Table 1 Discovery methods of ALS-associated genes (Adapted from Goutmann et al- Emerging insights into the complex genetics and pathophysiology of amyotrophic lateral sclerosis [31])
From: Advances in sequencing technologies for amyotrophic lateral sclerosis research
Gene by Discovery Method | Chromosomal Position | Inheritance Pattern | ALSoD Category | Pathogenic Mechanism | fALS | sALS | Year of Discovery | References |
|---|---|---|---|---|---|---|---|---|
Linkage Analysis | ||||||||
 ALS2 | 2q33.1 | AR | Tenuous | Trafficking and degradation of proteins | < 1% | < 1% | 2001 | [32] |
 C9orf72 | 9p21.2 | AD | Definitive ALS gene | Repeat expansion, Trafficking, degradation of proteins, RNA foci, DPRs | 40% | 7% | 2011 | |
 DAO | 12q24.11 | AD | Moderate evidence | Oxidative stress | < 1% | < 1% | 2010 | [33] |
 DCTN1 | 2p13.1 | AD, AR | Tenuous | Trafficking and degradation of proteins | < 1% | < 1% | 2003 | [34] |
 ERBB4 | 2q34 | AD | Moderate evidence | Neuronal cell migration and development | < 1% | < 1% | 2013 | [35] |
 FUS | 16p11.2 | AD | Definitive ALS gene | RNA processing/splicing | 4% | 1% | 2009 | |
 GLT8D1 | 3p21.1 | AD | Tenuous | Unknown | < 1% | < 1% | 2019 | [37] |
 hnRNPA1 | 12q13.13 | AD | Definitive ALS gene | RNA processing/splicing | < 1% | < 1% | 2013 | [38] |
 hnRNPA2B1 | 7p15.2 | AD | Tenuous | RNA processing/splicing | < 1% | < 1% | 2013 | [38] |
 MATR3 | 5q31.2 | AD | Tenuous | RNA processing/splicing | < 1% | < 1% | 2014 | [39] |
 SETX | 9q34.13 | AD | Tenuous | RNA processing/splicing | < 1% | < 1% | 1998 | [40] |
 SOD1 | 21q22.11 | AD, AR | Definitive ALS gene | Gain of toxic protein | 12% | 1-2% | 1993 | [25] |
 SPG11 | 15q21.11 | AR | Tenuous | DNA Repair damage | < 1% | < 1% | 2010 | |
 TARDBP | 1p36.22 | AD | Definitive ALS gene | RNA processing/splicing | 4% | 1% | 2008 | |
 UBQLN2 | Xp11.21 | XL | Definitive ALS gene | Trafficking and degradation of proteins | < 1% | < 1% | 2011 | [45] |
 VAPB | 20q13.32 | AD | Definitive ALS gene | Trafficking and degradation of proteins | < 1% | < 1% | 2004 | [46] |
Candidate Gene Analysis | ||||||||
 ANG | 14q11.2 | AD | Moderate evidence | RNA processing/splicing | < 1% | < 1% | 2006 | [47] |
 ATXN2 | 12q24.12 | AD | Clinical modifier | RNA processing/splicing | < 1% | < 1% | 2010 | [48] |
 CHMP2B | 3p11.2 | AD | Moderate evidence | Trafficking and degradation of proteins | < 1% | < 1% | 2006 | [49] |
 CHRNA3 | 15q24 | N/A | N/A | Synaptic dysfunction | < 1% | < 1% | 2009 | [50] |
 EWSR1 | 22q12.2 | N/A | Tenuous | RNA processing/splicing | < 1% | < 1% | 2012 | [51] |
 FIG4 | 6q21 | AD | Moderate evidence | Trafficking and degradation of proteins | < 1% | < 1% | 2009 | [52] |
 GLE1 | 9q34.11 | N/A | Moderate evidence | RNA processing/splicing | N/A | N/A | 2016 | [53] |
