<i>ADGRV1</i> is implicated in myoclonic epilepsy

Myers, Kenneth A.; Nasioulas, Steven; Boys, Amber; McMahon, Jacinta M.; Slater, Howard R.; Lockhart, Paul J.; Sart, Desirée du; Scheffer, Ingrid E.

doi:10.1111/epi.13980

Cited by 35 publications

(33 citation statements)

References 44 publications

(85 reference statements)

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“…Knockout mice without exons 2–4 of Avlgr1b were prone to experience audiogenic reflex seizure, although obvious cerebral histological abnormalities were not proven [ 29 ]. Differing from previous patients with ultra-rare ADGRV1 variants [ 26 , 30 ], our patient showed febrile seizures with afebrile seizures.…”

Section: Discussioncontrasting

confidence: 76%

“…On the other hand, ADGRV 1 variation plays a part in developing epilepsy with myoclonic seizures, although the inheritance manner may be different in various patients [ 30 ]. The function of ADGRV1 is unestablished, but multiple calcium exchanger b-repeats in the ectodomain imply a contribution to protein–protein interaction that may be calcium mediated [ 31 ].…”

Section: Discussionmentioning

confidence: 99%

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Identification of Missense ADGRV1 Mutation as a Candidate Genetic Cause of Familial Febrile Seizure 4

Han

Lee

et al. 2020

Children

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Febrile seizure (FS) is related to a febrile illness (temperature > 38 °C) not caused by an infection of central nervous system, without neurologic deficits in children aged 6–60 months. The family study implied a polygenic model in the families of proband(s) with single FS, however in families with repeated FS, inheritance was matched to autosomal dominance with reduced disease penetrance. A 20 month-old girl showed recurrent FS and afebrile seizures without developmental delay or intellectual disability. The seizures disappeared after 60 months without anti-seizure medication. The 35 year-old proband’s mother also experienced five episodes of simple FS and two episodes of unprovoked seizures before 5 years old. Targeted exome sequencing was conducted along with epilepsy/seizure-associated gene-filtering to identify the candidate causative mutation. As a result, a heterozygous c.2039A>G of the ADGRV1 gene leading to a codon change of aspartic acid to glycine at the position 680 (rs547076322) was identified. This protein’s glycine residue is highly conserved, and its allele frequency is 0.00002827 in the gnomAD population database. ADGRV1 mutation may have an influential role in the occurrence of genetic epilepsies, especially those with febrile and afebrile seizures. Further investigation of ADGRV1 mutations is needed to prove that it is a significant susceptible gene for febrile and/or afebrile seizures in early childhood.

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Section: Discussioncontrasting

confidence: 76%

Section: Discussionmentioning

confidence: 99%

Identification of Missense ADGRV1 Mutation as a Candidate Genetic Cause of Familial Febrile Seizure 4

Han

Lee

et al. 2020

Children

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“…While this needs to be functionally validated, it may widen our concept of the genetic spectrum of epilepsy in adulthood, which may in turn guide the development of adequate treatment options. ADGRV1 haploinsufficiency may be an important contributor to the development of genetic epilepsies, particularly those with myoclonic seizures (Myers et al, 2018). In our study, three APEs with the ADGRV1 heterozygous variant (p.His1859Arg) had either focal or generalized epilepsy, which might be plausible if a focal myoclonic seizure was confused with a focal motor seizure, as is occasionally the case in outpatient clinics.…”

Section: Genotype-phenotype Correlationsupporting

confidence: 50%

Peer Review #3 of "Genetic characteristics of non-familial epilepsy (v0.1)"

2019

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Background. Knowledge 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 nonfamilial epilepsies with heterogeneous phenotypes that last until or start in adulthood. Methods. We sought to determine the contribution of known epilepsy-associated genes 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 epilepsy-associated genes 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. Results. Possible 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 earlyonset epilepsies. These potentially pathogenic variants, which were identified in genes that

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“…Furthermore, several severe patients carried variants in genes that were previously described to worsen phenotypes (POLG , SCN2A , CACNA1A , and CACNA1G), strengthening those associations (Calhoun et al, ; Gaily et al, ; Hawkins et al, ; Ohmori et al, ). GPR98 , a gene implicated in myoclonic epilepsy (Myers et al, ), showed the highest overrepresentation of variants in severe patients in three categories of variants, and SCN10A , another sodium channel alpha‐subunit gene, was most often implicated in mild patients. One relatively severe patient carried a GABRA3 variant (family 6); several GABA receptor genes have already been suggested as potential SCN1A modifiers (Miller et al, ).…”

Section: Discussionmentioning

confidence: 99%

Modifier genes in SCN1A‐related epilepsy syndromes

Lange

Mulder

Slot

et al. 2020

Molec Gen & Gen Med

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Background: SCN1A is one of the most important epilepsy-related genes, with pathogenic variants leading to a range of phenotypes with varying disease severity. Different modifying factors have been hypothesized to influence SCN1A-related phenotypes. We investigate the presence of rare and more common variants in epilepsy-related genes as potential modifiers of SCN1A-related disease severity. Methods: 87 patients with SCN1A-related epilepsy were investigated. Whole-exome sequencing was performed by the Beijing Genomics Institute (BGI). Functional variants in 422 genes associated with epilepsy and/or neuronal excitability were investigated. Differences in proportions of variants between the epilepsy genes and four control gene sets were calculated, and compared to the proportions of variants in the same genes in the ExAC database. Results: Statistically significant excesses of variants in epilepsy genes were observed in the complete cohort and in the combined group of mildly and severely affected patients, particularly for variants with minor allele frequencies of <0.05.Patients with extreme phenotypes showed much greater excesses of epilepsy gene variants than patients with intermediate phenotypes. Conclusion:Our results indicate that relatively common variants in epilepsy genes, which would not necessarily be classified as pathogenic, may play a large role in modulating SCN1A phenotypes. They may modify the phenotypes of both severely and mildly affected patients. Our results may be a first step toward meaningful testing of modifier gene variants in regular diagnostics for individual patients, to provide a better estimation of disease severity for newly diagnosed patients. K E Y W O R D SDravet, epilepsy, GEFS+, modifier genes, phenotypic variability, SCN1A

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ADGRV1 is implicated in myoclonic epilepsy

Cited by 35 publications

References 44 publications

Identification of Missense ADGRV1 Mutation as a Candidate Genetic Cause of Familial Febrile Seizure 4

Identification of Missense ADGRV1 Mutation as a Candidate Genetic Cause of Familial Febrile Seizure 4

Peer Review #3 of "Genetic characteristics of non-familial epilepsy (v0.1)"

Modifier genes in SCN1A‐related epilepsy syndromes

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