Table 2.
Identified variants in ALS associated genes.
| Gene | cDNA | Protein | Zygosity | MAF_EA (%) | MAF (%) in this study | dbSNP | Pat-ID | Gender | Subtype | AAO (years) | Reference | MT | PolyPhen2 | SIFT | NG2 | NN |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| ALS disease genes | ||||||||||||||||
| ALS2 | c.4119A > G | p.I1373M | het | 0.52 | 0.63 | rs61757691 | #422 | f | sALS | 61 | Kenna et al., 2013 | Disease causing | benign | tolerated | – | – |
| ALS2 | c.1816-8C > T | p.? | het | 0.25 | 1.25 | rs185911369 | #26∗∗ | m | PLS | 66 | – | Polymorphism | – | – | no effect | no effect |
| ALS2 | c.1816-8C > T | p.? | het | 0.25 | 1.25 | rs185911369 | #524 | f | sALS | 60 | – | Polymorphism | – | – | no effect | no effect |
| ALS2 | c.1127_1129 delAAG | p.E375del | het | – | 0.63 | – | #45 | f | sPLS | 43 | – | Disease causing | – | – | – | – |
| ATXN2 | c.2049A > T | p.L683F | het | – | 0.63 | – | #34 | f | ALS-FTD | 54 | – | Disease causing | possibly damaging | damaging | – | – |
| C9orf72 | c.956C > A | p.P319Q | het | – | 0.63 | – | #37a | m | sALS | 50 | – | Disease causing | probably damaging | tolerated | – | – |
| FIG4 | c.1940A > G | p.Y647C | het | 0.01 | 0.63 | rs150301327 | #10∗ | m | sALS | 71 | Chow et al., 2009 | Disease causing | benign | damaging | – | – |
| FIG4 | c.1910C > A | p.P637Q | het | – | 0.63 | – | #44 | f | ALS | 88 | – | Polymorphism | benign | tolerated | – | – |
| SETX | c.3229G > A | p.D1077N | het | 0.14 | 0.63 | rs145097270 | #571 | m | sALS | 49 | Kenna et al., 2013 | Polymorphism | possibly damaging | damaging | – | – |
| SETX | c.7358A > G | p.K2453R | het | – | 0.63 | – | #29 | f | sALS | 73 | – | Polymorphism | benign | tolerated | – | – |
| SPG11 | c.6950G > A | p.G2317D | het | <0.01 | 0.63 | rs79186522 | #23 | f | flail leg | 69 | – | Polymorphism | benign | tolerated | – | – |
| SPG11 | c.5381T > C | p.L1794P | het | <0.01 | 0.63 | rs201689565 | #729∗∗ | m | sALS | 40 | – | Disease causing | probably damaging | damaging | – | – |
| SPG11 | c.3577A > G | p.I1193V | het | 0 | 0.63 | – | #747 | f | sALS | 69 | – | Polymorphism | benign | tolerated | – | – |
| TARDBP | c.931A > G | p.M311V | het | – | 0.63 | rs80356725 | #741 | f | sALS | 64 | Lemmens et al., 2009 | Disease causing | benign | tolerated | – | – |
| VAPB | c.166C > T | p.P56S | het | – | 0.63 | rs74315431 | #3 | m | fALS | 41 | Nishimura et al., 2004; Aliaga et al., 2013 | Disease causing | probably damaging | damaging | – | – |
| VAPB | c.390T > G | p.D130E | het | 0.15 | 0.63 | rs146459055 | #22 | f | sALS | 67 | Suzuki et al., 2009 | Disease causing | benign | tolerated | – | – |
| VAPB | c.479_481 delCTT | p.S160del | het | 0.28 | 0.63 | rs566283411 | #677 | f | sALS | 72 | Landers et al., 2008 | Disease causing | – | – | – | – |
