Exome Sequencing uncovers Homozygous Stop-Gained variant in the SYNE1 Gene Leading to Spinocerebellar Ataxia

Abstract

ABSTRACT Background &Objective: Spectrin Repeat-Containing Nuclear Envelope Protein 1 (SYNE1) is important gene for maintaining neuronal structure and function, particularly in the cerebellum, the brain region responsible for coordinating movement. The genetic mutation in SYNE1 gene, which encodes Nesprin-1 protein leads to autosomal recessive form of spinocerebellar Ataxia OMIM (608441). This cerebellar dysfunction causes progressive balance and coordination problems, including reflexes and cognitive impairment. To understand genetic mutations in SYNE1 gene that are linked with Autosomal Recessive Spinocerebellar Ataxia type 8 (SCAR8) and Autosomal Recessive Cerebellar Ataxia type 1 (ARCA1). Methodology: The study was done in the Center of Excellence in Genomic Medicine and Research (CEGMR) during 2023-2024. Firstly, Whole Exome Sequencing (WES) was carried out to identify the mutation, followed by Sanger sequencing to validate the WES results. Results: WES identified a novel homozygous stop-gained variant, NM_182961.3:c.352C>T (p.Arg118Ter), in the SYNE1 gene in a 32-year-old Saudi patient. This alteration was associated with progressive cerebellar atrophy, impaired fine motor skills, muscular weakness, and speech and learning deficits. The variant was independently confirmed by Sanger sequencing. Conclusions: The patient’s phenotype was consistent with previously reported ARCA1 and SCAR8. To our knowledge and based on the currently available literature, this may represent the first reported Saudi family with a SYNE1 mutation associated with these conditions. This finding advances the genetic and molecular characterization of these rare disorders, highlights the utility of molecular diagnostics, and supports the establishment of a local database of disease-associated variants to improve diagnosis, management, and future research in the Saudi population.