Genetic background of febrile seizures.

DOI 10.1515/revneuro-2013-0053 Rev. Neurosci. 2014; 25(1): 129–161

Amene Saghazadeh, Mario Mastrangelo and Nima Rezaei*

Genetic background of febrile seizures Abstract: Febrile seizures (FSs) occur in children older than 1 month and without prior afebrile seizures in the absence of a central nervous system infection or acute electrolyte imbalance. Their pathogenesis is multifactorial. The most relevant familial studies evidence an occurrence rate ranging from 10% to 46% and median recurrence rate of 36% in children with positive familial history for FS. The main twin studies demonstrated a higher concordance rate in monozygotic twins with FS than in dizygotic ones. Linkage studies have proposed 11 chromosomal locations responsible to FS attributed to FEB1 to FEB11. Populationbased association studies have shown at least one positive association for 14 of 41 investigated genes with FS. The proinflammatory cytokine interleukin 1β (IL-1β) was the most investigated and also gene associated with susceptibility to FS. A possible role in the overlapping of epilepsy and FS was found for 16 of 36 investigated genes. SCN1A, IL-1β, CHRNA4, and GABRG2 were the most commonly involved genes in this context. The genetic background of FS involves the regulation of different processes, including individual and familial susceptibility, modulation of immune response, and neuronal excitability and interactions with exogenous agents such as viruses. Keywords: central nervous system; febrile seizures; genetics. *Corresponding author: Nima Rezaei, Molecular Immunology Research Center and Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran, e-mail: [email protected]; Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children’s Medical Center, Tehran University of Medical Sciences, Dr. Qarib St, Tehran 14194, Iran; and Department of Infection and Immunity, School of Medicine and Biomedical Sciences, The University of Sheffield, Sheffield, UK Amene Saghazadeh: Molecular Immunology Research Center and Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran Mario Mastrangelo: Pediatric Neurology Division, Department of Pediatrics, Child Neurology and Psychiatry, ‘Sapienza-University of Rome’, Rome, Italy

Introduction Febrile seizures (FSs) are defined as seizures ‘in association with a febrile illness in the absence of a central nervous system infection or acute electrolyte imbalance in children

older than 1 month of age without prior afebrile seizures’ (Guidelines for Epidemiologic Studies on Epilepsy, 1993). They are the most frequent epileptic manifestation in early infancy, affecting an estimated 2–5% of children, and occur between 3 months and 5 years of age, with a peak of incidence at 18 months and a prevalence of about 3–7% in children up to 7 years (Fetveit, 2008; Cross, 2012; Sfaihi et al., 2012). A history of FS during the pediatric years has been reported in 6–15% of all epileptic patients, with a higher risk of developing epilepsy being observed in those younger than 14 years and in subjects with previous complex FS (with focal semiology, lasting T 315C > T 588T > C C588T rs209348 – rs209353 – rs211037 – –Allele C rs211029 – rs766349 – rs989694 – Position 3145 in intron G- > A, A/A, A/G, G/G and alleles A, G rs211014 allele A –Gen. AA Intron 2 allele I Allele RN2 1/1 –

–Allele A rs3812718

SNP2305748 SNP2298771 alleles and gen. rs3812718

Variant

Yes Yes Yes Yes Yes Yes

Yes Yes No No No No No No No No No No Yes No No Yes No No No No

No (no carrier) Yes No Yes No No No Yes

Yes No

No No Yes

Association/sig. difference

Southern China Southern China Taiwanese Turkish Turkish Taiwanese

Taiwanese Taiwanese Austrian/Austrian and German Austrian West European Caucasian (Switzerland) Taiwanese Taiwanese Caucasian (Australia) Taiwanese Caucasian (Australia) Caucasian (Australia) Caucasian (Australia) Egyptian Taiwanese Taiwanese Japanese Japanese Japanese Indian London Ireland London Ireland London Ireland Korean London Ireland London Ireland London Ireland Taiwanese

Population

104/83 104/83 104/143 72/106 72/106 51/83

102/80 102/80 49/93 102/80 49/93 49/93 49/93 100/120 104/83 104/83 94/106 94/106 94/106 41/100 91/364 82/284 91/364 82/284 91/364 82/284 66/94 91/364 82/284 91/364 82/284 91/364 82/284 104/83

89 trios 102/199

104/83 104/83 55/701

No. of subjects

FS FS FS FS FS FS

FS FS FS FS FS FS FS FS FS FS FS FS FS FS FS FS FS FS FS FS

FS FS FS FS Simple FS Simple FS Simple FS Simple FS

FS FS

FS FS FS

Syndrome

Xiumin et al. (2007) Xiumin et al. (2007) Chou et al. (2010) Serdaroğlu et al. (2009) Serdaroğlu et al. (2009) Tsai et al. (2002b)

Chou et al. (2003b) Chou et al. (2003b) Nakayama et al. (2003b) Nakayama et al. (2003b) Nakayama et al. (2003b) Ponnala et al. (2012) Kinirons et al. (2006) Kinirons et al. (2006) Kinirons et al. (2006) Kinirons et al. (2006) Kinirons et al. (2006) Kinirons et al. (2006) Cho et al. (2005) Kinirons et al. (2006) Kinirons et al. (2006) Kinirons et al. (2006) Kinirons et al. (2006) Kinirons et al. (2006) Kinirons et al. (2006) Chou et al. (2003b)

Chou et al. (2003a) Chou et al. (2003a) Mulley et al. (2004) Chou et al. (2003a) Mulley et al. (2004) Mulley et al. (2004) Mulley et al. (2004) Salam et al. (2012)

Schlachter et al. (2009) Le Gal et al. (2011)

Chou et al. (2003c) Chou et al. (2003c) Schlachter et al. (2009)

Reference

138 A. Saghazadeh et al.: Genetics of febrile seizures

IL-10

IL-8

IL-6 promoter

Gene (alias)

Chr. location

(Table 2 Continued)

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Haplotype 3 –/–

–174 –572 Position: 2767 -251 A/T (rs4073) Gen./alleles – – Position: 627 592A/C (rs1800872) gen. – – Haplotype 1 in order: 1082A/G(rs1800896), 819T/C(rs1800871), 592A/C(rs1800872) ACC/ACC Haplotype 2 ACC/–

– 1/2 – – 2/2 1/4 F (allele 1) F (allele 2) Alleles and genotypes Position: 572 -572 C/G (rs1800796) gen./alleles – – –572 GG gen. –174 GG gen. and G allele –597 –597 GG gen.

Variant

Yes No No No No No No No No No No Yes Yes No

No No No Yes

No No No No

No No Yes Yes No Yes

No No Yes No No No Yes Yes No No No


– – – – – – – – – – – – – –

– – Taiwanese Northern area of Japan

Turkish Turkish Taiwanese Northern area of Japan

– Turkish Turkish Turkish Turkish

Japanese Turkish Taiwanese Japanese Turkish Japanese Taiwanese Taiwanese Turkish Taiwanese Northern area of Japan

Population

NM NM 104/143 249/225 186/225 63/225 104/143 249/225 186/225 63/225 249/225 186/225 63/225 249/225 186/225 63/225 249/225 186/225 63/225 249/225 186/225 63/225

27/18 72/106 51/83 27/18 72/106 27/18 51/83 51/83 73/152 104/143 249/225 186/225 63/225 77/85 90/93 71/88 NM

No. of subjects Complex FS FS FS FS Simple FS/ complex FS – FS FS Simple FS Complex FS FS FS Simple FS Complex FS FS Simple FS Complex FS FS Simple FS Complex FS FS Simple FS Complex FS FS Simple FS Complex FS

