RT Journal Article
SR Electronic
T1 Delineating the genetic heterogeneity of ALS using targeted high-throughput sequencing
JF Journal of Medical Genetics
JO J Med Genet
FD BMJ Publishing Group Ltd
SP 776
OP 783
DO 10.1136/jmedgenet-2013-101795
VO 50
IS 11
A1 Kevin P Kenna
A1 Russell L McLaughlin
A1 Susan Byrne
A1 Marwa Elamin
A1 Mark Heverin
A1 Elaine M Kenny
A1 Paul Cormican
A1 Derek W Morris
A1 Colette G Donaghy
A1 Daniel G Bradley
A1 Orla Hardiman
YR 2013
UL http://jmg.bmj.com/content/50/11/776.abstract
AB Background Over 100 genes have been implicated in the aetiology of amyotrophic lateral sclerosis (ALS). A detailed understanding of their independent and cumulative contributions to disease burden may help guide various clinical and research efforts. Methods Using targeted high-throughput sequencing, we characterised the variation of 10 Mendelian and 23 low penetrance/tentative ALS genes within a population-based cohort of 444 Irish ALS cases (50 fALS, 394 sALS) and 311 age-matched and geographically matched controls. Results Known or potential high-penetrance ALS variants were identified within 17.1% of patients (38% of fALS, 14.5% of sALS). 12.8% carried variants of Mendelian disease genes (C9orf72 8.78%; SETX 2.48%; ALS2 1.58%; FUS 0.45%; TARDBP 0.45%; OPTN 0.23%; VCP 0.23%. ANG, SOD1, VAPB 0%), 4.7% carried variants of low penetrance/tentative ALS genes and 9.7% (30% of fALS, 7.1% of sALS) carried previously described ALS variants (C9orf72 8.78%; FUS 0.45%; TARDBP 0.45%). 1.6% of patients carried multiple known/potential disease variants, including all identified carriers of an established ALS variant (p<0.01); TARDBP:c.859G>A(p.[G287S]) (n=2/2 sALS). Comparison of our results with those from studies of other European populations revealed significant differences in the spectrum of disease variation (p=1.7×10−4). Conclusions Up to 17% of Irish ALS cases may carry high-penetrance variants within the investigated genes. However, the precise nature of genetic susceptibility differs significantly from that reported within other European populations. Certain variants may not cause disease in isolation and concomitant analysis of disease genes may prove highly important.