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Title: Multiplex families with epilepsy: Success of clinical and molecular genetic characterization
Austin Authors: Afawi, Zaid;Oliver, Karen L;Kivity, Sara;Mazarib, Aziz;Blatt, Ilan;Neufeld, Miriam Y;Helbig, Katherine L;Goldberg-Stern, Hadassa;Misk, Adel J;Straussberg, Rachel;Walid, Simri;Mahajnah, Muhammad;Lerman-Sagie, Tally;Ben-Zeev, Bruria;Kahana, Esther;Masalha, Rafik;Kramer, Uri;Ekstein, Dana;Shorer, Zamir;Wallace, Robyn H;Mangelsdorf, Marie;MacPherson, James N;Carvill, Gemma L;Mefford, Heather C;Jackson, Graeme D ;Scheffer, Ingrid E ;Bahlo, Melanie;Gecz, Jozef;Heron, Sarah E;Corbett, Mark A;Mulley, John C;Dibbens, Leanne M;Korczyn, Amos D;Berkovic, Samuel F 
Affiliation: Austin Health, Heidelberg, Victoria, Australia
Florey Institute of Neuroscience and Mental Health, Heidelberg, Victoria, Australia
Sackler School of Medicine, Tel Aviv University, Ramat Aviv, Israel
Epilepsy Research Centre, University of Melbourne, Austin Health, Heidelberg, Victoria, Australia
Epilepsy Unit, Schneider Children's Medical Center of Israel, Petach Tikvah, Israel
Department of Neurology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
Department of Neurology, The Chaim Sheba Medical Center, Tel Hashomer, Israel
Shaare Zedek Medical Center, Jerusalem, Israel
Department of Neurology, Western Galilee Hospital, Nahariya, Israel
Pediatric Neurology and Child Development Center, Hillel Yaffe Medical Center, Hadera, Israel
Ruth and Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel
Pediatric Neurology Unit, Wolfson Medical Center, Holon, Israel
The Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Ramat Gan, Israel
Department of Neurology, Barzilai Medical Center, Ashkelon, Israel
Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
Department of Neurology and Pediatric Neurology Unit, Soroka University Medical Center, Beer-Sheva, Israel
Pediatric Neurology Unit, Dana Children's Hospital, Tel Aviv, Israel
Department of Neurology, Agnes Ginges Center of Neurogenetics, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
School of Biomedical Sciences, Charles Sturt University, Wagga Wagga, NSW, Australia
Queensland Brain Institute, University of Queensland, Brisbane, Queensland, Australia
Wessex Regional Genetics Laboratory, Salisbury NHS Foundation Trust, Salisbury, UK
Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, USA
Department of Pediatrics, University of Melbourne, Royal Children's Hospital, Parkville, Victoria, Australia
Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia
Department of Mathematics and Statistics & Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia
School of Paediatrics and Reproductive Health, University of Adelaide, Adelaide, South Australia, Australia
School of Molecular and Biomedical Science, University of Adelaide, Adelaide, South Australia, Australia
Epilepsy Research Program, School of Pharmacy and Medical Sciences, University of Adelaide, Adelaide, South Australia, Australia
Sansom Institute for Health Research, University of Adelaide, Adelaide, South Australia, Australia
SA Pathology at Women's and Children's Hospital, Adelaide, South Australia, Australia
Issue Date: 23-Feb-2016
Date: 2016-02-22
Publication information: Neurology 2016; 86(8): 713-722
Abstract: Objective: To analyze the clinical syndromes and inheritance patterns of multiplex families with epilepsy toward the ultimate aim of uncovering the underlying molecular genetic basis. Methods: Following the referral of families with 2 or more relatives with epilepsy, individuals were classified into epilepsy syndromes. Families were classified into syndromes where at least 2 family members had a specific diagnosis. Pedigrees were analyzed and molecular genetic studies were performed as appropriate. Results: A total of 211 families were ascertained over an 11-year period in Israel. A total of 169 were classified into broad familial epilepsy syndrome groups: 61 generalized, 22 focal, 24 febrile seizure syndromes, 33 special syndromes, and 29 mixed. A total of 42 families remained unclassified. Pathogenic variants were identified in 49/211 families (23%). The majority were found in established epilepsy genes (e.g., SCN1A, KCNQ2, CSTB), but in 11 families, this cohort contributed to the initial discovery (e.g., KCNT1, PCDH19, TBC1D24). We expand the phenotypic spectrum of established epilepsy genes by reporting a familial LAMC3 homozygous variant, where the predominant phenotype was epilepsy with myoclonic-atonic seizures, and a pathogenic SCN1A variant in a family where in 5 siblings the phenotype was broadly consistent with Dravet syndrome, a disorder that usually occurs sporadically. Conclusion: A total of 80% of families were successfully classified, with pathogenic variants identified in 23%. The successful characterization of familial electroclinical and inheritance patterns has highlighted the value of studying multiplex families and their contribution towards uncovering the genetic basis of the epilepsies.
DOI: 10.1212/WNL.0000000000002404
ORCID: 0000-0002-1121-9513
Journal: Neurology
PubMed URL:
Type: Journal Article
Subjects: Epilepsy
Genetic Predisposition to Disease
Genetic Testing
Appears in Collections:Journal articles

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