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

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.

SUBMITTER: Kelly M

PROVIDER: S-EPMC6452443 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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

Kelly McKenna M Park Meredith M Mihalek Ivana I Rochtus Anne A Gramm Marie M Pérez-Palma Eduardo E Axeen Erika Takle ET Hung Christina Y CY Olson Heather H Swanson Lindsay L Anselm Irina I Briere Lauren C LC High Frances A FA Sweetser David A DA Kayani Saima S Snyder Molly M Calvert Sophie S Scheffer Ingrid E IE Yang Edward E Waugh Jeff L JL Lal Dennis D Bodamer Olaf O Poduri Annapurna A

Epilepsia 20190125 3

<h4>Objective</h4>To characterize the phenotypic spectrum associated with GNAO1 variants and establish genotype-protein structure-phenotype relationships.<h4>Methods</h4>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.<h4>Results</h4>The 14 patients in our cohort, including one sibling pair, had 13 distinct, heterozygous GNAO1 v ...[more]

PMID: 30682224

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Project description:OBJECTIVE:To characterize the features associated with PCDH19-related epilepsy, also known as "female-limited epilepsy." METHODS:We analyzed data from participants enrolled in the PCDH19 Registry, focusing on the seizure-related, developmental, neurobehavioral, and sleep-related features. We evaluated variants for pathogenicity based on previous reports, population databases, and in silico predictions, and included individuals with pathogenic or potentially pathogenic variants. We performed a retrospective analysis of medical records and administered a targeted questionnaire to characterize current or past features in probands and genotype-positive family members. RESULTS:We included 38 individuals with pathogenic or potentially pathogenic variants in PCDH19: 21 de novo, 5 maternally inherited, 7 paternally inherited, and 5 unknown. All 38 had epilepsy; seizure burden varied, but typical features of clustering of seizures and association with fever were present. Thirty individuals had intellectual disability (ID), with a wide range of severity reported; notably, 8/38 (22%) had average intellect. Behavioral and sleep dysregulation were prominent, in 29/38 (76%) and 20/38 (53%), respectively. Autistic features were present in 22/38 (58%), of whom 12 had a formal diagnosis of autism spectrum disorder. We had additional data from 5 genotype-positive mothers, all with average intellect and 3 with epilepsy, and from 1 genotype-positive father. SIGNIFICANCE:Our series represents a robust cohort with carefully curated PCDH19 variants. We observed seizures as a core feature with a range of seizure types and severity. Whereas the majority of individuals had ID, we highlight the possibility of average intellect in the setting of PCDH19-related epilepsy. We also note the high prevalence and severity of neurobehavioral phenotypes associated with likely pathogenic variants in PCDH19. Sleep dysregulation was also a major area of concern. Our data emphasize the importance of appropriate referrals for formal neuropsychological evaluations as well as the need for formal prospective studies to characterize the PCDH19-related neurodevelopmental syndrome in children and their genotype-positive parents.

Dataset Information

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

Publications

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

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