TY - JOUR
T1 - Multiplex families with epilepsy
T2 - Success of clinical and molecular genetic characterization
AU - Afawi, Zaid
AU - Oliver, Karen L.
AU - Kivity, Sara
AU - Mazarib, Aziz
AU - Blatt, Ilan
AU - Neufeld, Miriam Y.
AU - Helbig, Katherine L.
AU - Goldberg-Stern, Hadassa
AU - Misk, Adel J.
AU - Straussberg, Rachel
AU - Walid, Simri
AU - Mahajnah, Muhammad
AU - Lerman-Sagie, Tally
AU - Ben-Zeev, Bruria
AU - Kahana, Esther
AU - Masalha, Rafik
AU - Kramer, Uri
AU - Ekstein, Dana
AU - Shorer, Zamir
AU - Wallace, Robyn H.
AU - Mangelsdorf, Marie
AU - MacPherson, James N.
AU - Carvill, Gemma L.
AU - Mefford, Heather C.
AU - Jackson, Graeme D.
AU - Scheffer, Ingrid E.
AU - Bahlo, Melanie
AU - Gecz, Jozef
AU - Heron, Sarah E.
AU - Corbett, Mark
AU - Mulley, John C.
AU - Dibbens, Leanne M.
AU - Korczyn, Amos D.
AU - Berkovic, Samuel F.
N1 - Publisher Copyright:
© 2016 American Academy of Neurology.
PY - 2016/2/23
Y1 - 2016/2/23
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84959235712&partnerID=8YFLogxK
U2 - 10.1212/WNL.0000000000002404
DO - 10.1212/WNL.0000000000002404
M3 - Article
C2 - 26802095
AN - SCOPUS:84959235712
SN - 0028-3878
VL - 86
SP - 713
EP - 722
JO - Neurology
JF - Neurology
IS - 8
ER -