# Investigating Repeat Expansions in NIPA1, NOP56, and NOTCH2NLC Genes: A Closer Look at Amyotrophic Lateral Sclerosis Patients from Southern Italy

## TL;DR

This study examines the role of repeat expansions in three genes among ALS patients in southern Italy to better understand the genetic factors involved in the disease.

## Contribution

This is the first study to screen ALS patients from southern Italy for repeat expansions in NIPA1, NOP56, and NOTCH2NLC genes.

## Key findings

- Repeat expansions in NIPA1, NOP56, and NOTCH2NLC were not significantly associated with ALS in southern Italy.
- Longer repeat lengths showed moderate associations with clinical features like age at onset and family history.
- The distribution of repeat expansions was similar between ALS patients and healthy controls.

## Abstract

The discovery of hexanucleotide repeats expansion (RE) in Chromosome 9 Open Reading frame 72 (C9orf72) as the major genetic cause of amyotrophic lateral sclerosis (ALS) and the association between intermediate repeats in Ataxin-2 (ATXN2) with the disorder suggest that repetitive sequences in the human genome play a significant role in ALS pathophysiology. Investigating the frequency of repeat expansions in ALS in different populations and ethnic groups is therefore of great importance. Based on these premises, this study aimed to define the frequency of REs in the NIPA1, NOP56, and NOTCH2NLC genes and the possible associations between phenotypes and the size of REs in the Italian population. Using repeat-primed-PCR and PCR-fragment analyses, we screened 302 El-Escorial-diagnosed ALS patients and compared the RE distribution to 167 age-, gender-, and ethnicity-matched healthy controls. While the REs distribution was similar between the ALS and control groups, a moderate association was observed between longer RE lengths and clinical features such as age at onset, gender, site of onset, and family history. In conclusion, this is the first study to screen ALS patients from southern Italy for REs in NIPA1, NOP56, and NOTCH2NLC genes, contributing to our understanding of ALS genetics. Our results highlighted that the extremely rare pathogenic REs in these genes do not allow an association with the disease.