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 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

19 Citations (Scopus)

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 (US)
Pages (from-to)991-999
Number of pages9
JournalAmerican Journal of Human Genetics
Volume99
Issue number4
DOIs
StatePublished - Oct 6 2016
Externally publishedYes

Fingerprint

Megalencephaly
Phenotype
Intellectual Disability
Body Patterning
Port-Wine Stain
Hypertelorism
Exome
Eyebrows
Developmental Disabilities
Muscle Hypotonia
Epigenomics
Genes
Embryonic Development
Transcription Factors
Alleles
Messenger RNA
Growth
Proteins

Keywords

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

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

De Novo Truncating Variants in ASXL2 Are Associated with a Unique and Recognizable Clinical Phenotype. / Shashi, Vandana; Pena, Loren D M; Kim, Katherine; Burton, Barbara; Hempel, Maja; Schoch, Kelly; Walkiewicz, Magdalena; McLaughlin, Heather M.; Cho, Megan; Stong, Nicholas; Hickey, Scott E.; Shuss, Christine M.; Bacino, A.; Lee, Brendan H.; Balasubramanyam, Ashok; Burrage, Lindsay C.; Clark, Gary D.; Craigen, William J.; Dhar, Shweta U.; Emrick, Lisa T.; Graham, Brett H.; Jain, Mahim; Lalani, Seema R.; Lewis, Richard A.; Moretti, Paolo M.; Nicholas, Sarah K.; Orange, Jordan S.; Posey, Jennifer E.; Potocki, Lorraine; Rosenfeld, Jill A.; Scott, Daryl A.; Hanchard, Neil A.; Alyssa, Tran A.; Mercedes, Alejandro E.; Mashid, Azamian S.; Bellen, Hugo J.; Yamamoto, Shinya; Wangler, Michael F.; Westerfield, Monte; Postlethwait, John H.; Eng, Christine M.; Yang, Yaping; Muzny, Donna M.; Ward, Patricia A.; Ramoni, Rachel B.; McCray, Alexa T.; Kohane, Issac S.; Holm, Ingrid A.; Might, Matthew; Mazur, Paul; Splinter, Kimberly; Esteves, Cecilia; Shashi, Vandana; Jiang, Yong hui; Pena, Loren D M; McConkie-Rosell, Allyn; Schoch, Kelly; Spillmann, Rebecca C.; Sullivan, Jennifer A.; Walley, Nicole M.; Goldstein, David B.; Stong, Nicholas; Beggs, Alan H.; Loscalzo, Joseph; MacRae, Calum A.; Silverman, Edwin K.; Stoler, Joan M.; Sweetser, David A.; Maas, Richard L.; Krier, Joel B.; Rodan, Lance H.; Walsh, Chris A.; Cooper, Cynthia M.; Pallais, Juan C.; Donnell-Fink, Laurel A.; Krieg, Elizabeth L.; Lincoln, Sharyn A.; Briere, Lauren C.; Jacob, Howard J.; Worthey, Elizabeth A.; Lazar, Joe; Strong, Kim A.; Handley, Lori H.; Newberry, J. Scott; Bick, David P.; Schroeder, Molly C.; Brown, Donna M.; Birch, Camille L.; Levy, Shawn E.; Boone, Braden E.; Dorset, Dan C.; Jones, Angela L.; Manolio, Teri A.; Mulvihill, John J.; Wise, Anastasia L.; Dayal, Jyoti G.; Eckstein, David J.; Krasnewich, Donna M.; Loomis, Carson R.; Mamounas, Laura A.; Iglesias, Brenda; Martin, Casey; Koeller, David; Metz, Thomas O.; Ashley, Euan A.; Fisher, Paul G.; Bernstein, Jonathan A.; Wheeler, Matt T.; Zornio, Patricia A.; Waggott, Daryl M.; Dries, Annika M.; Kohler, Jennefer N.; Dipple, Katrina M.; Nelson, Stan F.; Palmer, Christina G S; Vilain, Eric; Allard, Patrick; Dell Angelica, Esteban C.; Lee, Hane; Sinsheimer, Janet S.; Papp, Jeanette C.; Dorrani, Naghmeh; Herzog, Matthew R.; Barseghyan, Hayk; Adams, David R.; Adams, Christopher J.; Burke, Elizabeth A.; Chao, Katherine R.; Davids, Mariska; Draper, David D.; Estwick, Tyra; Frisby, Trevor S.; Frost, Kate; Gahl, William A.; Gartner, Valerie; Godfrey, Rena A.; Goheen, Mitchell; Golas, Gretchen A.; Gordon, Mary G.; Groden, Catherine A.; Gropman, Andrea L.; Hackbarth, Mary E.; Hardee, Isabel; Johnston, Jean M.; Koehler, Alanna E.; Latham, Lea; Latour, Yvonne L.; Lau, Chyau Yueh C; Lee, Paul R.; Levy, Denise J.; Liebendorder, Adam P.; Macnamara, Ellen F.; Maduro, Valerie V.; Malicdan, May V.; Markello, Thomas C.; McCarty, Alexandra J.; Murphy, Jennifer L.; Nehrebecky, Michele E.; Novacic, Donna; Pusey, Barbara N.; Sadozai, Sarah; Schaffer, Katherine E.; Sharma, Prashant; Soldatos, Ariane G.; Thomas, Sara P.; Tifft, Cynthia J.; Tolman, Nathanial J.; Toro, Camilo; Valivullah, Zaheer M.; Wahl, Colleen E.; Warburton, Mike; Weech, Alec A.; Wolfe, Lynne A.; Yu, Guoyun; Hamid, Rizwan; Newman, John H.; Phillips, John A.; Cogan, Joy D.; Freemark, Michael S.; Bellet, Jane S.; Keels, Martha Ann; Bonner, Melanie J.; El-Dairi, Maysantoine; Butler, Megan; Kranz, Peter G.; Stumpel, Constance T R M; 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.