FS FS FS FS FS FS FS FS FS FS FS Simple FS

Syndrome

Ishizaki et al. (2009) Ishizaki et al. (2009) Ishizaki et al. (2009) Ishizaki et al. (2009) Ishizaki et al. (2009) Ishizaki et al. (2009) Ishizaki et al. (2009) Ishizaki et al. (2009) Ishizaki et al. (2009) Ishizaki et al. (2009) Ishizaki et al. (2009)

Ishizaki et al. (2009) Ishizaki et al. (2009)

Ishizaki et al. (2009) Ishizaki et al. (2009) Chou et al. (2010) Ishizaki et al. (2009)

Nur et al. (2012a) Nur et al. (2012a) Chou et al. (2010) Ishizaki et al. (2009)

Ishizaki et al. (2009) Nur et al. (2012a) Nur et al. (2012a) Nur et al. (2012a) Nur et al. (2012a)

Matsuo et al. (2006) Serdaroğlu et al. (2009) Tsai et al. (2002b) Matsuo et al. (2006) Serdaroğlu et al. (2009) Matsuo et al. (2006) Tsai et al. (2002b) Tsai et al. (2002b) Haspolat et al. (2005) Chou et al. (2010) Ishizaki et al. (2009) Ishizaki et al. (2009)

Reference

A. Saghazadeh et al.: Genetics of febrile seizures 139

IL-1β

TNF-α promoter

Gene (alias)

2q24

Chr. location

(Table 2 Continued)

Position: 850 – -1037 T/C (rs1799724) gen./ alleles – – Position: 511 – – -31C/T-511C/T (31TT-511CC) – – – -31C/T-511C/T (31CT-511CT) – – – -31C/T-511C/T (31CC-511TT) – – – -511 C/T (rs16944) – – – -511 polymorphism -511 gen. 1.1 -511 gen. 1.2 -511 gen. 2.2 -511 allele 1 -511 allele 2 -511 carrier of allele 2 -511 noncarrier of allele 2 -511 CC -511 CT -511 TT

-1082 gen. -1082 G allele -1082 Position: 308 – –

Variant

No No No No No No No No No No No No No No No Yes No Yes No No No No No No No No Yes Yes No No No Yes

No No No

No Yes Yes No No No


– – Taiwanese Taiwanese Japanese Japanese Japanese Japanese Japanese Japanese Japanese Japanese Japanese Japanese Japanese Japanese Japanese Japanese Japanese Japanese Japanese German Finish Finish Finish Finish Finish Finish Finish Turkish Turkish Turkish

Iranian Iranian Northern area of Japan

Turkish Turkish Chinese Taiwanese Iranian Iranian

Population

186/225 63/225 104/83 54/83 27/18 219/158 60/158 108/158 61/158 219/158 60/158 108/158 61/158 219/158 60/158 108/158 61/158 118/225 249/225 186/225 63/225 99/126 35/400 35/400 35/400 35/400 35/400 35/400 35/400 90/106 90/106 90/106

85/15 100/130 249/225

90/127 90/127 60/40 104/143 100/130 85/15

No. of subjects

Simple FS Complex FS FS FS FS FS Familial FS Sporadic FS Complex FS FS Familial FS Sporadic FS Complex FS FS Familial FS Sporadic FS Complex FS Sporadic FS FS Simple FS Complex FS FS FS FS FS FS FS FS FS FS FS FS

FS FS FS FS FS Simple FS/ atypical FS – FS FS

Syndrome

Ishizaki et al. (2009) Ishizaki et al. (2009) Chou et al. (2010) Chou et al. (2003) Matsuo et al. (2006) Kira et al. (2005) Kira et al. (2005) Kira et al. (2005) Kira et al. (2005) Kira et al. (2005) Kira et al. (2005) Kira et al. (2005) Kira et al. (2005) Kira et al. (2005) Kira et al. (2005) Kira et al. (2005) Kira et al. (2005) Kira et al. (2010) Kira et al. (2010) Kira et al. (2010) Kira et al. (2010) Tilgen et al. (2002) Virta et al. (2002a) Virta et al. (2002a) Virta et al. (2002a) Virta et al. (2002a) Virta et al. (2002a) Virta et al. (2002a) Virta et al. (2002a) Serdaroğlu et al. (2009) Serdaroğlu et al. (2009) Serdaroğlu et al. (2009)

Khoshdel et al. (2012) Khoshdel et al. (2012) Ishizaki et al. (2009)

Nur et al. (2012) Nur et al. (2012) Gao et al. (2007) Chou et al. (2010) Khoshdel et al. (2012) Khoshdel et al. (2012)

Reference


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CSNK1G1 IL-4 intron 3

CSNK1G2

PRIP1

CX43

SLC9A3

SLC9A1

SLC4A3

CNR1

Gene (alias)

19p13.3

Chr. location

(Table 2 Continued)

-511 allele T -511 -511 gen./alleles Exon 5 Exon 5 position +3953, E1/E2, E1/ E2 and alleles E1, E2 -511 -31 -511 rs806368 (3475 C/T) – – Ala867Asp (rs635311) – – 579 C/T (rs5810) – – Arg799Cys (rs2247114) – – rs3805787 – – rs771016 – – rs770657 – – IVS2+63C > T IVS2+33C > T 837C > T IVS11+65G > Ad 2241A > Gd rs2074882 rs740423 rs2277737 rs1059684 2 SNPs Allele RP1 Allele RP2 Gen. RP1/RP1

Variant

No No No No No No No No No No No No No No No No No No No No No No No No No Yes Yes No No No Yes Yes Yes No No No No

Yes No No No No


Korean Korean Korean Japanese – – Japanese – – Japanese – – Japanese Japanese Japanese Japanese Japanese Japanese Japanese Japanese Japanese Japanese Japanese Japanese Han Chinese Han Chinese Han Chinese Han Chinese Han Chinese Han Chinese Han Chinese Han Chinese Han Chinese Northern Han Chinese Taiwanese Taiwanese Taiwanese

Turkish Turkish Turkish Taiwanese Taiwanese

Population

72/174 72/174 40/33 249/225 186/225 63/225 249/225 186/225 63/225 249/225 186/225 63/225 249/225 186/225 63/225 249/225 186/225 63/225 249/225 186/225 63/225 249/225 186/225 63/225 60/101 60/101 60/101 60/101 60/101 53/101 53/101 53/101 53/101 50/50 51/83 51/83 51/83

90/106 73/152 92/132 104/143 51/83

No. of subjects

FS FS FS FS Simple FS Complex FS FS Simple FS Complex FS FS Simple FS Complex FS FS Simple FS Complex FS FS Simple FS Complex FS FS Simple FS Complex FS FS Simple FS Complex FS FS FS FS FS FS Familial FS – – – Simple FS FS FS FS

FS FS FS FS FS

Syndrome

Chung et al. (2006) Chung et al. (2006) Yoon et al. (2008) Kira et al. (2010) Kira et al. (2010) Kira et al. (2010) Kira et al. (2010) Kira et al. (2010) Kira et al. (2010) Kira et al. (2010) Kira et al. (2010) Kira et al. (2010) Kira et al. (2010) Kira et al. (2010) Kira et al. (2010) Kira et al. (2010) Kira et al. (2010) Kira et al. (2010) Kira et al. (2010) Kira et al. (2010) Kira et al. (2010) Kira et al. (2010) Kira et al. (2010) Kira et al. (2010) Yinan et al. (2004) Yinan et al. (2004) Yinan et al. (2004) Yinan et al. (2004) Yinan et al. (2004) Ma et al. (2004) Ma et al. (2004) Ma et al. (2004) Ma et al. (2004) Yu-jie et al. (2008) Tsai et al. (2002a) Tsai et al. (2002a) Tsai et al. (2002a)

Serdaroğlu et al. (2009) Haspolat et al. (2005) Nur et al. (2012) Chou et al. (2010) Tsai et al. (2002b)

