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Expanding the phenotype of ASXL3 ‐related syndrome: A comprehensive description of 45 unpublished individuals with inherited and de novo pathogenic variants in ASXL3
Author(s) -
Schirwani Schaida,
Albaba Shadi,
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,
Schrier Vergano Samantha,
Demirdas Serwet,
Dykzeul Natalie,
Cohen Julie S.,
Grand Katheryn,
Morel Dayna,
Slavotinek Anne,
Albassam Hessa F.,
Naik Swati,
Dean John,
Ragge Nicola,
Costa Cinzia,
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 AngeLine,
Kini Usha,
Alkuraya Fowzan S.,
Slegesky Valerie,
Meeks Naomi,
Girotto Paula,
Johnson Diana,
NewburyEcob Ruth,
Ockeloen Charlotte W.,
Prontera Paolo,
Lynch Sally Ann,
Li Dong,
Graham John M.,
Pierson Tyler Mark,
Balasubramanian Meena
Publication year - 2021
Publication title -
american journal of medical genetics part a
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.064
H-Index - 112
eISSN - 1552-4833
pISSN - 1552-4825
DOI - 10.1002/ajmg.a.62465
Subject(s) - phenotype , missense mutation , hypertelorism , genetics , hypotonia , biology , intellectual disability , gene
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this international collaborative study, we have undertaken a detailed clinical and molecular analysis of 45 previously unpublished individuals with ASXL3 ‐related syndrome, as well as a review of all previously published individuals.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.