# Comprehensive identification of pathogenic tandem repeat expansions in sporadic amyotrophic lateral sclerosis: advantages of long-read vs. short-read sequencing

## TL;DR

This study compares long-read and short-read sequencing for identifying genetic mutations in sporadic ALS, finding long-read sequencing more effective.

## Contribution

Demonstrates the superiority of long-read sequencing over short-read sequencing in detecting pathogenic tandem repeat expansions in sporadic ALS.

## Key findings

- Short-read sequencing identified expansions in HTT, ATXN2, and CACNA1A genes in one patient, but these were not confirmed by long-read sequencing.
- Long-read sequencing detected a large C9orf72 expansion missed by short-read sequencing.
- Long-read sequencing is more accurate for identifying pathogenic tandem repeat expansions in ALS.

## Abstract

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder presenting progressive weakness of the bulbar and extremity muscles, leading to a wide-ranging clinical phenotype. More than 30 genes have been associated to genetically inherited ALS yet, approximately 85%–90% of ALS cases are sporadic. Short tandem repeats expansions, have recently been found in clinically diagnosed ALS patients and are currently investigated as potential genetic biomarkers. In this paper we compare the investigation of pathological tandem repeat expansions on a group of ALS patients by comparing the standard short-read sequencing (SRS) technique with a long-read-sequencing (LRS) method which has recently become more accessible. Blood samples from 47 sporadic ALS cases were subjected to SRS by Illumina Whole Genome Sequencing. The genome-wide tandem repeat expansions were genotyped using GangSTR, while wANNOVAR was used for variant annotation. Uncertain cases were further explored using LRS. SRS identified pathological expansions in HTT, ATXN2, and CACNA1A genes in one patient, which were not confirmed with LRS. The latter identified large tandem repeat expansions in the C9orf72 gene of one patient that were missed by SRS. Our findings suggest that LRS should be preferred to SRS for accurate identification of pathological tandem repeat expansions.