Reference



SCN2A IL-1α C3 promoter

LGI1

IMPA2

KCNQ2

BDNF

CHRNB2

Gene (alias)

19p13

18p11.2

20q13.3

1

Chr. location

(Table 2 Continued)

Gen. RP1/RP2 Gen. RP2/RP2 SNP2072659-CC SNP2072659-CG SNP2072659-GG SNP2072659-allele C SNP2072659-allele G SNP2072660-TT SNP2072660-TC SNP2072660-CC SNP2072660-allele T SNP2072660-allele C Val66Met (SNP6265) SNP6265 SNP1801508 SNP1801475 A/A –A/C –C/C –Allele A –Allele C rs28661588 rs3786282 rs12956247 rs2075825 -708G > A a -461C > Ta IVS4+28C > T IVS5-13-14ins Aa 558C > Aa rs2075825 rs11545506 IVS6+18T/C (rs1108877) IVS2-19A/G R19K -889 position HAP1 – HAP2 – HAP3 – HAP4 –

Variant

No No No No No No No No No No No No No No No (no carrier) No No No No No No No No No No No No No No Yes No No No No No No No No No No No No No

Association/sig. difference Taiwanese Taiwanese Taiwanese Taiwanese Taiwanese Taiwanese Taiwanese Taiwanese Taiwanese Taiwanese Taiwanese Taiwanese Taiwanese Korean Taiwanese Taiwanese Taiwanese Taiwanese Taiwanese Taiwanese Caucasian (USA) Caucasian (USA) Caucasian (USA) Caucasian (USA) Caucasian (USA) Caucasian (USA) Caucasian (USA) Caucasian (USA) Caucasian (USA) Chinese Chinese Japanese Japanese Japanese Turkish Switzerland Austrian Switzerland Austrian Switzerland Austrian Switzerland Austrian

Population

51/83 51/83 104/83 104/83 104/83 104/83 104/83 104/83 104/83 104/83 104/83 104/83 104/83 30/30 77/83 77/83 77/83 77/83 77/83 77/83 96/96 96/96 96/96 96/96 96/96 96/96 96/96 96/96 96/96 56/63 56/63 62 families (230)/105 93/100 73/152 97/196 148/255 97/196 148/255 97/196 148/255 97/196 148/255

No. of subjects FS FS FS FS FS FS FS FS FS FS FS FS FS FS FS FS FS FS FS FS FS FS FS FS FS FS FS FS FS FS FS FS FS FS FS FS FS FS FS FS FS FS FS

Syndrome

Tsai et al. (2002a) Tsai et al. (2002a) Peng et al. (2004) Peng et al. (2004) Peng et al. (2004) Peng et al. (2004) Peng et al. (2004) Peng et al. (2004) Peng et al. (2004) Peng et al. (2004) Peng et al. (2004) Peng et al. (2004) Chou et al. (2004) Kim et al. (2008) Chou et al. (2002) Chou et al. (2002) Chou et al. (2002) Chou et al. (2002) Chou et al. (2002) Chou et al. (2002) Blair et al. (2007) Blair et al. (2007) Blair et al. (2007) Blair et al. (2007) Blair et al. (2007) Blair et al. (2007) Blair et al. (2007) Blair et al. (2007) Blair et al. (2007) Zhao et al. (2010) Zhao et al. (2010) Nakayama et al. (2003a) Nakayama et al. (2003a) Nakayama et al. (2002) Haspolat et al. (2005) Jamali et al. (2010) Jamali et al. (2010) Jamali et al. (2010) Jamali et al. (2010) Jamali et al. (2010) Jamali et al. (2010) Jamali et al. (2010) Jamali et al. (2010)

Reference


Toll-like receptor 3 TRIF NPY MDR1 HCN2 GPX4 NRTN CAPS APOE rs3775291 rs11466719 5671 C/T gen./alleles C3435T delPPP allele frequency 4 SNPs 3 SNPs 1 SNP 1 SNP –

HAP5 – GF100472 allele (CA)11

Variant

No No No No Yes No No No No No

Protective No A trend (24% vs. 30%) Yes Yes


Austrian Austrian and Switzerland/ Austrian and Switzerland Japanese Japanese Taiwanese Indian Australian Han Chinese Han Chinese Han Chinese Han Chinese Turkey

Switzerland Austrian Switzerland

Population

27/18 27/18 56/55 41/100 NM 60/101 60/101 60/101 60/101 69/75

148/255 245/451

97/196 148/255 97/196

No. of subjects

FS FS FS FS FS Simple FS Simple FS Simple FS Simple FS FS

FS FS

FS FS FS

Syndrome

Matsuo et al. (2006) Matsuo et al. (2006) Lin et al. (2007) Ponnala et al. (2012) Dibbens et al. (2010) Yinan et al. (2006) Yinan et al. (2006) Yinan et al. (2006) Yinan et al. (2006) Giray et al. (2008)

Jamali et al. (2010) Jamali et al. (2010)

Jamali et al. (2010) Jamali et al. (2010) Jamali et al. (2010)

Reference


R19K rs3943809 gen. rs1680331 gen. rs12614399 Exon 7-21 C > T delPPP -511 -31 SNP211037 SNP6265

Variant No Yes Yes Yes No Yes No No No No

Association

Japanese White Caucasian (London) White Caucasian (London) White Caucasian (London) Han Chinese Australian Korean Korean Korean Korean

Population

35/100 25/291 23/281 25/186 155/135 NM 23/174 23/174 20/94 19/30

No. of subjects

Afebrile seizures including GEFS+ IGEFS+ IGEFS+ IGEFS+ GEFS+ GEFS+ GEFS+ GEFS+ GEFS+ GEFS+

Syndrome

Nakayama et al. (2002) Makoff et al. (2010) Makoff et al. (2010) Makoff et al. (2010) Gao et al. (2010) Dibbens et al. (2010) Chung et al. (2006) Chung et al. (2006) Cho et al. (2005) Kim et al. (2008)

Reference

GABRG2, γ-aminobutyric acid A (GABA) receptor, γ 2; GEFS+, generalized epilepsy with FS plus; gen., genotype; IGEFS+, idiopathic generalized epilepsy with febrile seizures; NM, not mentioned; SNP, single nucleotide polymorphism.

SCN2A SCN1A HCN2 IL-1β GABRG2 BDNF

Gene

Table 3 PBASs on patients with idiopathic epilepsy and history of FS (IEFS+).

Chr. location, chromosomal location; CNR1, cannabinoid receptor 1 (brain); CX43, connexin 43; GABRG2, γ-aminobutyric acid A receptor, γ 2; gen., genotype; GPX4, glutathione peroxidase 4; HAP, haplotype; IMPA2, inositol(myo)-1(or 4)-monophosphatase 2; KCNQ2, potassium voltage-gated channel, KQT-like subfamily, member 2; MDR1, ATP-binding cassette, subfamily B (MDR/TAP), member 1; NM, not mentioned; NPY, neuropeptide Y; NRTN, neurturin; PRIP1, phospholipase C-like 1; Sig. difference, significant difference; SLC4A3, solute carrier family 4 anion exchanger, member 3; SLC9A1, solute carrier family 9, subfamily A (NHE1, cation proton antiporter 1), member 1; SLC9A3, solute carrier family 9, subfamily A (NHE3, cation proton antiporter 3), member 3; SNP, single nucleotide polymorphism; TRIF, toll-like receptor adaptor molecule 1.

