Clinical whole-exome sequencing reveals a novel missense pathogenic variant of GNAO1 in a patient with infantile-onset epilepsy

Law, Chun Yiu; Chang, Sharon Tzu-Lun; Cho, Sun Young; Yau, Eric; Ng, Grace S.F.; Fong, Nai-Chung; Lam, Ching‐Wan

doi:10.1016/j.cca.2015.10.011

Cited by 33 publications

(30 citation statements)

References 21 publications

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“…1 The 7 patients we are reporting harbored 6 different mutations, one of which was evident in 2 patients (figure 1). Two of the 6 mutations have been reported previously [p.(Arg209Cys) and p.(Gly40Arg)], 3,5 while 4 are novel [p.(Ser47Gly), c.723+1G>A, p.(Ile56Thr), and p.(Glu246Gly)]. The c.723+1G>A splicing mutation, likely resulting in abnormal mRNA splicing, was found in patient 3, who died at 4 years of age and exhibited the most severe phenotype.…”

Section: Discussionmentioning

confidence: 85%

“…A different mutation leading to the same amino acid change (c.118G>A [p.(Gly40Arg)]) has previously been described in a patient with infantile-onset epilepsy. 3 In patient 7, we identified the novel c.737A>G [p.(Glu246Gly)] missense variant. A different nucleotide change in the same amino acid position, c.736G>A [p.(Glu246Lys)], had been reported as disease causing in patients exhibiting developmental delay, intellectual disability, and a paroxysmal movement disorder.…”

Section: Resultsmentioning

confidence: 99%

“…De novo GNAO1 mutations (MIM 139311) were initially identified in children with early-onset epileptic encephalopathy (EOEE) and severe developmental delay, 1–3 with later development of dyskinetic movement disorders 1,4–6 and in children exhibiting developmental delay and severe dyskinesia without seizures. 7,8 …”

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confidence: 99%

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GNAO1 encephalopathy

et al. 2017

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Objective:To describe better the motor phenotype, molecular genetic features, and clinical course of GNAO1-related disease.Methods:We reviewed clinical information, video recordings, and neuroimaging of a newly identified cohort of 7 patients with de novo missense and splice site GNAO1 mutations, detected by next-generation sequencing techniques.Results:Patients first presented in early childhood (median age of presentation 10 months, range 0–48 months), with a wide range of clinical symptoms ranging from severe motor and cognitive impairment with marked choreoathetosis, self-injurious behavior, and epileptic encephalopathy to a milder phenotype, featuring moderate developmental delay associated with complex stereotypies, mainly facial dyskinesia and mild epilepsy. Hyperkinetic movements were often exacerbated by specific triggers, such as voluntary movement, intercurrent illnesses, emotion, and high ambient temperature, leading to hospital admissions. Most patients were resistant to drug intervention, although tetrabenazine was effective in partially controlling dyskinesia for 2/7 patients. Emergency deep brain stimulation (DBS) was life saving in 1 patient, resulting in immediate clinical benefit with complete cessation of violent hyperkinetic movements. Five patients had well-controlled epilepsy and 1 had drug-resistant seizures. Structural brain abnormalities, including mild cerebral atrophy and corpus callosum dysgenesis, were evident in 5 patients. One patient had a diffuse astrocytoma (WHO grade II), surgically removed at age 16.Conclusions:Our findings support the causative role of GNAO1 mutations in an expanded spectrum of early-onset epilepsy and movement disorders, frequently exacerbated by specific triggers and at times associated with self-injurious behavior. Tetrabenazine and DBS were the most useful treatments for dyskinesia.

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Section: Discussionmentioning

confidence: 85%

Section: Resultsmentioning

confidence: 99%

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GNAO1 encephalopathy

et al. 2017

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“…Five variants previously reported in the literature, in other patients, are present in Patient 1 (p.G40R), 4,15 Patient 6 (p.R209C), 12 Patient 7 (p.R209H), 6,7,9,11 Patient 9 (p.Y231C), 4 and Patient 11 (p.I279N). 2 Variants in our cohort affecting the previously implicated GNAO1 G40 amino acid site 4,15 are present in Patient 2 (p.G40W) and Patients 3 and 4 (p.G40E).…”

Section: Genetic Variants In Gnao1mentioning

confidence: 77%

“…[2][3][4][5][6][7][8][9][10][11][12][13][14][15][16] GNAO1 encodes a G-protein α subunit that, along with dimerized β and γ subunits, forms a heterotrimeric G-protein complex. [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16] GNAO1 encodes a G-protein α subunit that, along with dimerized β and γ subunits, forms a heterotrimeric G-protein complex.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2019

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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.

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Postsynaptic movement disorders: clinical phenotypes, genotypes, and disease mechanisms

Abela¹,

Kurian²

2018

J of Inher Metab Disea

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Movement disorders comprise a group of heterogeneous diseases with often complex clinical phenotypes. Overlapping symptoms and a lack of diagnostic biomarkers may hamper making a definitive diagnosis. Next-generation sequencing techniques have substantially contributed to unraveling genetic etiologies underlying movement disorders and thereby improved diagnoses. Defects in dopaminergic signaling in postsynaptic striatal medium spiny neurons are emerging as a pathogenic mechanism in a number of newly identified hyperkinetic movement disorders. Several of the causative genes encode components of the cAMP pathway, a critical postsynaptic signaling pathway in medium spiny neurons. Here, we review the clinical presentation, genetic findings, and disease mechanisms that characterize these genetic postsynaptic movement disorders.

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Clinical whole-exome sequencing reveals a novel missense pathogenic variant of GNAO1 in a patient with infantile-onset epilepsy

Cited by 33 publications

References 21 publications

GNAO1 encephalopathy

GNAO1 encephalopathy

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

Postsynaptic movement disorders: clinical phenotypes, genotypes, and disease mechanisms

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