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 language | English (US) |
|---|---|
| Pages (from-to) | 991-999 |
| Number of pages | 9 |
| Journal | American Journal of Human Genetics |
| Volume | 99 |
| Issue number | 4 |
| DOIs | |
| State | Published - Oct 6 2016 |
| Externally published | Yes |
Keywords
- ASXL2
- developmental delay
- glabellar nevus flammeus
- intellectual disability
- macrocephaly
- whole-exome sequencing
ASJC Scopus subject areas
- Genetics
- Genetics(clinical)
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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 M.; 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 journal › Article › peer-review
}
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.
AU - Emrick, Lisa T.
AU - Graham, Brett H.
AU - Jain, Mahim
AU - Lalani, Seema R.
AU - Lewis, Richard A.
AU - Moretti, Paolo M.
AU - Nicholas, Sarah K.
AU - Orange, Jordan S.
AU - Posey, Jennifer E.
AU - Potocki, Lorraine
AU - Rosenfeld, Jill A.
AU - Scott, Daryl A.
AU - Hanchard, Neil A.
AU - Alyssa, Tran A.
AU - Mercedes, Alejandro E.
AU - Mashid, Azamian S.
AU - Bellen, Hugo J.
AU - Yamamoto, Shinya
AU - Wangler, Michael F.
AU - Westerfield, Monte
AU - Postlethwait, John H.
AU - Eng, Christine M.
AU - Yang, Yaping
AU - Muzny, Donna M.
AU - Ward, Patricia A.
AU - Ramoni, Rachel B.
AU - McCray, Alexa T.
AU - Kohane, Issac S.
AU - Holm, Ingrid A.
AU - Might, Matthew
AU - Mazur, Paul
AU - Splinter, Kimberly
AU - Esteves, Cecilia
AU - Shashi, Vandana
AU - Jiang, Yong hui
AU - Pena, Loren D.M.
AU - McConkie-Rosell, Allyn
AU - Schoch, Kelly
AU - Spillmann, Rebecca C.
AU - Sullivan, Jennifer A.
AU - Walley, Nicole M.
AU - Goldstein, David B.
AU - Stong, Nicholas
AU - Beggs, Alan H.
AU - Loscalzo, Joseph
AU - MacRae, Calum A.
AU - Silverman, Edwin K.
AU - Stoler, Joan M.
AU - Sweetser, David A.
AU - Maas, Richard L.
AU - Krier, Joel B.
AU - Rodan, Lance H.
AU - Walsh, Chris A.
AU - Cooper, Cynthia M.
AU - Pallais, Juan C.
AU - Donnell-Fink, Laurel A.
AU - Krieg, Elizabeth L.
AU - Lincoln, Sharyn A.
AU - Briere, Lauren C.
AU - Jacob, Howard J.
AU - Worthey, Elizabeth A.
AU - Lazar, Joe
AU - Strong, Kim A.
AU - Handley, Lori H.
AU - Newberry, J. Scott
AU - Bick, David P.
AU - Schroeder, Molly C.
AU - Brown, Donna M.
AU - Birch, Camille L.
AU - Levy, Shawn E.
AU - Boone, Braden E.
AU - Dorset, Dan C.
AU - Jones, Angela L.
AU - Manolio, Teri A.
AU - Mulvihill, John J.
AU - Wise, Anastasia L.
AU - Dayal, Jyoti G.
AU - Eckstein, David J.
AU - Krasnewich, Donna M.
AU - Loomis, Carson R.
AU - Mamounas, Laura A.
AU - Iglesias, Brenda
AU - Martin, Casey
AU - Koeller, David M.
AU - Metz, Thomas O.
AU - Ashley, Euan A.
AU - Fisher, Paul G.
AU - Bernstein, Jonathan A.
AU - Wheeler, Matt T.
AU - Zornio, Patricia A.
AU - Waggott, Daryl M.
AU - Dries, Annika M.
AU - Kohler, Jennefer N.
AU - Dipple, Katrina M.
AU - Nelson, Stan F.
AU - Palmer, Christina G.S.
AU - Vilain, Eric
AU - Allard, Patrick
AU - Dell Angelica, Esteban C.
AU - Lee, Hane
AU - Sinsheimer, Janet S.
AU - Papp, Jeanette C.
AU - Dorrani, Naghmeh
AU - Herzog, Matthew R.
AU - Barseghyan, Hayk
AU - Adams, David R.
AU - Adams, Christopher J.
AU - Burke, Elizabeth A.
AU - Chao, Katherine R.
AU - Davids, Mariska
AU - Draper, David D.
AU - Estwick, Tyra
AU - Frisby, Trevor S.
AU - Frost, Kate
AU - Gahl, William A.
AU - Gartner, Valerie
AU - Godfrey, Rena A.
AU - Goheen, Mitchell
AU - Golas, Gretchen A.
AU - Gordon, Mary G.
AU - Groden, Catherine A.
AU - Gropman, Andrea L.
AU - Hackbarth, Mary E.
AU - Hardee, Isabel
AU - Johnston, Jean M.
AU - Koehler, Alanna E.
AU - Latham, Lea
AU - Latour, Yvonne L.
AU - Lau, Chyau Yueh C.
AU - Lee, Paul R.
AU - Levy, Denise J.
AU - Liebendorder, Adam P.
AU - Macnamara, Ellen F.
AU - Maduro, Valerie V.
AU - Malicdan, May V.
AU - Markello, Thomas C.
AU - McCarty, Alexandra J.
AU - Murphy, Jennifer L.
AU - Nehrebecky, Michele E.
AU - Novacic, Donna
AU - Pusey, Barbara N.
AU - Sadozai, Sarah
AU - Schaffer, Katherine E.
AU - Sharma, Prashant
AU - Soldatos, Ariane G.
AU - Thomas, Sara P.
AU - Tifft, Cynthia J.
AU - Tolman, Nathanial J.
AU - Toro, Camilo
AU - Valivullah, Zaheer M.
AU - Wahl, Colleen E.
AU - Warburton, Mike
AU - Weech, Alec A.
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
AU - Kranz, Peter G.
AU - Stumpel, Constance T.R.M.
AU - Klinkenberg, Sylvia
AU - Oberndorff, Karin
AU - Alawi, Malik
AU - Santer, Rene
AU - Petrovski, Slavé
AU - Kuismin, Outi
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
N1 - Funding Information: We are grateful to the inidividuals and their families who contributed to this study and allowed us to publish their information and pictures. We thank I. Jantke for skillful technical assistance. This work was supported by the Undiagnosed Diseases Network (1U01HG007672-01 to V.S.) and the Deutsche Forschungsgemeinschaft (KO 4576/1-1 to F.K.). The authors disclose the following: the Department of Molecular and Human Genetics at Baylor College of Medicine derives revenue from molecular testing offered at the Baylor Genetics Laboratories (M.W.); D.B.G. has received consultancy fees and has equity ownership in Pairnomix LLC; H.M.M. and M.C. are employees of GeneDx; B.B. has received honoraria, consulting fees, or funding for clinical trials from Sanofi- Genzyme, Shire, Biomarin, Ultragenyx, Alexion, Armagen, and ReGenX Bio; and E.A.A. from the Undiagnosed Diseases Network is a co-founder of Personalis Inc. Publisher Copyright: © 2016
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 -