Chr. location

Gene (alias)

(Table 2 Continued)


GABRG2

Gene (alias)

5q33

Chr. location

Intronic polymorphisms-AA Intronic polymorphisms-GG Intronic polymorphisms-AG Intronic polymorphisms-allele A Intronic polymorphisms-allele G SNP211037-CC SNP211037-TC SNP211037-TT SNP211037-allele C SNP211037-allele T Exon 5 C588T T/T, T/C, C/C, alleles T and C Exon 3 allele A Exon 5 allele C rs209348 – – – – – – – – – rs209353 – – – – – – – – – rs211037 – – – – – – – –

Variant

Table 4 A series of PBASs of epilepsy.

No No No No No No No No No No No No No No No No No No No No No No No No No Yes No No No No No

No No No No No Yes No No Yes No No

Association

Chinese Chinese London London London London London Ireland Ireland Ireland Ireland Ireland London London London London London Ireland Ireland Ireland Ireland Ireland London London London London London Ireland Ireland Ireland Ireland

Taiwanese Taiwanese Taiwanese Taiwanese Taiwanese Taiwanese Taiwanese Taiwanese Taiwanese Taiwanese German

Population

68/internal controls 68/internal controls 677/372 99/372 103/372 145/372 201/372 684/284 121/284 109/284 256/284 223/284 677/372 99/372 103/372 145/372 201/372 684/284 121/284 109/284 256/284 223/284 677/372 99/372 103/372 145/372 201/372 684/284 121/284 109/284 256/284

77/83 77/83 77/83 77/83 77/83 77/83 77/83 77/83 77/83 77/83 135/154

No. of subjects

CAE CAE Epilepsy IGE SLK-HS SLK-non-HS SLU Epilepsy IGE SLK-HS SLK-non-HS SLU Epilepsy IGE SLK-HS SLK-non-HS SLU Epilepsy IGE SLK-HS SLK-non-HS SLU Epilepsy IGE SLK-HS SLK-non-HS SLU Epilepsy IGE SLK-HS SLK-non-HS

IGE IGE IGE IGE IGE IGE IGE IGE IGE IGE IAE

Syndrome

Lu et al. (2002) Lu et al. (2002) Kinirons et al. (2006) Kinirons et al. (2006) Kinirons et al. (2006) Kinirons et al. (2006) Kinirons et al. (2006) Kinirons et al. (2006) Kinirons et al. (2006) Kinirons et al. (2006) Kinirons et al. (2006) Kinirons et al. (2006) Kinirons et al. (2006) Kinirons et al. (2006) Kinirons et al. (2006) Kinirons et al. (2006) Kinirons et al. (2006) Kinirons et al. (2006) Kinirons et al. (2006) Kinirons et al. (2006) Kinirons et al. (2006) Kinirons et al. (2006) Kinirons et al. (2006) Kinirons et al. (2006) Kinirons et al. (2006) Kinirons et al. (2006) Kinirons et al. (2006) Kinirons et al. (2006) Kinirons et al. (2006) Kinirons et al. (2006) Kinirons et al. (2006)

Chou et al. (2007) Chou et al. (2007) Chou et al. (2007) Chou et al. (2007) Chou et al. (2007) Chou et al. (2007) Chou et al. (2007) Chou et al. (2007) Chou et al. (2007) Chou et al. (2007) Kananura et al. (2002)

Ref.



Chr. location

20q13.3 20q13.3

KCNQ2 CHRNA4

Gene (alias)

(Table 4 Continued)

– – – – rs211029 – – – – – – – – – rs766349 – – – – – – – – – rs989694 – – – – – – – – – C315T exon 3 C588T exon 5 1187+2T/G rs1801545 – – Ser252Leu Ser252Leu Ser543Ser

Variant

No No No No No No Yes No No No No No No No No No Yes No No No No No No No No No No Yes No No No No No No No No Yes Yes Yes No Yes Yes Yes

Association Ireland Brazilian North India Korean London London London London London Ireland Ireland Ireland Ireland Ireland London London London London London Ireland Ireland Ireland Ireland Ireland London London London London London Ireland Ireland Ireland Ireland Ireland Korean Korean Scottish German German German Korean Japanese Taiwanese

Population

223/284 98/130 395/199 23/94 677/372 99/372 103/372 145/372 201/372 684/284 121/284 109/284 256/284 223/284 677/372 99/372 103/372 145/372 201/372 684/284 121/284 109/284 256/284 223/284 677/372 99/372 103/372 145/372 201/372 684/284 121/284 109/284 256/284 223/284 35/207 35/207 A family/72 583/457 234/457 265/457 A kindred/8 A family/100 75/80

No. of subjects SLU JME Epilepsy IGE Epilepsy IGE SLK-HS SLK-non-HS SLU Epilepsy IGE SLK-HS SLK-non-HS SLU Epilepsy IGE SLK-HS SLK-non-HS SLU Epilepsy IGE SLK-HS SLK-non-HS SLU Epilepsy IGE SLK-HS SLK-non-HS SLU Epilepsy IGE SLK-HS SLK-non-HS SLU CAE CAE BFNC IGE JME IAE ADNFLE ADNFLE IGE

Syndrome

Kinirons et al. (2006) Gitaí et al. (2012) Kumari et al. (2010) Yeon et al. (2007) Kinirons et al. (2006) Kinirons et al. (2006) Kinirons et al. (2006) Kinirons et al. (2006) Kinirons et al. (2006) Kinirons et al. (2006) Kinirons et al. (2006) Kinirons et al. (2006) Kinirons et al. (2006) Kinirons et al. (2006) Kinirons et al. (2006) Kinirons et al. (2006) Kinirons et al. (2006) Kinirons et al. (2006) Kinirons et al. (2006) Kinirons et al. (2006) Kinirons et al. (2006) Kinirons et al. (2006) Kinirons et al. (2006) Kinirons et al. (2006) Kinirons et al. (2006) Kinirons et al. (2006) Kinirons et al. (2006) Kinirons et al. (2006) Kinirons et al. (2006) Kinirons et al. (2006) Kinirons et al. (2006) Kinirons et al. (2006) Kinirons et al. (2006) Kinirons et al. (2006) Kim et al. (2012) Kim et al. (2012) Lee et al. (2000) Neubauer et al. (2008) Neubauer et al. (2008) Neubauer et al. (2008) Cho et al. (2003) Hirose et al. (1999) Lee et al. (2007)

Ref.



Gene (alias)

Chr. location

(Table 4 Continued)

SNP1044396 Ser252Phe T265I c.555C > T CC, CT, TT, alleles C, T c.594C > T CC, CT, TT, alleles C, T 1674+14C > T AA, AG, GG, alleles A, G 1674+11C > T F(T) –TT –CT –CC Ser248Phe Ser248Phe HaeIIIbp 145–S5, allele A – – –Allele G – – CfoI bp594 allele T – – – –Allele C – – – CfoI bp1545 allele T – – – –Allele C – – – StyIbp 1674+14 allele A – – – –Allele G – – – Three FokI polymorphisms

Variant

Yes Yes No No No Yes Yes No No No No No No No No No No Yes No Yes No No No No No No No No No No No No No No No No No No No No No No

Association Spanish German Polish Polish Polish Polish Polish Polish Polish German Kuwaiti Arab German German German German German German German German German Caucasian (London) German German German Caucasian German German German Caucasian German German German Caucasian German German German Caucasian German German German Caucasian Kuwaiti Arab

Population

A family A family/193 92/137 92/137 92/137 184/444 92/222 92/222 92/222 103/92 123/100 97/88 58/88 48/88 97/88 58/88 48/88 94/92 55/92 47/92 182/178 94/92 55/92 47/92 182/178 97/81 60/81 45/81 182/178 97/81 60/81 45/81 182/178 98/94 59/94 48/94 182/178 98/94 59/94 48/94 182/178 123/100

No. of subjects ADNFLE NFLE JME JME JME JME JME JME JME IGE IGE IGE JME IAE IGE JME IAE IGE JME IAE IGE IGE JME IAE IGE IGE JME IAE IGE IGE JME IAE IGE IGE JME IAE IGE IGE JME IAE IGE IGE

Syndrome

Sáenz et al. (1999) Leniger et al. (2003) Rozycka et al. (2009) Rozycka et al. (2009) Rozycka et al. (2009) Rozycka et al. (2009) Rozycka et al. (2009) Rozycka et al. (2009) Rozycka et al. (2009) Steinlein et al. (1997) Haider et al. (2005) Steinlein et al. (1997) Steinlein et al. (1997) Steinlein et al. (1997) Steinlein et al. (1997) Steinlein et al. (1997) Steinlein et al. (1997) Steinlein et al. (1997) Steinlein et al. (1997) Steinlein et al. (1997) Chioza et al. (2000) Steinlein et al. (1997) Steinlein et al. (1997) Steinlein et al. (1997) Chioza et al. (2000) Steinlein et al. (1997) Steinlein et al. (1997) Steinlein et al. (1997) Chioza et al. (2000) Steinlein et al. (1997) Steinlein et al. (1997) Steinlein et al. (1997) Chioza et al. (2000) Steinlein et al. (1997) Steinlein et al. (1997) Steinlein et al. (1997) Chioza et al. (2000) Steinlein et al. (1997) Steinlein et al. (1997) Steinlein et al. (1997) Chioza et al. (2000) Haider et al. (2005)

Ref.



Gene (alias)

SCN1A

2q24

Chr. location

(Table 4 Continued)

Intron 2 384_20 G/C Intron 6 965_21 T/C Exon 8 1131 A/C Intron 8 1171_9,10 TT/DTT Exon 9 1212 G/A Exon 10 1625 (R542Q) G/A Exon 11 1811 (R604H) G/A Exon 12 2095 (V699I) G/A Exon 13 2292 C/T Intron 13 2416_37 C/A Exon 16 3199 (T1067A) A/G Exon 16 3241 (G1081R) G/A Exon 17 3481 (A1161T) G/A Exon 17 3521 (T1174S) C/G Intron 23 4476_33 G/A Exon 25 4731 T/C Exon 26 5418 G/A c.1162T > C;p.Y388H Thr1067Ala (rs2298771) AG –AA and GG and alleles A and G rs3812718 – rs1020853 (IVS5N+5 G > A) rs2298771 – – rs10188577 – – rs4667866 – – rs13405797 – – rs1461197 – – rs2169312 – –

Exon 18 3610 (W1204R) T/C

Variant

Yes Significant No No No No Yes No No No No No Yes No Yes No No No Yes Yes No No No No No Yes (allele A) No No No No No Yes (allele C) No No No No No No No No No

Yes

Association

German German German German German German German German German German German German German German German German German German Newfoundland North India North India Han Chinese H. Chinese H. Chinese H. Chinese H. Chinese H. Chinese H. Chinese H. Chinese H. Chinese H. Chinese H. Chinese H. Chinese H. Chinese H. Chinese H. Chinese H. Chinese H. Chinese H. Chinese H. Chinese H. Chinese

German

Population

Four generations Pedigree/236 226/268 226/185 226/96 226/194 226/96 226/96 A RR, RK, KK and alleles R and K D2S111 D2S124 R19K IVS7-A32G Exon 2 c.858T > C C/C, C/T, T/T, f(C) Exon 4 c.1239G > C G/G, G/C, C/C, f(G) – – – Exon 5 c.1584+7C > T T/T, T/C, C/C, f(T) – – – Intron 6 c.1825+22_1825+42del21 171/171, 171/192, 192/192, f(171) – – Intron 7 c.1990+24_1990+57dup34 200/200, 200/234, 234/234, f(200) – – rs10408159 T/T, T/C, C/C, f(T) – – – rs4919872 T/T, T/C, C/C, f(T) –

C1419G

Variant

No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No

No No No No No No No No No No

No

Association

Italian Italian Korean Korean German German German German German German German German German German German German German German German German German German German German German German German German German German

Caucasian (London) Caucasian Caucasian German German German German German German German North India

Population

NM NM 162/391 162/391 450/455 122/455 196/455 193/455 393/275 96/275 163/275 175/274 452/459 122/459 197/459 193/459 453/460 124/460 197/460 195/460 456/460 124/460 198/460 196/460 393/275 95/275 163/275 175/275 383/275 93/275

180/193 187/198 115/109 71/109 44/109 172/182 172/182 172/182 172/182 336/160

177/192

No. of subjects

IGE with tonic-clonic seizures IGE with tonic-clonic seizures Epilepsy Epilepsy IGE CAE IAE JME IGE CAE IAE JME IGE CAE IAE JME IGE CAE IAE JME IGE CAE IAE JME IGE CAE IAE JME IGE CAE

IGE IGE IGE JME IAE IGE IGE IGE IGE Sporadic epilepsy

IGE

Syndrome

Volzone et al. (2007) Volzone et al. (2007) Yoon et al. (2012) Yoon et al. (2012) Tang et al. (2008) Tang et al. (2008) Tang et al. (2008) Tang et al. (2008) Tang et al. (2008) Tang et al. (2008) Tang et al. (2008) Tang et al. (2008) Tang et al. (2008) Tang et al. (2008) Tang et al. (2008) Tang et al. (2008) Tang et al. (2008) Tang et al. (2008) Tang et al. (2008) Tang et al. (2008) Tang et al. (2008) Tang et al. (2008) Tang et al. (2008) Tang et al. (2008) Tang et al. (2008) Tang et al. (2008) Tang et al. (2008) Tang et al. (2008) Tang et al. (2008) Tang et al. (2008)

Chioza et al. (2002) Chioza et al. (2002) Steinlein et al. (1999) Steinlein et al. (1999) Steinlein et al. (1999) Haug et al. (2001) Haug et al. (2001) Haug et al. (2001) Haug et al. (2001) Lakhan et al. (2009)

Chioza et al. (2002)

Ref.



CHRNB2 SCN1B IL-1α IL-1Ra APOE

-491A/T -ε4 allele –

– – delPPP SNP2072659 Exon 3 C121W mutation -889 – – –Allele T

Variant

No No No No No No No No Yes No No No Yes No

Association German German Australian Taiwanese Kuwaiti Arab Turkish Japanese Japanese Chinese Japanese Japanese Han Chinese Han Chinese UK

Population

159/275 169/275 NM 77/83 123/100 47/99 50/112 53/112 117/95 50/112 53/112 558/735 558/560 752/384

No. of subjects IAE JME IGE IGE IGE MTLE-HS TLE-HS+ TLE-HSEpilepsy TLE-HS+ TLE-HSEpilepsy TLE Epilepsy

Syndrome

Tang et al. (2008) Tang et al. (2008) Dibbens et al. (2010) Lee et al. (2007) Haider et al. (2005) Ozkara et al. (2006) Kanemoto et al. (2000) Kanemoto et al. (2000) Lu et al. (2009) Kanemoto et al. (2000) Kanemoto et al. (2000) Fu et al. (2010) Fu et al. (2010) Cavalleri et al. (2005)

Ref.


A trend (43% vs. 35%) A trend (21% vs. 12%) No A trend (70% vs. 45.4%) No No No No No No

Association German German Japanese Korean Han Chinese Taiwanese Taiwanese Taiwanese Han Chinese Han Chinese

Population

43/126 43/126 68/225 20/33 60/101 18/38 18/38 18/38 54/90 54/90

No. of subjects

0.25 0.33 0.29 NM 0.652 0.719 0.718 NM NM

p-Value

FS FS Simple FS Simple FS FS FS+FH/FS-FH – Familial FS Familial FS

Syndrome

Tilgen et al. (2002) Tilgen et al. (2002) Kira et al. (2010) Yoon et al. (2008) Ma et al. (2005b) Lin et al. (2007) Lin et al. (2007) Lin et al. (2007) Sun et al. (2005) Sun et al. (2005)

Reference

FS+FH, patients with FS and positive familial history; FS-FH, FS without familial history; gen., genotype; NM, not mentioned; NPY, neuropeptide Y.

