Imperial College London


Faculty of MedicineDepartment of Brain Sciences

Professor of Neurology and Genomic Medicine



m.johnson Website




E419Burlington DanesHammersmith Campus






BibTex format

author = {Feng, Y-CA and Howrigan, DP and Abbott, LE and Tashman, K and Cerrato, F and Singh, T and Heyne, H and Byrnes, A and Churchhouse, C and Watts, N and Solomonson, M and Lal, D and Heinzen, EL and Dhindsa, RS and Stanley, KE and Cavalleri, GL and Hakonarson, H and Helbig, I and Krause, R and May, P and Weckhuysen, S and Petrovski, S and Kamalakaran, S and Sisodiya, SM and Cossette, P and Cotsapas, C and De, Jonghe P and Dixon-Salazar, T and Guerrini, R and Kwan, P and Marson, AG and Stewart, R and Depondt, C and Dlugos, DJ and Scheffer, IE and Striano, P and Freyer, C and McKenna, K and Regan, BM and Bellows, ST and Leu, C and Bennett, CA and Johns, EMC and Macdonald, A and Shilling, H and Burgess, R and Weckhuysen, D and Bahlo, M and OBrien, TJ and Todaro, M and Stamberger, H and Andrade, DM and Sadoway, TR and Mo, K and Krestel, H and Gallati, S and Papacostas, SS and Kousiappa, I and Tanteles, GA and trbová, K and Vlková, M and Sedláková, L and Lauthová, P and Klein, KM and Rosenow, F },
doi = {10.1016/j.ajhg.2019.05.020},
journal = {The American Journal of Human Genetics},
pages = {267--282},
title = {Ultra-rare genetic variation in the epilepsies: A whole-exome sequencing study of 17,606 individuals},
url = {},
volume = {105},
year = {2019}

RIS format (EndNote, RefMan)

