Retrospective genotype-phenotype analysis in a 305 patient cohort referred for testing of a targeted epilepsy panel

Hesse, Andrew; Bevilacqua, Jennifer; Shankar, Kritika; Reddi, Honey V.

doi:10.1016/j.eplepsyres.2018.05.004

Cited by 13 publications

(9 citation statements)

References 45 publications

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“…SLC35A2 ‐related disorders show a wide phenotypic spectrum and comparing clinical findings of our patient with those of previously reported patients allows us to identify both common and different features (Table ) (Appenzeller et al, ; Bosch et al, ; Demos et al, ; Dörre et al, ; Hesse et al, ; Hino‐Fukuyo et al, ; Kimizu et al, ; Kodera et al, ; Ng et al, , ; Vals et al, ; Westenfield et al, ; Yates et al, ). Most cases had neurological disorders including developmental delay (100%, 61/61), seizures (84%, 52/62), and hypotonia (92%, 54/59).…”

Section: Discussionmentioning

confidence: 65%

“…These 62 patients comprised both men and women and most of the patients showed seizures leading to diagnosis of epileptic encephalopathy. The clinical spectrum of these patients includes developmental delay, microcephaly, dysmorphic features, ocular and skeletal abnormalities, infantile-onset seizures, hypotonia, cerebral and cerebellar atrophy, and thin corpus callosum (Table S2) (Appenzeller et al, 2017;Bosch et al, 2016;Demos et al, 2017;Dörre et al, 2015;Hesse et al, 2018;Hino-Fukuyo et al, 2015;Kimizu et al, 2017;Kodera et al, 2013;Ng et al, 2013Ng et al, , 2019Vals et al, 2019;Westenfield et al, 2018;Yates et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

“…The SLC35A2 protein has 10 transmembrane domains and transports UDP-galactose, which is a substrate for glycosylation, from cytoplasm into the Golgi or endoplasmic reticulum (ER) lumens (Hadley et al, 2014). To date, 53 de novo variants in SLC35A2 have been identified in 62 patients with congenital disorders of glycosylation (CDGs) (MIM#300896) including 30 missense, four nonsense, 13 frameshift, one splice site, three in-frame deletion, and two variants affecting translation initiation codon (Table S1) (Appenzeller et al, 2017;Bosch et al, 2016;Demos et al, 2017;Dörre et al, 2015;Hesse, Bevilacqua, Shankar, & Reddi, 2018;Hino-Fukuyo et al, 2015;Kimizu et al, 2017;Kodera et al, 2013;Ng et al, 2013Ng et al, , 2019Vals et al, 2019;Westenfield et al, 2018;Yates et al, 2018). These 62 patients comprised both men and women and most of the patients showed seizures leading to diagnosis of epileptic encephalopathy.…”

Section: Introductionmentioning

confidence: 99%

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A case of de novo splice site variant in SLC35A2 showing developmental delays, spastic paraplegia, and delayed myelination

Miyamoto

Nakashima

Ohashi

et al. 2019

Molec Gen & Gen Med

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Background Congenital disorders of glycosylation (CDGs) are genetic diseases caused by pathogenic variants of genes involved in protein or lipid glycosylation. De novo variants in the SLC35A2 gene, which encodes a UDP‐galactose transporter, are responsible for CDGs with an X‐linked dominant manner. Common symptoms related to SLC35A2 variants include epilepsy, psychomotor developmental delay, hypotonia, abnormal facial and skeletal features, and various magnetic resonance imaging (MRI) findings. Methods Whole‐exome sequencing was performed on the patient's DNA, and candidate variants were confirmed by Sanger sequencing. cDNA analysis was performed to assess the effect of the splice site variant using peripheral leukocytes. The X‐chromosome inactivation pattern was studied using the human androgen receptor assay. Results We identified a de novo splice site variant in SLC35A2 (NM_005660.2: c.274+1G>A) in a female patient who showed severe developmental delay, spastic paraplegia, mild cerebral atrophy, and delayed myelination on MRI, but no seizures. The variant led to an aberrant splicing resulting in an in‐frame 33‐bp insertion, which caused an 11‐amino acid insertion in the presumptive cytoplasmic loop. X‐inactivation pattern was random. Partial loss of galactose and sialic acid of the N‐linked glycans of serum transferrin was observed. Conclusion This case would expand the phenotypic spectrum of SLC35A2‐related disorders to delayed myelination with spasticity and no seizures.

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Section: Discussionmentioning

confidence: 65%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A case of de novo splice site variant in SLC35A2 showing developmental delays, spastic paraplegia, and delayed myelination

Miyamoto

Nakashima

Ohashi

et al. 2019

Molec Gen & Gen Med

View full text Add to dashboard Cite

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“…To date, 71 epilepsy-related missense mutations were reported. Electrophysiological tests were performed in 35 mutations previously ( Endele et al, 2010 ; de Ligt et al, 2012 ; Carvill et al, 2013 ; DeVries and Patel, 2013 ; Lemke et al, 2013 ; Lesca et al, 2013 ; Conroy et al, 2014 ; Venkateswaran et al, 2014 ; Yuan et al, 2014 ; Fainberg et al, 2016 ; Retterer et al, 2016 ; Serraz et al, 2016 ; Singh et al, 2016 ; Swanger et al, 2016 ; Monies et al, 2017 ; von Stulpnagel et al, 2017 ; Dazzo et al, 2018 ; Hesse et al, 2018 ; Lindy et al, 2018 ; Lionel et al, 2018 ; Miao et al, 2018 ; Xu et al, 2018 ; Yang et al, 2018 ; Snoeijen-Schouwenaars et al, 2019 ; Strehlow et al, 2019 ). Among the 35 tested mutations, 10 mutations were demonstrated to cause gain of function (GOF), 16 mutations led to loss of function (LOF), and 9 mutations had no detectable electrophysiological changes in the aspects investigated.…”

Section: Resultsmentioning

confidence: 99%

GRIN2A Variants Associated With Idiopathic Generalized Epilepsies

Liu

Lin

et al. 2021

Front. Mol. Neurosci.

