Whole-exome-sequencing identifies mutations in histone acetyltransferase gene KAT6B in individuals with the Say-Barber-Biesecker variant of Ohdo syndrome.

Genetic Medicine, St. Mary's Hospital, Manchester Academic Health Sciences Centre, School of Biomedicine, University of Manchester, Manchester M13 9WL, UK.
The American Journal of Human Genetics (Impact Factor: 10.99). 11/2011; 89(5):675-81. DOI: 10.1016/j.ajhg.2011.10.008
Source: PubMed

ABSTRACT Say-Barber-Biesecker-Young-Simpson syndrome (SBBYSS or Ohdo syndrome) is a multiple anomaly syndrome characterized by severe intellectual disability, blepharophimosis, and a mask-like facial appearance. A number of individuals with SBBYSS also have thyroid abnormalities and cleft palate. The condition usually occurs sporadically and is therefore presumed to be due in most cases to new dominant mutations. In individuals with SBBYSS, a whole-exome sequencing approach was used to demonstrate de novo protein-truncating mutations in the highly conserved histone acetyltransferase gene KAT6B (MYST4/MORF)) in three out of four individuals sequenced. Sanger sequencing was used to confirm truncating mutations of KAT6B, clustering in the final exon of the gene in all four individuals and in a further nine persons with typical SBBYSS. Where parental samples were available, the mutations were shown to have occurred de novo. During mammalian development KAT6B is upregulated specifically in the developing central nervous system, facial structures, and limb buds. The phenotypic features seen in the Qkf mouse, a hypomorphic Kat6b mutant, include small eyes, ventrally placed ears and long first digits that mirror the human phenotype. This is a further example of how perturbation of a protein involved in chromatin modification might give rise to a multisystem developmental disorder.

Download full-text


Available from: Tim Thomas, Jul 02, 2015
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The human brain is a highly specialized organ containing nearly 170 billion cells with specific functions. Development of the brain requires adequate proliferation, proper cell migration, differentiation and maturation of progenitors. This is in turn dependent on spatial and temporal coordination of gene transcription, which requires the integration of both cell intrinsic and environmental factors. Histone acetyltransferases (HATs) are one family of proteins that modulate expression levels of genes in a space- and time-dependent manner. HATs and their molecular complexes are able to integrate multiple molecular inputs and mediate transcriptional levels by acetylating histone proteins. In mammals, 19 HATs have been described and are separated into five families (p300/CBP, MYST, GNAT, NCOA and transcription-related HATs). During embryogenesis, individual HATs are expressed or activated at specific times and locations to coordinate proper development. Not surprisingly, mutations in HATs lead to severe developmental abnormalities in the nervous system and increased neurodegeneration. This review focuses on our current understanding of HATs and their biological roles during neural development.
    Cell and Tissue Research 05/2014; DOI:10.1007/s00441-014-1835-7 · 3.33 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    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 ( 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.
    Human Mutation 11/2012; 33(11):1520-5. DOI:10.1002/humu.22141 · 5.05 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Gene discovery has been one of the most important advances in our understanding of human disorders. Early linkage and positional cloning strategies have now given way to next generation sequencing (NGS) with age-old help from biostatistical and bioinformatical input. In this chapter, we present the importance of getting the basics right, namely, how the best phenotyping in the clinical domain will provide a higher chance of a successful NGS experiment. In addition, we show getting the correct submission of DNA samples to NGS providers is dependent on the type of inheritance pattern that may or may not be apparent. We discuss one of the most crucial decisions for investigators when designing a study, namely choosing a trio, quad or cohort for analysis. Following on from this, we compare and contrast the underlying technology adopted by provider companies as they vie for customers and submissions. Each platform has advantages and disadvantages based on false calls, coverage, and read depth; however, some of these issues may be solved with the third wave of sequencing technology development in early commercial roll-out. Lastly, we provide a bioinformatic filtering overview of a "quad"-based submission and show how 3 million SNPs and indels can be reduced to a biologically plausible and experimentally manageable n≤50 gene variants.
    01/2012; 89:1-26. DOI:10.1016/B978-0-12-394287-6.00001-X