Journal Article

Expanding the phenotype of ASXL3-related syndrome: A comprehensive description of 45 unpublished individuals with inherited and de novo pathogenic variants in ASXL3


Purpose. The study aimed at widening the clinical and genetic spectrum of ASXL3-related syndrome, a neurodevelopmental disorder, caused by truncating variants in the ASXL3 gene. Methods. In this international collaborative study, we have undertaken a detailed clinical and molecular analysis of 45 previously unpublished individuals with ASXL3-related syndrome, as well as a review of all previously published individuals. We have reviewed the rather limited functional characterisation of pathogenic variants in ASXL3 and discuss current understanding of the consequences of the different ASXL3 variants. Results. In this comprehensive analysis of ASXL3-related syndrome, we define its natural history and clinical evolution occurring with age. We report familial ASXL3 pathogenic variants, characterise the phenotype in mildly affected individuals and discuss non-penetrance. We also discuss the role of missense variants in ASXL3. We delineate a variable but consistent phenotype. The most characteristic features are neurodevelopmental delay with consistently limited speech, significant neuro-behavioural issues, hypotonia and feeding difficulties. Distinctive features include down-slanting palpebral fissures, hypertelorism, tubular nose with a prominent nasal bridge and low-hanging columella. Conclusion. The presented data will inform clinical management of individuals with ASXL3-related syndrome and improve interpretation of new ASXL3 sequence variants. 

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Embargo end: 2022-08-24


Schirwani, Schaida
Carere, Deanna Alexis
Guillen Sacoto, Maria J.
Milan Zamora, Francisca
Si Yue
Rabin, Rachel
Pappas, John
Renaud, Deborah L.
Hauser, Natalie
Reid, Evan
Blanchet, Patricia
Foulds, Nichola
Dixit, Abhijit
Fisher, Richard
Armstrong, Ruth
Isidor, Bertrand
Cogne, Benjamin
Vergano, Samantha Schrier
Demirdas, Serwet
Dykzeul, Natalie
Cohen, Julie S.
Grand, Katheryn
Morel, Dayna
Slavotinek, Anne
Albassam, Hessa F.
Naik, Swati
Dean, John
Ragge, Nicola
Cinzia, Costa
Tedesco, Maria Giovanna
Harrison, Rachel E.
Bouman, Arjan
Palen, Emily
Challman, Thomas D.
Willemsen, Marjolein H.
Vogt, Julie
Cunniff, Christopher
Bergstrom, Katherine
Walia, Jagdeep S.
Bruel, Ange-Line
Kini, Usha
Alkuraya, Fowzan S.
Slegesky, Valerie
Meeks, Naomi
Girotto, Paula
Johnson, Diana
DDD study
Newbury-Ecob, Ruth
Ockeloen, Charlotte W.
Prontera, Paolo
Lynch, Sally Ann
Li Dong
Graham, John M., Jr.
Balasubramanian Meena

Oxford Brookes departments

Department of Biological and Medical Sciences


Year of publication: Not yet published.
Date of RADAR deposit: 2021-08-24

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This RADAR resource is the Accepted Manuscript of Expanding the phenotype of ASXL3-related syndrome: A comprehensive description of 45 unpublished individuals with inherited and de novo pathogenic variants in ASXL3


  • Owner: Joseph Ripp
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