Citations 2
Heterozygous variants in PRPF8 are associated with neurodevelopmental disorders
O’Grady, Lauren , Vergano, Samantha A. Schrier , Hoffman, Trevor L. , Sarco, Dean, Cherny, Sara , Bryant, Emily , Schultz‐Rogers, Laura , Sacharow, Stephanie , Immken, LaDonna, Holder, Susan, Blackwell, Rebecca R., Buchanan, Catherine A., Yusupov, Roman, Lecoquierre, François , Guerrot, Anne‐Marie , Rodan, Lance H. , Vries, Bert B.A. de , Kamsteeg, Erik Jan, Palomares‐Bralo, María , Brown, Natasha J. , Klee, Eric W. , Babovic‐Vuksanovic, Dusica , Rhodes, Lindsay, Person, Richard, Begtrup, Amber, Keller‐Ramey, Jennifer, Santiago‐Sim, Teresa, Schnur, Rhonda E. , Gold, Nina B. , Schrier Vergano, Samantha , Lecoquierre, Francois , Rodan, Lance , de Vries, Bert B A , Santos Simarro, Fernando , Palomares-Bralo, Maria , Babovic-Vuksanovic, Dusica, Sweetser, David A , Chung, Wendy K. , Pais, Lynn , Ferrer, Alejandro , Begtrup, Amber Hogart
American Journal of Medical Genetics Part A | May 11, 2022 | Volume: 188 | Issue: 9 | Pages: 2750-2759
Abstract The pre‐mRNA‐processing factor 8, encoded by PRPF8, is a scaffolding component of a spliceosome complex involved in the removal of introns from mRNA precursors. Previously, heterozygous pathogenic variants in PRPF8 have been associated with autosomal dominant retinitis pigmentosa. More recently, PRPF8 was suggested as a candidate gene for autism spectrum disorder due to the enrichment of sequence variants in this gene in individuals with neurodevelopmental disorders. We report 14 individuals with various forms of neurodevelopmental conditions, found to have heterozygous, predominantly de novo, missense, and loss‐of‐function variants in PRPF8 . These individuals have clinical features that may represent a new neurodevelopmental syndrome.
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.