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https://hdl.handle.net/2440/99703
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Type: | Journal article |
Title: | Multiplex families with epilepsy: success of clinical and molecular genetic characterization |
Author: | Afawi, Z. Oliver, K.L. Kivity, S. Mazarib, A. Blatt, I. Neufeld, M.Y. Helbig, K.L. Goldberg-Stern, H. Misk, A.J. Straussberg, R. Walid, S. Mahajnah, M. Lerman-Sagie, T. Ben-Zeev, B. Kahana, E. Masalha, R. Kramer, U. Ekstein, D. Shorer, Z. Wallace, R.H. et al. |
Citation: | Neurology, 2016; 86(8):713-722 |
Publisher: | Lippincott Williams & Wilkins |
Issue Date: | 2016 |
ISSN: | 0028-3878 1526-632X |
Statement of Responsibility: | Zaid Afawi, Karen L. Oliver, Sara Kivity, Aziz Mazarib, Ilan Blatt, Miriam Y. Neufeld, Katherine L. Helbig, Hadassa Goldberg-Stern, Adel J. Misk, Rachel Straussberg, Simri Walid, Muhammad Mahajnah, Tally Lerman-Sagie, Bruria Ben-Zeev, Esther Kahana, Rafik Masalha, Uri Kramer, Dana Ekstein, Zamir Shorer, Robyn H. Wallace, Marie Mangelsdorf, James N. MacPherson, Gemma L. Carvill, Heather C. Mefford, Graeme D. Jackson, Ingrid E. Scheffer, Melanie Bahlo, Jozef Gecz, Sarah E. Heron, Mark Corbett, John C. Mulley, Leanne M. Dibbens, Amos D. Korczyn and Samuel F. Berkovic |
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. |
Keywords: | Humans Epilepsy Genetic Predisposition to Disease Cohort Studies Pedigree Family Israel Female Male Genetic Testing |
Rights: | © 2016 American Academy of Neurology |
DOI: | 10.1212/WNL.0000000000002404 |
Grant ID: | http://purl.org/au-research/grants/nhmrc/628952 http://purl.org/au-research/grants/arc/FT100100764 |
Published version: | http://dx.doi.org/10.1212/wnl.0000000000002404 |
Appears in Collections: | Aurora harvest 7 Medicine publications |
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