Table 1 |.
Summary of ALS-associated genes
| Year | Locus | Gene | Inheritance | Familial (%)a | Sporadic (%)a | Disease-associated mechanism | Other associated phenotypesb | Refs. |
|---|---|---|---|---|---|---|---|---|
| 1993 | 21q22.11 | SOD1 | Autosomal dominant, autosomal recessive, de novo | 12 | 1–2 | Oxidative stress, excitotoxicity, mitochondrial dysfunction, axonal transport disruption | Frontotemporal dementia, spastic tetraplegia and axial hypotonia | 19 |
| 1994 | 22q12.2 | NEFH | Autosomal dominant | Unknown | Unknown | Axonal transport disruption | Axonal Charcot-Marie-Tooth disease type 2CC | 212 |
| 2001 | 2q33.1 | ALS2 | Autosomal recessive | Unknown | Unknown | Vesicular trafficking defects | Juvenile primary lateral sclerosis, infantile hereditary spastic paraplegia | 213 |
| 2003 | 2p13.1 | DCTN1 | Autosomal dominant | Unknown | Unknown | Axonal transport disruption | Distal hereditary motor neuropathy type VIIB, Perry syndrome | 214 |
| 2004 | 20q13.32 | VAPB | Autosomal dominant | Unknown | Unknown | Proteostasis defects | Finkel-type spinal muscular atrophy | 215 |
| 2004 | 9q34.13 | SETX | Autosomal dominant | Unknown | Unknown | Altered ribostasis | Autosomal recessive spinocerebellar ataxia type 1 | 216 |
| 2006 | 3p11.2 | CHMP2B | Autosomal dominant | Unknown | Unknown | Proteostasis defects, vesicular trafficking defects | Frontotemporal dementia | 217,218 |
| 2008 | 1p36.22 | TARDBP | Autosomal dominant, autosomal recessive, de novo | 4 | 1 | Altered ribostasis, nucleocytoplasmic transport defects | Frontotemporal dementia | 38,39 |
| 2009 | 16p11.2 | FUS | Autosomal dominant, autosomal recessive, de novo | 4 | 1 | Altered ribostasis, nucleocytoplasmic transport defects | Frontotemporal dementia, essential tremor | 46,47 |
| 2010 | 9p13.3 | VCP | Autosomal dominant, de novo | 1 | 1 | Proteostasis defects | Frontotemporal dementia, Charcot-Marie-Tooth disease type 2Y, inclusion body myopathy with early-onset Paget disease | 144 |
| 2010 | 15q21.1 | SPG11 | Autosomal recessive | Unknown | Unknown | DNA damage | Hereditary spastic paraplegia, Charcot-Marie-Tooth disease type 2X | 219 |
| 2010 | 10p13 | OPTN | Autosomal dominant, autosomal recessive | <1 | <1 | Autophagy, inflammation | Adult-onset primary open-angle glaucoma | 220 |
| 2011 | Xp11.21 | UBQLN2 | X-linked dominant | <1 | <1 | Proteostasis defects | None | 221 |
| 2011 | 5q35.3 | SQSTM1 | Autosomal dominant | 1 | <1 | Autophagy, inflammation | Frontotemporal dementia, distal myopathy, childhood-onset neurodegeneration with ataxia, dystonia and gaze palsy, Paget disease of bone-3 | 222 |
| 2011 | 9p21.2 | C9orf72 | Autosomal dominant | 40 | 7 | Autophagy, global RNA alterations, intracellular trafficking defects, nucleocytoplasmic transport defects, proteostasis defects | Frontotemporal dementia | 55,56 |
| 2012 | 17p13.2 | PFN1 | Autosomal dominant | <1 | <1 | Impaired axonal growth and cytoskeletal organization | None | 223 |
| 2013 | 7p15.2 | HNRNPA2B1 | Autosomal dominant | Unknown | Unknown | Altered ribostasis | Inclusion body myositis with early-onset Paget disease with or without frontotemporal dementia 2, multisystem proteinopathy | 224 |
| 2013 | 12q13.13 | HNRNPA1 | Autosomal dominant, de novo | Unknown | Unknown | Altered ribostasis | Inclusion body myositis with early-onset Paget disease with or without frontotemporal dementia 3, multisystem proteinopathy | 224 |
| 2014 | 2q35 | TUBA4A | Autosomal dominant | <1 | <1 | Impaired axonal growth and cytoskeletal organization | Frontotemporal dementia | 225 |
| 2014 | 5q31.2 | MATR3 | Autosomal dominant | <1 | <1 | Altered ribostasis | Distal myopathy with vocal cord and pharyngeal weakness | 226 |
| 2014 | 22q11.23 | CHCHD10 | Autosomal dominant | <1 | <1 | Mitochondrial dysfunction | Frontotemporal dementia, spinal muscular atrophy (Jokela type), isolated mitochondrial myopathy | 227 |
| 2015 | 12q14.2 | TBK1 | Autosomal dominant | <1 | <1 | Autophagy, inflammation | Frontotemporal dementia | 112 |
| 2016 | 4q33 | NEK1 | Not established | 2 | 2 | DNA damage, impaired cytoskeletal organization and cell cycle | Short-rib thoracic dysplasia 6 with or without polydactylism | 112,114 |
| 2016 | 16p13.3 | CCNF | Autosomal dominant | 4 | 2 | Proteostasis defects | Frontotemporal dementia | 228 |
| 2016 | 21q22.3 | CFAP410 | Not established | Unknown | Unknown | Impaired cytoskeletal organization | Axial spondylometaphyseal dysplasia, retinal dystrophy with macular staphyloma | 107 |
| 2017 | 10q22.3 | ANXA11 | Autosomal dominant | Unknown | Unknown | Dysregulation of calcium homeostasis and stress granule dynamics | Inclusion body myopathy and brain white matter abnormalities | 229 |
| 2018 | 12q13.3 | KIF5A | Autosomal dominant | <1 | <1 | Impaired cytoskeletal organization and axonal transport | Charcot-Marie-Tooth type 2, hereditary spastic paraplegia | 72,73 |
| 2018 | 10q24.31 | ERLIN1 | Autosomal recessive | Unknown | Unknown | Dysregulation of inositol 1,4,5-trisphosphate intracellular ion channels | Hereditary spastic paraplegia | 78 |
| 2019 | 3p21.1 | GLT8D1 | Autosomal dominant | Unknown | Unknown | Impaired ganglioside synthesis | None | 230 |
| 2019 | 17q21.2 | DNAJC7 | Not established | Unknown | Unknown | Not established | None | 84 |
| 2021 | 4p16.3 | HTT | Autosomal dominant | Unknown | Unknown | Not established/nucleocytoplasmic transport defects | Huntington disease, Lopes-Maciel-Rodan syndrome | 91 |
| 2022 | 9q22.31 | SPTLC1 | De novo | Unknown | Unknown | Disruption of sphingolipid metabolism | Hereditary sensory and autonomic neuropathy type 1A | 97,98 |
Genes are listed chronologically based on their year of discovery.
a
Percentage of amyotrophic lateral sclerosis (ALS) cases explained by mutations in the corresponding disease-causing genes.
b
Phenotypes associated with the genes extracted from the Online Mendelian Inheritance in Man database.