EFHC1 variants in juvenile myoclonic epilepsy: reanalysis according to NHGRI and ACMG guidelines for assigning disease causality

Bailey, Julia N.; Patterson, Christopher; Nijs, Laurence de; Durón, Reyna M.; Nguyễn, Việt Hương; Tanaka, Miyabi; Medina, Marco T.; Jara‐Prado, Aurelio; Martínez‐Juárez, Iris E.; Ochoa, Adriana; Molina, Yolli; Suzuki, Toshimitsu; Alonso, María Elisa; Wight, Jenny E.; Lin, Ye; Guilhoto, Laura Maria de Figueiredo Ferreira; Yacubian, Elza Márcia Targas; Machado‐Salas, Jesús; Daga, Andrea; Yamakawa, Kazuhiro; Grisar, Thierry; Lakaye, Bernard; Delgado‐Escueta, Antonio V.

doi:10.1038/gim.2016.86

Cited by 31 publications

(30 citation statements)

References 71 publications

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“…The significance of EFHC1 was questioned after some variants published in early reports were subsequently found to be present in population databases without seizures such as the Genome Aggregation Database (gnomAD) . Despite these findings, a recent systematic review provided evidence that EFHC1 variants are indeed a contributing liability factor in JME . The recognition that a condition is probably multifactorial should not necessarily dissuade a physician from referring their patient for genetic counseling, if they are interested, as the individual and/or family members may benefit from recurrence risk counseling based on available empiric recurrence risks, and also a discussion on prenatal risks due to fetal exposure to various antiepileptic medication …”

Section: Genetic Generalized Epilepsy Syndromesmentioning

confidence: 99%

“…55 Despite these findings, a recent systematic review provided evidence that EFHC1 variants are indeed a contributing liability factor in JME. 56 The recognition that a condition is probably multifactorial should not necessarily dissuade a physician from referring their patient for genetic counseling, if they are interested, as the individual and/or family members may benefit from recurrence risk counseling based on available empiric recurrence risks, 13,57 and also a discussion on prenatal risks due to fetal exposure to various antiepileptic medication. [58][59][60] Not all GGEs are multifactorial, and there are convincing monogenic, highly penetrant, non-syndromic, causes for GGE.…”

Section: Focal-onset Seizuresmentioning

confidence: 99%

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Epilepsy genetics: Current knowledge, applications, and future directions

2018

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The rapid pace of disease gene discovery has resulted in tremendous advances in the field of epilepsy genetics. Clinical testing with comprehensive gene panels, exomes, and genomes are now available and have led to higher diagnostic rates and insights into the underlying disease processes. As such, the contribution to the care of patients by medical geneticists, neurogeneticists and genetic counselors are significant; the dysmorphic examination, the necessary pre- and post-test counseling, the selection of the appropriate next-generation sequencing-based test(s), and the interpretation of sequencing results require a care provider to have a comprehensive working knowledge of the strengths and limitations of the available testing technologies. As the underlying mechanisms of the encephalopathies and epilepsies are better understood, there may be opportunities for the development of novel therapies based on an individual's own specific genotype. Drug screening with in vitro and in vivo models of epilepsy can potentially facilitate new treatment strategies. The future of epilepsy genetics will also probably include other-omic approaches such as transcriptomes, metabolomes, and the expanded use of whole genome sequencing to further improve our understanding of epilepsy and provide better care for those with the disease.