-511 allele 2 -511 gen. 2/2 -511 C/T(rs16944) -511 CT 9 polymorphisms -5671 C/T –TC –Allele T rs7249419 rs11437855

IL-1β HCN2 NPY CAPS

Variant

Gene

Table 5 PBASs on patients with FS and familial history.

ADNFLE, autosomal dominant nocturnal frontal lobe epilepsy; BFNC, benign familial neonatal convulsion; Chr. location, chromosomal location; CHRNB2, cholinergic receptor nicotinic β polypeptide 2 (neuronal); EFS+, epilepsy with history of FSs; EFS-, epilepsy without history of FSs; GABRG2, γ-aminobutyric acid A receptor, γ 2; GEFS+, generalized epilepsy with FS plus; H. Chinese, Han Chinese; HS, hippocampal sclerosis; IAE, idiopathic absence epilepsy; IGE, idiopathic generalized epilepsy; IPEAF, idiopathic partial epilepsy with auditory features; JME, juvenile myoclonic epilepsy; KCNQ2, potassium voltage-gated channel, KQT-like subfamily, member 2; MTLE, mesial TLE; MTS, mesial temporal sclerosis; NFLE, nocturnal frontal lobe epilepsy; NM, not mentioned; PE, partial epilepsy; SLK, symptomatic localization-related cause known; SLU, symptomatic localization-related cause unknown; SNP, single nucleotide polymorphism.

Chr. location

Gene (alias)

(Table 4 Continued)


SCN1A

GABBR1

IL-1α C3 promoter

IL-1β

Gene

19p13

2q14

2q21–q34

Chr. location

rs3812718 -511 –Allele T –Allele T -511 -3953 -889 GF100472 Gen. –Alleles rs339392 Alleles Gen. rs2230199 Alleles Gen. rs428453 Alleles Gen. rs344550 Alleles Gen. rs379527 Alleles Gen. HAP1 – HAP2 – HAP3 – HAP4 – HAP5 – G1465A

Variant

Table 6 PBASs on patients with TLE and history of FS (TLEFS+).

Brought to you by | Harvard University Authenticated | 128.103.149.52 Download Date | 6/11/14 6:45 AM No No Yes No Yes No Protective No Protective Protective No No No

No No

No No

No No

No No

Yes

No Yes Yes Yes No Yes No No No No No


South Indian South Indian South Indian South Indian German Japanese Japanese Turkish Turkish Turkish France/Switzerland – – – – – – – – – – – – Austrian France/Switzerland Austrian France/Switzerland Austrian France/Switzerland Austrian France/Switzerland Austrian Caucasian (USA)

Population 138/65 203/282 138/282 65/282 43/126 35/163 31/163 28/19 28/19 28/19 57/196 57/196 57/196 57/196 57/196 57/196 57/196 57/196 57/196 57/196 57/196 57/196 57/196 46/255 57/196 46/255 57/196 46/255 57/196 46/255 57/196 46/255 120/118

No. of subjects

MTLE MTLE MTLE MTLE MTLE MTLE MTLE MTLE MTLE MTLE MTLE MTLE NL-TLE

MTLE MTLE

MTLE MTLE

MTLE MTLE

MTLE MTLE

MTLE

MTLE-HS-FS+/MTLE-HS-FSMTLE-HS/healthy MTLE-HS-FS+/healthy MTLE-HS-FS-/healthy NM-TLE TLE+HS+PFC TLE+HS-PFC MTLE-HS-FS+/MTLE-HS-FSMTLE-HS-FS+/MTLE-HS-FSMTLE-HS-FS+/MTLE-HS-FSMTLE

Syndrome

0.8300 0.0001 0.0010 0.0060 0.0016 0.15 0.66 0.47 0.67 0.128 0.036 0.752 0.856 0.971 0.927 0.778 0.722 0.53 0.582 0.474 0.126 0.005 0.458 0.007 0.379 0.003 0.998 0.0003 0.00008 0.102 0.03 0.988

p-Value

Jamali et al. (2010) Jamali et al. (2010) Jamali et al. (2010) Jamali et al. (2010) Jamali et al. (2010) Jamali et al. (2010) Jamali et al. (2010) Jamali et al. (2010) Jamali et al. (2010) Jamali et al. (2010) Jamali et al. (2010) Jamali et al. (2010) Ma et al. (2005a)





Jamali et al. (2010)

Balan et al. (2012) Balan et al. (2012) Balan et al. (2012) Balan et al. (2012) Tilgen et al. (2002) Kanemoto et al. (2003b) Kanemoto et al. (2003b) Ozkara et al. (2006) Ozkara et al. (2006) Ozkara et al. (2006) Jamali et al. (2010)

Reference


KCNJ10

MMP-9

Gene

(Table 6 Continued)

1

20

Chr. location

rs3918279 rs1805088 rs41427445 rs6017724 rs3918253 rs55789927 rs2274755 rs17576 rs2236416 rs6104427 rs2274756 rs3918261 rs3918262 rs3918282 rs13925 rsrs20544 rs9509 rs17375748 Allele T rs1186685 Allele C rs4656873 Allele T rs1186679 Allele A rs1890532 Allele C rs946420 Allele T rs2820585 Allele T rs1053074 rs2486253 rs1130183 rs12729701 rs2820553 rs12402969 rs1186689

Variant

Brought to you by | Harvard University Authenticated | 128.103.149.52 Download Date | 6/11/14 6:45 AM No No No No No No No

Yes

Yes

Yes

Yes

Yes

Yes

No No No No No No No No No No No No No No No No No No Yes


Caucasian (USA) Norwegian Norwegian Norwegian Norwegian Norwegian Norwegian Norwegian Norwegian Norwegian Norwegian Norwegian Norwegian Norwegian Norwegian Norwegian Norwegian Norwegian Caucasian (Norway) Caucasian (Norway) Caucasian (Norway) Caucasian (Norway) Caucasian (Norway) Caucasian (Norway) Caucasian (Norway) Caucasian (Norway) Caucasian (Norway) Caucasian (Norway) Caucasian (Norway) Caucasian (Norway) Caucasian (Norway) Caucasian (Norway)

Population 120/100 102/105 102/105 102/105 102/105 102/105 102/105 102/105 102/105 102/105 102/105 102/105 102/105 102/105 102/105 102/105 102/105 102/105 102/105 102/105 102/105 102/105 102/105 102/105 102/105 102/105 102/105 102/105 102/105 102/105 102/105 102/105

No. of subjects

TLEFS+/TLEFSTLEFS+/TLEFSTLEFS+/TLEFSTLEFS+/TLEFSTLEFS+/TLEFSTLEFS+/TLEFSTLEFS+/TLEFS-

TLEFS+/TLEFS-

TLEFS+/TLEFS-

TLEFS+/TLEFS-

TLEFS+/TLEFS-

TLEFS+/TLEFS-

TLEFS+/TLEFS-

NL-TLE TLEFS+/TLEFSTLEFS+/TLEFSTLEFS+/TLEFSTLEFS+/TLEFSTLEFS+/TLEFSTLEFS+/TLEFSTLEFS+/TLEFSTLEFS+/TLEFSTLEFS+/TLEFSTLEFS+/TLEFSTLEFS+/TLEFSTLEFS+/TLEFSTLEFS+/TLEFSTLEFS+/TLEFSTLEFS+/TLEFSTLEFS+/TLEFSTLEFS+/TLEFSTLEFS+/TLEFS-