In: American Journal of Human Genetics, Vol. 99, No. 4, 06.10.2016, p. 991-999.

Research output: Contribution to journalArticle

Shashi, V, Pena, LDM, Kim, K, Burton, B, Hempel, M, Schoch, K, Walkiewicz, M, McLaughlin, HM, Cho, M, Stong, N, Hickey, SE, Shuss, CM, Bacino, A, Lee, BH, Balasubramanyam, A, Burrage, LC, Clark, GD, Craigen, WJ, Dhar, SU, Emrick, LT, Graham, BH, Jain, M, Lalani, SR, Lewis, RA, Moretti, PM, Nicholas, SK, Orange, JS, Posey, JE, Potocki, L, Rosenfeld, JA, Scott, DA, Hanchard, NA, Alyssa, TA, Mercedes, AE, Mashid, AS, Bellen, HJ, Yamamoto, S, Wangler, MF, Westerfield, M, Postlethwait, JH, Eng, CM, Yang, Y, Muzny, DM, Ward, PA, Ramoni, RB, McCray, AT, Kohane, IS, Holm, IA, Might, M, Mazur, P, Splinter, K, Esteves, C, Shashi, V, Jiang, YH, Pena, LDM, McConkie-Rosell, A, Schoch, K, Spillmann, RC, Sullivan, JA, Walley, NM, Goldstein, DB, Stong, N, Beggs, AH, Loscalzo, J, MacRae, CA, Silverman, EK, Stoler, JM, Sweetser, DA, Maas, RL, Krier, JB, Rodan, LH, Walsh, CA, Cooper, CM, Pallais, JC, Donnell-Fink, LA, Krieg, EL, Lincoln, SA, Briere, LC, Jacob, HJ, Worthey, EA, Lazar, J, Strong, KA, Handley, LH, Newberry, JS, Bick, DP, Schroeder, MC, Brown, DM, Birch, CL, Levy, SE, Boone, BE, Dorset, DC, Jones, AL, Manolio, TA, Mulvihill, JJ, Wise, AL, Dayal, JG, Eckstein, DJ, Krasnewich, DM, Loomis, CR, Mamounas, LA, Iglesias, B, Martin, C, Koeller, D, Metz, TO, Ashley, EA, Fisher, PG, Bernstein, JA, Wheeler, MT, Zornio, PA, Waggott, DM, Dries, AM, Kohler, JN, Dipple, KM, Nelson, SF, Palmer, CGS, Vilain, E, Allard, P, Dell Angelica, EC, Lee, H, Sinsheimer, JS, Papp, JC, Dorrani, N, Herzog, MR, Barseghyan, H, Adams, DR, Adams, CJ, Burke, EA, Chao, KR, Davids, M, Draper, DD, Estwick, T, Frisby, TS, Frost, K, Gahl, WA, Gartner, V, Godfrey, RA, Goheen, M, Golas, GA, Gordon, MG, Groden, CA, Gropman, AL, Hackbarth, ME, Hardee, I, Johnston, JM, Koehler, AE, Latham, L, Latour, YL, Lau, CYC, Lee, PR, Levy, DJ, Liebendorder, AP, Macnamara, EF, Maduro, VV, Malicdan, MV, Markello, TC, McCarty, AJ, Murphy, JL, Nehrebecky, ME, Novacic, D, Pusey, BN, Sadozai, S, Schaffer, KE, Sharma, P, Soldatos, AG, Thomas, SP, Tifft, CJ, Tolman, NJ, Toro, C, Valivullah, ZM, Wahl, CE, Warburton, M, Weech, AA, Wolfe, LA, Yu, G, Hamid, R, Newman, JH, Phillips, JA, Cogan, JD, Freemark, MS, Bellet, JS, Keels, MA, Bonner, MJ, El-Dairi, M, Butler, M, Kranz, PG, Stumpel, CTRM, Klinkenberg, S, Oberndorff, K, Alawi, M, Santer, R, Petrovski, S, Kuismin, O, Korpi-Heikkilä, S, Pietilainen, O, Aarno, P, Kurki, MI, Hoischen, A, Need, AC, Goldstein, DB & Kortüm, F 2016, 'De Novo Truncating Variants in ASXL2 Are Associated with a Unique and Recognizable Clinical Phenotype', American Journal of Human Genetics, vol. 99, no. 4, pp. 991-999. https://doi.org/10.1016/j.ajhg.2016.08.017
