De Novo Truncating Variants in ASXL2 Are Associated with a Unique and Recognizable Clinical Phenotype

  • Am J Hum Genet. 2016 Oct 6;99(4):991-999. doi: 10.1016/j.ajhg.2016.08.017.
Vandana Shashi  1 ,  Loren D M Pena  2 ,  Katherine Kim  3 ,  Barbara Burton  3 ,  Maja Hempel  4 ,  Kelly Schoch  2 ,  Magdalena Walkiewicz  5 ,  Heather M McLaughlin  6 ,  Megan Cho  6 ,  Nicholas Stong  7 ,  Scott E Hickey  8 ,  Christine M Shuss  8 ,  Undiagnosed Diseases Network  9 ,  Michael S Freemark  10 ,  Jane S Bellet  11 ,  Martha Ann Keels  12 ,  Melanie J Bonner  13 ,  Maysantoine El-Dairi  14 ,  Megan Butler  15 ,  Peter G Kranz  16 ,  Constance T R M Stumpel  17 ,  Sylvia Klinkenberg  18 ,  Karin Oberndorff  19 ,  Malik Alawi  20 ,  Rene Santer  21 ,  Slavé Petrovski  22 ,  Outi Kuismin  23 ,  Satu Korpi-Heikkilä  24 ,  Olli Pietilainen  25 ,  Palotie Aarno  26 ,  Mitja I Kurki  27 ,  Alexander Hoischen  28 ,  Anna C Need  29 ,  David B Goldstein  7 ,  Fanny Kortüm  4
Affiliations
  • 1. Division of Medical Genetics, Department of Pediatrics, Duke Health, Durham, NC 27710, USA. Electronic address: [email protected].
  • 2. Division of Medical Genetics, Department of Pediatrics, Duke Health, Durham, NC 27710, USA.
  • 3. Department of Pediatrics, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL 60611, USA.
  • 4. Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
  • 5. Baylor College of Medicine, Houston, TX 77030, USA.
  • 6. GeneDx, Gaithersburg, MD 20877, USA.
  • 7. Institute for Genomic Medicine, Columbia University, New York, NY 10032, USA.
  • 8. Division of Molecular and Human Genetics, Nationwide Children's Hospital, Columbus, OH 43082, USA.
  • 9. NIH Common Fund, Bethesda, MD 20892, USA.
  • 10. Division of Endocrinology and Diabetes, Department of Pediatrics, Duke Health, Durham, NC 27710, USA.
  • 11. Departments of Pediatrics and Dermatology, Duke Health, Durham, NC 27710, USA.
  • 12. Departments of Pediatrics and Surgery, Duke Health, Durham, NC 27710, USA.
  • 13. Psychiatry and Behavioral Sciences, Duke Health, Durham, NC 27710, USA.
  • 14. Duke Eye Center, Duke Health, Durham, NC 27710, USA.
  • 15. Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Duke Health, Durham, NC 27710, USA.
  • 16. Division of Neuroradiology, Department of Radiology, Duke Health, Durham, NC 27710, USA.
  • 17. Department of Clinical Genetics and School for Oncology & Developmental Biology, Maastricht University Medical Center, 6202 AZ Maastricht, the Netherlands.
  • 18. Department of Neurology, Maastricht University Medical Center, 6202 AZ Maastricht, the Netherlands.
  • 19. Department of Pediatrics, Zuyderland Medical Center, 6162 BG Sittard, the Netherlands.
  • 20. Bioinformatics Service Facility, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany; Center for Bioinformatics, University of Hamburg, 20246 Hamburg, Germany; Heinrich-Pette-Institute, Leibniz-Institute for Experimental Virology, Virus Genomics, 20246 Hamburg, Germany.
  • 21. Department of Paediatrics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
  • 22. Institute for Genomic Medicine, Columbia University, New York, NY 10032, USA; Department of Medicine, Austin Health and Royal Melbourne Hospital, University of Melbourne, Melbourne, VIC 3050, Australia.
  • 23. PEDEGO Research Unit, Medical Research Center Oulu, Oulu University Hospital and University of Oulu, 90014 Oulu, Finland; Department of Clinical Genetics, Oulu University Hospital, 90029 Oulu, Finland; Institute for Molecular Medicine Finland, University of Helsinki, 00290 Helsinki, Finland.
  • 24. Northern Ostrobothnia Hospital District, Center for Intellectual Disability Care, 90220 Oulu, Finland.
  • 25. Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Harvard Stem Cell Institute, Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
  • 26. Institute for Molecular Medicine Finland, University of Helsinki, 00290 Helsinki, Finland; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Psychiatric and Neurodevelopmental Genetics Unit, Department of Psychiatry, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Neurology, Massachusetts General Hospital, Boston, MA USA, 02114.
  • 27. Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Psychiatric and Neurodevelopmental Genetics Unit, Department of Psychiatry, Massachusetts General Hospital, Boston, MA 02114, USA; Genetic Analysis Platform, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • 28. Department of Human Genetics, Donders Centre for Neuroscience, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands.
  • 29. Division of Brain Sciences, Department of Medicine, Imperial College London, London W12 0NN, UK.
PMID: 27693232 DOI: 10.1016/j.ajhg.2016.08.017
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.

Keywords
ASXL2; developmental delay; glabellar nevus flammeus; intellectual disability; macrocephaly; whole-exome sequencing.