Multiplex families with epilepsy: success of clinical and molecular genetic characterization

Afawi, Zaid, Oliver, Karen L., Kivity, Sara, Mazarib, Aziz, Blatt, Ilan, Neufeld, Miriam, 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, Mulley, John C., Dibbens, Leanne M., Korczyn, Amos D. and Berkovic, Samuel F. (2016) Multiplex families with epilepsy: success of clinical and molecular genetic characterization. Neurology, 86 8: 713-722. doi:10.1212/WNL.0000000000002404

Author Afawi, Zaid
Oliver, Karen L.
Kivity, Sara
Mazarib, Aziz
Blatt, Ilan
Neufeld, Miriam
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
Mulley, John C.
Dibbens, Leanne M.
Korczyn, Amos D.
Berkovic, Samuel F.
Title Multiplex families with epilepsy: success of clinical and molecular genetic characterization
Journal name Neurology   Check publisher's open access policy
ISSN 1526-632X
Publication date 2016-02-23
Year available 2016
Sub-type Article (original research)
DOI 10.1212/WNL.0000000000002404
Open Access Status Not yet assessed
Volume 86
Issue 8
Start page 713
End page 722
Total pages 10
Place of publication Philadelphia, PA, United States
Publisher Lippincott Williams & Wilkins
Collection year 2017
Language eng
Formatted 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.
Keyword Multiplex families
Molecular genetic basis
Syndromes and inheritance patterns
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
Queensland Brain Institute Publications
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