Imperial College London
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Dr. Anna C. Need

Faculty of Medicine, Department of Brain Sciences

Honorary Lecturer
 
 
 
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Contact

 

+44 (0)20 3313 8436a.need Website

 
 
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Location

 

7N2aCommonwealth BuildingHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@article{Shashi:2016:10.1016/j.ajhg.2016.08.017,
author = {Shashi, V and Pena, LD and Kim, K and Burton, B and Hempel, M and Schoch, K and Walkiewicz, M and McLaughlin, HM and Cho, M and Stong, N and Hickey, SE and Shuss, CM and Undiagnosed, Diseases Network and Freemark, MS and Bellet, JS and Keels, MA and Bonner, MJ and El-Dairi, M and Butler, M and Kranz, PG and Stumpel, CT and Klinkenberg, S and Oberndorff, K and Alawi, M and Santer, R and Petrovski, S and Kuismin, O and Korpi-Heikkilä, S and Pietilainen, O and Aarno, P and Kurki, MI and Hoischen, A and Need, AC and Goldstein, DB and Kortüm, F},
doi = {10.1016/j.ajhg.2016.08.017},
journal = {American Journal of Human Genetics},
pages = {991--999},
title = {De Novo Truncating Variants in ASXL2 Are Associated with a Unique and Recognizable Clinical Phenotype},
url = {http://dx.doi.org/10.1016/j.ajhg.2016.08.017},
volume = {99},
year = {2016}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
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.
AU  - Shashi,V
AU  - Pena,LD
AU  - Kim,K
AU  - Burton,B
AU  - Hempel,M
AU  - Schoch,K
AU  - Walkiewicz,M
AU  - McLaughlin,HM
AU  - Cho,M
AU  - Stong,N
AU  - Hickey,SE
AU  - Shuss,CM
AU  - Undiagnosed,Diseases Network
AU  - Freemark,MS
AU  - Bellet,JS
AU  - Keels,MA
AU  - Bonner,MJ
AU  - El-Dairi,M
AU  - Butler,M
AU  - Kranz,PG
AU  - Stumpel,CT
AU  - Klinkenberg,S
AU  - Oberndorff,K
AU  - Alawi,M
AU  - Santer,R
AU  - Petrovski,S
AU  - Kuismin,O
AU  - Korpi-Heikkilä,S
AU  - Pietilainen,O
AU  - Aarno,P
AU  - Kurki,MI
AU  - Hoischen,A
AU  - Need,AC
AU  - Goldstein,DB
AU  - Kortüm,F
DO  - 10.1016/j.ajhg.2016.08.017
EP  - 999
PY  - 2016///
SN  - 1537-6605
SP  - 991
TI  - De Novo Truncating Variants in ASXL2 Are Associated with a Unique and Recognizable Clinical Phenotype
T2  - American Journal of Human Genetics
UR  - http://dx.doi.org/10.1016/j.ajhg.2016.08.017
UR  - http://hdl.handle.net/10044/1/41685
VL  - 99
ER  -
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