Expanding the phenotype of <scp><i>ASXL3</i></scp>‐related syndrome: A comprehensive description of 45 unpublished individuals with inherited and de novo pathogenic variants in <scp><i>ASXL3</i></scp>
Schaida Schirwani, Shadi Albaba, Deanna Alexis Carere, María J. Guillen Sacoto, Francisca Milan Zamora, Yue Si, Rachel Rabin, John Pappas, Deborah L. Renaud, Natalie Hauser, Evan Reid, Patricia Blanchet, Nichola Foulds, Abhijit Dixit, Richard Fisher, Ruth Armstrong, Bertrand Isidor, Benjamin Cogné, Samantha A. Schrier Vergano, Serwet Demirdas, Natalie Dykzeul, Julie S. Cohen, Katheryn Grand, Dayna Morel Swols, Anne Slavotinek, Hessa F. Albassam, Swati Naik, John Dean, Nicola Ragge, Cinzia Costa, Maria Giovanna Tedesco, Rachel Harrison, Arjan Bouman, Emily Palen, Thomas D. Challman, Marjolein H. Willemsen, Julie Vogt, Christopher Cunniff, Katherine Bergstrom, Jagdeep S. Walia, Ange‐Line Bruel, Usha Kini, Fowzan S. Alkuraya, Valerie Slegesky, Naomi Meeks, Paula Natale Girotto, Diana Johnson, DDD Study, Ruth Newbury‐Ecob, Charlotte W. Ockeloen, Paolo Prontera, Sally Ann Lynch, Dong Li, John M. Graham, Tyler Mark Pierson, Meena Balasubramanian
Abstract
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. 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this international collaborative study, we have undertaken a detailed clinical and molecular analysis of 45 previously unpublished individuals with ASXL3-related syndrome, as well as a review of all previously published individuals.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 characterization of pathogenic variants in ASXL3 and discuss current understanding of the consequences of the different ASXL3 variants. 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, characterize the phenotype in mildly affected individuals and discuss nonpenetrance. 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-behavioral issues, hypotonia, and feeding difficulties. Distinctive features include downslanting palpebral fissures, hypertelorism, tubular nose with a prominent nasal bridge, and low-hanging columella. The presented data will inform clinical management of individuals with ASXL3-related syndrome and improve interpretation of new ASXL3 sequence variants.