# The landscape of non-reference SINE-VNTR-Alus in amyotrophic lateral sclerosis

## TL;DR

This study explores rare genetic insertions called SVAs in people with ALS, finding some that may be linked to the disease.

## Contribution

The study is the first to characterize non-reference SVA insertions in a large ALS cohort, identifying rare variants in the NEK1 gene.

## Key findings

- 2831 non-reference SVA insertions were identified in 4403 ALS genomes, with 95% being rare.
- Three rare SVA insertions in the ALS-related gene NEK1 were found in four individuals with ALS.
- Rare NEK1 SVA insertions were significantly more frequent in ALS patients compared to non-neuro controls.

## Abstract

The fatal neurodegenerative disease, amyotrophic lateral sclerosis (ALS), leads to the degeneration of motor neurons in the brain and spinal cord. Many different genetic variants are known to increase the risk of developing ALS, however much of the disease heritability is still to be identified. To identify novel genetic factors, we characterised SINE-VNTR-Alu (SVA) presence/absence variation in 4403 genomes from the New York Genome Center (NYGC) ALS consortium. SVAs are a type of retrotransposon able to mobilise in the human genome generating new insertions that can modulate gene expression and mRNA splicing and to date 33 insertions are known to cause a range of genetic diseases. In the NYGC ALS consortium sequence data 2831 non-reference genome SVAs were identified and 95% of these insertions were rare with an insertion allele frequency of less than 0.01. Association analysis of the common SVAs with ALS risk, age at onset and survival did not identify any SVAs that survived correction for multiple testing. However, there were three different rare SVA insertions in the ALS associated gene NEK1 identified in four different individuals with ALS. The frequency of these rare insertions in NEK1 was significantly higher in the individuals with ALS from the NYGC ALS consortium compared to the gnomAD SV non-neuro controls (p = 0.0002). This study was the first to characterise non-reference SVA presence/absence variation in a large cohort of ALS individuals identifying insertions as potential candidates involved in disease development for further investigation.