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Genetics of Epileptic Encephalopathies: From Gene Discovery to Clinical Diagnosis...
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Genetics of Epileptic Encephalopathies: From Gene Discovery to Clinical Diagnosis and Management Implications of Genetic Diagnoses

A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Human Genomics and Genetic Diseases".

Deadline for manuscript submissions: closed (30 September 2022) | Viewed by 21744

Special Issue Editors

Dr. David Dyment

E-Mail Website
Guest Editor
Department of Genetics, Children’s Hospital of Eastern Ontario, Ottawa, ON, Canada
Interests: epilepsy genetics; Dravet syndrome; recognizable malformation syndromes
Dr. Saadet Mercimek-Andrews

E-Mail Website
Guest Editor
Department of Medical Genetics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 1H9, Canada
Interests: epilepsy genetics; neurometabolic disorders; neurogenetic disorders

Special Issue Information

Dear Colleagues,

Background: Epilepsy is a common neurological disorder in the general population. Epileptic encephalopathy is characterized by cognitive dysfunction associated with ongoing epileptiform activity and refractory seizures. Application of exome and genome sequencing in the research setting has in the last ten years led to the discovery of novel genetic epilepsies. Epileptic encephalopathy is heterogenous, and there are likely more than 1000 genetic disorders associated with it. In recent years, next generation sequencing technologies such as targeted panels and exome sequencing have increased the genetic diagnosis in patients with epilepsy in neurology and genetic clinics. Molecular genetic diagnoses and the type of underlying genetic disease (e.g., SCN1A, SCN2A, and KCNQ2 associated epilepsies or some of the inherited metabolic disorders) can guide physicians in the management of epilepsy.

Scope: This Special Issue in Genes will focus on the genetic basis of epileptic encephalopathies, recently discovered genetic epilepsies, and treatable inherited metabolic disorders.

What kind of papers we are looking for: In this Special Issue of Genes, we extend an invitation for reviews on the current state of genetics in epileptic encephalopathies, as well as original research articles that focus on the discovery of genetic variations or mutations that could be used to distinguish clinically relevant disease or predict therapeutic efficacies and outcomes. We look forward to your contributions and encourage you to send an abstract of your proposed manuscript to the Guest Editors (Drs. Andrews and Dyment) for assessment of their suitability in this Special issue.

Dr. David Dyment
Dr. Saadet Mercimek-Andrews
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Genes is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • epileptic encephalopathy
  • genetic epilepsies
  • inherited metabolic disorders
  • exome sequencing
  • genome sequencing

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Published Papers (7 papers)

