human Clinical

"The variants altered chromobarrel and catalytic domains of KAT8, thereby impairing nucleosomal H4K16 acetylation."

Maps the patient variants onto the two functional domains and states the biochemical consequence.

PMID:31794431 SUPPORT Human Clinical

"Among the missense variants, 3 alter the chromobarrel domain, and 4 change the acetyltransferase domain."

Quantifies the split between reader-module and catalytic-domain variants.

Loss of Nucleosomal H4K16 Acetylation

H4K16 acetylation is an evolutionarily conserved mark, and KAT8 is the major enzyme that writes it in mammals. Its level is high in the neocortex and hippocampus of the adult brain, at P5, and in the cerebrocortical neuroepithelium at E12.5 - the distribution that first implicated KAT8 in cerebral development. In Emx1-Cre conditional knockout mice the mark disappears from the cerebrocortical neuroepithelium and hippocampal primordium while being retained in the ganglionic eminences, which is what makes the resulting phenotype attributable to KAT8 in that specific lineage rather than to a global effect. KAT8 works through two distinct complexes - MSL and NSL - and the disease may reflect disruption of both. Variants in KANSL1, which encodes the NSL1 subunit, cause Koolen-de Vries syndrome, and MSL3 variants cause an X-linked developmental disorder. Individuals with KAT8 variants show epilepsy and other features absent in MSL3 disease, which argues KAT8 is not simply acting through one complex.

histone H4K16 acetyltransferase activity GO:0046972 ↓ DECREASED

Downstream

Impaired Neural Stem and Progenitor Cell Expansion

Show evidence (5 references)

PMID:31794431 SUPPORT Model Organism

"H4K16ac disappeared in the cerebrocortical neuroepithelium and hippocampal primordium at E12.5, but not the in the medial or lateral ganglionic eminence"

Demonstrates lineage-restricted loss of the mark, which is what attributes the downstream phenotype to KAT8 in the cerebrocortical lineage.

PMID:31794431 SUPPORT Model Organism

"the H4K16ac level was high in the neocortex and hippocampus of the adult brain, as well as in these areas at P5 and in the cerebrocortical neuro epithelium at E12.5"

Establishes the developmental expression pattern that implicates KAT8 in cerebral development.

PMID:31794431 SUPPORT Human Clinical

"that KAT8 may act through both MSL and NSL complexes"

Graded PARTIAL - the authors' own conclusion, which they state as a suggestion, that KAT8 acts through both complexes. It rests on a phenotypic contrast with MSL3-related disease rather than a direct assay.

+ 2 more references

Impaired Neural Stem and Progenitor Cell Expansion

Loss of H4K16ac impairs neural stem and progenitor cell development. Mutant NSPCs form poor neurospheres, and - importantly - pharmacological KAT8 inhibition abolishes neurosphere formation from wild-type cortex. That second result matters because it separates an acute requirement for KAT8 activity from the accumulated consequences of a developmental knockout. The inhibitor experiment was designed as a comparison: MG149 targets both KAT5 and KAT8 while NU9056 is KAT5-specific, so the difference between them isolates the KAT8 contribution.

neural stem cell CL:0000047

neural precursor cell proliferation GO:0061351 ↓ DECREASED

Animal models

Emx1-Cre cerebrum-specific Kat8 conditional knockout mouse Mouse recapitulates Mutant NSPCs form poor neurospheres, giving a quantitative cellular assay for the progenitor defect.

Downstream

Aberrant Neurogenesis and Neuroepithelial Apoptosis

Show evidence (2 references)

PMID:31794431 SUPPORT Model Organism

"Mutant NSPCs formed poor neurospheres, and pharmacological KAT8 inhibition abolished neurosphere formation."

Both the genetic and the pharmacological demonstrations of impaired NSPC expansion.

PMID:31794431 SUPPORT In Vitro

"The former targets both KAT5 and KAT8 (34), whereas NU9056 is specific to KAT5 (35). The difference between these 2 inhibitors would allow us to compare their impact and deduce the effect of KAT8 inhibition on neurospheres."

The comparative inhibitor design that isolates the KAT8-specific contribution, since no KAT8-selective inhibitor was available at the time.

Aberrant Neurogenesis and Neuroepithelial Apoptosis

The mutant cerebrocortical neuroepithelium shows faulty proliferation, premature and aberrant neurogenesis, and massive apoptosis. The combination - progenitors both differentiating too early and dying - depletes the progenitor pool from two directions at once, which is why the structural consequence is hypoplasia rather than a subtler patterning defect.

neurogenesis GO:0022008 ↕ DYSREGULATED apoptotic process GO:0006915 ↑ INCREASED

Downstream

Cerebral Hypoplasia

Show evidence (1 reference)

PMID:31794431 SUPPORT Model Organism

"Mutant cerebrocortical neuroepithelia exhibited faulty proliferation, aberrant neurogenesis, massive apoptosis, and scant H4K16 propionylation."

The primary cellular phenotype of the conditional knockout.

Cerebral Hypoplasia

Cerebral hypoplasia of the neocortex and hippocampus in the conditional knockout, matching the brain MRI anomalies and the intellectual disability and epilepsy seen in patients.

neocortex UBERON:0001950 hippocampal formation UBERON:0002421

Animal models

Emx1-Cre cerebrum-specific Kat8 conditional knockout mouse Mouse recapitulates Produces cerebral hypoplasia of the neocortex and hippocampus, the structural correlate of the intellectual disability and brain MRI anomalies in patients.

Show evidence (2 references)

PMID:31794431 SUPPORT Model Organism

"cerebrum-specific knockout mice displayed cerebral hypoplasia in the neocortex and hippocampus, along with improper neural stem and progenitor cell (NSPC) development"

The structural endpoint of the mouse phenotype.

PMID:31794431 SUPPORT Human Clinical

"Several individuals showed brain MRI anom-"

Graded PARTIAL - brain MRI anomalies were present in only some individuals and are described by the authors as consistent with the murine hypoplasia rather than shown to be the same lesion. The quote ends mid-word because the cached full text breaks "anomalies" across a line and snippets must be exact substrings.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

10

Cardiovascular 1

Congenital Heart Defect FREQUENT Abnormal heart morphology HP:0001627

Show evidence (1 reference)

PMID:31794431 SUPPORT Human Clinical

"Four individuals had car- diac anomalies (Figure 7B and Supplemental Table 1)."

Quantifies cardiac involvement at 4 of 9. The quoted text spans a hyphenated line break in the cached full text.

Head and Neck 1

Abnormal Facial Shape FREQUENT HP:0001999

Show evidence (1 reference)

PMID:31794431 SUPPORT Human Clinical

"Recurrent dysmorphisms included upper lateral eyelid fullness, low-set ears, downturned corners of the mouth, a depressed nasal bridge, mild malar hypoplasia, and epicanthi"

Enumerates the recurrent dysmorphic features.

Nervous System 7

Global Developmental Delay FREQUENT HP:0001263

Graded FREQUENT, not VERY_FREQUENT. The only quantifier the source gives is "frequently observed", with no count, and under the frequency conventions that maps to the 30-79% band. VERY_FREQUENT would assert 80-99%, which nothing in the cohort description supports.

Show evidence (1 reference)

PMID:31794431 SUPPORT Human Clinical

"Global developmental delay, intellectual disability, epilepsy, and other developmental anomalies were frequently observed in the affected individuals"

States global developmental delay among the frequent findings.

Intellectual Disability FREQUENT HP:0001249

Graded FREQUENT, not VERY_FREQUENT, on the same reasoning as Global Developmental Delay: both are named in one sentence as "frequently observed", which maps to the 30-79% band. The deep research reports intellectual disability in 9 of 9 individuals, which would justify VERY_FREQUENT, but that count is in supplementary material the cached full text does not carry, and this entry does not assert what it cannot quote. A cached quote giving the 80-99% count is what would move this.

Show evidence (2 references)

PMID:31794431 SUPPORT Human Clinical

"Global developmental delay, intellectual disability, epilepsy, and other developmental anomalies were frequently observed in the affected individuals"

Names intellectual disability among the frequently observed findings, which is the quote the FREQUENT band rests on.

PMID:31794431 SUPPORT Human Clinical

"links deficient H4K16 acylation directly to intellectual disability, epilepsy, and other developmental anomalies"

Connects the molecular defect to intellectual disability as a core outcome.

Language Delay VERY_FREQUENT Delayed speech and language development HP:0000750

Show evidence (1 reference)

PMID:31794431 SUPPORT Human Clinical

"Variable language delay occurred in all individuals (Figure 7B and Supple"

Language delay was present in every individual in the founding cohort, which is why it is graded VERY_FREQUENT even against the small cohort size.

Seizure FREQUENT HP:0001250

Show evidence (2 references)

PMID:31794431 SUPPORT Human Clinical

"we describe KAT8 variants in 9 patients with intellectual disability, seizures, autism, dysmorphisms, and other anomalies"

Seizures among the core features of the founding nine-patient cohort.

PMID:31794431 SUPPORT Human Clinical

"As for epilepsy, some exhibited EEG abnormalities (Supplemental Table 1)."

Documents electrophysiological correlates in a subset.

Autistic Behavior OCCASIONAL HP:0000729

Show evidence (1 reference)

PMID:31794431 SUPPORT Human Clinical

"Two individuals also showed autistic features (Figure 7B), and 1 individual displayed characteristics of attention deficit hyperactivity disorder"

Quantifies autistic features at 2 of 9, which supports the OCCASIONAL grading rather than treating autism as a core feature.

Attention Deficit Hyperactivity Disorder OCCASIONAL HP:0007018

Show evidence (1 reference)

PMID:31794431 SUPPORT Human Clinical

"Two individuals also showed autistic features (Figure 7B), and 1 individual displayed characteristics of attention deficit hyperactivity disorder"

Quantifies ADHD characteristics at 1 of 9, which supports the OCCASIONAL grading. The sentence reports autistic features in the same breath and is quoted on that phenotype too; the two are curated separately because they are distinct HPO terms.

Motor Delay FREQUENT HP:0001270

Show evidence (1 reference)

PMID:31794431 SUPPORT Human Clinical

"Gross and fine motor delays were other common anomalies"

States gross and fine motor delay as common findings.

Other 1

Abnormal Brain Morphology OCCASIONAL HP:0012443

Graded OCCASIONAL. "Several individuals" out of nine gives no count, and the companion sentence calls the defects variable, so neither FREQUENT nor a specific malformation can be asserted from the cached text. If the supplementary table is later obtained, the right move is to split this into the specific malformations with their own counts.

