A Novel homozygous ALS2 splice site variant causes a motor neuron disease in an Iranian family

Introduction & Objectives: Recessive pathogenic variants in the alsin Rho guanine nucleotide exchange factor (ALS2) gene lead to three distinct neurodegenerative disorders comprising infantile-onset ascending hereditary spastic paralysis (IAHSP), juvenile primary lateral sclerosis (JPLS), and juvenile amyotrophic lateral sclerosis (JALS), which are early-onset motor neuron diseases with the upper motor neuron and/or the lower motor neuron involvement. The goal of this study is to identify the underlying genetic cause of a neuromuscular disease in a consanguineous Iranian family by applying whole-exome sequencing (WES).Materials & Methods: Clinical manifestations were surveyed in affected individuals of a consanguineous Iranian family with a neuromuscular disorder. We performed WES, bioinformatics analysis, Sanger validation and co-segregation analysis in this family to find the causative variant.Results: We report a novel ALS2 splice site variant co-segregating patients presenting with spastic tetraparesis, emotional lability, dysarthria, hyperreflexia and becoming wheelchair bound. This homozygous variant is predicted to affect the RCC1 (regulator of chromatin condensation)-like domain, encoding a putative guanine exchange factor for Ran guanosine triphosphatase, causing a loss of ALS2 function due to instability of the mutant protein. In silico evaluations confirmed the pathogenic effect of the variant. It was classified as pathogenic according to the ACMG variant interpretation guideline.Conclusions: This study highlights the importance of using WES as a powerful tool for constituting a quick and accurate genetic diagnosis of complex neuromuscular phenotypes. We recommend screening the ALS2 gene in Iranian cases with a family history of neuromuscular disorder.

کلیدواژه ها:

ALS2 ، Alsin ، motor neuron disease ، whole-exome sequencing