| VCP | c.1194+3G > A | p.? | het | 0.05 | 0.63 | rs183223259 | #20 | f | ALS-FTD | 70 | – | Disease causing | – | – | no effect | effect |
| ALS candidate genes, modifiers, risk factors | ||||||||||||||||
| ATXN1 | c.1117C > T | p.R373C | het | <0.01 | 0.63 | – | #34 | f | ALS-FTD | 54 | – | Disease causing | Probably damaging | Damaging | – | – |
| ATXN1 | c.511C > A | p.R171S | het | 0 | 0.63 | – | #38 | f | ALS-FTD | 70 | – | Disease causing | Probably damaging | Damaging | – | – |
| DPP6 | c.746C > T | p.T249M | het | – | 0.63 | – | #428 | m | sALS | 64 | – | Disease causing | Possibly damaging | Tolerated | – | – |
| FGGY | c.1221 + 2T > C | p.? | het | 0.45 | 3.13 | rs41287704 | #5 | m | sALS | 58 | Kenna et al., 2013 | Disease causing | – | – | Effect | Effect |
| FGGY | c.1221 + 2T > C | p.? | het | 0.45 | 3.13 | rs41287704 | #21 | f | sALS | 61 | Kenna et al., 2013 | Disease causing | – | – | Effect | Effect |
| FGGY | c.1221 + 2T > C | p.? | het | 0.45 | 3.13 | rs41287704 | #732 | m | sALS | 61 | Kenna et al., 2013 | Disease causing | – | – | Effect | Effect |
| FGGY | c.1221 + 2T > C | p.? | het | 0.45 | 3.13 | rs41287704 | #739 | m | sALS | 72 | Kenna et al., 2013 | Disease causing | – | – | Effect | Effect |
| FGGY | c.1221 + 2T > C | p.? | het | 0.45 | 3.13 | rs41287704 | #33 | m | sALS | 63 | Kenna et al., 2013 | Disease causing | – | – | Effect | Effect |
| FGGY | c.1435T > C | p.C479R | het | <0.01 | 0.63 | – | #703 | m | fALS | 76 | – | Disease causing | Probably damaging | Damaging | – | – |
| FGGY | c.979A > C | p.N327H | het | 0.13 | 1.25 | rs34026954 | #28 | f | ALS | 67 | Kenna et al., 2013 | Disease causing | Probably damaging | Damaging | – | – |
| FGGY | c.979A > C | p.N327H | het | 0.13 | 1.25 | rs34026954 | #38 | f | ALS-FTD | 70 | Kenna et al., 2013 | Disease causing | Probably damaging | Damaging | – | – |
| GLE1 | c.398G > A | p.R133Q | het | <0.01 | 0.63 | – | #37b | m | sALS | 74 | – | Disease causing | Benign | Tolerated | – | – |
| GRN | c.545C > T | p.T182M | het | 0.03 | 0.63 | rs63750479 | #16 | m | sALS | 67 | Guerreiro et al., 2010 | Polymorphism | Benign | Tolerated | – | – |
| GRN | c.229G > A | p.V77I | het | 0.01 | 0.63 | rs148531161 | #749 | m | sALS | 46 | Yu et al., 2010 | Polymorphism | Benign | Tolerated | – | – |
| GRN | c.361G > A | p.V121M | het | 0 | 0.63 | – | #28 | f | ALS | 67 | – | Polymorphism | Benign | Damaging | – | – |
| GRN | c.970G > A | p.A324T | het | 0.12 | 0.63 | rs63750541 | #36 | m | flail arm | 39 | Sleegers et al., 2008; Kenna et al., 2013 | Polymorphism | Benign | Tolerated | – | – |
| ITPR2 | c.2831C > T | p.P944L | het | <0.01 | 0.63 | rs377598368 | #22 | f | sALS | 67 | – | Disease causing | Benign | Tolerated | – | – |
| ITPR2 | c.3485T > G | p.V1162G | het | 0.15 | 0.63 | rs61757114 | #373∗ | f | sALS | 72 | Kenna et al., 2013 | Disease causing | Benign | Tolerated | – | – |
