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

TitleThe KAT6B-related disorders genitopatellar syndrome and Ohdo/SBBYS syndrome have distinct clinical features reflecting distinct molecular mechanisms.
Publication TypeJournal Article
Year of Publication2012
AuthorsCampeau, PM, Lu, JT, Dawson, BC, Fokkema, IFAC, Robertson, SP, Gibbs, RA, Lee, BH
JournalHum Mutat
Volume33
Issue11
Pagination1520-5
Date Published2012 Nov
ISSN1098-1004
KeywordsAbnormalities, Multiple, Base Sequence, Blepharophimosis, Blepharoptosis, Craniofacial Abnormalities, Databases, Nucleic Acid, DNA, Female, Genetic Association Studies, Haploinsufficiency, Heart Defects, Congenital, Histone Acetyltransferases, Humans, Intellectual Disability, Kidney, Male, Molecular Sequence Data, Mutation, Patella, Psychomotor Disorders, Scrotum, Sequence Deletion, Urogenital Abnormalities
Abstract

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.

DOI10.1002/humu.22141
Alternate JournalHum. Mutat.
PubMed ID22715153
PubMed Central IDPMC3696352
Grant ListP01 ES011253 / ES / NIEHS NIH HHS / United States
P01 HD022657 / HD / NICHD NIH HHS / United States
P01 HD070394 / HD / NICHD NIH HHS / United States
P01 HD22657 / HD / NICHD NIH HHS / United States
U54 HG003273 / HG / NHGRI NIH HHS / United States
/ / Canadian Institutes of Health Research / Canada
/ / Howard Hughes Medical Institute / United States
/ / Howard Hughes Medical Institute / United States