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

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dc.citation.issue2
dc.citation.volume19
dc.contributor.authorBailey, Julia N.
dc.contributor.authorPatterson, Christopher
dc.contributor.authorde Nijs, Laurence
dc.contributor.authorDuron, Reyna M.
dc.contributor.authorViet-Huong Nguyen
dc.contributor.authorTanaka, Miyabi
dc.contributor.authorMedina, Marco T.
dc.contributor.authorJara-Prado, Aurelio
dc.contributor.authorMartinez-Juarez, Iris E.
dc.contributor.authorOchoa, Adriana
dc.contributor.authorMolina, Yolli
dc.contributor.authorSuzuki, Toshimitsu
dc.contributor.authorAlonso, Maria E.
dc.contributor.authorWight, Jenny E.
dc.contributor.authorLin, Yu-Chen
dc.contributor.authorGuilhoto, Laura [UNIFESP]
dc.contributor.authorTargas Yacubian, Elza Marcia [UNIFESP]
dc.contributor.authorMachado-Salas, Jesus
dc.contributor.authorDaga, Andrea
dc.contributor.authorYamakawa, Kazuhiro
dc.contributor.authorGrisar, Thierry M.
dc.contributor.authorLakaye, Bernard
dc.contributor.authorDelgado-Escueta, Antonio V.
dc.coverageNew York
dc.date.accessioned2020-07-17T14:03:11Z
dc.date.available2020-07-17T14:03:11Z
dc.date.issued2017
dc.description.abstractPurpose: EFHCI variants are the most common mutations in inheritecianyodonic and grand mal donic-tonic-donic (CTC) convulsions of juvenile myodonic epilepsy (JME). We reanalyzed 54 EFHC1 variants associated with epilepsy from 17 cohorts based on National Human Genome Research Institute (NHGRI) and American College of Medical Genetics and Genomics (ACMG) guidelines for interpretation of sequence variants. Methods: We calculated Bayesian LOD scores for variants in coinheritance, unconditional exact tests and odds ratios (OR) in case-control associations, allele frequencies in genome databases, and predictions for conservation/pathogenicity We reviewed whether variants damage EFHC1 functions, whether efhc1(-/-) KO mice recapitulate CTC convulsions and "microdysgenesis" neuropathology, and whether supermlmerary synaptic and dendritic phenotypes can be rescued in the fly model when EFHCI is overexpressed. We rated strengths of evidence and applied ACMG combinatorial criteria for classifying variants. Results: Nine variants were classified as "pathogenic;' 14 as "likely pathogenic:' 9 as "benign," and 2 as "likely benign." Twenty variants of unknown significance had an insufficient number of ancesfrymatched controls, but ORs exceeded 5 when compared with racial/ ethnic-matched Exome Aggregation Consortium (ExAC) controls. Conclusions: NHGRI gene-level evidence and variant-level evidence establish EFHC1 as the first non-ion channel microtubuleassociated protein whose mutations disturb R-type VDCC and TRPM2 calcium currents in overgrown synapses and dendrites within abnormally migrated dislocated neurons, thus explaining " CTC convulsions and "microdysgenesis" neuropathology of JME.en
dc.description.affiliationVA GLAHS UCLA, Epilepsy Genet Gen Lab, Neurol & Res Serv, Los Angeles, CA 90095 USA
dc.description.affiliationGENESS Int Consortium, Los Angeles, CA 90095 USA
dc.description.affiliationUniv Calif Los Angeles, Fielding Sch Publ Hlth, Dept Epidemiol, Los Angeles, CA 90095 USA
dc.description.affiliationUniv Liege, GIGA Neurosci, Liege, Belgium
dc.description.affiliationUniv Tecnol Centroamer UNITEC, Fac Ciencias Salud, Tegucigalpa, Honduras
dc.description.affiliationChapman Univ, Sch Pharm, Irvine, CA USA
dc.description.affiliationUniv Calif Los Angeles, David Geffen Sch Med, Dept Neurol, Los Angeles, CA 90095 USA
dc.description.affiliationNatl Autonomous Univ Honduras, Tegucigalpa, Honduras
dc.description.affiliationNatl Inst Neurol & Neurosurg, Mexico City, DF, Mexico
dc.description.affiliationRIKEN, Brain Sci Inst, Neurogenet Lab, Saitama, Japan
dc.description.affiliationUniv Fed Sao Paulo UNIFESP EPM, Unidade Pesquisa & Tratamento Epilepsias UNIPETE, Sao Paulo, Brazil
dc.description.affiliationEugenio Medea Sci Inst, Conegliano & Dulbecco Telethon Inst, Padua, Italy
dc.description.affiliationUnifespUniv Fed Sao Paulo UNIFESP EPM, Unidade Pesquisa & Tratamento Epilepsias UNIPETE, Sao Paulo, Brazil
dc.description.sourceWeb of Science
dc.description.sponsorshipNational Institutes of Health
dc.description.sponsorshipVACO Merit Review Grant
dc.description.sponsorshipCONACYT
dc.description.sponsorshipIDNIH: 1R01NS055057
dc.description.sponsorshipIDNIH: HHSN2682012000081
dc.description.sponsorshipIDVACO Merit Review Grant: 5IO1CS000743
dc.format.extent144-156
dc.identifierhttp://dx.doi.org/10.1038/gim.2016.86
dc.identifier.citationGenetics In Medicine. New York, v. 19, n. 2, p. 144-156, 2017.
dc.identifier.doi10.1038/gim.2016.86
dc.identifier.issn1098-3600
dc.identifier.urihttps://repositorio.unifesp.br/handle/11600/55208
dc.identifier.wosWOS:000393534200002
dc.language.isoeng
dc.publisherNature Publishing Group
dc.relation.ispartofGenetics In Medicine
dc.rightsinfo:eu-repo/semantics/openAccess
dc.subjectcausalityen
dc.subjectEFHCIen
dc.subjectjuvenile myodonic epilepsyen
dc.subjectwhole-exome sequencingen
dc.titleEFHC1 variants in juvenile myoclonic epilepsy: reanalysis according to NHGRI and ACMG guidelines for assigning disease causalityen
dc.typeinfo:eu-repo/semantics/article
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