Missense substitutions at a conserved 14-3-3 binding site in HDAC4 cause a novel intellectual disability syndrome
Emma Wakeling,
Meriel McEntagart,
Michael Bruccoleri,
Charles Shaw-Smith,
Karen L. Stals,
Matthew Wakeling,
Angela Barnicoat,
Clare Beesley,
Andrea K. Hanson-Kahn,
Mary Kukolich,
David A. Stevenson,
Philippe M. Campeau,
Sian Ellard,
Sarah H. Elsea,
Xiang-Jiao Yang,
Richard C. Caswell
Affiliations
Emma Wakeling
North East Thames Regional Genetics Service, Great Ormond Street Hospital for Children NHS Foundation Trust, Great Ormond Street, London WC1N 3JH, UK; Corresponding author
Meriel McEntagart
Medical Genetics, Floor 0 Jenner Wing, St George’s University Hospitals NHS Foundation Trust, Cranmer Terrace, London SW17 0RE, UK
Michael Bruccoleri
Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, Quebec, QC H3A 1A3, Canada; Department of Medicine, McGill University Health Center, Montreal, Quebec, QC H3A 1A3, Canada
Charles Shaw-Smith
Department of Clinical Genetics, Royal Devon and Exeter NHS Foundation Trust, Exeter EX1 2ED, UK
Karen L. Stals
Exeter Genomics Laboratory, Royal Devon and Exeter NHS Foundation Trust, Exeter EX2 5DW, UK
Matthew Wakeling
Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter EX2 5DW, UK
Angela Barnicoat
North East Thames Regional Genetics Service, Great Ormond Street Hospital for Children NHS Foundation Trust, Great Ormond Street, London WC1N 3JH, UK
Clare Beesley
Rare & Inherited Disease Laboratory, North Thames Genomic Laboratory Hub, Great Ormond Street Hospital for Children NHS Foundation Trust, 37 Queen Square, London WC1N 3BH, UK
Andrea K. Hanson-Kahn
Department of Genetics, Stanford University School of Medicine, 300 Pasteur Drive, H315, Stanford, CA 94305-5208, USA; Department of Pediatrics, Division of Medical Genetics, Stanford University, 300 Pasteur Drive, H315, Stanford, CA 94305-5208, USA
Mary Kukolich
Clinical Genetics, Cook Children’s Medical Center, Fort Worth, TX 76104, USA
David A. Stevenson
Department of Pediatrics, Division of Medical Genetics, Stanford University, 300 Pasteur Drive, H315, Stanford, CA 94305-5208, USA
Philippe M. Campeau
Department of Pediatrics, CHU Sainte-Justine Hospital, University of Montreal, Montreal, Quebec, QC H3T 1C4, Canada
Sian Ellard
Exeter Genomics Laboratory, Royal Devon and Exeter NHS Foundation Trust, Exeter EX2 5DW, UK
Sarah H. Elsea
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
Xiang-Jiao Yang
Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, Quebec, QC H3A 1A3, Canada; Department of Medicine, McGill University Health Center, Montreal, Quebec, QC H3A 1A3, Canada; Department of Biochemistry, McGill University Health Center, Montreal, Quebec, QC, Canada
Richard C. Caswell
Exeter Genomics Laboratory, Royal Devon and Exeter NHS Foundation Trust, Exeter EX2 5DW, UK; Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter EX2 5DW, UK; Corresponding author
Summary: Histone deacetylases play crucial roles in the regulation of chromatin structure and gene expression in the eukaryotic cell, and disruption of their activity causes a wide range of developmental disorders in humans. Loss-of-function alleles of HDAC4, a founding member of the class IIa deacetylases, have been reported in brachydactyly-mental retardation syndrome (BDMR). However, while disruption of HDAC4 activity and deregulation of its downstream targets may contribute to the BDMR phenotype, loss of HDAC4 function usually occurs as part of larger deletions of chromosome 2q37; BDMR is also known as chromosome 2q37 deletion syndrome, and the precise role of HDAC4 within the phenotype remains uncertain. Thus, identification of missense variants should shed new light on the role of HDAC4 in normal development. Here, we report seven unrelated individuals with a phenotype distinct from that of BDMR, all of whom have heterozygous de novo missense variants that affect a major regulatory site of HDAC4, required for signal-dependent 14-3-3 binding and nucleocytoplasmic shuttling. Two individuals possess variants altering Thr244 or Glu247, whereas the remaining five all carry variants altering Pro248, a key residue for 14-3-3 binding. We propose that the variants in all seven individuals impair 14-3-3 binding (as confirmed for the first two variants by immunoprecipitation assays), thereby identifying deregulation of HDAC4 as a pathological mechanism in a previously uncharacterized developmental disorder.