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Research

Jump to: Review, Other

14 pages, 315 KiB  
Article
Phenotypic and Genotypic Spectrum of Early-Onset Developmental and Epileptic Encephalopathies—Data from a Romanian Cohort
by Anca-Lelia Riza, Ioana Streață, Eugenia Roza, Magdalena Budișteanu, Catrinel Iliescu, Carmen Burloiu, Mihaela-Amelia Dobrescu, Stefania Dorobanțu, Adina Dragoș, Andra Grigorescu, Tiberiu Tătaru, Mihai Ioana and Raluca Teleanu
Genes 2022, 13(7), 1253; https://doi.org/10.3390/genes13071253 - 15 Jul 2022
Cited by 6 | Viewed by 2822
Abstract
Early-onset developmental epileptic encephalopathy (DEE) refers to an age-specific, diverse group of epilepsy syndromes with electroclinical anomalies that are associated with severe cognitive, behavioral, and developmental impairments. Genetic DEEs have heterogeneous etiologies. This study includes 36 Romanian patients referred to the Regional Centre [...] Read more.
Early-onset developmental epileptic encephalopathy (DEE) refers to an age-specific, diverse group of epilepsy syndromes with electroclinical anomalies that are associated with severe cognitive, behavioral, and developmental impairments. Genetic DEEs have heterogeneous etiologies. This study includes 36 Romanian patients referred to the Regional Centre for Medical Genetics Dolj for genetic testing between 2017 and 2020. The patients had been admitted to and clinically evaluated at Doctor Victor Gomoiu Children’s Hospital and Prof. Dr. Alexandru Obregia Psychiatry Hospital in Bucharest. Panel testing was performed using the Illumina® TruSight™ One “clinical exome” (4811 genes), and the analysis focused on the known genes reported in DEEs and clinical concordance. The overall diagnostic rate was 25% (9/36 cases). Seven cases were diagnosed with Dravet syndrome (likely pathogenic/pathogenic variants in SCN1A) and two with Genetic Epilepsy with Febrile Seizures Plus (SCN1B). For the diagnosed patients, seizure onset was <1 year, and the seizure type was generalized tonic-clonic. Four additional plausible variants of unknown significance in SCN2A, SCN9A, and SLC2A1 correlated with the reported phenotype. Overall, we are reporting seven novel variants. Comprehensive clinical phenotyping is crucial for variant interpretation. Genetic assessment of patients with severe early-onset DEE can be a powerful diagnostic tool for clinicians, with implications for the management and counseling of the patients and their families. Full article
(This article belongs to the Special Issue Genetics of Epileptic Encephalopathies: From Gene Discovery to Clinical Diagnosis and Management Implications of Genetic Diagnoses)
14 pages, 2310 KiB  
Article
The Benefit of Multigene Panel Testing for the Diagnosis and Management of the Genetic Epilepsies
by Heather Leduc-Pessah, Alexandre White-Brown, Taila Hartley, Daniela Pohl and David A. Dyment
Genes 2022, 13(5), 872; https://doi.org/10.3390/genes13050872 - 13 May 2022
Cited by 5 | Viewed by 2311
Abstract
With the increasing use of genetic testing in pediatric epilepsy, it is important to describe the diagnostic outcomes as they relate to clinical care. The goal of this study was to assess the diagnostic yield and impact on patient care of genetic epilepsy [...] Read more.
With the increasing use of genetic testing in pediatric epilepsy, it is important to describe the diagnostic outcomes as they relate to clinical care. The goal of this study was to assess the diagnostic yield and impact on patient care of genetic epilepsy panel testing. We conducted a retrospective chart review of patients at the Children’s Hospital of Eastern Ontario (CHEO) who had genetic testing between the years of 2013–2020. We identified 227 patients that met criteria for inclusion. The majority of patients had their testing performed as “out-of-province” tests since province-based testing during this period was limited. The diagnostic yield for multi-gene epilepsy panel testing was 17% (39/227) and consistent with the literature. Variants of unknown significance (VUS) were reported in a significant number of undiagnosed individuals (77%; 128/163). A higher diagnostic rate was observed in patients with a younger age of onset of seizures (before one year of age; 32%; 29/90). A genetic diagnosis informed prognosis, recurrence risk counselling and expedited access to resources in all those with a diagnosis. A direct change in clinical management as a result of the molecular diagnosis was evident for 9% (20/227) of patients. The information gathered in this study provides evidence of the clinical benefits of genetic testing in epilepsy and serves as a benchmark for comparison with the current provincial Ontario Epilepsy Genetic Testing Program (OEGTP) that began in 2020. Full article
(This article belongs to the Special Issue Genetics of Epileptic Encephalopathies: From Gene Discovery to Clinical Diagnosis and Management Implications of Genetic Diagnoses)
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9 pages, 848 KiB  
Article
SCN1A Variants as the Underlying Cause of Genetic Epilepsy with Febrile Seizures Plus in Two Multi-Generational Colombian Families
by Diana M. Cornejo-Sanchez, Anushree Acharya, Thashi Bharadwaj, Lizeth Marin-Gomez, Pilar Pereira-Gomez, Liz M. Nouel-Saied, University of Washington Center for Mendelian Genomics, Deborah A. Nickerson, Michael J. Bamshad, Heather C. Mefford, Isabelle Schrauwen, Jaime Carrizosa-Moog, William Cornejo-Ochoa, Nicolas Pineda-Trujillo and Suzanne M. Leal
Genes 2022, 13(5), 754; https://doi.org/10.3390/genes13050754 - 25 Apr 2022
Cited by 2 | Viewed by 3159
Abstract
Genetic epilepsy with febrile seizures plus (GEFS+) is an autosomal dominant disorder with febrile or afebrile seizures that exhibits phenotypic variability. Only a few variants in SCN1A have been previously characterized for GEFS+, in Latin American populations where studies on the genetic and [...] Read more.
Genetic epilepsy with febrile seizures plus (GEFS+) is an autosomal dominant disorder with febrile or afebrile seizures that exhibits phenotypic variability. Only a few variants in SCN1A have been previously characterized for GEFS+, in Latin American populations where studies on the genetic and phenotypic spectrum of GEFS+ are scarce. We evaluated members in two multi-generational Colombian Paisa families whose affected members present with classic GEFS+. Exome and Sanger sequencing were used to detect the causal variants in these families. In each of these families, we identified variants in SCN1A causing GEFS+ with incomplete penetrance. In Family 047, we identified a heterozygous variant (c.3530C > G; p.(Pro1177Arg)) that segregates with GEFS+ in 15 affected individuals. In Family 167, we identified a previously unreported variant (c.725A > G; p.(Gln242Arg)) that segregates with the disease in a family with four affected members. Both variants are located in a cytoplasmic loop region in SCN1A and based on our findings the variants are classified as pathogenic and likely pathogenic, respectively. Our results expand the genotypic and phenotypic spectrum associated with SCN1A variants and will aid in improving molecular diagnostics and counseling in Latin American and other populations. Full article
(This article belongs to the Special Issue Genetics of Epileptic Encephalopathies: From Gene Discovery to Clinical Diagnosis and Management Implications of Genetic Diagnoses)
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14 pages, 825 KiB  
Article
Prevalence of Congenital Disorders of Glycosylation in Childhood Epilepsy and Effects of Anti-Epileptic Drugs on the Transferrin Isoelectric Focusing Test
by Grace Silver, Shalini Bahl, Dawn Cordeiro, Abhinav Thakral, Taryn Athey and Saadet Mercimek-Andrews
Genes 2021, 12(8), 1227; https://doi.org/10.3390/genes12081227 - 10 Aug 2021
Cited by 5 | Viewed by 2680
Abstract
Introduction: Childhood epilepsy is one of the most common neurological problems. The transferrin isoelectric focusing (TIEF) test is a screening test for congenital disorders of glycosylation (CDG). We identified abnormal TIEF test in children with epilepsy in our epilepsy genetics clinic. To determine [...] Read more.
Introduction: Childhood epilepsy is one of the most common neurological problems. The transferrin isoelectric focusing (TIEF) test is a screening test for congenital disorders of glycosylation (CDG). We identified abnormal TIEF test in children with epilepsy in our epilepsy genetics clinic. To determine if an abnormal TIEF test is associated with anti-epileptic medications or abnormal liver functions, we performed a retrospective cohort study. Methods: This study was performed between January 2012 and March 2020. Electronic patient charts were reviewed. Standard non-parametric statistical tests were applied using R statistical software. Fischer’s exact test was used for comparisons. Results: There were 206 patients. The TIEF test was abnormal in 11% (23 out of 206) of the patients. Nine patients were diagnosed with CDG: PMM2-CDG (n = 5), ALG3-CDG (n = 1), ALG11-CDG (n = 2), SLC35A2-CDG (n = 1). We report 51 different genetic diseases in 84 patients. Two groups, (1) abnormal TIEF test; (2) normal TIEF test, showed statistically significant differences for abnormal liver functions and for valproic acid treatment. Conclusion: The TIEF test guided CDG diagnosis in 2.9% of the patients. Due to the high prevalence of CDG (4.4%) in childhood epilepsy, the TIEF test might be included into the diagnostic investigations to allow earlier and cost-effective diagnosis. Full article
(This article belongs to the Special Issue Genetics of Epileptic Encephalopathies: From Gene Discovery to Clinical Diagnosis and Management Implications of Genetic Diagnoses)
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Review

