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

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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GeneReview available — KAT6B

Authoritative clinical overview · Recommended first read

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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 OE0.06 (0.03–0.13)

0≤0.351.4

Missense OE0.76 (0.71–0.80)

0≤0.61.4

Synonymous OE0.98

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

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 · LOEUF 0.13

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.PMID:29226580

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).PMID:24458743

LOFThe few reported patients with KAT6B haploinsufficiency had a much milder phenotype, though with some features overlapping those of SBBS.PMID:25424711

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