Genomic Portrait of a Sporadic Amyotrophic Lateral Sclerosis Case in a Large Spinocerebellar Ataxia Type 1 Family.

Giovanna Morello,Francesca Luisa Conforti,Rossella Spataro,Maria Guarnaccia,Antonio Gianmaria Spampinato,Giulia Gentile,Salvatore Salomone,Vincenzo La Bella,Sebastiano Cavallaro

doi:10.3390/jpm10040262

Abstract

Background: Repeat expansions in the spinocerebellar ataxia type 1 (SCA1) gene ATXN1 increases the risk for amyotrophic lateral sclerosis (ALS), supporting a relationship between these disorders. We recently reported the co-existence, in a large SCA1 family, of a clinically definite ALS individual bearing an intermediate ATXN1 expansion and SCA1 patients with a full expansion, some of which manifested signs of lower motor neuron involvement. Methods: In this study, we employed a systems biology approach that integrated multiple genomic analyses of the ALS patient and some SCA1 family members. Results: Our analysis identified common and distinctive candidate genes/variants and related biological processes that, in addition to or in combination with ATXN1, may contribute to motor neuron degeneration phenotype. Among these, we distinguished ALS-specific likely pathogenic variants in TAF15 and C9ORF72, two ALS-linked genes involved in the regulation of RNA metabolism, similarly to ATXN1, suggesting a selective role for this pathway in ALS pathogenesis. Conclusions: Overall, our work supports the utility to apply personal genomic information for characterizing complex disease phenotypes.

Highlights

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by severe muscle weakness with atrophy caused by the loss of motor neurons (MNs) in the motor cortex, brainstem, and spinal cord [1]
We used a set of parallel high-throughput genomic approaches, targeted mutational analysis focused on a restricted number of amyotrophic lateral sclerosis (ALS) genes including (i) an NGS-based targeted mutational analysis focused on a restricted number of ALS genes and characterized by high coverage, (ii) a high-resolution exon-targeted CNVs analysis of ALS-related and characterized by high coverage, (ii) a high-resolution exon-targeted genes expanded to those concerning other neurological disorders, and (iii) GO- and pathway-based
CNVs analysis of ALS-related genes expanded to those concerning other neurological disorders, and analyses of genetic variants identified in the ALS patient by NeuroArray aCGH and whole-exome sequencing (WES)

Summary

Introduction

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by severe muscle weakness with atrophy caused by the loss of motor neurons (MNs) in the motor cortex, brainstem, and spinal cord [1]. The genetic and molecular architecture of ALS is complex as the disease is associated with a multitude of causative genes and biological pathways. Repeat expansions in the spinocerebellar ataxia type 1 (SCA1) gene ATXN1 increases the risk for amyotrophic lateral sclerosis (ALS), supporting a relationship between these disorders. We recently reported the co-existence, in a large SCA1 family, of a clinically definite ALS individual bearing an intermediate ATXN1 expansion and SCA1 patients with a full expansion, some of which manifested signs of lower motor neuron involvement. Conclusions: Overall, our work supports the utility to apply personal genomic information for characterizing complex disease phenotypes

Objectives

Methods

Results

Conclusion