Exome sequencing of case-unaffected-parents trios reveals recessive and de novo genetic variants in sporadic ALS

Abstract

The contribution of genetic variants to sporadic amyotrophic lateral sclerosis (ALS) remains largely unknown. Either recessive or de novo variants could result in an apparently sporadic occurrence of ALS. In an attempt to find such variants we sequenced the exomes of 44 ALS-unaffected-parents trios. Rare and potentially damaging compound heterozygous variants were found in 27% of ALS patients, homozygous recessive variants in 14% and coding de novo variants in 27%. In 20% of patients more than one of the above variants was present. Genes with recessive variants were enriched in nucleotide binding capacity, ATPase activity, and the dynein heavy chain. Genes with de novo variants were enriched in transcription regulation and cell cycle processes. This trio study indicates that rare private recessive variants could be a mechanism underlying some case of sporadic ALS, and that de novo mutations are also likely to play a part in the disease.

The role of de novo mutations in the development of amyotrophic lateral sclerosis

“…This resulted in an average of 0.84 coding de novo mutations per trio, which is higher compared with previous studies in ALS with de novo mutation rates of 0.53 (Chesi et al., ) and 0.39 (Steinberg et al., ) (mean difference with previous studies combined 0.38, 95% confidence interval [CI] 0.14–0.62, P = 0.003), but consistent with the expected distribution in the general population (Samocha et al., ) (mean difference 0.14, 95% CI −0.06 to 0.34, P = 0.16).…”

Genetic ablation of IP3receptor 2 increases cytokines and decreases survival ofSOD1G93Amice

“…This genetic association was not replicated in other studies (9,10). Although recent exome sequencing of case-unaffected–parents trios identified a de novo variant in ITPR2 (11), the potential role of this variant remains unclear. The higher ITPR2 gene expression in ALS also remains intriguing due to the important role of the gene product of ITPR2 , the inositol 1,4,5-trisphosphate receptor 2 ( IP 3 R2 ), in calcium signalling.…”

Charcot–Marie–Tooth disease type 2G redefined by a novel mutation in LRSAM1

“…The results in patients' cells show increased transcription of NEDD4L, a gene encoding another E3 ubiquitin ligase targeting TSG101. 40 PLA2G4C encodes a membrane-bound phospholipase that hydrolyses glycerophospholipids into various signaling molecule precursors, 41 but its potential role in neurodegeneration has yet to be explored. Double knockout studies 36 have revealed that mutations in a functionally redundant gene often lead to a minor or no phenotype, whereas targeting the compensatory gene pair together substantially increases severity, for example, dystrophin and utrophin A in a mouse model of Duchenne muscular dystrophy.…”