Clinical and Molecular Delineation of KAT6B-Related Disorders: Novel Variants and Refined Genotype-Phenotype Correlations.

KAT6B

De novo KAT6B variants including a noncanonical intronic variant associated with an approximately 50% reduction in transcript abundance, supporting a dosage-sensitive mechanism

KAT6B-related disorders (KRDs) form a spectrum of developmental disorders ranging from genitopatellar syndrome (GPS) to Say-Barber-Biesecker-Young-Simpson syndrome (SBBYSS), with intermediate phenotypes increasingly recognised, yet the molecular basis of phenotypic variability remains incompletely understood. Through detailed clinical phenotyping and trio-based exome sequencing, the authors describe two unrelated individuals carrying novel de novo KAT6B variants: a nonsense variant (c.5347G>T, p.Glu1783Ter) associated with a predominantly SBBYSS-like phenotype, and a noncanonical intronic variant (c.3665-21C>A) associated with a severe multisystem phenotype overlapping the GPS spectrum, for which RNA sequencing of peripheral blood shows preserved canonical exon 17-18 splicing but an approximately 50% reduction in KAT6B transcript abundance, supporting a dosage-sensitive pathogenic mechanism. An updated review of 203 published individuals, covering 133 distinct pathogenic variants, confirms exon 18 as the major mutational hotspot and suggests domain-specific genotype-phenotype trends, with enrichment of SBBYSS-like phenotypes among variants affecting the histone acetyltransferase (HAT) domain. Both patients also had severe upper airway dysfunction with obstructive sleep apnoea (OSA), which the authors present as a clinically relevant but likely underrecognised manifestation across the KRD spectrum.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

Two patients do not change the picture of KRDs: the interest lies elsewhere, in the transcriptomic evidence for a noncanonical intronic variant (about 50% transcript reduction), which the authors themselves present as an argument for a potential functional variant and which is not sufficient, on its own, to establish the pathogenicity of the variant. The domain-specific trends, including enrichment of SBBYSS-like phenotypes for the HAT domain, are drawn from a compilation of the literature and remain suggestive. As for upper airway involvement, it is observed in only two patients: it justifies looking for it at follow-up, but no frequency can be inferred from it.

Analysis by Dr Thibaut Benquey