Syndrome

0.556 0.665 0.202 0.165 0.433 0.364 0.188 0.569 0.574 0.269 0.511 0.590 0.728 0.516 0.325 0.357 0.780 0.025 0.009 0.019 0.021 0.041 0.024 0.020 0.365 0.702 0.749 0.593 0.757 0.604 0.078

p-Value

Heuser et al. (2010b) Heuser et al. (2010b) Heuser et al. (2010b) Heuser et al. (2010b) Heuser et al. (2010) Heuser et al. (2010b) Heuser et al. (2010b)

Heuser et al. (2010b)






Ma et al. (2005a) Heuser et al. (2010a) Heuser et al. (2010a) Heuser et al. (2010a) Heuser et al. (2010a) Heuser et al. (2010a) Heuser et al. (2010a) Heuser et al. (2010a) Heuser et al. (2010a) Heuser et al. (2010a) Heuser et al. (2010a) Heuser et al. (2010a) Heuser et al. (2010a) Heuser et al. (2010a) Heuser et al. (2010a) Heuser et al. (2010a) Heuser et al. (2010a) Heuser et al. (2010a) Heuser et al. (2010b)

Reference


KCNJ9 Between KCNJ10 and KCNJ9


rs12122979 rs1186688 rs11265313 rs7512587 rs6690889 rs1186675 rs6677510 rs11265317 rs2737702 rs2737703 rs2753268 rs2494211 rs4656874 Allele T rs6658419 rs7534307 rs1321650 rs1321649 rs6683605 rs6683709 rs4656875 rs749226 rs4656876 rs2180752

Variant

No No No No No No No No No No

No No No No No No No No No No No No Yes


Caucasian (Norway) Caucasian (Norway) Caucasian (Norway) Caucasian (Norway) Caucasian (Norway) Caucasian (Norway) Caucasian (Norway) Caucasian (Norway) Caucasian (Norway) Caucasian (Norway) Caucasian (Norway) Caucasian (Norway) Caucasian (Norway) Caucasian (Norway) Caucasian (Norway) Caucasian (Norway) Caucasian (Norway) Caucasian (Norway) Caucasian (Norway) Caucasian (Norway) Caucasian (Norway) Caucasian (Norway) Caucasian (Norway

Population 102/105 102/105 102/105 102/105 102/105 102/105 102/105 102/105 102/105 102/105 102/105 102/105 102/105 102/105 102/105 102/105 102/105 102/105 102/105 102/105 102/105 102/105 102/105

No. of subjects

TLEFS+/TLEFSTLEFS+/TLEFSTLEFS+/TLEFSTLEFS+/TLEFSTLEFS+/TLEFSTLEFS+/TLEFSTLEFS+/TLEFSTLEFS+/TLEFSTLEFS+/TLEFSTLEFS+/TLEFS-

TLEFS+/TLEFSTLEFS+/TLEFSTLEFS+/TLEFSTLEFS+/TLEFSTLEFS+/TLEFSTLEFS+/TLEFSTLEFS+/TLEFSTLEFS+/TLEFSTLEFS+/TLEFSTLEFS+/TLEFSTLEFS+/TLEFSTLEFS+/TLEFSTLEFS+/TLEFS-

Syndrome

0.232 0.077 0.313 0.080 0.121 0.919 0.117 0.944 0.145 0.153 0.052 0.174 0.026 0.118 0.341 0.119 0.115 0.119 0.178 0.150 0.118 0.096 0.096

p-Value

Heuser et al. (2010b) Heuser et al. (2010b) Heuser et al. (2010b) Heuser et al. (2010b) Heuser et al. (2010b) Heuser et al. (2010b) Heuser et al. (2010b) Heuser et al. (2010b) Heuser et al. (2010b) Heuser et al. (2010b)

Heuser et al. (2010b) Heuser et al. (2010b) Heuser et al. (2010b) Heuser et al. (2010b) Heuser et al. (2010b) Heuser et al. (2010b) Heuser et al. (2010b) Heuser et al. (2010b) Heuser et al. (2010b) Heuser et al. (2010b) Heuser et al. (2010b) Heuser et al. (2010b) Heuser et al. (2010b)

Reference

Chr. location, chromosomal location; GABBR1, γ-aminobutyric acid B receptor 1; gen., genotype; HAP, haplotype; HS, hippocampal sclerosis; MMP-9, matrix metalopeptidase 9; MTLE, mesial TLE; NL-TLE, nonlesional TLE; NM-TLE, nonmesial temporal lobe epilepsy; PFC, prolonged febrile convulsion; sig. difference, significant difference; TLEFS+, TLE with history of FS; TLEFS-, TLE without history of FS.

1

1

Chr. location

Gene

(Table 6 Continued)


154 A. Saghazadeh et al.: Genetics of febrile seizures Table 7 PBASs on patients with focal epilepsy and history of febrile seizures (FESFS+). Gene

Variant

SCN1A

rs3812718

Association/sig. Population difference

–

No

Austrian/Austrian and German Austrian Australian Australian Australian/European Han Chinese Han Chinese Han Chinese West European Caucasian (Switzerland) –

rs1020853 – – rs2298771 – – rs10188577 – –

No No No No No No No No Yes

Han Chinese Han Chinese Han Chinese Han Chinese Han Chinese Han Chinese Han Chinese Han Chinese Han Chinese

CHRNA4 GABRG2 IL-1β

rs4667866 – – rs13405797 – – rs1461197 – – rs2169312 – –

No No No No No No No No No No No No

Han Chinese Han Chinese Han Chinese Han Chinese Han Chinese Han Chinese Han Chinese Han Chinese Han Chinese Han Chinese Han Chinese Han Chinese

– – – –

Ser543Ser rs211037 Position -511

Yes Yes No No No No No Yes No

No No No

UK UK UK

No. of Syndrome subjects 90/701 90/486 76/482 23/124 76/701 97/631 97/848 728/848 62/199

Reference

FESFS+/healthy FESFS+/FESFS EFS+/EFS FESFS+ and FS/FESFS- EFS+/healthy FESFS+/FESFS FESFS+/healthy FESFS ± /healthy FESFS+/healthy

164/312 Pure FS+FESFS+/ healthy+FEFFS97/631 FESFS+/FESFS97/848 FESFS+/healthy 728/848 FESFS ± /healthy 97/631 FESFS+/healthy 97/848 FESFS+/FESFS728/848 FESFS+/healthy 97/631 97/848 FESFS+/FESFS728/848 FESFS+/healthy FESFS ± /healthy 97/631 FESFS ± /healthy 97/848 FESFS+/FESFS728/848 FESFS+/healthy 97/631 FESFS ± /healthy 97/848 FESFS+/FESFS728/848 FESFS+/healthy 97/631 FESFS ± /healthy 97/848 FESFS+/FESFS728/848 FESFS+/healthy 97/631 FESFS ± /healthy 97/848 FESFS+/FESFS728/848 FESFS+/healthy FESFS ± /healthy 107/384 EFS+/healthy 107/384 EFS+/healthy 107/384 EFS+/healthy

Schlachter et al. (2009) Schlachter et al. (2009) Petrovski et al. (2009) Petrovski et al. (2009) Petrovski et al. (2009) Zhang et al. (2010) Zhang et al. (2010) Zhang et al. (2010) Le Gal et al. (2011)

Le Gal et al. (2011)

Zhang et al. (2010) Zhang et al. (2010) Zhang et al. (2010) Zhang et al. (2010) Zhang et al. (2010) Zhang et al. (2010) Zhang et al. (2010) Zhang et al. (2010) Zhang et al. (2010)

Zhang et al. (2010) Zhang et al. (2010) Zhang et al. (2010) Zhang et al. (2010) Zhang et al. (2010) Zhang et al. (2010) Zhang et al. (2010) Zhang et al. (2010) Zhang et al. (2010) Zhang et al. (2010) Zhang et al. (2010) Zhang et al. (2010) Cavalleri et al. (2005) Cavalleri et al. (2005) Cavalleri et al. (2005)