| ITPR2 | c.1834G > A | p.A612T | het | <0.01 | 0.63 | rs199523133 | #422 | f | sALS | 61 | – | Disease causing | Possibly damaging | Tolerated | – | – |
| ITPR2 | c.8002G > A | p.A2668T | het | 0.21 | 0.63 | rs61757116 | #677 | f | sALS | 72 | Kenna et al., 2013 | Disease causing | Benign | Tolerated | – | – |
| ITPR2 | c.3635C > T | p.A1212V | het | <0.01 | 0.63 | rs368911384 | #741 | f | sALS | 64 | Kenna et al., 2013 | Disease causing | Probably damaging | Tolerated | – | – |
| ITPR2 | c.1447G > A | p.V483I | het | 0 | 0.63 | – | #29 | f | sALS | 73 | – | Disease causing | Probably damaging | Tolerated | – | – |
| ITPR2 | c.3539G > A | p.R1180Q | het | 0.62 | 0.63 | rs35862420 | #36 | m | flail arm | 39 | Kenna et al., 2013 | Disease causing | Benign | Tolerated | – | – |
| KIFAP3 | c.518-5T > A | p.? | het | – | 0.63 | – | #419 | m | sALS | 72 | – | Polymorphism | – | – | Effect | No effect |
| KIFAP3 | c.1301T > G | p.F434C | het | 0.23 | 0.63 | rs116755924 | #52 | m | sALS | 45 | – | Disease causing | Probably damaging | Damaging | – | – |
| NEFH | c.1235G > A | p.R412Q | het | 0.01 | 0.63 | – | #534 | m | sALS | 58 | – | Disease causing | Possibly damaging | Damaging | – | – |
| PON3 | c.217G > T | p.G73C | het | – | 0.63 | – | #47 | m | sALS | 78 | – | Disease causing | Probably damaging | Damaging | – | – |
| SLC1A2 | c.236C > G | p.A79G | het | 0.04 | 0.63 | rs377633002 | #524 | f | sALS | 60 | Meyer et al., 1998 | Disease causing | Benign | Tolerated | – | – |
| UNC13A | c.3080C > T | p.P1027L | het | 1.83 | 0.63 | rs200328448 | #10∗ | m | sALS | 71 | Koppers et al., 2013; Kenna et al., 2013 | Disease causing | Possibly damaging | Damaging | – | – |
| UNC13A | c.182C > T | p.T61M | het | 0.45 | 0.63 | rs140141294 | #26∗∗ | m | PLS | 66 | Koppers et al., 2013; Kenna et al., 2013 | Disease causing | Possibly damaging | Tolerated | – | – |
| UNC13A | c.1073A > G | p.Y358C | het | – | 0.63 | – | #30 | m | sALS | 60 | – | Polymorphism | Possibly damaging | Tolerated | – | – |
| UTR variants | ||||||||||||||||
| APEX1 | c.∗2A > T | p.? | het | 0.5 | 0.63 | rs17112002 | #47 | m | sALS | 78 | – | |||||
| FUS | c.-37C > T | p.? | het | – | 0.63 | – | #422 | f | sALS | 61 | – | |||||
| FUS | c.∗41G > A | p.? | het | 0.86 | 0.63 | rs80301724 | #741 | f | sALS | 64 | Sproviero et al., 2012 | |||||
| SOD1 | c.-8A > C | p.? | het | – | 0.63 | – | #46 | f | ALS-FTD | 75 | – | |||||
| VAPB | c.-33C > G | p.? | het | – | 0.63 | rs201547974 | #676 | f | sALS | 51 | – | |||||
| Synonymous variants | ||||||||||||||||
| ATXN2 | c.2088C > T | p.(=) | het | – | 0.63 | – | #22 | f | sALS | 67 | – | |||||
| DAO | c.723C > T | p.(=) | het | 0.23 | 1.25 | rs149956241 | #25∗∗ | f | flail leg | 54 | – | |||||
| DAO | c.723C > T | p.(=) | het | 0.23 | 1.25 | rs149956241 | #41 | m | sALS | 42 | – | |||||