Shashi, Vandana ; Pena, Loren D M ; Kim, Katherine ; Burton, Barbara ; Hempel, Maja ; Schoch, Kelly ; Walkiewicz, Magdalena ; McLaughlin, Heather M. ; Cho, Megan ; Stong, Nicholas ; Hickey, Scott E. ; Shuss, Christine M. ; Bacino, A. ; Lee, Brendan H. ; Balasubramanyam, Ashok ; Burrage, Lindsay C. ; Clark, Gary D. ; Craigen, William J. ; Dhar, Shweta U. ; Emrick, Lisa T. ; Graham, Brett H. ; Jain, Mahim ; Lalani, Seema R. ; Lewis, Richard A. ; Moretti, Paolo M. ; Nicholas, Sarah K. ; Orange, Jordan S. ; Posey, Jennifer E. ; Potocki, Lorraine ; Rosenfeld, Jill A. ; Scott, Daryl A. ; Hanchard, Neil A. ; Alyssa, Tran A. ; Mercedes, Alejandro E. ; Mashid, Azamian S. ; Bellen, Hugo J. ; Yamamoto, Shinya ; Wangler, Michael F. ; Westerfield, Monte ; Postlethwait, John H. ; Eng, Christine M. ; Yang, Yaping ; Muzny, Donna M. ; Ward, Patricia A. ; Ramoni, Rachel B. ; McCray, Alexa T. ; Kohane, Issac S. ; Holm, Ingrid A. ; Might, Matthew ; Mazur, Paul ; Splinter, Kimberly ; Esteves, Cecilia ; Shashi, Vandana ; Jiang, Yong hui ; Pena, Loren D M ; McConkie-Rosell, Allyn ; Schoch, Kelly ; Spillmann, Rebecca C. ; Sullivan, Jennifer A. ; Walley, Nicole M. ; Goldstein, David B. ; Stong, Nicholas ; Beggs, Alan H. ; Loscalzo, Joseph ; MacRae, Calum A. ; Silverman, Edwin K. ; Stoler, Joan M. ; Sweetser, David A. ; Maas, Richard L. ; Krier, Joel B. ; Rodan, Lance H. ; Walsh, Chris A. ; Cooper, Cynthia M. ; Pallais, Juan C. ; Donnell-Fink, Laurel A. ; Krieg, Elizabeth L. ; Lincoln, Sharyn A. ; Briere, Lauren C. ; Jacob, Howard J. ; Worthey, Elizabeth A. ; Lazar, Joe ; Strong, Kim A. ; Handley, Lori H. ; Newberry, J. Scott ; Bick, David P. ; Schroeder, Molly C. ; Brown, Donna M. ; Birch, Camille L. ; Levy, Shawn E. ; Boone, Braden E. ; Dorset, Dan C. ; Jones, Angela L. ; Manolio, Teri A. ; Mulvihill, John J. ; Wise, Anastasia L. ; Dayal, Jyoti G. ; Eckstein, David J. ; Krasnewich, Donna M. ; Loomis, Carson R. ; Mamounas, Laura A. ; Iglesias, Brenda ; Martin, Casey ; Koeller, David ; Metz, Thomas O. ; Ashley, Euan A. ; Fisher, Paul G. ; Bernstein, Jonathan A. ; Wheeler, Matt T. ; Zornio, Patricia A. ; Waggott, Daryl M. ; Dries, Annika M. ; Kohler, Jennefer N. ; Dipple, Katrina M. ; Nelson, Stan F. ; Palmer, Christina G S ; Vilain, Eric ; Allard, Patrick ; Dell Angelica, Esteban C. ; Lee, Hane ; Sinsheimer, Janet S. ; Papp, Jeanette C. ; Dorrani, Naghmeh ; Herzog, Matthew R. ; Barseghyan, Hayk ; Adams, David R. ; Adams, Christopher J. ; Burke, Elizabeth A. ; Chao, Katherine R. ; Davids, Mariska ; Draper, David D. ; Estwick, Tyra ; Frisby, Trevor S. ; Frost, Kate ; Gahl, William A. ; Gartner, Valerie ; Godfrey, Rena A. ; Goheen, Mitchell ; Golas, Gretchen A. ; Gordon, Mary G. ; Groden, Catherine A. ; Gropman, Andrea L. ; Hackbarth, Mary E. ; Hardee, Isabel ; Johnston, Jean M. ; Koehler, Alanna E. ; Latham, Lea ; Latour, Yvonne L. ; Lau, Chyau Yueh C ; Lee, Paul R. ; Levy, Denise J. ; Liebendorder, Adam P. ; Macnamara, Ellen F. ; Maduro, Valerie V. ; Malicdan, May V. ; Markello, Thomas C. ; McCarty, Alexandra J. ; Murphy, Jennifer