EFS+, epilepsy with history of FS; EFS-, epilepsy without history of FS; FESFS+, FES with FS; FESFS-, FES without history of FS; GABRG2, γ-aminobutyric acid A receptor, γ 2; Sig. difference, significant difference.

an Asian population, while there were no positive associations for two studies on a Caucasian population (Chou et al., 2003a; Mulley et al., 2004; Cavalleri et al., 2005). Class 4 (R = 0.42) includes the SCN1A gene with an equally distributed number of investigations between Asian and Caucasian populations (Tables 2 and 3) (Chou et al., 2003c; Petrovski et al., 2009; Schlachter et al., 2009; Gao et al., 2010; Zhang et al., 2010; Le Gal et al., 2011; Balan et al., 2012). Class 5 (R = 0.50) includes the SCN2A and IMPA2 genes. They have been equally investigated in Asian and Caucasian populations, but the total number of investigations was low (Tables 2 and 3) (Nakayama et al., 2002; Blair et al., 2007; Makoff et al., 2010; Zhao et al., 2010). Class 6

(R = 0.60) includes the gene encoding for IL-1Ra. Both the investigations on this gene in Caucasian populations were restricted to Turkish populations (Table 2) (Haspolat et al., 2005; Serdaroğlu et al., 2009). Class 7 (R = 0.62) includes the GABRG2 gene. Only 25% of all the investigations on this gene were related to Caucasian populations (Table 2) (Cavalleri et al., 2005; Kinirons et al., 2006). Class 8 (R = 0.75) includes the gene encoding for IL-10. Seventy-five percent of all the investigations on this gene involved Asian populations (Table 2) (Gao et al., 2007; Ishizaki et al., 2009; Chou et al., 2010). Class 9 (R = 1.00) includes the genes encoding for complement component 3 (C3), CSNK1G2, potassium inwardly



rectifying channel, subfamily J, member 9 (KCNJ9), and a region between KCNJ9 and KCNJ10. The two investigations on the CSNK1G2 gene were both realized on Chinese populations (Table 2) (Yinan et al., 2004; Ma et al., 2004).

FSs and epilepsy A few PBASs were focused on the later occurrence of epilepsy in children with early-onset FS. Tables 2, 3, 6, and 7 summarize the results of (1) PBASs on FSs that were not followed by epilepsy or epileptic syndrome (Table 2), (2) PBASs on focal epilepsy syndrome (FES) and history of FS [FES with FS plus (FESFS+)] (Table 7), (3) PBASs on TLE and history of FS [TLE with FS plus or (TLEFS+)] (Table 6), and (4) PBASs on idiopathic epilepsy and history of FS [idiopathic epilepsy and FS plus (IEFS+)] (Table 3). Among 47 PBASs, evidences for the role of 16/36 investigated genes in the overlap between FS and epilepsy were obtained. These genes could be easily categorized into three coherent groups: (1) genes that have at least one positive association with both FS and epilepsy (SCN1A, CHRNA4, GABRG2, and IL-1β), (2) genes that have no positive associations with both FS and epilepsy [sodium channel voltage-gated type 1 β subunit (SCN1B), TNF-α, cholinergic receptor nicotinic β polypeptide 2 (CHRNB2), leucine-rich, glioma inactivated 1 (LGI1), IL-1α, SCN2A, and apolipoprotein E (APOE)], and (3) genes that have a positive association with FS alone or epilepsy alone (IL1Ra, IL-6, BDNF, HCN2, and KCNQ2). If we excluded the third group of genes, the remaining groups can be linked to FS and epilepsy, as summarized in robot-like Figure 6.

Conclusions The pathogenesis of FS is multifactorial, and it is probably based on interactions between several factors including individual and familial susceptibility, modulation of immune response, regulation of neuronal excitability, and exogenous agents such as viruses. We have discussed the actual insights into the links between these elements and FS. However, the various steps of these interactions remain largely unknown. The availability of modern molecular genetic diagnostic techniques, such as whole exome sequencing, will probably expand in the next decades of our knowledge on this topic. Although most of the FSs are self-limiting, the definition of the basis of genetic predisposition for the development of recurrent FS with poor prognosis, febrile status epilepticus, or epileptic syndromes following infantile FS will represent an

Investigated genes of population -based association studies of FS SCN1B, SCN1A, CHRNA4, GABRG2, IL -1Ra, IL -6, IL -8, IL -10, TNF -alpha, IL -1β, CNR1, SLC4A3, SLC9A1, SLC9A3, CX43, PRIP1, CSNK1G1, CSNK1G2, IL -4, CHRNB2, BDNF, IL -1α, C3, Toll -like-receptor3, TRIF, NPY, KCNQ2, IMPA2, LGI1, SCN2A, HCN2, MDR1, GPX4, CAPS, NRTN, AND APOE

Similar investigated genes between population-based association studies of FS and epilepsy SCN1B, SCN1A, CHRNA4, GABRG2, IL -1Ra, IL -6, TNFalpha, IL -1beta, CHRNB2, BDNF, KCNQ2, LGI1, SCN2A, IL -1alpha, HCN2 AND APOE

IL -1Ra , IL -6, BDNF, HCN2 , AND KCNQ2

SCN1A, CHRNA4, GABRG2 , AND IL -1β

1

SCN1B, TNF-α, CHRNB2, LGI1, IL -1α, SCN2A, AND APOE

2

Figure 6 Robot-like figure on the overlaps between the genetic etiology of FS and epilepsy. Investigated genes that are involved both in epileptic syndromes and FS have been characterized in two steps: (a) searching for PBASs on FS and related investigated genes (36 genes) and (b) gathering all PBASs on epilepsy in which the investigated genes on FS have been screened (16 genes). Then, two questions were considered: (1) Which genes are associated with susceptibility to both FS and epileptic syndromes? And (2) which genes are associated with susceptibility to neither FS nor epileptic syndromes?

important future target for researchers because of their important clinical implications. Acknowledgements: We thank Dr. Masih Shafiei for his assistance in managing the reference list and Mr. Davoud Zand for his valuable technical contribution in preparing tables. This study was supported by a grant from Tehran University of Medical Sciences. Received November 16, 2013; accepted December 5, 2013; previously published online January 8, 2014



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Febrile seizures and genetic epilepsy with febrile seizures plus (GEFS+).

Febrile seizures.

Febrile seizures.

Febrile seizures.

Epilepsy After Febrile Seizures: Twins Suggest Genetic Influence.

Febrile seizures in children.

Phenobarbital for febrile seizures.

Vagus nerve stimulation for genetic epilepsy with febrile seizures plus (GEFS+) accompanying seizures with impaired consciousness.

Consequences of febrile seizures in childhood.

Incidence of febrile seizures in The Netherlands.

Diurnal and seasonal occurrence of febrile seizures.

Generation of Febrile Seizures and Subsequent Epileptogenesis.

A prospective study of recurrent febrile seizures.

Prenatal and perinatal antecedents of febrile seizures.

Novel GABRG2 mutations cause familial febrile seizures.

Association between hypocapnia and febrile seizures.

Vaccines and Febrile Seizures: Quantifying the Risk.

Recent Research on Febrile Seizures: A Review.

Melatonin's Effect in Febrile Seizures and Epilepsy.

Febrile seizures: etiology, prevalence, and geographical variation.

The best medicine for febrile seizures.

Febrile Seizures and Febrile Seizure Syndromes: An Updated Overview of Old and Current Knowledge.

Origins of temporal lobe epilepsy: febrile seizures and febrile status epilepticus.

Genetic aspects of febrile convulsions.