 NEFH | 22q12.2 | AD, AR | Tenuous | Trafficking and degradation of proteins | < 1% | < 1% | 1999 | [54] |
 PON1-3 | 7q21.3 | N/A | Tenuous | Lipid metabolism | < 1% | < 1% | 2009 | [55] |
 PRPH | 12q13.12 | AD, AR | Tenuous | Trafficking and degradation of proteins | < 1% | < 1% | 2004 | [56] |
 SIGMAR1 | 9p13.3 | AR | Tenuous | Trafficking and degradation of proteins | < 1% | < 1% | 2011 | [49] |
 SQSTM1 | 5q35.3 | AD | Tenuous | Trafficking and degradation of proteins | ~ 1% | < 1% | 2011 | [57] |
 TAF15 | 17q12 | N/A | Tenuous | RNA processing/splicing | N/A | N/A | 2011 | [58] |
GWAS | ||||||||
 CFAP410 (C21orf2) | 21q22.3 | N/A | Strong evidence | Cytoskeletal defects | < 1% | < 1% | 2016 | [59] |
 CAMTA1 | 1p36.31-p36.23 | AD | Clinical modifier | Trafficking and degradation of proteins | N/A | N/A | 2016 | [60] |
 CCNF | 16p13.3 | AD | Strong evidence |  | ~ 1-3.3% | < 1% | 2016 | [59] |
 KIF5A | 12q13.3 | AD | Definitive ALS gene | Axonal pathology | N/A | N/A | 2018 | [61] |
 NIPA1 | 15q11.2 | AD | Strong evidence | Repeat expansion | N/A | N/A | 2019 | [62] |
 SARM1 | 17q11.2 | N/A | Moderate evidence | Axonal pathology | N/A | N/A | 2021 | [63] |
 TIA1 | 2p13.3 | AD | Tenuous | Oxidative stress | ~ 2.2% | < 1% | 2017 | [64] |
 UNC13A | 19p13.11 | N/A | Definitive ALS gene | Synaptic dysfunction | N/A | N/A | 2012 | |
WES/WGS | ||||||||
 ANXA11 | 10q22.3 | AD | Definitive ALS gene | Trafficking and degradation of proteins | ~ 1% | ~ 1.7% | 2017 | [67] |
 CHCHD10 | 22q11.23 | AD | Definitive ALS gene | Trafficking and degradation of proteins (Mitochondria) | < 1% | < 1% | 2014 | |
 DNAJC7 | 17q21.2 | N/A | Moderate evidence | Trafficking and degradation of proteins | < 1% | < 1% | 2019 | [70] |
 NEK1 | 4q33 | AD | Definitive ALS gene | Trafficking and degradation of proteins | ~ 1-2% | < 1% | 2015 | |
 PFN1 | 17p13.2 | AD | Definitive ALS gene | Trafficking and degradation of proteins | < 1% | < 1% | 2012 | [75] |
 TBK1 | 12q14.2 | AD | Definitive ALS gene | Trafficking and degradation of proteins | ~ 3% | < 1% | 2015 | |
 TUBA4A | 2q35 | AD | Strong evidence | Trafficking and degradation of proteins | < 1% | < 1% | 2014 | |
 VCP | 9p13.3 | AD | Definitive ALS gene | Trafficking and degradation of proteins | 1% | 1% | 2010 | [81] |
 ERLIN2 Homozygosity mapping | 10q24.31 | AR | Tenuous | Lipid transport | N/A | N/A | 2012 | [82] |
 EPHA4 Functional study | 2q36.1 | N/A | Definitive ALS gene | Axonal pathology | N/A | N/A | 2012 | [83] |
 OPTN Homozygosity mapping | 10p13 | AD, AR | Definitive ALS gene | Trafficking and degradation of proteins | 1% | < 1% | 2010 | [84] |
 VEGFA Functional testing | 6p21.1 | N/A | Tenuous | Angiogenesis | N/A | N/A | 2009 | [85] |