Spectrum of neurodevelopmental disease associated with the GNAO1 guanosine triphosphate–binding region. (25th January 2019)

• Record Type: Journal Article
• Authors: Kelly, McKenna; Park, Meredith; Mihalek, Ivana; Rochtus, Anne; Gramm, Marie; Pérez‐Palma, Eduardo; Axeen, Erika Takle; Hung, Christina Y.; Olson, Heather; Swanson, Lindsay; Anselm, Irina; Briere, Lauren C.; High, Frances A.; Sweetser, David A.; Kayani, Saima; Snyder, Molly; Calvert, Sophie; Scheffer, Ingrid E.; Yang, Edward; Waugh, Jeff L.; Lal, Dennis; Bodamer, Olaf; Poduri, Annapurna
• Other Names: Adams David R. investigator.; Aday Aaron investigator.; Alejandro Mercedes E. investigator.; Allard Patrick investigator.; Ashley Euan A. investigator.; Azamian Mahshid S. investigator.; Bacino Carlos A. investigator.; Baker Eva investigator.; Balasubramanyam Ashok investigator.; Barseghyan Hayk investigator.; Batzli Gabriel F. investigator.; Beggs Alan H. investigator.; Behnam Babak investigator.; Bellen Hugo J. investigator.; Bernstein Jonathan A. investigator.; Bican Anna investigator.; Bick David P. investigator.; Birch Camille L. investigator.; Bonner Devon investigator.; Boone Braden E. investigator.; Bostwick Bret L. investigator.; Brokamp Elly investigator.; Brown Donna M. investigator.; Brush Matthew investigator.; Burke Elizabeth A. investigator.; Burrage Lindsay C. investigator.; Butte Manish J. investigator.; Chen Shan investigator.; Clark Gary D. investigator.; Coakley Terra R. investigator.; Cogan Joy D. investigator.; Colley Heather A. investigator.; Cooper Cynthia M. investigator.; Cope Heidi investigator.; Craigen William J. investigator.; D'Souza Precilla investigator.; Davids Mariska investigator.; Davidson Jean M. investigator.; Dayal Jyoti G. investigator.; Dell'Angelica Esteban C. investigator.; Dhar Shweta U. investigator.; Dipple Katrina M. investigator.; Donnell‐Fink Laurel A. investigator.; Dorrani Naghmeh investigator.; Dorset Daniel C. investigator.; Douine Emilie D. investigator.; Draper David D. investigator.; Dries Annika M. investigator.; Eckstein David J. investigator.; Emrick Lisa T. investigator.; Eng Christine M. investigator.; Enns Gregory M. investigator.; Eskin Ascia investigator.; Esteves Cecilia investigator.; Estwick Tyra investigator.; Fairbrother Laura investigator.; Fernandez Liliana investigator.; Ferreira Carlos investigator.; Fieg Elizabeth L. investigator.; Fisher Paul G. investigator.; Fogel Brent L. investigator.; Friedman Noah D. investigator.; Gahl William A. investigator.; Glanton Emily investigator.; Godfrey Rena A. investigator.; Goldman Alica M. investigator.; Goldstein David B. investigator.; Gould Sarah E. investigator.; Gourdine Jean‐Philippe F. investigator.; Groden Catherine A. investigator.; Gropman Andrea L. investigator.; Haendel Melissa investigator.; Hamid Rizwan investigator.; Hanchard Neil A. investigator.; High Francis investigator.; Holm Ingrid A. investigator.; Hom Jason investigator.; Howerton Ellen M. investigator.; Huang Yong investigator.; Jamal Fariha investigator.; Jiang Yong‐hui investigator.; Johnston Jean M. investigator.; Jones Angela L. investigator.; Karaviti Lefkothea investigator.; Koeller David M. investigator.; Kohane Isaac S. investigator.; Kohler Jennefer N. investigator.; Korrick Susan investigator.; Koziura Mary investigator.; Krier Joel B. investigator.; Kyle Jennifer E. investigator.; Lalani Seema R. investigator.; Lau C. Christopher investigator.; Lazar Jozef investigator.; LeBlanc Kimberly investigator.; Lee Brendan H. investigator.; Lee Hane investigator.; Levy Shawn E. investigator.; Lewis Richard A. investigator.; Lincoln Sharyn A. investigator.; Loo Sandra K. investigator.; Loscalzo Joseph investigator.; Maas Richard L. investigator.; Macnamara Ellen F. investigator.; MacRae Calum A. investigator.; Maduro Valerie V. investigator.; Majcherska Marta M. investigator.; Malicdan May Christine V. investigator.; Mamounas Laura A. investigator.; Manolio Teri A. investigator.; Markello Thomas C. investigator.; Marom Ronit investigator.; Martin Martin G. investigator.; Martínez‐Agosto Julian A. investigator.; Marwaha Shruti investigator.; May Thomas investigator.; McConkie‐Rosell Allyn investigator.; McCormack Colleen E. investigator.; McCray Alexa T. investigator.; Merker Jason D. investigator.; Metz Thomas O. investigator.; Might Matthew investigator.; Moretti Paolo M. investigator.; Morimoto Marie investigator.; Mulvihill John J. investigator.; Murdock David R. investigator.; Murphy Jennifer L. investigator.; Muzny Donna M. investigator.; Nehrebecky Michele E. investigator.; Nelson Stan F. investigator.; Newberry J. Scott investigator.; Newman John H. investigator.; Nicholas Sarah K. investigator.; Novacic Donna investigator.; Orange Jordan S. investigator.; Orengo James P. investigator.; Pallais J. Carl investigator.; Palmer Christina G. S. investigator.; Papp Jeanette C. investigator.; Parker Neil H. investigator.; Pena Loren D. M. investigator.; Phillips John A. investigator.; Posey Jennifer E. investigator.; Postlethwait John H. investigator.; Potocki Lorraine investigator.; Pusey Barbara N. investigator.; Reuter Chloe M. investigator.; Rives Lynette investigator.; Robertson Amy K. investigator.; Rodan Lance H. investigator.; Rosenfeld Jill A. investigator.; Sampson Jacinda B. investigator.; Samson Susan L. investigator.; Schoch Kelly investigator.; Scott Daryl A. investigator.; Shakachite Lisa investigator.; Sharma Prashant investigator.; Shashi Vandana investigator.; Signer Rebecca investigator.; Silverman Edwin K. investigator.; Sinsheimer Janet S. investigator.; Smith Kevin S. investigator.; Spillmann Rebecca C. investigator.; Stoler Joan M. investigator.; Stong Nicholas investigator.; Sullivan Jennifer A. investigator.; Tan Queenie K.‐G. investigator.; Tifft Cynthia J. investigator.; Toro Camilo investigator.; Tran Alyssa A. investigator.; Urv Tiina K. investigator.; Vilain Eric investigator.; Vogel Tiphanie P. investigator.; Waggott Daryl M. investigator.; Wahl Colleen E. investigator.; Walley Nicole M. investigator.; Walsh Chris A. investigator.; Wan Jijun investigator.; Wangler Michael F. investigator.; Ward Patricia A. investigator.; Waters Katrina M. investigator.; Webb‐Robertson Bobbie‐Jo M. investigator.; Westerfield Monte investigator.; Wheeler Matthew T. investigator.; Wise Anastasia L. investigator.; Wolfe Lynne A. investigator.; Worthey Elizabeth A. investigator.; Yamamoto Shinya investigator.; Yang Yaping investigator.; Yoon Amanda J. investigator.; Yu Guoyun investigator.; Zastrow Diane B. investigator.; Zhao Chunli investigator.; Zheng Allison investigator.;
• Is Part Of: Epilepsia. Volume 60:issue 3(2019)
• Page Start: 406
• Page End: 418
• Publication Date: 2019-01-25
• Subjects: developmental and epileptic encephalopathy -- GNAO1 -- mosaicism -- movement disorders; Epilepsy -- Periodicals; 616.853
• DOI: 10.1111/epi.14653
• Languages: English
• ISSNs: 0013-9580