AB - Sequencing-based studies have identified novel risk genes associated with severe epilepsies and revealed an excess of rare deleterious variation in less-severe forms of epilepsy. To identify the shared and distinct ultra-rare genetic risk factors for different types of epilepsies, we performed a whole-exome sequencing (WES) analysis of 9,170 epilepsy-affected individuals and 8,436 controls of European ancestry. We focused on three phenotypic groups: severe developmental and epileptic encephalopathies (DEEs), genetic generalized epilepsy (GGE), and non-acquired focal epilepsy (NAFE). We observed that compared to controls, individuals with any type of epilepsy carried an excess of ultra-rare, deleterious variants in constrained genes and in genes previously associated with epilepsy; we saw the strongest enrichment in individuals with DEEs and the least strong in individuals with NAFE. Moreover, we found that inhibitory GABAA receptor genes were enriched for missense variants across all three classes of epilepsy, whereas no enrichment was seen in excitatory receptor genes. The larger gene groups for the GABAergic pathway or cation channels also showed a significant mutational burden in DEEs and GGE. Although no single gene surpassed exome-wide significance among individuals with GGE or NAFE, highly constrained genes and genes encoding ion channels were among the lead associations; such genes included CACNA1G, EEF1A2, and GABRG2 for GGE and LGI1, TRIM3, and GABRG2 for NAFE. Our study, the largest epilepsy WES study to date, confirms a convergence in the genetics of severe and less-severe epilepsies associated with ultra-rare coding variation, and it highlights a ubiquitous role for GABAergic inhibition in epilepsy etiology.
AU - Feng,Y-CA
AU - Howrigan,DP
AU - Abbott,LE
AU - Tashman,K
AU - Cerrato,F
AU - Singh,T
AU - Heyne,H
AU - Byrnes,A
AU - Churchhouse,C
AU - Watts,N
AU - Solomonson,M
AU - Lal,D
AU - Heinzen,EL
AU - Dhindsa,RS
AU - Stanley,KE
AU - Cavalleri,GL
AU - Hakonarson,H
AU - Helbig,I
AU - Krause,R
AU - May,P
AU - Weckhuysen,S
AU - Petrovski,S
AU - Kamalakaran,S
AU - Sisodiya,SM
AU - Cossette,P
AU - Cotsapas,C
AU - De,Jonghe P
AU - Dixon-Salazar,T
AU - Guerrini,R
AU - Kwan,P
AU - Marson,AG
AU - Stewart,R
AU - Depondt,C
AU - Dlugos,DJ
AU - Scheffer,IE
AU - Striano,P
AU - Freyer,C
AU - McKenna,K
AU - Regan,BM
AU - Bellows,ST
AU - Leu,C
AU - Bennett,CA
AU - Johns,EMC
AU - Macdonald,A
AU - Shilling,H
AU - Burgess,R
AU - Weckhuysen,D
AU - Bahlo,M
AU - OBrien,TJ
AU - Todaro,M
AU - Stamberger,H
AU - Andrade,DM
AU - Sadoway,TR
AU - Mo,K
AU - Krestel,H
AU - Gallati,S
AU - Papacostas,SS
AU - Kousiappa,I
AU - Tanteles,GA
AU - trbová,K
AU - Vlková,M
AU - Sedláková,L
AU - Lauthová,P
AU - Klein,KM
AU - Rosenow,F
AU - Reif,PS
AU - Knake,S
AU - Kunz,WS
AU - Zsurka,G
AU - Elger,CE
AU - Bauer,J
AU - Rademacher,M
AU - Pendziwiat,M
AU - Muhle,H
AU - Rademacher,A
AU - van,Baalen A
AU - von,Spiczak S
AU - Stephani,U
AU - Afawi,Z
AU - Korczyn,AD
AU - Kanaan,M
AU - Canavati,C
AU - Kurlemann,G
AU - Müller-Schlüter,K
AU - Kluger,G
AU - Häusler,M
AU - Blatt,I
AU - Lemke,JR
AU - Krey,I
AU - Weber,YG
AU - Wolking,S
AU - Becker,F
AU - Hengsbach,C
AU - Rau,S
AU - Maisch,AF
AU - Steinhoff,BJ
AU - Schulze-Bonhage,A
AU - Schubert-Bast,S
AU - Schreiber,H
AU - Borggräfe,I
AU - Schankin,CJ
AU - Mayer,T
AU - Korinthenberg,R
AU - Brockmann,K
AU - Kurlemann,G
AU - Dennig,D
AU - Madeleyn,R
AU - Kälviäinen,R
AU - Auvinen,P
AU - Saarela,A
AU - Linnankivi,T
AU - Lehesjoki,A-E
AU - Rees,MI
AU - Chung,S-K
AU - Pickrell,WO
AU - Powell,R
AU - Schneider,N
AU - Balestrini,S
AU - Zagaglia,S
AU - Braatz,V
AU - Johnson,MR
AU - Auce,P
AU - Sills,GJ
AU - Baum,LW
AU - Sham,PC
AU - Cherny,SS
AU - Lui,CHT
AU - Barii,N
AU - Delanty,N
AU - Doherty,CP
AU - Shukralla,A
AU - McCormack,M
AU - El-Naggar,H
AU - Canafoglia,L
AU - Franceschetti,S
AU - Castellotti,B
AU - Granata,T
AU - Zara,F
AU - Iacomino,M
AU - Madia,F
AU - Vari,MS
AU - Mancardi,MM
AU - Salpietro,V
AU - Bisulli,F
AU - Tinuper,P
AU - Licchetta,L
AU - Pippucci,T
AU - Stipa,C
AU - Minardi,R
AU - Gambardella,A
AU - Labate,A
AU - Annesi,G
AU - Manna,L
AU - Gagliardi,M
AU - Parrini,E
AU - Mei,D
AU - Vetro,A
AU - Bianchini,C
AU - Montomoli,M
AU - Doccini,V
AU - Marini,C
AU - Suzuki,T
AU - Inoue,Y
AU - Yamakawa,K
AU - Tumiene,B
AU - Sadleir,LG
AU - King,C
AU - Mountier,E
AU - Caglayan,SH
AU - Arslan,M
AU - Yapc,Z
AU - Yis,U
AU - Topaloglu,P
AU - Kara,B T
DO - 10.1016/j.ajhg.2019.05.020
EP - 282
PY - 2019///
SN - 0002-9297
SP - 267
TI - Ultra-rare genetic variation in the epilepsies: A whole-exome sequencing study of 17,606 individuals
T2 - The American Journal of Human Genetics
UR -
UR -
VL - 105
ER -