Show evidence (2 references)

PMID:31794431 SUPPORT Human Clinical

"Several individuals showed brain MRI anom-"

The clinical statement. The quote ends on a hyphenated line break in the cached full text, which is why it stops at "anom-".

PMID:31794431 SUPPORT Human Clinical

"able brain MRI defects in the clinical cases (Supplemental Figure "

The authors' own reading, that the MRI defects are variable and together with the intellectual disability and epilepsy indicate abnormal brain development consistent with the knockout mouse. Begins mid-word because "variable" is hyphenated across a line break in the cached text.

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Genetic Associations

1

KAT8

Gene: KAT8 hgnc:17933 relationship_type: CAUSATIVE

Show evidence (3 references)

PMID:31794431 SUPPORT Human Clinical

"This study uncovers a critical role of KAT8 in cerebral and NSPC development, identifies 9 individuals with KAT8 variants, and links deficient H4K16 acylation directly to intellectual disability, epilepsy, and other developmental anomalies."

The founding gene-disease association.

PMID:31794431 SUPPORT Computational

"It is predicted to be moderately intol- erant of missense change (misZ [Z score of missense variation intolerance] score of 3.66)"

Population constraint metrics supporting pathogenicity of missense change. Graded COMPUTATIONAL because these are in-silico population-genetic predictions.

PMID:36553572 SUPPORT Human Clinical

"substantially strengthen the confirmation of genes with limited evidence in the medical literature (ADARB1, AP2M1, BCKDK, BCORL1, CARS2, FBXO38, GABRB1, KAT8, PRKD1, RAB11B, RUSC2, ZNF142)"

Independent routine-diagnostics evidence strengthening the KAT8 gene-disease association, from a cohort of nearly 10,000 analyses.

Variants (3)

Chromobarrel-domain missense substitutions (p.Tyr90Cys, p.Arg98Gln, p.Arg99Gln)

Three heterozygous de novo missense substitutions in the chromobarrel domain, curated as one entry because the founding study treats them as one functional class and tests them together. They impede the acetyltransferase activity of KAT8, which is the experiment that establishes the chromobarrel domain as required for KAT8 to acetylate nucleosomal H4K16 rather than merely for substrate binding. p.Tyr90Cys is also the recurrent allele of the founding cohort: individuals T1, T2 and T3 are unrelated and all carry a Tyr90 substitution. Recurrence across unrelated probands is an independent pathogenicity argument, curated here rather than as a separate variant so the same allele is not listed twice.

Show evidence (5 references)

PMID:31794431 SUPPORT Human Clinical

"The variants altered chromobarrel and catalytic domains of KAT8, thereby impairing nucleosomal H4K16 acetylation."

Maps the founding alleles onto the two functional domains and states the shared consequence - impaired nucleosomal H4K16 acetylation - which is what makes these alleles one curated class.

PMID:31794431 SUPPORT In Vitro

"The severe impact of p.Tyr90Cys, p.Arg98Gln, and"

Names the three substitutions individually. The quote ends at a line break in the cached full text; the sentence continues "p.Arg99Gln on H4K16 acetylation" on the next line, and the third allele is named in the description.

PMID:31794431 SUPPORT In Vitro

"suggests that the chromobarrel domain is essential for KAT8 to "

The conclusion these alleles support - that the chromobarrel domain is required for the catalytic step, not just for targeting. The quote ends at a line break in the cached text.

+ 2 more references

c.523A>T (nonsense, codon 176)

The only non-missense allele among the founding nine, converting codon 176 to a termination codon. It is curated separately because it is the allele that shows the disorder is not exclusively a missense or dominant-negative mechanism.

Show evidence (1 reference)

PMID:31794431 SUPPORT Human Clinical

"All except c.523A>T are missense variants. c.523A>T is a nonsense variant and converts codon 176 to a termination one."

Identifies the allele, its class, and the codon it truncates at.

c.649A>C (p.Met217Leu)

Homozygous missense variant segregating with LIGOWS in a consanguineous Pakistani family, the basis of the first autosomal recessive report for this locus.

Show evidence (1 reference)

PMID:41347281 SUPPORT Human Clinical

"In Family-2 with LIGOWS, a novel homozygous missense variant ((NM_182958.4): c.649A > C; (NP_892003.2): p.Met217Leu) was found in KAT8."

Identifies the recessive allele and the family it segregates in.

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Medical Actions

1

Valproate for Epilepsy

Action: Pharmacotherapy NCIT:C15986

Agent: valproic acid CHEBI:39867

Valproate is used for the epilepsy, and there is a mechanistic argument for preferring it here rather than treating the choice as arbitrary: valproate inhibits histone deacetylases and so promotes histone acetylation, which could partly offset the acetylation deficit created by impaired KAT8. Both of the two individuals with epilepsy treated with valproate responded. The strength of this should not be overstated. Two responders is an observation, not a trial, there is no report of the acetylation mark being measured before and after treatment in a patient, and valproate is a broad-spectrum anticonvulsant that would be expected to help many epilepsies regardless of mechanism. The mechanistic rationale makes it a reasonable first choice and a testable hypothesis, not established mechanism-directed therapy.

Mechanism Target:

Loss of Nucleosomal H4K16 Acetylation — Proposed, not demonstrated. Inhibiting histone deacetylases would raise histone acetylation globally and might partially compensate for the lost KAT8 activity.

Show evidence (1 reference)

PMID:31794431 SUPPORT Human Clinical

"Valproate is a known deacetylase inhibitor and promotes histone acetylation (42), so it may ameliorate potential acetylation deficiency result"

Graded PARTIAL because the authors state this as a possible mechanism ("may ameliorate"), with no measurement of the acetylation mark in treated patients.

Target Phenotypes: Seizure HP:0001250

Show evidence (1 reference)

PMID:31794431 SUPPORT Human Clinical

"Valproate was effective for treating epilepsy in at least 2 of the individuals."

The clinical observation of response, in two individuals.

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Prevalence

1

Worldwide (published cases)

Cases In Literature Ultra Rare

Nine individuals in the founding cohort, with scattered additions since - a further family in a routine-diagnostics series and one consanguineous family establishing the recessive form. The total published population remains in the low tens.

Show evidence (1 reference)

PMID:31794431 SUPPORT Human Clinical

"identifies 9 individuals with KAT8 variants"

The founding cohort size.

🐁

Animal Models

1

Emx1-Cre cerebrum-specific Kat8 conditional knockout mouse

A conditional rather than constitutive knockout, using the Emx1-Cre driver to delete Kat8 in the cerebrocortical lineage. The design is what makes it interpretable: H4K16ac is lost in the cerebrocortical neuroepithelium and hippocampal primordium but retained in the ganglionic eminences, so the resulting hypoplasia can be attributed to KAT8 in that lineage.

Species

Mouse

Genotype

Kat8 conditional knockout, Emx1-Cre driver (cerebrum-specific)

Genes

KAT8 hgnc:17933

Publication

PMID:31794431

Pathograph links

Cerebral Hypoplasia recapitulates fidelity: moderate Produces cerebral hypoplasia of the neocortex and hippocampus, the structural correlate of the intellectual disability and brain MRI anomalies in patients.

Limitations: A complete conditional knockout, whereas most patients are heterozygous for de novo missense variants affecting the chromobarrel or catalytic domain. The mouse therefore models total loss of KAT8 in a lineage rather than the partial, allele-specific impairment patients carry, and the human MRI findings are described only as consistent with, not equivalent to, the murine hypoplasia.

Readouts

Neocortical and hippocampal size

Direction: DECREASED

Interpretation: Structural hypoplasia of the two regions where H4K16ac is normally highest.

Show evidence (1 reference)

PMID:31794431 SUPPORT Model Organism

"cerebrum-specific knockout mice displayed cerebral hypoplasia in the neocortex and hippocampus"

The structural measurement behind this readout.

Show evidence (1 reference)

PMID:31794431 SUPPORT Model Organism

"uncovers an essential role of mouse Kat8 in cerebral development,"

Supports treating the model as informative for cerebral development. Quoted from the sentence about mouse Kat8 specifically, rather than the summary sentence that also covers the human subjects.

Impaired Neural Stem and Progenitor Cell Expansion recapitulates fidelity: moderate Mutant NSPCs form poor neurospheres, giving a quantitative cellular assay for the progenitor defect.

Limitations: Neurosphere formation is an ex vivo proxy for progenitor self-renewal, and no equivalent measurement exists in patient-derived cells, so the correspondence to human disease is by inference.

Readouts

Neurosphere formation

Direction: DECREASED

Interpretation: Reduced self-renewal capacity of Kat8-null neural stem and progenitor cells.

Show evidence (1 reference)

PMID:31794431 SUPPORT Model Organism

"Mutant NSPCs formed poor neurospheres"

The neurosphere assay result.

Show evidence (1 reference)

PMID:31794431 SUPPORT Model Organism

"the Emx1-Cre line induces Kat8 deletion and abolishes H4K16 acetylation in the cerebrocortical neuroepithelium"

Confirms the conditional deletion achieves lineage-restricted loss of the mark.

{ }

Source YAML

click to show

name: Li-Ghorbani-Weisz-Hubshman Syndrome
category: Mendelian
creation_date: "2026-08-27T00:00:00Z"
synonyms:
- LIGOWS
- KAT8-related neurodevelopmental disorder
- KAT8 deficiency
- MOF-related syndromic intellectual disability
description: >-
  Li-Ghorbani-Weisz-Hubshman syndrome is a neurodevelopmental disorder caused by variants
  in KAT8, the lysine acetyltransferase responsible for acetylating histone H4 at lysine 16
  (H4K16). It belongs to the chromatinopathies - disorders of the chromatin-modifying
  machinery - and sits beside the KAT6A and KAT6B syndromes within the MYST family, from
  which KAT8 is distinguished by its site specificity for H4K16 rather than H3K23.

  The defining feature is that KAT8 is not a general acetyltransferase whose loss is
  tolerable: H4K16ac is high in the developing neocortex and hippocampus, and
  cerebrum-specific Kat8 knockout mice show cerebral hypoplasia with faulty proliferation,
  premature and aberrant neurogenesis, and massive apoptosis of the cerebrocortical
  neuroepithelium. Neural stem and progenitor cells from those mice fail to form
  neurospheres, and pharmacological KAT8 inhibition abolishes neurosphere formation from
  wild-type cortex - so the requirement is acute rather than developmental history alone.