L. ; Nehrebecky, Michele E. ; Novacic, Donna ; Pusey, Barbara N. ; Sadozai, Sarah ; Schaffer, Katherine E. ; Sharma, Prashant ; Soldatos, Ariane G. ; Thomas, Sara P. ; Tifft, Cynthia J. ; Tolman, Nathanial J. ; Toro, Camilo ; Valivullah, Zaheer M. ; Wahl, Colleen E. ; Warburton, Mike ; Weech, Alec A. ; Wolfe, Lynne A. ; Yu, Guoyun ; Hamid, Rizwan ; Newman, John H. ; Phillips, John A. ; Cogan, Joy D. ; Freemark, Michael S. ; Bellet, Jane S. ; Keels, Martha Ann ; Bonner, Melanie J. ; El-Dairi, Maysantoine ; Butler, Megan ; Kranz, Peter G. ; Stumpel, Constance T R M ; 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. / De Novo Truncating Variants in ASXL2 Are Associated with a Unique and Recognizable Clinical Phenotype. In: American Journal of Human Genetics. 2016 ; Vol. 99, No. 4. pp. 991-999.
@article{17644afc9dfa405e80ac4d8e1a0926d5,
title = "De Novo Truncating Variants in ASXL2 Are Associated with a Unique and Recognizable Clinical Phenotype",
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",
author = "Vandana Shashi and Pena, {Loren D M} and Katherine Kim and Barbara Burton and Maja Hempel and Kelly Schoch and Magdalena Walkiewicz and McLaughlin, {Heather M.} and Megan Cho and Nicholas Stong and Hickey, {Scott E.} and Shuss, {Christine M.} and A. Bacino and Lee, {Brendan H.} and Ashok Balasubramanyam and Burrage, {Lindsay C.} and Clark, {Gary D.} and Craigen, {William J.} and Dhar, {Shweta U.} and Emrick, {Lisa T.} and Graham, {Brett H.} and Mahim Jain and Lalani, {Seema R.} and Lewis, {Richard A.} and Moretti, {Paolo M.} and Nicholas, {Sarah K.} and Orange, {Jordan S.} and Posey, {Jennifer E.} and Lorraine Potocki and Rosenfeld, {Jill A.} and Scott, {Daryl A.} and Hanchard, {Neil A.} and Alyssa, {Tran A.} and Mercedes, {Alejandro E.} and Mashid, {Azamian S.} and Bellen, {Hugo J.} and Shinya Yamamoto and Wangler, {Michael F.} and Monte Westerfield and Postlethwait, {John H.} and Eng, {Christine M.} and Yaping Yang and Muzny, {Donna M.} and Ward, {Patricia A.} and Ramoni, {Rachel B.} and McCray, {Alexa T.} and Kohane, {Issac S.} and Holm, {Ingrid A.} and Matthew Might and Paul Mazur and Kimberly Splinter and Cecilia Esteves and Vandana Shashi and Jiang, {Yong hui} and Pena, {Loren D M} and Allyn McConkie-Rosell and Kelly Schoch and Spillmann, {Rebecca C.} and Sullivan, {Jennifer A.} and Walley, {Nicole M.} and Goldstein, {David B.} and Nicholas Stong and Beggs, {Alan H.} and Joseph Loscalzo and MacRae, {Calum A.} and Silverman, {Edwin K.} and Stoler, {Joan M.} and Sweetser, {David A.} and Maas, {Richard L.} and Krier, {Joel B.} and Rodan, {Lance H.} and Walsh, {Chris A.} and Cooper, {Cynthia M.} and Pallais, {Juan C.} and Donnell-Fink, {Laurel A.} and Krieg, {Elizabeth L.} and Lincoln, {Sharyn A.} and Briere, {Lauren C.} and Jacob, {Howard J.} and Worthey, {Elizabeth A.} and Joe Lazar and Strong, {Kim A.} and Handley, {Lori H.} and Newberry, {J. Scott} and Bick, {David P.