Abstract / Summary
KAT6B-related disorders (KRDs) comprise a spectrum of developmental disorders ranging from Genitopatellar syndrome (GPS) to Say-Barber-Biesecker-Young-Simpson syndrome (SBBYSS), with increasing recognition of intermediate phenotypes. Although genotype-phenotype correlations have progressively emerged, the molecular basis of phenotypic variability remains incompletely understood. We performed comprehensive clinical phenotyping and trio-based whole-exome sequencing (WES) in two unrelated individuals carrying novel de novo KAT6B variants. Transcriptomic analysis was undertaken for the noncanonical intronic variant using peripheral blood-derived RNA. An updated review of molecularly confirmed KRDs was also performed to reassess genotype-phenotype correlations and protein domain-specific variant distribution. Patient 1 carried a novel nonsense variant (c.5347G>T, p.Glu1783Ter) and presented with a predominantly SBBYSS-like phenotype. Patient 2 harbored a novel noncanonical intronic variant (c.3665-21C>A) associated with a severe multisystem phenotype overlapping the GPS spectrum. RNA sequencing demonstrated preserved canonical exon 17-18 splicing but an approximately 50% reduction in KAT6B transcript abundance, supporting a dosage-sensitive pathogenic mechanism. Review of 203 published individuals identified 133 distinct pathogenic variants, confirmed exon 18 as the major mutational hotspot, and suggested domain-specific genotype-phenotype trends, including enrichment of SBBYSS-associated phenotypes among variants affecting the histone acetyltransferase (HAT) domain. Both patients also exhibited severe upper airway dysfunction with obstructive sleep apnea (OSA). These findings expand the molecular and phenotypic spectrum of KRDs, provide supportive transcriptomic evidence for a potential functional intronic variant, refine current genotype-phenotype correlations, and highlight upper airway dysfunction as a clinically relevant but likely underrecognized manifestation across the KRD spectrum.