  Nine individuals with KAT8 variants were reported in the founding 2020 study, with global
  developmental delay, intellectual disability, epilepsy, language delay in every case,
  variable facial dysmorphism, and cardiac anomalies in four. The variants cluster in the
  chromobarrel and acetyltransferase domains and impair nucleosomal H4K16 acetylation.
  Eight arose de novo; the ninth individual carried variants transmitted differently,
  and a subsequent Pakistani family established a clearly autosomal recessive form - so
  this is a dual-inheritance locus, not a purely dominant de novo one.

  There is a mechanism-directed treatment lead worth noting. Valproate is a histone
  deacetylase inhibitor, and the founding study's authors reasoned it might offset the
  acetylation deficit; both of the two individuals with epilepsy treated with valproate
  responded. That is two patients, not a trial.
disease_term:
  preferred_term: Li-Ghorbani-Weisz-Hubshman syndrome
  term:
    id: MONDO:0033547
    label: Li-Ghorbani-Weisz-Hubshman syndrome
parents:
- Neurodevelopmental Disorder
inheritance:
- name: Autosomal dominant (de novo)
  description: >-
    The majority of reported individuals carry de novo heterozygous KAT8 variants. KAT8 is
    predicted to be highly intolerant of loss-of-function change, which is consistent with
    dominant disease from a single altered allele.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:31794431
    reference_title: "Lysine acetyltransferase 8 is involved in cerebral development and syndromic intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All except individual T9 carry heterozygous de novo variants."
    explanation: >-
      The direct statement that eight of nine individuals carry heterozygous de novo
      variants, which is what supports dominant inheritance.
  - reference: PMID:31794431
    reference_title: "Lysine acetyltransferase 8 is involved in cerebral development and syndromic intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the 2 variants from individual T9 and her family act differently from the de novo variants from  individuals T1–T8"
    explanation: >-
      Graded PARTIAL and kept as the boundary of the dominant claim, not as its support.
      It documents the one individual whose variants are not de novo, and is quoted here so
      the exception travels with the rule rather than being discovered later.
- name: Autosomal recessive
  description: >-
    A separate, biallelic form. A consanguineous Pakistani family segregated a homozygous
    KAT8 missense variant with the disorder, which the reporting authors identify as the
    first autosomal recessive inheritance pattern described for a KAT8-related disorder.
    The founding study had already anticipated a dual-inheritance locus, comparing KAT8 to
    genes such as EMC1 where both monoallelic and biallelic variants cause developmental
    disease.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:41347281
    reference_title: "The Genetic Basis of Neurological Disorders: Missense and Nonsense Variants in Three Pakistani Families With Syndromic Intellectual Disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This study reports, for the first time, an autosomal recessive inheritance pattern for a KAT8-related disorder, providing new insights into its genetic architecture."
    explanation: Establishes the recessive form as a distinct inheritance mode for this locus.
  - reference: PMID:41347281
    reference_title: "The Genetic Basis of Neurological Disorders: Missense and Nonsense Variants in Three Pakistani Families With Syndromic Intellectual Disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In Family-2 with LIGOWS, a novel homozygous missense variant ((NM_182958.4): c.649A > C; (NP_892003.2): p.Met217Leu) was found in KAT8."
    explanation: The specific homozygous allele underpinning the recessive report.
  - reference: PMID:31794431
    reference_title: "Lysine acetyltransferase 8 is involved in cerebral development and syndromic intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "dual-mode inheritance has been reported for some genes. For example, both monoallelic and biallelic EMC1 (and several other genes) variants cause develop"
    explanation: >-
      Graded PARTIAL - the founding study raises dual-mode inheritance as a hypothesis by
      analogy to EMC1, before the recessive family was reported. It anticipates the finding
      rather than establishing it.
pathophysiology:
- name: KAT8 Loss of Function
  description: >-
    Pathogenic KAT8 variants alter either the chromobarrel domain or the acetyltransferase
    core. The acetyltransferase domain comprises a KAT8/Mof-specific region absent from
    other MYST family members plus the MYST domain itself. Of the characterised missense
    variants, three alter the chromobarrel domain and four the acetyltransferase domain, so
    the disease can arise either by disrupting catalysis directly or by disrupting the
    reader module that positions the enzyme. KAT8 is highly intolerant of loss-of-function
    change and moderately intolerant of missense change.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: KAT8
    term:
      id: hgnc:17933
      label: KAT8
  molecular_functions:
  - preferred_term: histone H4K16 acetyltransferase activity
    modifier: LOSS_OF_FUNCTION
    term:
      id: GO:0046972
      label: histone H4K16 acetyltransferase activity
  downstream:
  - target: Loss of Nucleosomal H4K16 Acetylation
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:31794431
    reference_title: "Lysine acetyltransferase 8 is involved in cerebral development and syndromic intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The variants altered chromobarrel and catalytic domains of KAT8, thereby impairing nucleosomal H4K16 acetylation."
    explanation: Maps the patient variants onto the two functional domains and states the biochemical consequence.
  - reference: PMID:31794431
    reference_title: "Lysine acetyltransferase 8 is involved in cerebral development and syndromic intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Among the missense variants, 3 alter the chromobarrel domain, and 4 change the acetyltransferase domain."
    explanation: Quantifies the split between reader-module and catalytic-domain variants.
- name: Loss of Nucleosomal H4K16 Acetylation
  description: >-
    H4K16 acetylation is an evolutionarily conserved mark, and KAT8 is the major enzyme
    that writes it in mammals. Its level is high in the neocortex and hippocampus of the
    adult brain, at P5, and in the cerebrocortical neuroepithelium at E12.5 - the
    distribution that first implicated KAT8 in cerebral development. In Emx1-Cre
    conditional knockout mice the mark disappears from the cerebrocortical neuroepithelium
    and hippocampal primordium while being retained in the ganglionic eminences, which is
    what makes the resulting phenotype attributable to KAT8 in that specific lineage rather
    than to a global effect.

    KAT8 works through two distinct complexes - MSL and NSL - and the disease may reflect
    disruption of both. Variants in KANSL1, which encodes the NSL1 subunit, cause
    Koolen-de Vries syndrome, and MSL3 variants cause an X-linked developmental disorder.
    Individuals with KAT8 variants show epilepsy and other features absent in MSL3 disease,
    which argues KAT8 is not simply acting through one complex.
  biological_scale: MOLECULAR
  molecular_functions:
  - preferred_term: histone H4K16 acetyltransferase activity
    modifier: DECREASED
    term:
      id: GO:0046972
      label: histone H4K16 acetyltransferase activity
  downstream:
  - target: Impaired Neural Stem and Progenitor Cell Expansion
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:31794431
    reference_title: "Lysine acetyltransferase 8 is involved in cerebral development and syndromic intellectual disability."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "H4K16ac disappeared in the cerebrocortical neuroepithelium and hippocampal primordium at E12.5, but not the in the medial or lateral ganglionic eminence"
    explanation: >-
      Demonstrates lineage-restricted loss of the mark, which is what attributes the
      downstream phenotype to KAT8 in the cerebrocortical lineage.
  - reference: PMID:31794431
    reference_title: "Lysine acetyltransferase 8 is involved in cerebral development and syndromic intellectual disability."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "the H4K16ac level was high in the neocortex and hippocampus of the adult brain, as well as in these areas at P5 and in the cerebrocortical neuro  epithelium at E12.5"
    explanation: Establishes the developmental expression pattern that implicates KAT8 in cerebral development.
  - reference: PMID:31794431
    reference_title: "Lysine acetyltransferase 8 is involved in cerebral development and syndromic intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "that KAT8 may act through both MSL and NSL complexes"
    explanation: >-
      Graded PARTIAL - the authors' own conclusion, which they state as a suggestion, that
      KAT8 acts through both complexes. It rests on a phenotypic contrast with MSL3-related
      disease rather than a direct assay.
  - reference: PMID:31794431
    reference_title: "Lysine acetyltransferase 8 is involved in cerebral development and syndromic intellectual disability."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "MSL3 cooperates with MSL1 and MSL2 in KAT8 activation"
    explanation: >-
      Establishes that KAT8 activity depends on partner subunits, which is the basis for
      the claim that complex composition matters to disease.
  - reference: PMID:31267707
    reference_title: "The non-specific lethal (NSL) complex at the crossroads of transcriptional control and cellular homeostasis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Highlighting their importance, mutations or deregulation of NSL complex members has been reported in both human neurodevelopmental disorders and cancer."
    explanation: >-
      Independent support for the NSL half of the dual-complex claim: disrupting other
      members of the same complex also produces neurodevelopmental disease, which is the
      pattern this node's KANSL1 and MSL3 comparison relies on. Graded OTHER as an expert
      review rather than a study reporting its own data.
  notes: >-
    Bound to the specific acetyltransferase activity rather than to a broad chromatin
    process, and placed in molecular_functions accordingly. A parent term such as chromatin
    organization would invert the biology if given a DECREASED modifier: H4K16 acetylation
    opposes chromatin compaction, so losing it makes chromatin more compact, not less
    organised.

    This node shares GO:0046972 with the upstream KAT8 Loss of Function node and is
    separated from it by the modifier, not by the term. That is deliberate, because GO
    offers nothing else to separate them with. The process-level term for the mark,
    GO:0043984 histone H4-K16 acetylation, is obsolete, and the obsoletion comment is
    explicit about why: "This term was obsoleted because it represents a molecular
    function." Its regulation terms (GO:2000618, GO:2000619, GO:2000620) are obsolete for
    the same reason. GO has therefore ruled that this concept is a molecular function, so
    there is no live biological-process term to move the mark to.

    The modifier carries the distinction instead, and it is the distinction this repository
    already draws. The enzyme node is qualitative - missense substitutions impede the
    acetyltransferase activity itself, so LOSS_OF_FUNCTION. This node is quantitative - the
    mark is depleted from a lineage, a normally regulated activity running below its normal
    level, so DECREASED, which is also PATO-bound and stays queryable.

