Citations 2
Expanding the phenotype of ASXL3‐related syndrome: A comprehensive description of 45 unpublished individuals with inherited and de novo pathogenic variants in ASXL3
Schirwani, Schaida , Albaba, Shadi , Carere, Deanna Alexis , Sacoto, María J. Guillen , Zamora, Francisca Milan, Si, Yue , Rabin, Rachel , Renaud, Deborah L. , Hauser, Natalie , Blanchet, Patricia, Foulds, Nichola, Dixit, Abhijit , Fisher, Richard, Armstrong, Ruth, Isidor, Bertrand , Demirdas, Serwet , Dykzeul, Natalie, Cohen, Julie S. , Grand, Katheryn , Swols, Dayna Morel , Albassam, Hessa F., Naik, Swati , Ragge, Nicola , Tedesco, Maria Giovanna , Harrison, Rachel , Bouman, Arjan , Palen, Emily, Challman, Thomas D. , Willemsen, Marjolein H. , Vogt, Julie , Cunniff, Christopher , Bergstrom, Katherine , Bruel, Ange‐Line , Kini, Usha , Alkuraya, Fowzan S. , Slegesky, Valerie, Meeks, Naomi, Girotto, Paula Natale , Johnson, Diana , Study, DDD, Newbury‐Ecob, Ruth , Lynch, Sally Ann , Graham, John M. , Balasubramanian, Meena , Hauser, Natalie , Schrier Vergano, Samantha , Bouman, Arjan , Cunniff, Christopher , Bergstrom, Katherine , Bruel, Ange-Line , Alkuraya, Fowzan S , Prontera, Paolo , Li, Dong , Graham, John M , Zamora, Francisca Millan, Pappas, John , Reid, Evan , Cogné, Benjamin , Vergano, Samantha A. Schrier , Slavotinek, Anne , Naik, Swati, Dean, John , Costa, Cinzia , Walia, Jagdeep Singh , Study, DDD, Ockeloen, Charlotte W. , Li, Dong , Pierson, Tyler Mark
American Journal of Medical Genetics Part A | August 26, 2021 | Volume: 185 | Issue: 11 | Pages: 3446-3458
AbstractThe 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this international collaborative study, we have undertaken a detailed clinical and molecular analysis of 45 previously unpublished individuals with ASXL3‐related syndrome, as well as a review of all previously published individuals.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.
Predominant and novel de novo variants in 29 individuals with ALG13 deficiency: Clinical description, biomarker status, biochemical analysis, and treatmen
Ng, Bobby G. , Eklund, Erik A. , Shiryaev, Sergey A., Dong, Yin Yao , Abbott, Mary‐Alice , Asteggiano, Carla , Bamshad, Michael J. , Barr, Eileen , Bernstein, Jonathan A. , Chelakkadan, Shabeed, Ciliberto, Michael A. , Cousin, Janice, Gardiner, Fiona, Ghosh, Suman , Graf, W. , Grünewald, Stephanie , Hammond, Katherine, Hauser, Natalie , Hoganson, George, Houck, Kimberly , Kohler, Jennefer N., Liu, Pengfei , Madathil, Sujana , McCormack, Colleen E., Meeks, Naomi, Miller, Rebecca L. , Monaghan, Kristin G. , Nickerson, Deborah A. , Palculict, Timothy Blake, Papazoglu, Gabriela M., Pletcher, Beth A. , Scheffer, Ingrid E. , Schenone, Andrea, Schnur, Rhonda E. , Si, Yue , Rowe, Leah J., Russi, Alvaro H. Serrano, Russo, Rossana Sanchez , Thabet, Farouq , Tuite, Allysa , Villanueva, Marıá Mercedes, Webster, Richard , Wilson, Dorcas, Zalan, Alice, Wolfe, Lynne A. , Rhodes, Lindsay, Scheffer, Ingrid E , Ng, Bobby G , Christodoulou, John , Chung, Wendy K. , Morava, Éva , Larson, Austin , Miller, Rebecca, Monaghan, Kristin G. , Rowe, Leah J., Wang, Raymond , Rosenfeld, Jill A. , Freeze, Hudson H.
Journal of Inherited Metabolic Disease | July 18, 2020 | Volume: 43 | Issue: 6 | Pages: 1333-1348
Abstract Asparagine‐linked glycosylation 13 homolog ( ALG13 ) encodes a nonredundant, highly conserved, X‐linked uridine diphosphate (UDP)‐ N ‐acetylglucosaminyltransferase required for the synthesis of lipid linked oligosaccharide precursor and proper N‐linked glycosylation. De novo variants in ALG13 underlie a form of early infantile epileptic encephalopathy known as EIEE36, but given its essential role in glycosylation, it is also considered a congenital disorder of glycosylation (CDG), ALG13‐CDG. Twenty‐four previously reported ALG13‐CDG cases had de novo variants, but surprisingly, unlike most forms of CDG, ALG13‐CDG did not show the anticipated glycosylation defects, typically detected by altered transferrin glycosylation. Structural homology modeling of two recurrent de novo variants, p.A81T and p.N107S, suggests both are likely to impact the function of ALG13. Using a corresponding ALG13‐deficient yeast strain, we show that expressing yeast ALG13 with either of the highly conserved hotspot variants rescues the observed growth defect, but not its glycosylation abnormality. We present molecular and clinical data on 29 previously unreported individuals with de novo variants in ALG13 . This more than doubles the number of known cases. A key finding is that a vast majority of the individuals presents with West syndrome, a feature shared with other CDG types. Among these, the initial epileptic spasms best responded to adrenocorticotropic hormone or prednisolone, while clobazam and felbamate showed promise for continued epilepsy treatment. A ketogenic diet seems to play an important role in the treatment of these individuals.