Please use this identifier to cite or link to this item: http://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.
Kivity, S.
Mazarib, A.
Blatt, I.
Neufeld, M.
Helbig, K.
Goldberg-Stern, H.
Misk, A.
Straussberg, R.
Walid, S.
Mahajnah, M.
Lerman-Sagie, T.
Ben-Zeev, B.
Kahana, E.
Masalha, R.
Kramer, U.
Ekstein, D.
Shorer, Z.
Wallace, R.
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
RMID: 0030041864
DOI: 10.1212/WNL.0000000000002404
Grant ID: http://purl.org/au-research/grants/nhmrc/628952
http://purl.org/au-research/grants/arc/FT100100764
Appears in Collections:Medicine publications

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