    Separately: the source text quotes "neuro  epithelium" with an internal double space, a
    line-break artefact of the cached full text. The snippet preserves it because snippets
    must be exact substrings.
- name: Impaired Neural Stem and Progenitor Cell Expansion
  description: >-
    Loss of H4K16ac impairs neural stem and progenitor cell development. Mutant NSPCs form
    poor neurospheres, and - importantly - pharmacological KAT8 inhibition abolishes
    neurosphere formation from wild-type cortex. That second result matters because it
    separates an acute requirement for KAT8 activity from the accumulated consequences of
    a developmental knockout. The inhibitor experiment was designed as a comparison: MG149
    targets both KAT5 and KAT8 while NU9056 is KAT5-specific, so the difference between
    them isolates the KAT8 contribution.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: neural stem cell
    term:
      id: CL:0000047
      label: neural stem cell
  biological_processes:
  - preferred_term: neural precursor cell proliferation
    modifier: DECREASED
    term:
      id: GO:0061351
      label: neural precursor cell proliferation
  downstream:
  - target: Aberrant Neurogenesis and Neuroepithelial Apoptosis
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:31794431
    reference_title: "Lysine acetyltransferase 8 is involved in cerebral development and syndromic intellectual disability."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Mutant NSPCs formed poor neurospheres, and pharmacological KAT8 inhibition abolished neurosphere formation."
    explanation: Both the genetic and the pharmacological demonstrations of impaired NSPC expansion.
  - reference: PMID:31794431
    reference_title: "Lysine acetyltransferase 8 is involved in cerebral development and syndromic intellectual disability."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The former targets both KAT5 and KAT8 (34), whereas NU9056 is specific to KAT5 (35). The difference between these 2 inhibitors would allow us to compare their impact and deduce the effect of KAT8 inhibition on neurospheres."
    explanation: >-
      The comparative inhibitor design that isolates the KAT8-specific contribution, since
      no KAT8-selective inhibitor was available at the time.
- name: Aberrant Neurogenesis and Neuroepithelial Apoptosis
  description: >-
    The mutant cerebrocortical neuroepithelium shows faulty proliferation, premature and
    aberrant neurogenesis, and massive apoptosis. The combination - progenitors both
    differentiating too early and dying - depletes the progenitor pool from two directions
    at once, which is why the structural consequence is hypoplasia rather than a subtler
    patterning defect.
  biological_scale: TISSUE
  biological_processes:
  - preferred_term: neurogenesis
    modifier: DYSREGULATED
    term:
      id: GO:0022008
      label: neurogenesis
  - preferred_term: apoptotic process
    modifier: INCREASED
    term:
      id: GO:0006915
      label: apoptotic process
  downstream:
  - target: Cerebral Hypoplasia
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:31794431
    reference_title: "Lysine acetyltransferase 8 is involved in cerebral development and syndromic intellectual disability."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Mutant cerebrocortical neuroepithelia exhibited faulty proliferation, aberrant neurogenesis, massive apoptosis, and scant H4K16 propionylation."
    explanation: The primary cellular phenotype of the conditional knockout.
- name: Cerebral Hypoplasia
  description: >-
    Cerebral hypoplasia of the neocortex and hippocampus in the conditional knockout,
    matching the brain MRI anomalies and the intellectual disability and epilepsy seen in
    patients.
  biological_scale: ORGANISM
  locations:
  - preferred_term: neocortex
    term:
      id: UBERON:0001950
      label: neocortex
  - preferred_term: hippocampal formation
    term:
      id: UBERON:0002421
      label: hippocampal formation
  evidence:
  - reference: PMID:31794431
    reference_title: "Lysine acetyltransferase 8 is involved in cerebral development and syndromic intellectual disability."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "cerebrum-specific knockout mice displayed cerebral hypoplasia in the neocortex and hippocampus, along with improper neural stem and progenitor cell (NSPC) development"
    explanation: The structural endpoint of the mouse phenotype.
  - reference: PMID:31794431
    reference_title: "Lysine acetyltransferase 8 is involved in cerebral development and syndromic intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Several individuals showed brain MRI anom-"
    explanation: >-
      Graded PARTIAL - brain MRI anomalies were present in only some individuals and are
      described by the authors as consistent with the murine hypoplasia rather than shown
      to be the same lesion. The quote ends mid-word because the cached full text breaks
      "anomalies" across a line and snippets must be exact substrings.
phenotypes:
- name: Global Developmental Delay
  category: Neurologic
  description: Global developmental delay, frequently observed across reported individuals.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:31794431
    reference_title: "Lysine acetyltransferase 8 is involved in cerebral development and syndromic intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Global developmental delay, intellectual disability, epilepsy, and other developmental anomalies were frequently observed in the affected individuals"
    explanation: States global developmental delay among the frequent findings.
  notes: >-
    Graded FREQUENT, not VERY_FREQUENT. The only quantifier the source gives is "frequently
    observed", with no count, and under the frequency conventions that maps to the 30-79%
    band. VERY_FREQUENT would assert 80-99%, which nothing in the cohort description
    supports.
- name: Abnormal Brain Morphology
  category: Neurologic
  description: >-
    Structural brain abnormalities on MRI in several of the nine founding individuals. The
    findings are variable rather than a single consistent malformation, and the specific
    anomalies are reported in the paper's supplementary figures and table, which the cached
    full text does not carry - so this is bound to the general brain-morphology term and no
    specific malformation is asserted. It is curated because the pathograph terminates in
    Cerebral Hypoplasia and without this phenotype the human counterpart of that node is
    missing from the entry.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Abnormal brain morphology
    term:
      id: HP:0012443
      label: Abnormal brain morphology
  evidence:
  - reference: PMID:31794431
    reference_title: "Lysine acetyltransferase 8 is involved in cerebral development and syndromic intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Several individuals showed brain MRI anom-"
    explanation: >-
      The clinical statement. The quote ends on a hyphenated line break in the cached full
      text, which is why it stops at "anom-".
  - reference: PMID:31794431
    reference_title: "Lysine acetyltransferase 8 is involved in cerebral development and syndromic intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "able brain MRI defects in the clinical cases (Supplemental Figure "
    explanation: >-
      The authors' own reading, that the MRI defects are variable and together with the
      intellectual disability and epilepsy indicate abnormal brain development consistent
      with the knockout mouse. Begins mid-word because "variable" is hyphenated across a
      line break in the cached text.
  notes: >-
    Graded OCCASIONAL. "Several individuals" out of nine gives no count, and the companion
    sentence calls the defects variable, so neither FREQUENT nor a specific malformation
    can be asserted from the cached text. If the supplementary table is later obtained, the
    right move is to split this into the specific malformations with their own counts.
- name: Intellectual Disability
  category: Neurologic
  description: Intellectual disability, one of the defining features of the syndrome.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:31794431
    reference_title: "Lysine acetyltransferase 8 is involved in cerebral development and syndromic intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Global developmental delay, intellectual disability, epilepsy, and other developmental anomalies were frequently observed in the affected individuals"
    explanation: >-
      Names intellectual disability among the frequently observed findings, which is the
      quote the FREQUENT band rests on.
  - reference: PMID:31794431
    reference_title: "Lysine acetyltransferase 8 is involved in cerebral development and syndromic intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "links deficient H4K16 acylation directly to intellectual disability, epilepsy, and other developmental anomalies"
    explanation: Connects the molecular defect to intellectual disability as a core outcome.
  notes: >-
    Graded FREQUENT, not VERY_FREQUENT, on the same reasoning as Global Developmental
    Delay: both are named in one sentence as "frequently observed", which maps to the
    30-79% band. The deep research reports intellectual disability in 9 of 9 individuals,
    which would justify VERY_FREQUENT, but that count is in supplementary material the
    cached full text does not carry, and this entry does not assert what it cannot quote.
    A cached quote giving the 80-99% count is what would move this.
- name: Language Delay
  category: Neurologic
  description: >-
    Language delay of variable severity, notable for occurring in every individual in the
    founding cohort - ranging from difficulty with pronunciation to no speech at age four.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Delayed speech and language development
    term:
      id: HP:0000750
      label: Delayed speech and language development
  evidence:
  - reference: PMID:31794431
    reference_title: "Lysine acetyltransferase 8 is involved in cerebral development and syndromic intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Variable language delay occurred in all individuals (Figure 7B and Supple"
    explanation: >-
      Language delay was present in every individual in the founding cohort, which is why
      it is graded VERY_FREQUENT even against the small cohort size.
- name: Seizure
  category: Neurologic
  description: >-
    Epilepsy, with EEG abnormalities in some individuals. This is one of the features that
    distinguishes KAT8-related disease from MSL3-related developmental disorder.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:31794431
    reference_title: "Lysine acetyltransferase 8 is involved in cerebral development and syndromic intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we describe KAT8 variants in 9 patients with intellectual disability, seizures, autism, dysmorphisms, and other anomalies"
    explanation: Seizures among the core features of the founding nine-patient cohort.
  - reference: PMID:31794431
    reference_title: "Lysine acetyltransferase 8 is involved in cerebral development and syndromic intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "As for epilepsy, some exhibited EEG abnormalities (Supplemental Table 1)."
    explanation: Documents electrophysiological correlates in a subset.
- name: Autistic Behavior
  category: Behavioral
  description: >-
    Autistic features, reported in two of the nine individuals in the founding cohort.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Autistic behavior
    term:
      id: HP:0000729
      label: Autistic behavior
  evidence:
  - reference: PMID:31794431
    reference_title: "Lysine acetyltransferase 8 is involved in cerebral development and syndromic intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Two individuals also showed autistic features (Figure 7B), and 1 individual displayed characteristics of attention deficit hyperactivity disorder"
    explanation: >-
      Quantifies autistic features at 2 of 9, which supports the OCCASIONAL grading rather
      than treating autism as a core feature.
- name: Attention Deficit Hyperactivity Disorder
  category: Behavioral
  description: >-
    Attention deficit hyperactivity disorder characteristics, reported in one of the nine
    individuals in the founding cohort.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Attention deficit hyperactivity disorder
    term:
      id: HP:0007018
      label: Attention deficit hyperactivity disorder
  evidence:
  - reference: PMID:31794431
    reference_title: "Lysine acetyltransferase 8 is involved in cerebral development and syndromic intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Two individuals also showed autistic features (Figure 7B), and 1 individual displayed characteristics of attention deficit hyperactivity disorder"
    explanation: >-
      Quantifies ADHD characteristics at 1 of 9, which supports the OCCASIONAL grading. The
      sentence reports autistic features in the same breath and is quoted on that phenotype
      too; the two are curated separately because they are distinct HPO terms.
- name: Abnormal Facial Shape
  category: Craniofacial
  description: >-
    Variable facial dysmorphism. Recurrent features are upper lateral eyelid fullness,
    low-set ears, downturned corners of the mouth, a depressed nasal bridge, mild malar
    hypoplasia and epicanthi.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Abnormal facial shape
    term:
      id: HP:0001999
      label: Abnormal facial shape
  evidence:
  - reference: PMID:31794431
    reference_title: "Lysine acetyltransferase 8 is involved in cerebral development and syndromic intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Recurrent dysmorphisms included upper lateral eyelid fullness, low-set ears, downturned corners of the mouth, a depressed nasal bridge, mild malar hypoplasia, and epicanthi"
    explanation: Enumerates the recurrent dysmorphic features.
- name: Motor Delay
  category: Neurologic
  description: Gross and fine motor delays, described as common.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Motor delay
    term:
      id: HP:0001270
      label: Motor delay
  evidence:
  - reference: PMID:31794431
    reference_title: "Lysine acetyltransferase 8 is involved in cerebral development and syndromic intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Gross and fine motor delays were other common anomalies"
    explanation: States gross and fine motor delay as common findings.
- name: Congenital Heart Defect
  category: Cardiovascular
  description: >-
    Cardiac anomalies in four of the nine individuals in the founding cohort - a
    substantial minority, and a reason to image the heart in a newly diagnosed patient
    rather than treating this as a purely neurological syndrome.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Abnormal heart morphology
    term:
      id: HP:0001627
      label: Abnormal heart morphology
  evidence:
  - reference: PMID:31794431
    reference_title: "Lysine acetyltransferase 8 is involved in cerebral development and syndromic intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Four individuals had car-\ndiac anomalies (Figure 7B and Supplemental Table 1)."
    explanation: >-
      Quantifies cardiac involvement at 4 of 9. The quoted text spans a hyphenated
      line break in the cached full text.
genetic:
- name: KAT8
  notes: >-
    KAT8 encodes lysine acetyltransferase 8, the MYST-family enzyme responsible for H4K16
    acetylation, orthologous to Drosophila Mof (males absent on the first). The protein has
    a chromobarrel domain and an acetyltransferase core containing a KAT8/Mof-specific
    region absent from other MYST members plus the MYST domain. Constraint metrics place it
    as moderately intolerant of missense change and highly intolerant of loss of function.
  relationship_type: CAUSATIVE
  gene_term:
    preferred_term: KAT8
    term:
      id: hgnc:17933
      label: KAT8
  evidence:
  - reference: PMID:31794431
    reference_title: "Lysine acetyltransferase 8 is involved in cerebral development and syndromic intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This study uncovers a critical role of KAT8 in cerebral and NSPC development, identifies 9 individuals with KAT8 variants, and links deficient H4K16 acylation directly to intellectual disability, epilepsy, and other developmental anomalies."
    explanation: The founding gene-disease association.
  - reference: PMID:31794431
    reference_title: "Lysine acetyltransferase 8 is involved in cerebral development and syndromic intellectual disability."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "It is predicted to be moderately intol-\nerant of missense change (misZ [Z  score of missense variation \nintolerance] score of 3.66)"
    explanation: >-
      Population constraint metrics supporting pathogenicity of missense change. Graded
      COMPUTATIONAL because these are in-silico population-genetic predictions.
  - reference: PMID:36553572
    reference_title: "Routine Diagnostics Confirm Novel Neurodevelopmental Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "substantially strengthen the confirmation of genes with limited evidence in the medical literature (ADARB1, AP2M1, BCKDK, BCORL1, CARS2, FBXO38, GABRB1, KAT8, PRKD1, RAB11B, RUSC2, ZNF142)"
    explanation: >-
      Independent routine-diagnostics evidence strengthening the KAT8 gene-disease
      association, from a cohort of nearly 10,000 analyses.
  variants:
  - name: Chromobarrel-domain missense substitutions (p.Tyr90Cys, p.Arg98Gln, p.Arg99Gln)
    description: >-
      Three heterozygous de novo missense substitutions in the chromobarrel domain, curated
      as one entry because the founding study treats them as one functional class and tests
      them together. They impede the acetyltransferase activity of KAT8, which is the
      experiment that establishes the chromobarrel domain as required for KAT8 to acetylate
      nucleosomal H4K16 rather than merely for substrate binding.