Abstract

Summary: Objective: To characterize the phenotypic spectrum associated with GNAO1 variants and establish genotype‐protein structure‐phenotype relationships. Methods: We evaluated the phenotypes of 14 patients with GNAO1 variants, analyzed their variants for potential pathogenicity, and mapped them, along with those in the literature, on a three‐dimensional structural protein model. Results: The 14 patients in our cohort, including one sibling pair, had 13 distinct, heterozygous GNAO1 variants classified as pathogenic or likely pathogenic. We attributed the same variant in two siblings to parental mosaicism. Patients initially presented with seizures beginning in the first 3 months of life (8/14), developmental delay (4/14), hypotonia (1/14), or movement disorder (1/14). All patients had hypotonia and developmental delay ranging from mild to severe. Nine had epilepsy, and nine had movement disorders, including dystonia, ataxia, chorea, and dyskinesia. The 13 GNAO1 variants in our patients are predicted to result in amino acid substitutions or deletions in the GNAO1 guanosine triphosphate (GTP)‐binding region, analogous to those in previous publications. Patients with variants affecting amino acids 207‐221 had only movement disorder and hypotonia. Patients with variants affecting the C‐terminal region had the mildest phenotypes. Significance: GNAO1 encephalopathy most frequently presents with seizures beginning in the first 3 months of life. Concurrent movement disorders are also a prominent feature in the spectrum of GNAO1 encephalopathy. All variants affected the GTP‐binding domain of GNAO1, highlighting the importance of this region for G‐protein signaling and neurodevelopment.