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Objective: The objective of this study is to explore the role of GRIN2A gene in idiopathic generalized epilepsies and the potential underlying mechanism for phenotypic variation.Methods: Whole-exome sequencing was performed in a cohort of 88 patients with idiopathic generalized epilepsies. Electro-physiological alterations of the recombinant N-methyl-D-aspartate receptors (NMDARs) containing GluN2A mutants were examined using two-electrode voltage-clamp recordings. The alterations of protein expression were detected by immunofluorescence staining and biotinylation. Previous studies reported that epilepsy related GRIN2A missense mutations were reviewed. The correlation among phenotypes, functional alterations, and molecular locations was analyzed.Results: Three novel heterozygous missense GRIN2A mutations (c.1770A > C/p.K590N, c.2636A > G/p.K879R, and c.3199C > T/p.R1067W) were identified in three unrelated cases. Electrophysiological analysis demonstrated R1067W significantly increased the current density of GluN1/GluN2A NMDARs. Immunofluorescence staining indicated GluN2A mutants had abundant distribution in the membrane and cytoplasm. Western blotting showed the ratios of surface and total expression of the three GluN2A-mutants were significantly increased comparing to the wild type. Further analysis on the reported missense mutations demonstrated that mutations with severe gain-of-function were associated with epileptic encephalopathy, while mutations with mild gain of function were associated with mild phenotypes, suggesting a quantitative correlation between gain-of-function and phenotypic severity. The mutations located around transmembrane domains were more frequently associated with severe phenotypes and absence seizure-related mutations were mostly located in carboxyl-terminal domain, suggesting molecular sub-regional effects.Significance: This study revealed GRIN2A gene was potentially a candidate pathogenic gene of idiopathic generalized epilepsies. The functional quantitative correlation and the molecular sub-regional implication of mutations helped in explaining the relatively mild clinical phenotypes and incomplete penetrance associated with GRIN2A variants.

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“…“Genotype-phenotype correlations” were gradually used for depicting the statistical relationship between the genetic composition of an individual and characteristics of interest on the basis of computational methods. [56,57] Although “Genotype-phenotype correlations” was absent from the list of high-frequency MeSH terms, it is the new trend in the future. With the prosperity of big data from genetic techniques, phenotyping has become the bottleneck of collaborations among clinicians, medical informaticists, and statistical geneticists.…”

Section: Discussionmentioning

confidence: 99%

Mapping the knowledge structure and trends of epilepsy genetics over the past decade

et al. 2019

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Introduction: Over the past 10 years, epilepsy genetics has made dramatic progress. This study aimed to analyze the knowledge structure and the advancement of epilepsy genetics over the past decade based on co-word analysis of medical subject headings (MeSH) terms. Methods: Scientific publications focusing on epilepsy genetics from the PubMed database (January 2009–December 2018) were retrieved. Bibliometric information was analyzed quantitatively using Bibliographic Item Co-Occurrence Matrix Builder (BICOMB) software. A knowledge social network analysis and publication trend based on the high-frequency MeSH terms was built using VOSviewer. Results: According to the search strategy, a total of 5185 papers were included. Among all the extracted MeSH terms, 86 high-frequency MeSH terms were identified. Hot spots were clustered into 5 categories including: “ion channel diseases,” “beyond ion channel diseases,” “experimental research & epigenetics,” “single nucleotide polymorphism & pharmacogenetics,” and “genetic techniques”. “Epilepsy,” “mutation,” and “seizures,” were located at the center of the knowledge network. “Ion channel diseases” are typically in the most prominent position of epilepsy genetics research. “Beyond ion channel diseases” and “genetic techniques,” however, have gradually grown into research cores and trends, such as “intellectual disability,” “infantile spasms,” “phenotype,” “exome,” “ deoxyribonucleic acid (DNA) copy number variations,” and “application of next-generation sequencing.” While ion channel genes such as “SCN1A,” “KCNQ2,” “SCN2A,” “SCN8A” accounted for nearly half of epilepsy genes in MeSH terms, a number of additional beyond ion channel genes like “CDKL5,” “STXBP1,” “PCDH19,” “PRRT2,” “LGI1,” “ALDH7A1,” “MECP2,” “EPM2A,” “ARX,” “SLC2A1,” and more were becoming increasingly popular. In contrast, gene therapies, treatment outcome, and genotype-phenotype correlations were still in their early stages of research. Conclusion: This co-word analysis provides an overview of epilepsy genetics research over the past decade. The 5 research categories display publication hot spots and trends in epilepsy genetics research which could consequently supply some direction for geneticists and epileptologists when launching new projects.

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Retrospective genotype-phenotype analysis in a 305 patient cohort referred for testing of a targeted epilepsy panel

Cited by 13 publications

References 45 publications

A case of de novo splice site variant in SLC35A2 showing developmental delays, spastic paraplegia, and delayed myelination

A case of de novo splice site variant in SLC35A2 showing developmental delays, spastic paraplegia, and delayed myelination

GRIN2A Variants Associated With Idiopathic Generalized Epilepsies

Mapping the knowledge structure and trends of epilepsy genetics over the past decade

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