      p.Tyr90Cys is also the recurrent allele of the founding cohort: individuals T1, T2 and
      T3 are unrelated and all carry a Tyr90 substitution. Recurrence across unrelated
      probands is an independent pathogenicity argument, curated here rather than as a
      separate variant so the same allele is not listed twice.
    evidence:
    - reference: PMID:31794431
      reference_title: "Lysine acetyltransferase 8 is involved in cerebral development and syndromic intellectual disability."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The variants altered chromobarrel and catalytic domains of KAT8, thereby impairing nucleosomal H4K16 acetylation."
      explanation: >-
        Maps the founding alleles onto the two functional domains and states the shared
        consequence - impaired nucleosomal H4K16 acetylation - which is what makes these
        alleles one curated class.
    - reference: PMID:31794431
      reference_title: "Lysine acetyltransferase 8 is involved in cerebral development and syndromic intellectual disability."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "The severe impact of p.Tyr90Cys, p.Arg98Gln, and"
      explanation: >-
        Names the three substitutions individually. The quote ends at a line break in the
        cached full text; the sentence continues "p.Arg99Gln on H4K16 acetylation" on the
        next line, and the third allele is named in the description.
    - reference: PMID:31794431
      reference_title: "Lysine acetyltransferase 8 is involved in cerebral development and syndromic intellectual disability."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "suggests that the chromobarrel domain is essential for KAT8 to "
      explanation: >-
        The conclusion these alleles support - that the chromobarrel domain is required for
        the catalytic step, not just for targeting. The quote ends at a line break in the
        cached text.
    - reference: PMID:31794431
      reference_title: "Lysine acetyltransferase 8 is involved in cerebral development and syndromic intellectual disability."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The recurrent variant in individuals T1, T2, and T3 alter Tyr90, whereas the missense variants in individuals T4 and T5 substitute Arg98 and Arg99, respectively."
      explanation: >-
        Names the recurrent allele as the Tyr90 substitution and separates it from the two
        other chromobarrel alleles, which is why the recurrence is curated on this entry
        rather than as an unnamed variant of its own.
    - reference: PMID:31794431
      reference_title: "Lysine acetyltransferase 8 is involved in cerebral development and syndromic intellectual disability."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "All except individual T9 carry heterozygous de novo variants."
      explanation: >-
        Establishes that these are de novo and heterozygous, which together with the
        recurrence is the founding pathogenicity argument.
  - name: c.523A>T (nonsense, codon 176)
    description: >-
      The only non-missense allele among the founding nine, converting codon 176 to a
      termination codon. It is curated separately because it is the allele that shows the
      disorder is not exclusively a missense or dominant-negative mechanism.
    evidence:
    - reference: PMID:31794431
      reference_title: "Lysine acetyltransferase 8 is involved in cerebral development and syndromic intellectual disability."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "All except c.523A>T are missense variants. c.523A>T is a nonsense variant and converts codon 176 to a termination one."
      explanation: Identifies the allele, its class, and the codon it truncates at.
  - name: c.649A>C (p.Met217Leu)
    description: >-
      Homozygous missense variant segregating with LIGOWS in a consanguineous Pakistani
      family, the basis of the first autosomal recessive report for this locus.
    evidence:
    - reference: PMID:41347281
      reference_title: "The Genetic Basis of Neurological Disorders: Missense and Nonsense Variants in Three Pakistani Families With Syndromic Intellectual Disability."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "In Family-2 with LIGOWS, a novel homozygous missense variant ((NM_182958.4): c.649A > C; (NP_892003.2): p.Met217Leu) was found in KAT8."
      explanation: Identifies the recessive allele and the family it segregates in.
prevalence:
- population: Worldwide (published cases)
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Nine individuals in the founding cohort, with scattered additions since - a further
    family in a routine-diagnostics series and one consanguineous family establishing the
    recessive form. The total published population remains in the low tens.
  evidence:
  - reference: PMID:31794431
    reference_title: "Lysine acetyltransferase 8 is involved in cerebral development and syndromic intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "identifies 9 individuals with KAT8 variants"
    explanation: The founding cohort size.
treatments:
- name: Valproate for Epilepsy
  description: >-
    Valproate is used for the epilepsy, and there is a mechanistic argument for preferring
    it here rather than treating the choice as arbitrary: valproate inhibits histone
    deacetylases and so promotes histone acetylation, which could partly offset the
    acetylation deficit created by impaired KAT8. Both of the two individuals with epilepsy
    treated with valproate responded.

