KAT6B – blepharophimosis - intellectual disability syndrome, SBBYS type

KAT6B encodes lysine acetyltransferase 6B, a member of the MYST family of histone acetyltransferases, and is essential for normal craniofacial and neurodevelopment. Heterozygous de novo variants in KAT6B cause Say-Barber-Biesecker-Young-Simpson syndrome (SBBYSS), also known as blepharophimosis - intellectual disability syndrome, SBBYS type, characterized by blepharophimosis, mask-like facies, intellectual disability, hypotonia, and patellar anomalies (PMID:22077973).

Multiple studies have identified recurrent de novo truncating and splice-altering variants clustered in the terminal exons of KAT6B in individuals with SBBYSS. A synonymous substitution, c.3147G>A (p.Pro1049=), creates a cryptic splice site leading to aberrant exon skipping and protein truncation in three unrelated patients (PMID:26334766). A representative variant is c.3147G>A (p.Pro1049=), demonstrating how even synonymous changes can disrupt KAT6B function.

The variant spectrum in SBBYSS is dominated by protein‐truncating alleles (nonsense, frameshift, splice) in exons 16–18, with rare missense variants in proximal exons causing atypical phenotypes. To date, over 30 unrelated probands have been reported with de novo truncating KAT6B variants, consistently absent in parents and unaffected controls ([PMID:22077973]).

Functional assays in patient-derived fibroblasts show reduced histone H3 and H4 acetylation, confirming loss of KAT6B acetyltransferase activity. In Kat6b+/- mice, haploinsufficiency leads to learning, memory, and social deficits mirroring SBBYSS; treatment with histone deacetylase inhibitors or acetyl donors restores histone acetylation and rescues cognitive and behavioral phenotypes (PMID:38557491).

No conflicting evidence has been reported; all pathogenic variants are de novo and fully penetrant. There is no evidence for autosomal recessive inheritance or common benign variation in the general population impacting the same protein domains.

Collectively, the genetic and experimental data establish a definitive gene–disease relationship between KAT6B and SBBYSS. Clinical testing for KAT6B variants is recommended in patients with blepharophimosis and intellectual disability when FOXL2 testing is negative. Emerging epigenetic therapies targeting histone acetylation offer potential postnatal interventions.

Key Take-home: Heterozygous de novo truncating variants in KAT6B cause autosomal dominant SBBYSS; genetic diagnosis enables precise management and opens avenues for epigenetic therapy.

References

• American journal of human genetics • 2011 • Whole-exome sequencing identifies mutations in histone acetyltransferase gene KAT6B in individuals with the Say-Barber-Biesecker variant of Ohdo syndrome. PMID:22077973
• American journal of medical genetics. Part A • 2015 • A recurrent synonymous KAT6B mutation causes Say-Barber-Biesecker/Young-Simpson syndrome by inducing aberrant splicing. PMID:26334766
• The Journal of clinical investigation • 2024 • Increasing histone acetylation improves sociability and restores learning and memory in KAT6B-haploinsufficient mice. PMID:38557491

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