2. Academic Validation
  3. Mutations in Histone Acetylase Modifier BRPF1 Cause an Autosomal-Dominant Form of Intellectual Disability with Associated Ptosis

Mutations in Histone Acetylase Modifier BRPF1 Cause an Autosomal-Dominant Form of Intellectual Disability with Associated Ptosis

  • Am J Hum Genet. 2017 Jan 5;100(1):105-116. doi: 10.1016/j.ajhg.2016.11.010.
Francesca Mattioli 1,  Elise Schaefer 2,  Alex Magee 3,  Paul Mark 4,  Grazia M Mancini 5,  Klaus Dieterich 6,  Gretchen Von Allmen 7,  Marielle Alders 8,  Charles Coutton 9,  Marjon van Slegtenhorst 5,  Gaëlle Vieville 9,  Mark Engelen 8,  Jan Maarten Cobben 8,  Jane Juusola 10,  Aurora Pujol 11,  Jean-Louis Mandel 12,  Amélie Piton 13
Affiliations

Affiliations

  • 1 Institut de Genetique et de Biologie Moleculaire et Cellulaire, 67400 Illkirch-Graffenstaden, France; INSERM U964, 67400 Illkirch-Graffenstaden, France; CNRS UMR 7104, 67400 Illkirch-Graffenstaden, France; Université de Strasbourg, 67400 Illkirch, France; Chaire de Génétique Humaine, Collège de France, 67400 Illkirch, France.
  • 2 Service de Génétique Médicale, Hôpitaux Universitaires de Strasbourg, Institut de Génétique Médicale d'Alsace, 67000 Strasbourg, France.
  • 3 Genetic Medicine, Belfast City Hospital, Belfast BT9 7AB, Ireland.
  • 4 Spectrum Health Medical Group, Grand Rapids, MI 49544, USA.
  • 5 Department of Clinical Genetics, Erasmus MC, Rotterdam 3015, the Netherlands.
  • 6 Service de Génétique Clinique, Centre Hospitalier Universitaire de Grenoble site Nord, Hôpital Couple-Enfant, 38700 Grenoble, France.
  • 7 Department of Pediatrics, McGovern Medical School, University of Texas in Houston, Houston, TX 77030, USA.
  • 8 Department of Clinical Genetic, Academic Medical Center, Amsterdam 1100, the Netherlands.
  • 9 INSERM 1209, CNRS UMR 5309, Laboratoire de Génétique Chromosomique, Centre Hospitalier Universitaire Grenoble Alpes, Institut Albert Bonniot, Université Grenoble Alpes, 38706 Grenoble, France.
  • 10 GeneDx, Gaithersburg 20877, USA.
  • 11 Neurometabolic Diseases Laboratory, Institute of Neuropathology, Institut d'Investigació Biomèdica de Bellvitge, 08908 Barcelona, Spain; Center for Biomedical Research on Rare Diseases U759, L'Hospitalet de Llobregat, 08908 Barcelona, Spain; Catalan Institution for Research and Advanced Studies, 08010 Barcelona, Spain.
  • 12 Institut de Genetique et de Biologie Moleculaire et Cellulaire, 67400 Illkirch-Graffenstaden, France; INSERM U964, 67400 Illkirch-Graffenstaden, France; CNRS UMR 7104, 67400 Illkirch-Graffenstaden, France; Université de Strasbourg, 67400 Illkirch, France; Chaire de Génétique Humaine, Collège de France, 67400 Illkirch, France; Laboratoire de diagnostic génétique, Institut de Génétique Médicale d'Alsace, Hôpitaux Universitaires de Strasbourg, 67000 Strasbourg, France; University of Strasbourg Institute for Advanced studies, 67000 Strasbourg, France. Electronic address: [email protected].
  • 13 Institut de Genetique et de Biologie Moleculaire et Cellulaire, 67400 Illkirch-Graffenstaden, France; INSERM U964, 67400 Illkirch-Graffenstaden, France; CNRS UMR 7104, 67400 Illkirch-Graffenstaden, France; Université de Strasbourg, 67400 Illkirch, France; Laboratoire de diagnostic génétique, Institut de Génétique Médicale d'Alsace, Hôpitaux Universitaires de Strasbourg, 67000 Strasbourg, France. Electronic address: [email protected].
PMID: 27939639 DOI: 10.1016/j.ajhg.2016.11.010
Abstract

Intellectual disability (ID) is a common neurodevelopmental disorder exhibiting extreme genetic heterogeneity, and more than 500 genes have been implicated in Mendelian forms of ID. We performed exome sequencing in a large family affected by an autosomal-dominant form of mild syndromic ID with ptosis, growth retardation, and hypotonia, and we identified an inherited 2 bp deletion causing a frameshift in BRPF1 (c.1052_1053del) in five affected family members. BRPF1 encodes a protein modifier of two histone acetyltransferases associated with ID: KAT6A (also known as MOZ or MYST3) and KAT6B (MORF or MYST4). The mRNA transcript was not significantly reduced in affected fibroblasts and most likely produces a truncated protein (p.Val351Glyfs∗8). The protein variant shows an aberrant cellular location, loss of certain protein interactions, and decreased histone H3K23 acetylation. We identified BRPF1 deletions or point mutations in six additional individuals with a similar phenotype. Deletions of the 3p25 region, containing BRPF1 and SETD5, cause a defined ID syndrome where most of the clinical features are attributed to SETD5 deficiency. We compared the clinical symptoms of individuals carrying mutations or small deletions of BRPF1 alone or SETD5 alone with those of individuals with deletions encompassing both BRPF1 and SETD5. We conclude that both genes contribute to the phenotypic severity of 3p25 deletion syndrome but that some specific features, such as ptosis and blepharophimosis, are mostly driven by BRPF1 haploinsufficiency.

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