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Section: Genetic Generalized Epilepsy Syndromesmentioning

confidence: 99%

Section: Focal-onset Seizuresmentioning

confidence: 99%

Epilepsy genetics: Current knowledge, applications, and future directions

2018

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“…This study also included JME mutations (H89R, Y355C, R372W, R436C, N519S, V556L, I619S, and Y631C) reported from India. The majority of these EFHC1 coding variants originated from Bangalore (R372W, R436C, N519S, V556L, I619S, and Y631C) and may not be pathogenic . Therefore, these are far from the New Delhi EFHC1 variants that are located primarily between DM10 (1) and DM10 (2) domains.…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, in a recent article Bailey et al 19 reanalyzed 54 EFHC1 variants associated with epilepsy from 17 cohorts and classified 9 variants as pathogenic. This study also included JME mutations (H89R, Y355C, R372W, R436C, N519S, V556L, I619S, and Y631C) reported from India.…”

Section: Discussionmentioning

confidence: 99%

EFHC1 mutation in Indian juvenile myoclonic epilepsy patient

et al. 2017

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SummaryObjectiveJuvenile myoclonic epilepsy (JME) is the most common form of idiopathic generalized epilepsies (IGEs) and is genetically heterogeneous. Mutations in EFHC1 cause JME. Because about 2 million people in India are affected by JME alone, we investigated the prevalence of mutations in the EFHC1 gene in the Indian population with JME. We studied 63 patients with JME and 80 healthy controls.MethodsClinical identification of JME was evaluated using established criteria. Following clinical evaluation of the patients and confirming presence of JME, blood samples were collected from each patient and healthy individual. Subsequently, genomic DNA was extracted from the blood samples. Eleven exons of the EFHC1 gene were individually amplified by polymerase chain reaction (PCR) for each DNA sample. The PCR products were then purified and sequenced commercially. The identified DNA variants were sequenced at least twice in both the forward and reverse directions and compared with the Exome Aggregation Consortium (ExAC) database.ResultsWe found five heterozygous and one homozygous variant. We found three novel coding variants 661C→T, 779 G →A, and 730 C→T, which lead to R221C, R260Q, and R244STOP amino acid substitutions, respectively. The coding variant 475 C→T, resulting in the amino acid substitution R159W, reported earlier as polymorphism, was also identified in both patient and control populations.SignificanceDetection of these three novel variants, excluding R159W, which is considered polymorphism, expands the range of possible mutations in the EFHC1 gene. The novel variants that we are reporting herein have not been mentioned before as occurring in JME patients of other ethnic population. Therefore, these novel coding variants may be confined to the Indian JME population. Further studies on the mutational spectrum of EFHC1 in a larger number of Indian JME patients concurrent with their mode of inheritance and underlying functional assays should establish whether EFHC1 could be a panethnic gene for JME.

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“…There is a large research community focusing on genetic variation study relating to human disease (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18). This community often performs their analysis in-house rather than using any of the currently available tools for variant analysis.…”

Section: Introductionmentioning

confidence: 99%

GeMSTONE: Orchestrated Prioritization of Human Germline Mutations in the Cloud

Chen

Beltrán

Wei

et al. 2016

Preprint

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Integrative analysis of whole-genome/exomesequencing data has been challenging, especially for the non-programming research community, as it requires simultaneously managing a large number of computational tools. Even computational biologists find it unexpectedly difficult to reproduce results from others or optimize their strategies in an endto-end workflow. We introduce Germline Mutation Scoring Tool fOr Next-generation sEquencing data (GeMSTONE), a cloud-based variant prioritization tool with high-level customization and a comprehensive collection of bioinformatics tools and data libraries (http://gemstone.yulab.org/). GeMSTONE generates and readily accepts a shareable 'recipe' file for each run to either replicate previous results or analyze new data with identical parameters and provides a centralized workflow for prioritizing germline mutations in human disease within a streamlined workflow rather than a pool of program executions.

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EFHC1 variants in juvenile myoclonic epilepsy: reanalysis according to NHGRI and ACMG guidelines for assigning disease causality

Cited by 31 publications

References 71 publications

Epilepsy genetics: Current knowledge, applications, and future directions

Epilepsy genetics: Current knowledge, applications, and future directions

EFHC1 mutation in Indian juvenile myoclonic epilepsy patient

GeMSTONE: Orchestrated Prioritization of Human Germline Mutations in the Cloud

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