Predictive value of EFHC1 variants for the long-term seizure outcome in juvenile myoclonic epilepsy

Podewils, Felix von; Kowoll, Victoria; Schroeder, Winnie; Geithner, J.; Wang, Irène; Gaida, Bernadette; Bombach, Paula; Kessler, Christof; Felbor, Ute; Runge, Uwe

doi:10.1016/j.yebeh.2014.12.016

Cited by 8 publications

(8 citation statements)

References 40 publications

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“…A compound heterozygosity test using CNVkit was negative in these two cases. It is known that EFHC1 Arg294His is a genetic cause of childhood absence epilepsy and juvenile myoclonus epilepsy (Von Podewils et al, 2015). However, APEs with EFHC1 Arg294Cys, an allelic variant of Arg294His, had acquired posttraumatic epilepsy in our study.…”

Section: Discussionmentioning

confidence: 99%

Genetic characteristics of non-familial epilepsy

Kang

Kim

Cho

et al. 2019

PeerJ

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BackgroundKnowledge of the genetic etiology of epilepsy can provide essential prognostic information and influence decisions regarding treatment and management, leading us into the era of precision medicine. However, the genetic basis underlying epileptogenesis or epilepsy pharmacoresistance is not well-understood, particularly in non-familial epilepsies with heterogeneous phenotypes that last until or start in adulthood.MethodsWe sought to determine the contribution of known epilepsy-associated genes (EAGs) to the causation of non-familial epilepsies with heterogeneous phenotypes and to the genetic basis underlying epilepsy pharmacoresistance. We performed a multi-center study for whole exome sequencing-based screening of 178 selected EAGs in 243 non-familial adult patients with primarily focal epilepsy (122 drug-resistant and 121 drug-responsive epilepsies). The pathogenicity of each variant was assessed through a customized stringent filtering process and classified according to the American College of Medical Genetics and Genomics guidelines.ResultsPossible causal genetic variants of epilepsy were uncovered in 13.2% of non-familial patients with primarily focal epilepsy. The diagnostic yield according to the seizure onset age was 25% (2/8) in the neonatal and infantile period, 11.1% (14/126) in childhood and 14.7% (16/109) in adulthood. The higher diagnostic yields were from ion channel-related genes and mTOR pathway-related genes, which does not significantly differ from the results of previous studies on familial or early-onset epilepsies. These potentially pathogenic variants, which were identified in genes that have been mainly associated with early-onset epilepsies with severe phenotypes, were also linked to epilepsies that start in or last until adulthood in this study. This finding suggested the presence of one or more disease-modifying factors that regulate the onset time or severity of epileptogenesis. The target hypothesis of epilepsy pharmacoresistance was not verified in our study. Instead, neurodevelopment-associated epilepsy genes, such as TSC2 or RELN, or structural brain lesions were more strongly associated with epilepsy pharmacoresistance.ConclusionsWe revealed a fraction of possible causal genetic variants of non-familial epilepsies in which genetic testing is usually overlooked. In this study, we highlight the importance of earlier identification of the genetic etiology of non-familial epilepsies, which leads us to the best treatment options in terms of precision medicine and to future neurobiological research for novel drug development. This should be considered a justification for physicians determining the hidden genetics of non-familial epilepsies that last until or start in adulthood.

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Section: Discussionmentioning

confidence: 99%

Genetic characteristics of non-familial epilepsy

Kang

Kim

Cho

et al. 2019

PeerJ

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“…14), were not available in 2004 when variants of the EF-hand domain (C-terminal) containing 1 gene (EFHC1) were reported as disease-causing mutations in myoclonic and grand mal clonic-tonic-clonic (CTC) convulsions produced by juvenile myoclonic epilepsy (JME). Consequently, all EFHC1 variants discovered in the first decade of this millennium and reported with respect to epilepsy or not [15][16][17][18][19][20][21][22][23][24][25][26][27][28] have not been "vetted" through NHGRI and ACMG guidelines. More importantly, both NHGRI and ACMG guidelines advise that "with evidence on variants evolving" and the "content of sequencing tests expanding, " "rigorous evaluation" and "reanalysis of variants are encouraged" to prevent misannotation of the pathogenicity of variants in public databases.…”

mentioning

confidence: 99%

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

Bailey

Patterson

Nijs

et al. 2017

Genetics in Medicine

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“…She had complaints of headache, frontal throbbing, and phonophobia, but no photophobia, nausea, or vomiting. The R294H variant was reported earlier in two probands of German JME patients who had a subtype of JME developing from childhood absence epilepsy …”

Section: Resultsmentioning

confidence: 62%

“…The R294H variant was reported earlier in two probands of German JME patients who had a subtype of JME developing from childhood absence epilepsy. 18 A male patient carrying the R159W allele had a mother with generalized seizures and myoclonus with awakening preponderance (Fig. 3B).…”

Section: Mutation Analysismentioning

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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Predictive value of EFHC1 variants for the long-term seizure outcome in juvenile myoclonic epilepsy

Cited by 8 publications

References 40 publications

Genetic characteristics of non-familial epilepsy

Genetic characteristics of non-familial epilepsy

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

EFHC1 mutation in Indian juvenile myoclonic epilepsy patient

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