} and Schroeder, {Molly C.} and Brown, {Donna M.} and Birch, {Camille L.} and Levy, {Shawn E.} and Boone, {Braden E.} and Dorset, {Dan C.} and Jones, {Angela L.} and Manolio, {Teri A.} and Mulvihill, {John J.} and Wise, {Anastasia L.} and Dayal, {Jyoti G.} and Eckstein, {David J.} and Krasnewich, {Donna M.} and Loomis, {Carson R.} and Mamounas, {Laura A.} and Brenda Iglesias and Casey Martin and David Koeller and Metz, {Thomas O.} and Ashley, {Euan A.} and Fisher, {Paul G.} and Bernstein, {Jonathan A.} and Wheeler, {Matt T.} and Zornio, {Patricia A.} and Waggott, {Daryl M.} and Dries, {Annika M.} and Kohler, {Jennefer N.} and Dipple, {Katrina M.} and Nelson, {Stan F.} and Palmer, {Christina G S} and Eric Vilain and Patrick Allard and {Dell Angelica}, {Esteban C.} and Hane Lee and Sinsheimer, {Janet S.} and Papp, {Jeanette C.} and Naghmeh Dorrani and Herzog, {Matthew R.} and Hayk Barseghyan and Adams, {David R.} and Adams, {Christopher J.} and Burke, {Elizabeth A.} and Chao, {Katherine R.} and Mariska Davids and Draper, {David D.} and Tyra Estwick and Frisby, {Trevor S.} and Kate Frost and Gahl, {William A.} and Valerie Gartner and Godfrey, {Rena A.} and Mitchell Goheen and Golas, {Gretchen A.} and Gordon, {Mary G.} and Groden, {Catherine A.} and Gropman, {Andrea L.} and Hackbarth, {Mary E.} and Isabel Hardee and Johnston, {Jean M.} and Koehler, {Alanna E.} and Lea Latham and Latour, {Yvonne L.} and Lau, {Chyau Yueh C} and Lee, {Paul R.} and Levy, {Denise J.} and Liebendorder, {Adam P.} and Macnamara, {Ellen F.} and Maduro, {Valerie V.} and Malicdan, {May V.} and Markello, {Thomas C.} and McCarty, {Alexandra J.} and Murphy, {Jennifer L.} and Nehrebecky, {Michele E.} and Donna Novacic and Pusey, {Barbara N.} and Sarah Sadozai and Schaffer, {Katherine E.} and Prashant Sharma and Soldatos, {Ariane G.} and Thomas, {Sara P.} and Tifft, {Cynthia J.} and Tolman, {Nathanial J.} and Camilo Toro and Valivullah, {Zaheer M.} and Wahl, {Colleen E.} and Mike Warburton and Weech, {Alec A.} and Wolfe, {Lynne A.} and Guoyun Yu and Rizwan Hamid and Newman, {John H.} and Phillips, {John A.} and Cogan, {Joy D.} and Freemark, {Michael S.} and Bellet, {Jane S.} and Keels, {Martha Ann} and Bonner, {Melanie J.} and Maysantoine El-Dairi and Megan Butler and Kranz, {Peter G.} and Stumpel, {Constance T R M} and Sylvia Klinkenberg and Karin Oberndorff and Malik Alawi and Rene Santer and Slav{\'e} Petrovski and Outi Kuismin and Satu Korpi-Heikkil{\"a} and Olli Pietilainen and Palotie Aarno and Kurki, {Mitja I.} and Alexander Hoischen and Need, {Anna C.} and Goldstein, {David B.} and Fanny Kort{\"u}m",
year = "2016",
month = "10",
day = "6",
doi = "10.1016/j.ajhg.2016.08.017",
language = "English (US)",
volume = "99",
pages = "991--999",
journal = "American Journal of Human Genetics",
issn = "0002-9297",
publisher = "Cell Press",
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}

