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

Vandana Shashi, Loren D.M. Pena, Katherine Kim, Barbara Burton, Maja Hempel, Kelly Schoch, Magdalena Walkiewicz, Heather M. McLaughlin, Megan Cho, Nicholas Stong, Scott E. Hickey, Christine M. Shuss, A. Bacino, Brendan H. Lee, Ashok Balasubramanyam, Lindsay C. Burrage, Gary D. Clark, William J. Craigen, Shweta U. Dhar, Lisa T. EmrickBrett H. Graham, Mahim Jain, Seema R. Lalani, Richard A. Lewis, Paolo M. Moretti, Sarah K. Nicholas, Jordan S. Orange, Jennifer E. Posey, Lorraine Potocki, Jill A. Rosenfeld, Daryl A. Scott, Neil A. Hanchard, Tran A. Alyssa, Alejandro E. Mercedes, Azamian S. Mashid, Hugo J. Bellen, Shinya Yamamoto, Michael F. Wangler, Monte Westerfield, John H. Postlethwait, Christine M. Eng, Yaping Yang, Donna M. Muzny, Patricia A. Ward, Rachel B. Ramoni, Alexa T. McCray, Issac S. Kohane, Ingrid A. Holm, Matthew Might, Paul Mazur, Kimberly Splinter, Cecilia Esteves, Vandana Shashi, Yong hui Jiang, Loren D.M. Pena, Allyn McConkie-Rosell, Kelly Schoch, Rebecca C. Spillmann, Jennifer A. Sullivan, Nicole M. Walley, David B. Goldstein, Nicholas Stong, Alan H. Beggs, Joseph Loscalzo, Calum A. MacRae, Edwin K. Silverman, Joan M. Stoler, David A. Sweetser, Richard L. Maas, Joel B. Krier, Lance H. Rodan, Chris A. Walsh, Cynthia M. Cooper, Juan C. Pallais, Laurel A. Donnell-Fink, Elizabeth L. Krieg, Sharyn A. Lincoln, Lauren C. Briere, Howard J. Jacob, Elizabeth A. Worthey, Joe Lazar, Kim A. Strong, Lori H. Handley, J. Scott Newberry, David P. Bick, Molly C. Schroeder, Donna M. Brown, Camille L. Birch, Shawn E. Levy, Braden E. Boone, Dan C. Dorset, Angela L. Jones, Teri A. Manolio, John J. Mulvihill, Anastasia L. Wise, Jyoti G. Dayal, David J. Eckstein, Donna M. Krasnewich, Carson R. Loomis, Laura A. Mamounas, Brenda Iglesias, Casey Martin, David M. Koeller, Thomas O. Metz, Euan A. Ashley, Paul G. Fisher, Jonathan A. Bernstein, Matt T. Wheeler, Patricia A. Zornio, Daryl M. Waggott, Annika M. Dries, Jennefer N. Kohler, Katrina M. Dipple, Stan F. Nelson, Christina G.S. Palmer, Eric Vilain, Patrick Allard, Esteban C. Dell Angelica, Hane Lee, Janet S. Sinsheimer, Jeanette C. Papp, Naghmeh Dorrani, Matthew R. Herzog, Hayk Barseghyan, David R. Adams, Christopher J. Adams, Elizabeth A. Burke, Katherine R. Chao, Mariska Davids, David D. Draper, Tyra Estwick, Trevor S. Frisby, Kate Frost, William A. Gahl, Valerie Gartner, Rena A. Godfrey, Mitchell Goheen, Gretchen A. Golas, Mary G. Gordon, Catherine A. Groden, Andrea L. Gropman, Mary E. Hackbarth, Isabel Hardee, Jean M. Johnston, Alanna E. Koehler, Lea Latham, Yvonne L. Latour, Chyau Yueh C. Lau, Paul R. Lee, Denise J. Levy, Adam P. Liebendorder, Ellen F. Macnamara, Valerie V. Maduro, May V. Malicdan, Thomas C. Markello, Alexandra J. McCarty, Jennifer L. Murphy, Michele E. Nehrebecky, Donna Novacic, Barbara N. Pusey, Sarah Sadozai, Katherine E. Schaffer, Prashant Sharma, Ariane G. Soldatos, Sara P. Thomas, Cynthia J. Tifft, Nathanial J. Tolman, Camilo Toro, Zaheer M. Valivullah, Colleen E. Wahl, Mike Warburton, Alec A. Weech, Lynne A. Wolfe, Guoyun Yu, Rizwan Hamid, John H. Newman, John A. Phillips, Joy D. Cogan, Michael S. Freemark, Jane S. Bellet, Martha Ann Keels, Melanie J. Bonner, Maysantoine El-Dairi, Megan Butler, Peter G. Kranz, Constance T.R.M. Stumpel, Sylvia Klinkenberg, Karin Oberndorff, Malik Alawi, Rene Santer, Slavé Petrovski, Outi Kuismin, Satu Korpi-Heikkilä, Olli Pietilainen, Palotie Aarno, Mitja I. Kurki, Alexander Hoischen, Anna C. Need, David B. Goldstein, Fanny Kortüm

Research output: Contribution to journalArticle

23 Scopus citations

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.

Original languageEnglish
Pages (from-to)991-999
Number of pages9
JournalAmerican journal of human genetics
Volume99
Issue number4
DOIs
StatePublished - Oct 6 2016
Externally publishedYes

Keywords

  • ASXL2
  • developmental delay
  • glabellar nevus flammeus
  • intellectual disability
  • macrocephaly
  • whole-exome sequencing

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    Shashi, V., Pena, L. D. M., Kim, K., Burton, B., Hempel, M., Schoch, K., Walkiewicz, M., McLaughlin, H. M., Cho, M., Stong, N., Hickey, S. E., Shuss, C. M., Bacino, A., Lee, B. H., Balasubramanyam, A., Burrage, L. C., Clark, G. D., Craigen, W. J., Dhar, S. U., ... Kortüm, F. (2016). De Novo Truncating Variants in ASXL2 Are Associated with a Unique and Recognizable Clinical Phenotype. American journal of human genetics, 99(4), 991-999. https://doi.org/10.1016/j.ajhg.2016.08.017