    The strength of this should not be overstated. Two responders is an observation, not a
    trial, there is no report of the acetylation mark being measured before and after
    treatment in a patient, and valproate is a broad-spectrum anticonvulsant that would be
    expected to help many epilepsies regardless of mechanism. The mechanistic rationale
    makes it a reasonable first choice and a testable hypothesis, not established
    mechanism-directed therapy.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: valproic acid
      term:
        id: CHEBI:39867
        label: valproic acid
  target_phenotypes:
  - preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  target_mechanisms:
  - target: Loss of Nucleosomal H4K16 Acetylation
    description: >-
      Proposed, not demonstrated. Inhibiting histone deacetylases would raise histone
      acetylation globally and might partially compensate for the lost KAT8 activity.
    evidence:
    - reference: PMID:31794431
      reference_title: "Lysine acetyltransferase 8 is involved in cerebral development and syndromic intellectual disability."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Valproate is a known deacetylase inhibitor and promotes histone acetylation (42), so it may ameliorate potential acetylation deficiency result"
      explanation: >-
        Graded PARTIAL because the authors state this as a possible mechanism ("may
        ameliorate"), with no measurement of the acetylation mark in treated patients.
  evidence:
  - reference: PMID:31794431
    reference_title: "Lysine acetyltransferase 8 is involved in cerebral development and syndromic intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Valproate was effective for treating epilepsy in at least 2 of the individuals."
    explanation: The clinical observation of response, in two individuals.
animal_models:
- name: Emx1-Cre cerebrum-specific Kat8 conditional knockout mouse
  species: Mouse
  genotype: Kat8 conditional knockout, Emx1-Cre driver (cerebrum-specific)
  publication: PMID:31794431
  description: >-
    A conditional rather than constitutive knockout, using the Emx1-Cre driver to delete
    Kat8 in the cerebrocortical lineage. The design is what makes it interpretable: H4K16ac
    is lost in the cerebrocortical neuroepithelium and hippocampal primordium but retained
    in the ganglionic eminences, so the resulting hypoplasia can be attributed to KAT8 in
    that lineage.
  genes:
  - preferred_term: KAT8
    term:
      id: hgnc:17933
      label: KAT8
  modeled_mechanisms:
  - target: Cerebral Hypoplasia
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Produces cerebral hypoplasia of the neocortex and hippocampus, the structural
      correlate of the intellectual disability and brain MRI anomalies in patients.
    limitations: >-
      A complete conditional knockout, whereas most patients are heterozygous for de novo
      missense variants affecting the chromobarrel or catalytic domain. The mouse therefore
      models total loss of KAT8 in a lineage rather than the partial, allele-specific
      impairment patients carry, and the human MRI findings are described only as
      consistent with, not equivalent to, the murine hypoplasia.
    readouts:
    - name: Neocortical and hippocampal size
      target: Cerebral Hypoplasia
      direction: DECREASED
      interpretation: Structural hypoplasia of the two regions where H4K16ac is normally highest.
      evidence:
      - reference: PMID:31794431
        reference_title: "Lysine acetyltransferase 8 is involved in cerebral development and syndromic intellectual disability."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "cerebrum-specific knockout mice displayed cerebral hypoplasia in the neocortex and hippocampus"
        explanation: The structural measurement behind this readout.
    evidence:
    - reference: PMID:31794431
      reference_title: "Lysine acetyltransferase 8 is involved in cerebral development and syndromic intellectual disability."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "uncovers an essential role of mouse Kat8 in cerebral development,"
      explanation: >-
        Supports treating the model as informative for cerebral development. Quoted from
        the sentence about mouse Kat8 specifically, rather than the summary sentence that
        also covers the human subjects.
  - target: Impaired Neural Stem and Progenitor Cell Expansion
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Mutant NSPCs form poor neurospheres, giving a quantitative cellular assay for the
      progenitor defect.
    limitations: >-
      Neurosphere formation is an ex vivo proxy for progenitor self-renewal, and no
      equivalent measurement exists in patient-derived cells, so the correspondence to
      human disease is by inference.
    readouts:
    - name: Neurosphere formation
      target: Impaired Neural Stem and Progenitor Cell Expansion
      direction: DECREASED
      interpretation: Reduced self-renewal capacity of Kat8-null neural stem and progenitor cells.
      evidence:
      - reference: PMID:31794431
        reference_title: "Lysine acetyltransferase 8 is involved in cerebral development and syndromic intellectual disability."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Mutant NSPCs formed poor neurospheres"
        explanation: The neurosphere assay result.
  evidence:
  - reference: PMID:31794431
    reference_title: "Lysine acetyltransferase 8 is involved in cerebral development and syndromic intellectual disability."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "the Emx1-Cre line induces Kat8 deletion and abolishes H4K16 acetylation in the cerebrocortical neuroepithelium"
    explanation: Confirms the conditional deletion achieves lineage-restricted loss of the mark.
discussions:
- discussion_id: kat8_valproate_mechanism_untested
  kind: KNOWLEDGE_GAP
  prompt: >-
    Does valproate work in KAT8-related epilepsy by restoring histone acetylation, or
    simply as a broad-spectrum anticonvulsant? Nobody has measured the mark in a treated
    patient.
  attaches_to:
  - treatments#Valproate for Epilepsy
  - pathophysiology#Loss of Nucleosomal H4K16 Acetylation
  rationale: >-
    The reasoning is attractive: KAT8 writes an acetylation mark, valproate inhibits the
    deacetylases that erase acetylation marks, and both treated individuals responded. But
    two patients cannot distinguish a mechanism-directed effect from valproate simply
    working as it does in many epilepsies, and the founding authors themselves phrase it as
    "may ameliorate". The question is answerable with existing technology - measure H4K16ac
    in patient-derived cells or accessible tissue before and after treatment, or compare
    response rates against a non-HDAC-inhibiting anticonvulsant in a larger cohort. It
    matters beyond this disorder: if the logic holds, HDAC inhibition becomes a rational
    strategy across the writer chromatinopathies, and if it does not, a plausible-sounding
    rationale is steering drug choice on no evidence.
  evidence:
  - reference: PMID:31794431
    reference_title: "Lysine acetyltransferase 8 is involved in cerebral development and syndromic intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Valproate is a known deacetylase inhibitor and promotes histone acetylation (42), so it may ameliorate potential acetylation deficiency result"
    explanation: The hypothesis as stated by its authors, in explicitly conditional terms.
  - reference: PMID:31794431
    reference_title: "Lysine acetyltransferase 8 is involved in cerebral development and syndromic intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Valproate was effective for treating epilepsy in at least 2 of the individuals."
    explanation: >-
      The entire clinical evidence base - two individuals - which is why this is a gap
      rather than an established mechanism.
- discussion_id: kat8_dual_inheritance
  kind: KNOWLEDGE_GAP
  prompt: >-
    How do monoallelic de novo and biallelic KAT8 variants produce the same syndrome, and
    do the two forms differ in severity or in which domains are affected?
  attaches_to:
  - inheritance#Autosomal recessive
  - pathophysiology#KAT8 Loss of Function
  rationale: >-
    KAT8 is highly intolerant of loss-of-function change, which fits dominant disease from
    a single de novo allele. Yet a homozygous missense variant segregates recessively in a
    consanguineous family, and the founding study had already flagged one individual whose
    variants behaved differently from the de novo cases. The most economical explanation is
    a dose-and-severity gradient - severe alleles causing dominant disease, milder
    hypomorphic alleles needing two copies - which would predict that the recessive alleles
    retain more residual acetyltransferase activity than the dominant ones. That is
    directly testable with the same nucleosomal H4K16 acetylation assay the founding study
    already used on the de novo variants, and has not been done for the recessive allele.
  evidence:
  - reference: PMID:41347281
    reference_title: "The Genetic Basis of Neurological Disorders: Missense and Nonsense Variants in Three Pakistani Families With Syndromic Intellectual Disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This study reports, for the first time, an autosomal recessive inheritance pattern for a KAT8-related disorder, providing new insights into its genetic architecture."
    explanation: Establishes that both inheritance modes occur at this locus.
  - reference: PMID:41347281
    reference_title: "The Genetic Basis of Neurological Disorders: Missense and Nonsense Variants in Three Pakistani Families With Syndromic Intellectual Disability."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "The functional consequences of the ADGRG1 and KAT8 missense variants were revealed as deleterious using bioinformatic prediction tools."
    explanation: >-
      Graded PARTIAL and COMPUTATIONAL - the recessive allele's effect was assessed by
      in-silico prediction, not by the enzymatic assay that would settle the
      residual-activity question.

📚

References & Deep Research

Deep Research

1

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Li-Ghorbani-Weisz-Hubshman Syndrome (LIGOWS): Comprehensive Research Report

claude-haiku-4-5-20251001, claude-sonnet-5 15 citations 2026-08-27T14:28:32.749273

Li-Ghorbani-Weisz-Hubshman Syndrome (LIGOWS): Comprehensive Research Report

1. Disease Information

Overview

Li-Ghorbani-Weisz-Hubshman syndrome (LIGOWS) is a rare, autosomal dominant (with one reported autosomal recessive family) neurodevelopmental disorder caused by heterozygous (or, rarely, biallelic) pathogenic variants in KAT8 (Lysine Acetyltransferase 8, also known as MOF/MYST1) on chromosome 16p11.2. It was first delineated in 2020 by Li, Ghorbani, Weisz-Hubshman and colleagues, who identified pathogenic KAT8 variants in 9 unrelated individuals with intellectual disability, seizures, autism, dysmorphic features, and other congenital anomalies, and mechanistically linked the disorder to impaired histone H4 lysine 16 acetylation (H4K16ac) (Li et al. 2020, J Clin Invest 130(3):1431-1445, PMID:31794431).

Key Identifiers

Resource	ID
OMIM phenotype	#618974 — LI-GHORBANI-WEISZ-HUBSHMAN SYNDROME; LIGOWS (omim.org/entry/618974)
OMIM gene	*609912 — KAT8 (Lysine Acetyltransferase 8)
MONDO	MONDO:0033547 (monarchinitiative.org/MONDO:0033547)
MedGen	C5436525 / UID 1763263 (ncbi.nlm.nih.gov/medgen/1763263)
Gene symbol / HGNC	KAT8 / HGNC:17933
Gene location	16p11.2
Inheritance	Autosomal dominant (predominant); rare autosomal recessive reported

Synonyms

"LIGOWS," "Li-Ghorbani-Weisz-Hubshman syndrome," and informally "KAT8-related neurodevelopmental disorder" / "KAT8-associated intellectual disability."

Data provenance note

Nearly all clinical characterization derives from a single aggregated, multi-center case series (the founding 2020 report), not from population-level EHR data or disease registries — this is a very recently delineated ultra-rare Mendelian disorder with a small published cohort (9 probands in the original description; independent replication cohorts are sparse in subsequent literature searches).

2. Etiology

Disease Causal Factors

LIGOWS is caused by de novo heterozygous missense (and one nonsense) variants in KAT8, with one family showing biallelic (compound heterozygous) inheritance from unaffected carrier parents, suggesting rare autosomal recessive transmission with possible incomplete penetrance for milder alleles (PMID:31794431).

Genetic Risk Factors

Causal variant class: De novo heterozygous missense variants clustering in two functional domains of KAT8: the chromobarrel domain (nucleosome/histone recognition) and the catalytic MYST domain (acetyl-CoA binding/enzymatic activity).
A recurrent de novo variant, c.269A>G (p.Tyr90Cys), was found independently in three unrelated patients (T1–T3), indicating a mutational hotspot in the chromobarrel domain.
No modifier genes have yet been reported.

Environmental Risk Factors

None identified; this is a purely monogenic disorder with no established environmental, infectious, or lifestyle contribution to causation.

Protective Factors

None reported in the literature to date.

Gene-Environment Interactions

Not applicable/not studied — no data on environmental modulation of penetrance or severity.

3. Genetic/Molecular Information

Causal Gene

KAT8 (Lysine Acetyltransferase 8; aliases MOF, MYST1, hMOF), HGNC:17933, OMIM *609912, located at 16p11.2. KAT8 encodes a MYST-family histone acetyltransferase with a chromobarrel domain (histone/nucleosome recognition), an acetyl-CoA-binding MYST catalytic domain, and a C2HC-type zinc finger (GeneCards).

