Please use this identifier to cite or link to this item: https://ahro.austin.org.au/austinjspui/handle/1/16400
Title: De novo truncating variants in ASXL2 are associated with a unique and recognizable clinical phenotype
Austin Authors: Shashi, Vandana;Pena, Loren DM;Kim, Katherine;Burton, Barbara;Hempel, Maja;Schoch, Kelly;Walkiewicz, Magdalena;McLaughlin, Heather M;Cho, Megan;Stong, Nicholas;Hickey, Scott E;Shuss, Christine M;Freemark, Michael S;Bellet, Jane S;Keels, Martha Ann;Bonner, Melanie J;El-Dairi, Maysantoine;Butler, Megan;Kranz, Peter G;Stumpel, Constance TRM;Klinkenberg, Sylvia;Oberndorff, Karin;Alawi, Malik;Santer, Rene;Petrovski, Slavé;Kuismin, Outi;Korpi-Heikkilä, Satu;Pietilainen, Olli;Aarno, Palotie;Kurki, Mitja I;Hoischen, Alexander;Need, Anna C;Goldstein, David B;Kortüm, Fanny
Institutional Author: Undiagnosed Diseases Network
Affiliation: Division of Medical Genetics, Department of Pediatrics, Duke Health, Durham, NC, USA
Department of Pediatrics, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL, USA
Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
Baylor College of Medicine, Houston, TX, USA
GeneDx, Gaithersburg, MD, USA
Institute for Genomic Medicine, Columbia University, New York, NY, USA
Division of Molecular and Human Genetics, Nationwide Children’s Hospital, Columbus, OH, USA
NIH Common Fund, Bethesda, MD, USA
Division of Endocrinology and Diabetes, Department of Pediatrics, Duke Health, Durham, NC, USA
Departments of Pediatrics and Dermatology, Duke Health, Durham, NC, USA
Departments of Pediatrics and Surgery, Duke Health, Durham, NC, USA
Psychiatry and Behavioral Sciences, Duke Health, Durham, NC, USA
Duke Eye Center, Duke Health, Durham, NC, USA
Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Duke Health, Durham, NC, USA
Division of Neuroradiology, Department of Radiology, Duke Health, Durham, NC, USA
Department of Clinical Genetics and School for Oncology & Developmental Biology, Maastricht University Medical Center, Maastricht, the Netherlands
Department of Neurology, Maastricht University Medical Center, Maastricht, the Netherlands
Department of Pediatrics, Zuyderland Medical Center, Sittard, the Netherlands
Bioinformatics Service Facility, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
Center for Bioinformatics, University of Hamburg, Hamburg, Germany
Heinrich-Pette-Institute, Leibniz-Institute for Experimental Virology, Virus Genomics, Hamburg, Germany
Department of Paediatrics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
Department of Medicine, Austin Health and Royal Melbourne Hospital, University of Melbourne, Melbourne, Victoria, Australia
PEDEGO Research Unit, Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland
Department of Clinical Genetics, Oulu University Hospital, Oulu, Finland
Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland
Northern Ostrobothnia Hospital District, Center for Intellectual Disability Care, Oulu, Finland
Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA
Harvard Stem Cell Institute, Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA
Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
Psychiatric and Neurodevelopmental Genetics Unit, Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA
Department of Neurology, Massachusetts General Hospital, Boston, MA, USA
Genetic Analysis Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA
Department of Human Genetics, Donders Centre for Neuroscience, Radboud University Medical Center, Nijmegen, the Netherlands
Division of Brain Sciences, Department of Medicine, Imperial College London, London, UK
Issue Date: 6-Oct-2016
Publication information: American Journal of Human Genetics 2016; 99(4): 991-999
Abstract: The ASXL genes (ASXL1, ASXL2, and ASXL3) participate in body patterning during embryogenesis and encode proteins involved in epigenetic regulation and assembly of transcription factors to specific genomic loci. Germline de novo truncating variants in ASXL1 and ASXL3 have been respectively implicated in causing Bohring-Opitz and Bainbridge-Ropers syndromes, which result in overlapping features of severe intellectual disability and dysmorphic features. ASXL2 has not yet been associated with a human Mendelian disorder. In this study, we performed whole-exome sequencing in six unrelated probands with developmental delay, macrocephaly, and dysmorphic features. All six had de novo truncating variants in ASXL2. A careful review enabled the recognition of a specific phenotype consisting of macrocephaly, prominent eyes, arched eyebrows, hypertelorism, a glabellar nevus flammeus, neonatal feeding difficulties, hypotonia, and developmental disabilities. Although overlapping features with Bohring-Opitz and Bainbridge-Ropers syndromes exist, features that distinguish the ASXL2-associated condition from ASXL1- and ASXL3-related disorders are macrocephaly, absence of growth retardation, and more variability in the degree of intellectual disabilities. We were also able to demonstrate with mRNA studies that these variants are likely to exert a dominant-negative effect, given that both alleles are expressed in blood and the mutated ASXL2 transcripts escape nonsense-mediated decay. In conclusion, de novo truncating variants in ASXL2 underlie a neurodevelopmental syndrome with a clinically recognizable phenotype. This report expands the germline disorders that are linked to the ASXL genes.
URI: http://ahro.austin.org.au/austinjspui/handle/1/16400
DOI: 10.1016/j.ajhg.2016.08.017
PubMed URL: https://pubmed.ncbi.nlm.nih.gov/27693232
Type: Journal Article
Subjects: ASXL2
Macrocephaly
Whole-exome sequencing
Developmental delay
Intellectual disability
Glabellar nevus flammeus
Appears in Collections:Journal articles

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