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9 pages, 254 KiB  
Review
SLC13A5 Deficiency Disorder: From Genetics to Gene Therapy
by Kimberly Goodspeed, Judy S. Liu, Kimberly L. Nye, Suyash Prasad, Chanchal Sadhu, Fatemeh Tavakkoli, Deborah A. Bilder, Berge A. Minassian and Rachel M. Bailey
Genes 2022, 13(9), 1655; https://doi.org/10.3390/genes13091655 - 15 Sep 2022
Cited by 8 | Viewed by 3663
Abstract
Epileptic encephalopathies may arise from single gene variants. In recent years, next-generation sequencing technologies have enabled an explosion of gene identification in monogenic epilepsies. One such example is the epileptic encephalopathy SLC13A5 deficiency disorder, which is caused by loss of function pathogenic variants [...] Read more.
Epileptic encephalopathies may arise from single gene variants. In recent years, next-generation sequencing technologies have enabled an explosion of gene identification in monogenic epilepsies. One such example is the epileptic encephalopathy SLC13A5 deficiency disorder, which is caused by loss of function pathogenic variants to the gene SLC13A5 that results in deficiency of the sodium/citrate cotransporter. Patients typically experience seizure onset within the first week of life and have developmental delay and intellectual disability. Current antiseizure medications may reduce seizure frequency, yet more targeted treatments are needed to address the epileptic and non-epileptic features of SLC13A5 deficiency disorder. Gene therapy may offer hope to these patients and better clinical outcomes than current available treatments. Here, we discuss SLC13A5 genetics, natural history, available treatments, potential outcomes and assessments, and considerations for translational medical research for an AAV9-based gene replacement therapy. Full article
(This article belongs to the Special Issue Genetics of Epileptic Encephalopathies: From Gene Discovery to Clinical Diagnosis and Management Implications of Genetic Diagnoses)

