The KAT6B‐related disorders genitopatellar syndrome and Ohdo/SBBYS syndrome have distinct clinical features reflecting distinct molecular mechanisms

Genitopatellar syndrome (GPS) and Say–Barber–Biesecker–Young–Simpson syndrome (SBBYSS or Ohdo syndrome) have both recently been shown to be caused by distinct mutations in the histone acetyltransferase KAT6B (a.k.a. MYST4/MORF). All variants are de novo dominant mutations that lead to protein truncation. Mutations leading to GPS occur in the proximal portion of the last exon and lead to the expression of a protein without a C‐terminal domain. Mutations leading to SBBYSS occur either throughout the gene, leading to nonsense‐mediated decay, or more distally in the last exon. Features present only in GPS are contractures, anomalies of the spine, ribs and pelvis, renal cysts, hydronephrosis, and agenesis of the corpus callosum. Features present only in SBBYSS include long thumbs and long great toes and lacrimal duct abnormalities. Several features occur in both, such as intellectual disability, congenital heart defects, and genital and patellar anomalies. We propose that haploinsufficiency or loss of a function mediated by the C‐terminal domain causes the common features, whereas gain‐of‐function activities would explain the features unique to GPS. Further molecular studies and the compilation of mutations in a database for genotype–phenotype correlations (www.LOVD.nl/KAT6B) might help tease out answers to these questions and understand the developmental programs dysregulated by the different truncations. Hum Mutat 33:1520–1525, 2012. © 2012 Wiley Periodicals, Inc.