| DCTN1 | c.3669T > C | p.(=) | het | 0 | 0.63 | – | #12 | m | sALS | 61 | – | |||||
| DCTN1 | c.3474A > G | p.(=) | het | – | 0.63 | – | #54 | f | ALS-FTD | 55 | – | |||||
| DPP6 | c.693T > C | p.(=) | het | – | 0.63 | – | #24∗ | m | sALS | 70 | Kenna et al., 2013 | |||||
| FUS | c.1080C > T | p.(=) | het | 0.05 | 0.63 | rs190724342 | #35 | f | sALS | 49 | Kenna et al., 2013 | |||||
| HEXA | c.1216C > T | p.(=) | het | 0.02 | 0.63 | rs140482769 | #7 | m | sALS | 71 | – | |||||
| HEXA | c.744C > T | p.(=) | het | – | 0.63 | – | #749 | m | sALS | 46 | – | |||||
| ITPR2 | c.4962G > A | p.(=) | het | 0.69 | 0.63 | rs191789657 | #16 | m | sALS | 67 | Kenna et al., 2013 | |||||
| ITPR2 | c.5569C > T | p.(=) | het | 0.12 | 1.25 | rs191281974 | #24∗ | m | sALS | 70 | Kenna et al., 2013 | |||||
| ITPR2 | c.5569C > T | p.(=) | het | 0.12 | 1.25 | rs191281974 | #40 | f | sALS | 43 | Kenna et al., 2013 | |||||
| ITPR2 | c.6162C > T | p.(=) | het | <0.01 | 0.63 | – | #31 | f | sALS | 47 | – | |||||
| NEFH | c.2061A > G | p.(=) | het | – | 0.63 | – | #16 | m | sALS | 67 | – | |||||
| NEFH | c.2646C > T | p.(=) | het | 0.01 | 0.63 | rs528790943 | #422 | f | sALS | 61 | Kenna et al., 2013 | |||||
| PON1 | c.603G > A | p.(=) | het | 0.17 | 0.63 | rs148452713 | #729∗∗ | m | sALS | 40 | Kenna et al., 2013 | |||||
| SETX | c.6675C > T | p.(=) | het | <0.01 | 0.63 | rs200382898 | #33 | m | sALS | 63 | - | |||||
| SLC1A2 | c.846C > A | p.(=) | het | <0.01 | 0.63 | rs376593061 | #46 | f | ALS-FTD | 75 | - | |||||
| SLC1A2 | c.450G > A | p.(=) | het | 0 | 0.63 | - | #52 | m | sALS | 45 | - | |||||
| SPG11 | c.6258G > T | p.(=) | het | 0.81 | 0.63 | rs150761878 | #13 | m | sALS | 73 | Kenna et al., 2013 | |||||
| UNC13A | c.771C > G | p.(=) | het | 3.02 | 0.63 | rs146739681 | #3 | m | fALS | 41 | Kenna et al., 2013 | |||||
| UNC13A | c.4560C > T | p.(=) | het | 0.1 | 0.63 | rs141334897 | #26∗∗ | m | PLS | 66 | - | |||||
| UNC13A | c.4143G > A | p.(=) | het | - | 0.63 | - | #26∗∗ | m | PLS | 66 | - | |||||
| UNC13A | c.2220G > A | p.(=) | het | 0.17 | 0.63 | rs201361019 | #32 | m | sALS | 46 | - | |||||
| VCP | c.832T > C | p.(=) | het | 0.04 | 0.63 | rs200670526 | #625 | m | fALS | 53 | - | |||||
∗Patients carry ≥30 C9orf72 repeat units. ∗∗Patients carry intermediate lenght C9orf72 repeats. MAF, minor allele frequency; MAF_EA is the maximum population frequency of the variant observed in the European American population in dbSNP, EVS or ExAC. AAO, age at onset; MT, MutationTaster (http://www.mutationtaster.org/); PolyPhen2 (http://genetics.bwh.harvard.edu/pph2/); SIFT (http://provean.jcvi.org/genome_submit_2.php); NG2, NetGene2 (https://www.cbs.dtu.dk/services/NetGene2/); NN, Splice Site Prediction by Neural Network (http://www.fruitfly.org/seq_tools/splice.html).