Other

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19 pages, 1388 KiB  
Case Report
Concomitant Calcium Channelopathies Involving CACNA1A and CACNA1F: A Case Report and Review of the Literature
by Donna Schaare, Sara M. Sarasua, Laina Lusk, Shridhar Parthasarathy, Liangjiang Wang, Ingo Helbig and Luigi Boccuto
Genes 2023, 14(2), 400; https://doi.org/10.3390/genes14020400 - 3 Feb 2023
Cited by 1 | Viewed by 2735
Abstract
Calcium channels are an integral component in maintaining cellular function. Alterations may lead to channelopathies, primarily manifested in the central nervous system. This study describes the clinical and genetic features of a unique 12-year-old boy harboring two congenital calcium channelopathies, involving the CACNA1A [...] Read more.
Calcium channels are an integral component in maintaining cellular function. Alterations may lead to channelopathies, primarily manifested in the central nervous system. This study describes the clinical and genetic features of a unique 12-year-old boy harboring two congenital calcium channelopathies, involving the CACNA1A and CACNA1F genes, and provides an unadulterated view of the natural history of sporadic hemiplegic migraine type 1 (SHM1) due to the patient’s inability to tolerate any preventative medication. The patient presents with episodes of vomiting, hemiplegia, cerebral edema, seizure, fever, transient blindness, and encephalopathy. He is nonverbal, nonambulatory, and forced to have a very limited diet due to abnormal immune responses. The SHM1 manifestations apparent in the subject are consistent with the phenotype described in the 48 patients identified as part of a systematic literature review. The ocular symptoms of CACNA1F align with the family history of the subject. The presence of multiple pathogenic variants make it difficult to identify a clear phenotype–genotype correlation in the present case. Moreover, the detailed case description and natural history along with the comprehensive review of the literature contribute to the understanding of this complex disorder and point to the need for comprehensive clinical assessments of SHM1. Full article
(This article belongs to the Special Issue Genetics of Epileptic Encephalopathies: From Gene Discovery to Clinical Diagnosis and Management Implications of Genetic Diagnoses)
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9 pages, 1635 KiB  
Case Report
A De Novo Missense Variant in TUBG2 in a Child with Global Developmental Delay, Microcephaly, Refractory Epilepsy and Perisylvian Polymicrogyria
by Salini Thulasirajah, Xueqi Wang, Erick Sell, Jorge Dávila, David A. Dyment and Kristin D. Kernohan
Genes 2023, 14(1), 108; https://doi.org/10.3390/genes14010108 - 29 Dec 2022
Cited by 3 | Viewed by 2763
Abstract
Polymicrogyria is a brain malformation characterized by excessive folding of the cortex. To date, numerous causes of polymicrogyria have been identified, including variants in the genes associated with tubulinopathies. Herein, we present a child with severe intellectual disability, refractory to treatment seizures, microcephaly [...] Read more.
Polymicrogyria is a brain malformation characterized by excessive folding of the cortex. To date, numerous causes of polymicrogyria have been identified, including variants in the genes associated with tubulinopathies. Herein, we present a child with severe intellectual disability, refractory to treatment seizures, microcephaly and MRI findings consistent with polymicrogyria, closed-lip schizencephaly, periventricular heterotopia and a dysplastic corpus callosum. Exome sequencing identified a de novo missense variant in TUBG2, a gene not associated with human disease. The variant, NM_016437.3 c.747G>A p.(Met249Ile), is absent from available control databases and is predicated to be deleterious by in silico prediction programs. Laboratory studies show that cultured lymphoblasts derived from the patient grew significantly faster than controls. Recombinant protein was expressed (recombinant wild type and mutant TUBG2-FLAG) in 293T cells and lower levels of TUBG2 mutant compared with controls were observed. Furthermore, co-immuno-precipitation in cells transfected demonstrated that the TUBG2–GCP2 interaction is increased due to the MUT recombinant protein versus WT recombinant protein. In closing, this work provides preliminary evidence that TUBG2 may represent a novel disease gene responsible for polymicrogyria. Full article
(This article belongs to the Special Issue Genetics of Epileptic Encephalopathies: From Gene Discovery to Clinical Diagnosis and Management Implications of Genetic Diagnoses)
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