TY - JOUR

T1 - De Novo Truncating Variants in ASXL2 Are Associated with a Unique and Recognizable Clinical Phenotype

AU - Shashi, Vandana

AU - Pena, Loren D M

AU - Kim, Katherine

AU - Burton, Barbara

AU - Hempel, Maja

AU - Schoch, Kelly

AU - Walkiewicz, Magdalena

AU - McLaughlin, Heather M.

AU - Cho, Megan

AU - Stong, Nicholas

AU - Hickey, Scott E.

AU - Shuss, Christine M.

AU - Bacino, A.

AU - Lee, Brendan H.

AU - Balasubramanyam, Ashok

AU - Burrage, Lindsay C.

AU - Clark, Gary D.

AU - Craigen, William J.

AU - Dhar, Shweta U.

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AU - Wahl, Colleen E.

AU - Warburton, Mike

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AU - Wolfe, Lynne A.

AU - Yu, Guoyun

AU - Hamid, Rizwan

AU - Newman, John H.

AU - Phillips, John A.

AU - Cogan, Joy D.

AU - Freemark, Michael S.

AU - Bellet, Jane S.

AU - Keels, Martha Ann

AU - Bonner, Melanie J.

AU - El-Dairi, Maysantoine

AU - Butler, Megan

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AU - Klinkenberg, Sylvia

AU - Oberndorff, Karin

AU - Alawi, Malik

AU - Santer, Rene

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AU - Korpi-Heikkilä, Satu

AU - Pietilainen, Olli

AU - Aarno, Palotie

AU - Kurki, Mitja I.

AU - Hoischen, Alexander

AU - Need, Anna C.

AU - Goldstein, David B.

AU - Kortüm, Fanny

PY - 2016/10/6

Y1 - 2016/10/6

N2 - 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.

AB - 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.

KW - ASXL2

KW - developmental delay

KW - glabellar nevus flammeus

KW - intellectual disability

KW - macrocephaly

KW - whole-exome sequencing

UR - http://www.scopus.com/inward/record.url?scp=84991615265&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84991615265&partnerID=8YFLogxK

U2 - 10.1016/j.ajhg.2016.08.017

DO - 10.1016/j.ajhg.2016.08.017

M3 - Article

C2 - 27693232

AN - SCOPUS:84991615265

VL - 99

SP - 991

EP - 999

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

SN - 0002-9297

IS - 4

ER -