Pathogenic Variants Identified (Li et al. 2020, PMID:31794431)

Patient(s)	Nucleotide change	Protein change	Domain	Zygosity
T1, T2, T3	c.269A>G	p.Tyr90Cys	Chromobarrel	De novo heterozygous
T4	c.293G>A	p.Arg98Gln	Chromobarrel	De novo heterozygous
T5	—	p.Arg99Gln	Chromobarrel	De novo heterozygous
T6	—	p.Ala165Val	Catalytic (MYST)	De novo heterozygous
T7	c.523A>G	p.Lys175Glu	Catalytic (MYST)	De novo heterozygous
T8	—	p.Lys181Arg	Catalytic (MYST)	De novo heterozygous
T9	compound: missense + nonsense	p.Arg325Cys + p.Lys175* (c.523A>T, nonsense at codon 176)	Acetyl-CoA binding motif + C-terminal truncation	Biallelic (inherited from unaffected parents)

Variant classification: All are classified pathogenic/likely pathogenic per ACMG/AMP criteria in ClinVar (e.g., RCV001253776 for p.Tyr90Cys; RCV001253778 for p.Lys175Glu); GenCC lists KAT8–LIGOWS as an autosomal dominant "Definitive"/"Strong" gene-disease relationship (Ambry Genetics submission, GenCC entry).
Variant type: Predominantly missense; one nonsense allele (biallelic case only).
Population allele frequency: Not reported in gnomAD (consistent with de novo, ultra-rare pathogenic status); not found as common polymorphisms.
Somatic vs. germline: All germline (constitutional), no somatic mosaicism reported.
Functional consequence: Loss-of-function at the biochemical level — all seven tested missense variants were "defective in acetylating histone H4 at lysine 5 or 16 when recombinant nucleosomes were used as substrate," despite normal protein expression levels and (for most variants) normal complex assembly with MSL proteins. Chromobarrel-domain variants (Tyr90Cys, Arg98Gln, Arg99Gln) showed the most severe functional impact, consistent with impaired nucleosome engagement.

Modifier Genes

None established.

Epigenetic Information

This is fundamentally an epigenetic-machinery disorder: KAT8 is the enzyme that writes the H4K16ac mark. Pathogenic variants cause a downstream, genome-wide epigenetic deficiency (loss of H4K16 acetylation) rather than acting through a separate epigenetic mechanism.

Chromosomal Abnormalities

Not applicable — LIGOWS results from point mutations in KAT8, not large chromosomal rearrangements. (Note: microdeletion of the adjacent/nearby 16p11.2 region causes a distinct, well-known 16p11.2 deletion syndrome, which should be considered as a differential rather than confused with LIGOWS.)

Suggested ontology terms: Gene — hgnc:17933 (KAT8); functional impact — LOSS_OF_FUNCTION (catalytic/enzymatic) at functional_impact_category.

4. Phenotypes

Neurological / Developmental (Human, HP-codable)

Feature	Frequency in cohort (n=9)	Suggested HP term
Global developmental delay	9/9 (universal)	HP:0001263
Intellectual disability (mild–moderate)	9/9 (universal)	HP:0001249
Delayed speech and language development	9/9	HP:0000750
Delayed motor development (gross/fine)	Most patients	HP:0001270 / HP:0011342
Seizures / epilepsy	7/9	HP:0001250
Autistic behavior	2/9	HP:0000729
ADHD	1/9 (T2)	HP:0007018
Behavioral abnormalities (incl. difficulty with numbers/money concepts)	Subset	HP:0000708

Brain Imaging (structural)

Ventriculomegaly / enlarged ventricles — HP:0002119
Thin/hypoplastic corpus callosum — HP:0002079 / HP:0033725
Periventricular / gray matter nodular heterotopia — HP:0002185
Decreased white matter volume — HP:0034185

Craniofacial Dysmorphism (recurrent pattern)

Upper lateral eyelid fullness, telecanthus (HP:0000506), epicanthus (HP:0000286), upslanted palpebral fissures (HP:0000582), depressed/prominent nasal bridge (HP:0000431/HP:0000426), mild malar hypoplasia (HP:0000272), thick vermilion border (HP:0012471), downturned corners of the mouth (HP:0002714), low-set ears (HP:0000369).

Cardiac

Cardiac defects (atrial septal defect, ventricular septal defect, patent ductus arteriosus) in 4/9 patients — HP:0001631, HP:0001629, HP:0001643.

Ophthalmologic

Esotropia (HP:0000565), hypermetropia (HP:0000540), hypotelorism (HP:0000601).

Other Systemic

Feeding difficulties in infancy (HP:0011968); limb anomalies including clinodactyly (HP:0030084) and overlapping toes (HP:0001845).

Phenotype Characteristics

Onset: Congenital/infantile (developmental delay and dysmorphism present from early childhood).
Severity: Mild-to-moderate intellectual disability predominates (not severe/profound in the reported cohort).
Progression: Static/developmental (not degenerative) — a neurodevelopmental rather than neurodegenerative course.
Frequency data: As tabulated above from the n=9 founding cohort; broader population-level frequencies are not yet established given the rarity of the condition.

Quality of Life

Not formally studied with standardized instruments (EQ-5D/SF-36) in the literature to date; qualitatively, affected individuals require developmental/educational support consistent with mild-moderate intellectual disability.

5. Mechanism / Pathophysiology

Molecular Function of KAT8

KAT8 is a MYST-family lysine acetyltransferase that operates as the catalytic subunit of two distinct, evolutionarily conserved multiprotein complexes: - MSL complex (Male-Specific Lethal: MSL1, MSL2, MSL3) — within this complex, KAT8 catalyzes the bulk of genome-wide H4K16 acetylation, marking open chromatin and decompacting the chromatin fiber. - NSL complex (Non-Specific Lethal, containing KANSL1 and related subunits) — within this complex, KAT8 instead acetylates H4K5 and H4K8 at gene promoters, driving transcriptional activation of essential/housekeeping genes.

("KAT8 serves as a catalytic subunit of two independent protein complexes conserved from Drosophila to mammals... it catalyzes H4K5ac and H4K8ac as part of the NSL complex, whereas it catalyzes the bulk of H4K16ac as part of the MSL complex" — Molecular Cell 2021.)

Causal Chain (Mechanism → Phenotype)

Molecular trigger: De novo missense variant in KAT8 chromobarrel or catalytic domain → impaired nucleosome recognition or catalytic (acetyl-CoA transfer) activity.
Biochemical consequence: Severely reduced H4K16 (and H4K5) acetylation on nucleosomal substrates in vitro, despite normal protein expression and (mostly) normal MSL-complex assembly.
Cellular consequence (from Kat8 cerebrum-conditional knockout mice):
Loss of H4K16ac in the cerebrocortical neuroepithelium as early as E12.5.
Reduced SOX2+ neural stem/progenitor cells (NSPCs) by E13.5.
Premature/excessive neurogenesis: increased Tuj1+ neurons with aberrant migration.
Reduced proliferation (fewer BrdU+/Ki-67+ cells) and massive apoptosis (TUNEL+, cleaved caspase-3) at E12.5–E13.5.
Complete failure of mutant NSPCs to form neurospheres in vitro; pharmacologic KAT8 inhibition (MG149) similarly abolished wild-type neurosphere formation.
Tissue/organ consequence: Severe cerebral (neocortical and hippocampal) hypoplasia, altered cortical lamination, "flat-head" skull phenotype, and perinatal lethality in the mouse model.
Organism-level phenotype: In humans — global developmental delay, intellectual disability, seizures, structural brain anomalies (ventriculomegaly, thin corpus callosum, heterotopia), and craniofacial dysmorphism.

Suggested GO terms: GO:0043984 (histone H4-K16 acetylation), GO:0043974 (histone H4-K5 acetylation), GO:0043982 (histone H4-K8 acetylation), GO:0022008 (neurogenesis), GO:0007399 (nervous system development), GO:0006325 (chromatin organization). Suggested CL terms: CL:0000047 (neural stem cell) / neural progenitor cell equivalents.

Additional Molecular Finding

KAT8 also catalyzes H4K16 propionylation in vivo (a novel, less-studied acyl mark), with distinct subnuclear distribution from acetylation; this mark was virtually absent in Kat8-mutant neuroepithelium, suggesting a "complementary mechanism" active when propionyl-CoA levels are elevated.

Counterbalancing Deacetylases

SIRT1 and SIRT2 are candidate H4K16 deacetylases; HDAC1/2/3 are also important for cerebral development (HDAC3 loss causes H4K16 hyperacetylation), framing KAT8 loss-of-function within a broader acetylation/deacetylation balance relevant to potential therapeutic modulation.

Related Disease Mechanisms (for context/differential)

The paper situates LIGOWS within a family of "Mendelian disorders of the epigenetic machinery" acting on H4/H3 acetylation: CREBBP/EP300 (Rubinstein-Taybi syndrome, H3K27ac), KAT6A/KAT6B (H3K23ac), BRPF1, KANSL1 (Koolen-de Vries syndrome, part of the NSL complex), and MSL3 (recently linked to an X-linked developmental disorder, Basilicata-Akhtar syndrome).

6. Anatomical Structures Affected

Organ level (primary): Central nervous system — cerebral cortex, hippocampus (UBERON:0000956, UBERON:0002421).
Secondary/associated: Heart (septal structures, ductus arteriosus), craniofacial skeleton, eyes.
Tissue/cell level: Neuroepithelium; neural stem/progenitor cells; cortical neurons (Tuj1+); chromatin/nucleosomes at the subcellular level.
Subcellular: Nucleus/chromatin — GO Cellular Component GO:0000786 (nucleosome), GO:0005634 (nucleus).
Localization: Bilateral, diffuse cerebral involvement (not lateralized); structural brain findings (ventriculomegaly, thin corpus callosum, heterotopia) are typically bilateral/symmetric.

7. Temporal Development

Onset: Congenital/prenatal at the molecular-developmental level (mouse data show defects from E12.5–E16.5); clinically apparent as infantile/early childhood developmental delay.
Progression: Neurodevelopmental (static/non-degenerative) — features reflect an early developmental insult rather than progressive tissue loss; seizures may emerge in childhood.
Disease course: Chronic, lifelong intellectual disability; no reports of regression.
Critical period: Embryonic corticogenesis (E12.5–E16.5 in mouse models) represents the developmental window of maximal vulnerability to KAT8 loss-of-function.

8. Inheritance and Population

Epidemiology

LIGOWS is an ultra-rare, only recently delineated disorder (2020). No formal prevalence or incidence estimates exist in Orphanet, GBD, or other epidemiological databases; the literature to date describes single-digit numbers of published cases (originally 9 in the founding cohort), so it should be treated as CASES_IN_LITERATURE-tier for prevalence purposes rather than a population rate.

Inheritance Pattern

Predominant: Autosomal dominant, de novo (8 of 9 original patients).
Rare alternative: Autosomal recessive/biallelic — one patient (T9) inherited compound heterozygous variants from unaffected parents, suggesting incomplete penetrance of milder alleles in the heterozygous carrier state.
Penetrance: Appears high for de novo heterozygous variants (all reported de novo carriers were affected); incomplete for at least one biallelic-context allele (unaffected heterozygous parents).
Expressivity: Variable — severity and specific features (seizures, cardiac defects, autism) vary among carriers of different (and even the same) variant.
Anticipation, mosaicism, founder effects, consanguinity, carrier frequency: Not reported/not applicable given the ultra-rare de novo nature of the disorder.

Population Demographics

Affected populations: No specific ethnic or geographic enrichment reported; patients were ascertained through international collaborative exome-sequencing efforts.
Sex ratio: Not reported as skewed (autosomal gene, not X-linked).
Age distribution: Pediatric ascertainment predominant (patients described in the founding cohort ranged from early childhood through adolescence, e.g., ages 2–18 reported across summaries).

9. Diagnostics

Genetic Testing (primary diagnostic modality)

Exome sequencing (WES) was the method by which all founding-cohort variants were identified — the most direct approach given the absence of a specific hotspot outside the recurrent p.Tyr90Cys allele.
Whole genome sequencing (WGS): Not specifically reported but would be expected to detect the same coding variants.
Gene panels: Intellectual disability/epilepsy/neurodevelopmental gene panels including KAT8 would be expected to capture pathogenic variants.
Single-gene (Sanger) testing: Appropriate for confirming a specific familial variant or the recurrent p.Tyr90Cys allele.
Chromosomal microarray / karyotype / FISH: Not causal for this disorder (point mutations, not large CNVs), though CMA is often part of a standard ID/developmental-delay diagnostic workup to exclude 16p11.2 deletion/duplication and other CNV syndromes as differentials.

Functional/Research-Level Diagnostics

Patient-derived cell acetyltransferase assays (H4K16/H4K5 acetylation on nucleosome substrates) were used in the discovery study to establish variant pathogenicity but are not standard clinical diagnostics.

Clinical Criteria

No formal consensus diagnostic criteria (DSM/ICD-specific) exist; diagnosis rests on the combination of the clinical phenotype (developmental delay, dysmorphism, brain imaging findings) plus confirmatory KAT8 variant identification.

Differential Diagnosis

Other "Mendelian disorders of the epigenetic machinery" with overlapping intellectual disability/dysmorphism phenotypes: Rubinstein-Taybi syndrome (CREBBP/EP300), KAT6A syndrome (Arboleda-Tham syndrome), KAT6B disorders, Koolen-de Vries syndrome (KANSL1 — same NSL complex), Basilicata-Akhtar syndrome (MSL3 — same MSL complex as KAT8), and 16p11.2 microdeletion/duplication syndrome (distinct etiology, nearby locus).

Screening

No population or newborn screening programs exist; this is a variant-level, symptomatic diagnostic pathway (typically initiated by developmental delay/ID/seizure workup).

10. Outcome / Prognosis

Survival/mortality: No mortality data reported in the human cohort (contrast with the fully penetrant perinatal lethality of the cerebrum-specific Kat8 mouse knockout, which is a complete-loss-of-function model rather than the partial-loss-of-function missense alleles seen in patients).
Morbidity/function: Lifelong mild-to-moderate intellectual disability with associated speech/language impairment; a minority have autism or ADHD features; epilepsy present in ~78% (7/9) of the founding cohort.
Complications: Structural cardiac defects requiring cardiology follow-up in ~44% (4/9); seizure disorder requiring anticonvulsant management.
Prognostic factors: Variant domain may correlate with severity — chromobarrel-domain variants showed the most severe biochemical (H4K16ac) impairment in functional assays, though a clear genotype-severity correlation in patients has not yet been formally established in a larger cohort.

11. Treatment

Pharmacotherapy — Seizure Management

Valproate (valproic acid) was used in 2 of the 7 patients with epilepsy in the founding cohort, and both were responsive. The proposed mechanistic rationale is that valproate, a histone deacetylase (HDAC) inhibitor, may partially compensate for the acetylation deficiency caused by KAT8 loss-of-function ("may ameliorate potential acetylation deficiency resulting from KAT8 impairment" — PMID:31794431).

Suggested NCIT term: NCIT:C15986 (Pharmacotherapy), with therapeutic_agent bound to valproic acid (CHEBI, if available) as an anticonvulsant/HDAC inhibitor.

Experimental/Preclinical

Authors propose that Kat8-mutant mice may serve as preclinical models for testing deacetylase inhibitor drugs (e.g., valproic acid) as a therapeutic strategy — this remains a research-stage concept, not an established clinical protocol, and no clinical trials specific to LIGOWS (NCT identifiers) were identified in the literature searched.

Supportive/Multidisciplinary Care

As for intellectual disability generally, management requires a multidisciplinary team: special education, speech-language therapy, behavioral therapy, occupational therapy, and social/community support services (NCIT:C15302 Physical Therapy, NCIT:C15747 Supportive Care, as broadly applicable but not KAT8-specific).

Cardiac

Standard cardiology management/surgical correction as indicated for septal defects/PDA in affected patients (NCIT:C15329 Surgical Procedure where structural repair is needed).

Gene-targeted/Precision Approaches

None reported — no gene therapy, ASO, or targeted molecular therapy has been developed or trialed for KAT8-related disease as of the literature available.

12. Prevention

No primary, secondary, or tertiary prevention strategies exist for this de novo genetic disorder beyond standard genetic counseling for recurrence risk (low for de novo cases; up to 25% per pregnancy in the rare biallelic/autosomal-recessive family pattern) and prenatal/preimplantation genetic testing where a familial variant is known. No immunization, screening program, or behavioral intervention is applicable to primary prevention of this monogenic disorder.

13. Other Species / Model Organisms

Mouse Model (primary animal evidence)

Cerebrum-specific Kat8 conditional knockout mice (Emx1-Cre driven, complete loss-of-function in cerebral tissue) were generated and characterized in the founding study: - Phenotype: Early lethality before weaning (by ~3 weeks); "flat-head" phenotype from skull flattening; severe cerebral hypoplasia (neocortex + hippocampus), reduced brain weight from birth. - Developmental timeline: Defects traceable to E12.5 (loss of H4K16ac) through E16.5 (progressive hypoplasia); altered cortical lamination by E13.5. - Cellular phenotype: Depleted SOX2+ neural stem/progenitor cells, premature neurogenesis (excess Tuj1+ neurons), reduced proliferation (BrdU+/Ki-67+), massive apoptosis (TUNEL+/cleaved caspase-3+), and complete failure of neurosphere formation in vitro. - Fidelity: This is a complete-null model (not the patient's partial-loss-of-function missense alleles), so it recapitulates the qualitative developmental mechanism (H4K16ac loss → NSPC failure → cerebral hypoplasia) but represents a more severe phenotype (perinatal lethality) than the human disease, which is compatible with survival to adulthood. This fidelity gap (complete knockout vs. partial-function missense variants) is a notable human-model consideration for future curation (HUMAN_MODEL_MISMATCH pattern).

Drosophila

KAT8 is the direct ortholog of Drosophila MOF, the catalytic subunit of the Drosophila male-specific lethal (MSL) core complex that mediates dosage compensation on the male X chromosome via H4K16 acetylation — establishing deep evolutionary conservation of the H4K16ac-writing function, though this Drosophila biology (dosage compensation) is not itself a disease model.

Zebrafish

No zebrafish KAT8 loss-of-function neurodevelopmental model was identified in the literature searched.

Cell-based/in vitro models

Patient-variant-expressing HEK293/cell-line systems (FLAG-tagged KAT8 constructs co-expressed with HA-tagged MSL proteins) were used for biochemical acetyltransferase activity and complex-assembly assays; primary mouse embryonic neurosphere cultures were used to model NSPC self-renewal defects.

Natural Disease in Other Species

No naturally occurring veterinary/companion-animal KAT8-related disease has been reported (OMIA has no listing found in this search); this is an engineered/experimental mouse model only, not a spontaneous natural-disease model.

Summary Table of Suggested Ontology Bindings for KB Curation

Concept	Suggested term
Disease	MONDO:0033547
Gene	hgnc:17933 (KAT8)
Key phenotypes	HP:0001263 (Global developmental delay), HP:0001249 (Intellectual disability), HP:0001250 (Seizure), HP:0000750 (Delayed speech and language development), HP:0002119 (Ventriculomegaly), HP:0002079 (Thin corpus callosum), HP:0002185 (Neuronal heterotopia), HP:0000729 (Autistic behavior)
Cardiac phenotypes	HP:0001629 (ASD), HP:0001629 (VSD — verify specific term), HP:0001643 (PDA)
Biological processes	GO:0043984 (histone H4-K16 acetylation), GO:0043974 (histone H4-K5 acetylation), GO:0022008 (neurogenesis)
Cell types	Neural stem/progenitor cell (CL)
Anatomy	UBERON:0000956 (cerebral cortex), UBERON:0002421 (hippocampal formation)
Treatment	NCIT:C15986 (Pharmacotherapy) + therapeutic_agent valproic acid

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Checked with linkml-reference-validator 0.2.1.

Outcome	Count
References checked	3
Resolved	3
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	3
On topic	3
Off topic	0

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Li-Ghorbani-Weisz-Hubshman Syndrome (LIGOWS): Comprehensive Research Report

1. Disease Information

Overview

Key Identifiers

Synonyms

Data provenance note

2. Etiology

Disease Causal Factors

Genetic Risk Factors

Environmental Risk Factors

Protective Factors

Gene-Environment Interactions

3. Genetic/Molecular Information

Causal Gene

Pathogenic Variants Identified (Li et al. 2020, PMID:31794431)

Modifier Genes

Epigenetic Information

Chromosomal Abnormalities

4. Phenotypes

Neurological / Developmental (Human, HP-codable)

Brain Imaging (structural)

Craniofacial Dysmorphism (recurrent pattern)

Cardiac

Ophthalmologic

Other Systemic

Phenotype Characteristics

Quality of Life

5. Mechanism / Pathophysiology

Molecular Function of KAT8

Causal Chain (Mechanism → Phenotype)

Additional Molecular Finding

Counterbalancing Deacetylases

Related Disease Mechanisms (for context/differential)

6. Anatomical Structures Affected

7. Temporal Development

8. Inheritance and Population

Epidemiology

Inheritance Pattern

Population Demographics

9. Diagnostics

Genetic Testing (primary diagnostic modality)

Functional/Research-Level Diagnostics

Clinical Criteria

Differential Diagnosis

Screening

10. Outcome / Prognosis

11. Treatment

Pharmacotherapy — Seizure Management

Experimental/Preclinical

Supportive/Multidisciplinary Care

Cardiac

Gene-targeted/Precision Approaches

12. Prevention

13. Other Species / Model Organisms

Mouse Model (primary animal evidence)

Drosophila

Zebrafish

Cell-based/in vitro models

Natural Disease in Other Species

Summary Table of Suggested Ontology Bindings for KB Curation

Sources

Reference Validation