KAT6B

Chr 10AD

lysine acetyltransferase 6B

Also known as: GTPTS, MORF, MOZ2, MYST4, ZC2HC6B, qkf, querkopf

NCBI Gene: 23522 ENSG00000156650 UniProt: Q8WYB5 OMIM: 605880

The protein functions as a histone acetyltransferase and component of the MOZ/MORF complex that regulates gene transcription and is necessary for RUNX2-dependent transcriptional activation in brain development. Mutations cause genitopatellar syndrome and SBBYSS syndrome through an autosomal dominant inheritance pattern. The gene is highly intolerant to loss-of-function variants, and disease predominantly occurs through haploinsufficiency mechanisms.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

The protein encoded by this gene is a histone acetyltransferase and component of the MOZ/MORF protein complex. In addition to its acetyltransferase activity, the encoded protein has transcriptional activation activity in its N-terminal end and transcriptional repression activity in its C-terminal end. This protein is necessary for RUNX2-dependent transcriptional activation and could be involved in brain development. Mutations have been found in patients with genitopatellar syndrome. A translocation of this gene and the CREBBP gene results in acute myeloid leukemias. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2012]

GeneReviews OMIM ResearchGenerating clinical summary…

MultiplemechanismADLOEUF 0.132 OMIM phenotypes

Clinical Summary— KAT6B

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Gene-Disease Validity (ClinGen)

KAT6B-related multiple congenital anomalies syndrome · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

62 unique Pathogenic / Likely Pathogenic· 179 VUS of 400 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — KAT6B

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.13LOEUF

pLI 1.000

Z-score 7.89

OE 0.06 (0.03–0.13)

Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?

2.89Z-score

OE missense 0.76 (0.71–0.80)

834 obs / 1104.0 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.06 (0.03–0.13)

0≤0.351.4

Missense OE?0.76 (0.71–0.80)

0≤0.61.4

Synonymous OE?0.98

0≤1.21.6

LoF obs/exp: 5 / 82.2Missense obs/exp: 834 / 1104.0Syn Z: 0.26

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveKAT6B-related genitopatellar syndromeDNAD

definitiveKAT6B-related Say-Barber-Biesecker-Young-Simpson syndromeLOFAD

This gene — mechanism propensity

0.16100th %ile

GOF

0.1999th %ile

LOF

0.86top 5%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function, gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median · 1 literature citation · 97% of P/LP variants are LoF · LOEUF 0.13 · ClinGen HI: Sufficient evidence for dosage pathogenicity

GOF1 literature citation

DN1 literature citation

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

DNTruncating variants in KAT6B leading to GPS appear to cluster within the proximal portion of exon 18, associated with a dominant-negative effect of the mutated protein, most likely.1

GOFThis mutation likely has a dominant-negative or gain-of-function effect, similar to those observed in other genetic disorders resulting from KAT6B mutations, including Say-Barber-Biesecker-Young-Simpson (SBBYSS) and genitopatellar syndrome (GTPTS).2

LOFThe few reported patients with KAT6B haploinsufficiency had a much milder phenotype, though with some features overlapping those of SBBS.3

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

ClinVar Variant Classifications

400 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic45

Likely Pathogenic17

VUS179

Likely Benign107

Benign10

Conflicting17

Pathogenic

Likely Pathogenic

179

VUS

107

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	44	0	0	1	45
Likely Pathogenic	16	1	0	0	17
VUS	6	164	9	0	179
Likely Benign	0	34	15	58	107
Benign	0	7	2	1	10
Conflicting	—				17
Total	66	206	26	60	375

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

8 pathogenic / likely-pathogenic (of 11) ClinVar copy-number / structural variants overlap KAT6B — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →