Amyotrophic lateral sclerosis/motor neuron disease

Gene: SOD1

Comment on mode of inheritance: MOI changed from "MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown" to "BOTH monoallelic and biallelic, autosomal or pseudoautosomal".

PMID: 7647793 identified homozygous variants in SOD1 in 14 affected people from 4 unrelated families (some were consanguineous) from Sweden or Finland with ALS. All affected individuals are homozgyous for the the same variant (D90A). Heterozygous carriers were not affected.

PMID: 9817920 studied 28 pedigrees with D90A from around the world. The authors found that 20 recessive familes have the same founder haplotype as PMID:7647793, regardless of location, and that heterozygous carriers in these families were also unaffected. In the dominant families, 5 were sporadic (no family history of ALS) and 3 were familial and several founders existed for these families. This study shows that D90A can cause disease in a dominant fashion just like all other SOD1 variants.

Recessive inheritance of ALS caused by D90A has also been reported in families from Russia, Germany, Iran, Italy, France, Australia, Canada, and US (PMID: 18608106, 10809943, 12442272, 11284995, 11127534, 23062701).

PMID: 11220750 identified a French family with ALS, where the affected individuals were compound heterozygous for D90A and D96N in SOD1.

Created: 1 Sep 2021, 9:15 a.m. | Last Modified: 1 Sep 2021, 9:15 a.m.

Panel Version: 1.37

Comment on mode of pathogenicity: Many missense variants on OMIM are reported to result in reduced function of SOD1 but see recent publication provided by reviewer PMID: 23687121.

Created: 15 Jun 2016, 1:29 p.m.

Comment on list classification: Promoted from amber to green due to expert review and is present on the NHNN panel. Multiple cases and different variants reported in OMIM.

Created: 15 Jun 2016, 1:27 p.m.

This gene is on the ALS/MND NGS Panel in the UCLH National Hospital for Neurology and Neurosurgery & Institute of Neurology (NHNN) Neurogenetics genetic testing manual.

Created: 13 Jun 2016, 9:14 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Green List (high evidence)

SOD1 is generally accepted to cause ALS predominantly through a gain-of-function mechanism, although loss of function may contribute some modifier effect to the phenotype.

Created: 26 Apr 2016, 3:11 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
amyotrophic lateral sclerosis

Publications

• 23687121

Mode of pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments