Investigating Copy Number Variations in Amyotrophic Lateral Sclerosis‐Causing Genes as a Rare Cause of Disease (2018)

Amyotrophic lateral sclerosis (ALS) is a predominantly adult‐onset motor neuron disease characterized by progressive loss of motor function leading to paralysis and death by respiratory failure within 3–5 years of disease onset. Approximately 10% of ALS cases have a familial origin (FALS) with the remainder of cases being sporadic (SALS). Many of the genetic defects in familial ALS remain unknown. Given that FALS and SALS cases are clinically indistinguishable, scientists believe that by discovering the mechanism of pathology of familial cases treatment can be applied for both familial and sporadic. In order to gain a more thorough understanding of the disease and the genetic underpinnings of FALS cases, we studied copy number variations (CNVs) in 10 ALS‐causative genes: Amyotrophic Lateral Sclerosis 2, Sequestosome‐1, TAR DNA binding protein‐43, Super Oxide Dismutase‐1, Fused in Sarcoma, Chromosome 9 Open Reading Frame 72, Profilin‐1, Ubiquilin‐2, Spatacsin vesicle trafficking associated gene and Valosin containing protein gene. CNVs are defined as quantitative variations in a DNA segment, that show a variable copy number compared with a reference genome. They can account for population diversity as well as human genetic disease. It is unknown whether rare CNVs in known familial ALS‐causing genes can cause disease. We hypothesized that duplications or deletions of known ALS‐causative genes may be pathogenic and account for a subset of cases with unknown etiology. Multiplex ligation‐dependent probe amplification, a semi‐quantitative technique used to determine relative copy number of up to 10 genes in a single multiplex PCR‐based reaction, was used to test our hypothesis. An amount of 277 FALS patients were screened for CNVs. We averaged each gene probe and established a baseline range within the standard deviation. Everything that had a value of one higher or lower from our average was considered a CNV. One‐copy lower was considered as a deletion and one‐copy higher was considered as an insertion. From the 277 FALS samples studied, we found that 14 (8 male and 6 female) samples showed potential duplications and deletions that may explain a subset of FALS cases. Moreover, healthy control samples will be screened in order to confirm insertions and deletions (CNVs) are only present in mutated genes, not wild‐type genes. Also, targeted approaches using next‐generation sequencing, such as region‐specific sequencing, will be used to validate our data. This data provides new genetic insights and shows how relevant gene modifications may play a role in familial ALS. Overall, the identification of novel CNVs in known ALS‐causing genes may provide new genetic insight into the disease. Support or Funding Information NS050641 Genetics of ALS, Les Turner ALS Foundation, Les Turner ALS Foundation/Herbert C. Wenske Foundation Professor, Foglia Family Foundation, Ride for Life and UPR‐NIH‐RISE: 5R25GM061151‐16. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .