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Epilepsia. 2019 Mar;60(3):406-418. doi: 10.1111/epi.14653. Epub 2019 Jan 25.

Spectrum of neurodevelopmental disease associated with the GNAO1 guanosine triphosphate-binding region.

Collaborators (194)

Adams DR, Aday A, Alejandro ME, Allard P, Ashley EA, Azamian MS, Bacino CA, Baker E, Balasubramanyam A, Barseghyan H, Batzli GF, Beggs AH, Behnam B, Bellen HJ, Bernstein JA, Bican A, Bick DP, Birch CL, Bonner D, Boone BE, Bostwick BL, Brokamp E, Brown DM, Brush M, Burke EA, Burrage LC, Butte MJ, Chen S, Clark GD, Coakley TR, Cogan JD, Colley HA, Cooper CM, Cope H, Craigen WJ, D'Souza P, Davids M, Davidson JM, Dayal JG, Dell'Angelica EC, Dhar SU, Dipple KM, Donnell-Fink LA, Dorrani N, Dorset DC, Douine ED, Draper DD, Dries AM, Eckstein DJ, Emrick LT, Eng CM, Enns GM, Eskin A, Esteves C, Estwick T, Fairbrother L, Fernandez L, Ferreira C, Fieg EL, Fisher PG, Fogel BL, Friedman ND, Gahl WA, Glanton E, Godfrey RA, Goldman AM, Goldstein DB, Gould SE, Gourdine JF, Groden CA, Gropman AL, Haendel M, Hamid R, Hanchard NA, High F, Holm IA, Hom J, Howerton EM, Huang Y, Jamal F, Jiang YH, Johnston JM, Jones AL, Karaviti L, Koeller DM, Kohane IS, Kohler JN, Korrick S, Koziura M, Krier JB, Kyle JE, Lalani SR, Lau CC, Lazar J, LeBlanc K, Lee BH, Lee H, Levy SE, Lewis RA, Lincoln SA, Loo SK, Loscalzo J, Maas RL, Macnamara EF, MacRae CA, Maduro VV, Majcherska MM, Malicdan MCV, Mamounas LA, Manolio TA, Markello TC, Marom R, Martin MG, Martínez-Agosto JA, Marwaha S, May T, McConkie-Rosell A, McCormack CE, McCray AT, Merker JD, Metz TO, Might M, Moretti PM, Morimoto M, Mulvihill JJ, Murdock DR, Murphy JL, Muzny DM, Nehrebecky ME, Nelson SF, Newberry JS, Newman JH, Nicholas SK, Novacic D, Orange JS, Orengo JP, Pallais JC, Palmer CGS, Papp JC, Parker NH, Pena LDM, Phillips JA 3rd, Posey JE, Postlethwait JH, Potocki L, Pusey BN, Reuter CM, Rives L, Robertson AK, Rodan LH, Rosenfeld JA, Sampson JB, Samson SL, Schoch K, Scott DA, Shakachite L, Sharma P, Shashi V, Signer R, Silverman EK, Sinsheimer JS, Smith KS, Spillmann RC, Stoler JM, Stong N, Sullivan JA, Tan QK, Tifft CJ, Toro C, Tran AA, Urv TK, Vilain E, Vogel TP, Waggott DM, Wahl CE, Walley NM, Walsh CA, Wan J, Wangler MF, Ward PA, Waters KM, Webb-Robertson BM, Westerfield M, Wheeler MT, Wise AL, Wolfe LA, Worthey EA, Yamamoto S, Yang Y, Yoon AJ, Yu G, Zastrow DB, Zhao C, Zheng A.

Author information

1
Epilepsy Genetics Program, Department of Neurology, Boston Children's Hospital, Boston, Massachusetts.
2
Dartmouth Medical School, Hanover, New Hampshire.
3
Division of Genetics and Genomics, Boston Children's Hospital, Boston, Massachusetts.
4
Cologne Center for Genomics, Cologne, Germany.
5
Department of Neurology, University of Virginia, Charlottesville, Virginia.
6
Division of Epilepsy and Clinical Neurophysiology, Boston Children's Hospital, Boston, Massachusetts.
7
Department of Neurology, Harvard Medical School, Boston, Massachusetts.
8
Department of Neurology, Boston Children's Hospital, Boston, Massachusetts.
9
Department of Medical Genetics, Massachusetts General Hospital, Boston, Massachusetts.
10
Department of Pediatrics, Neurology, and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, Texas.
11
Department of Neurology, Children's Health, Dallas, Texas.
12
Neuroscience Department, Lady Cilento Children's Hospital, Brisbane, Queensland, Australia.
13
Florey and Murdoch Children's Research Institute, Austin Health and Royal Children's Hospital, University of Melbourne, Melbourne, Victoria, Australia.
14
Department of Radiology, Boston Children's Hospital, Boston, Massachusetts.
15
Department of Radiology, Harvard Medical School, Boston, Massachusetts.
16
Department of Pediatrics, University of Texas Southwestern, Dallas, Texas.
17
Stanley Center for Psychiatric Research, Broad Institute, Cambridge, Massachusetts.
18
Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts.
19
Department of Pediatrics, Harvard Medical School, Boston, Massachusetts.
20
Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, Massachusetts.
21
F. M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, Massachusetts.

Abstract

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.

KEYWORDS:

GNAO1 ; developmental and epileptic encephalopathy; mosaicism; movement disorders

PMID:
30682224
PMCID:
PMC6452443
[Available on 2020-03-01]
DOI:
10.1111/epi.14653

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