Abstract
BackgroundSpinocerebellar ataxias (SСAs) are a highly heterogeneous group of inherited neurological disorders. The symptoms of ataxia vary in individual patients and even within the same SCA subtype. A study of a four-generation family with autosomal dominant (AD) non-progressive SCA with mild symptoms was conducted. The genotyping of this family revealed no frequent pathogenic mutations. So the objective of this study was to identify the genetic causes of the disease in this family with the technology of whole-exome sequencing (WES).Methods and resultsWES, candidate variant analysis with further Sanger sequencing, mRNA secondary structure prediction, and RSCU analysis were performed; a heterozygous missense mutation in ITPR1 was identified.ConclusionOur study confirms the fact that ITPR1 gene plays a certain role in the pathogenesis of SCAs, and, therefore, we suggest that c.4657G>A p.Val1553Met) is a disease-causing mutation in the family studied.
Highlights
Spinocerebellar ataxias (SСAs) are a highly heterogeneous group of inherited neurological disorders
Whole-exome sequencing whole-exome sequencing (WES) was performed in two affected individuals (II-2 and IV-1) and in unaffected family member (II-3) at the Next-generation sequencing (NGS) Core Facility of the Estonian Genome Center, University of Tartu, Estonia
Because the SCA was an autosomal dominant hereditary disorder and only one parent was affected, we focused on heterozygous nonsynonymous, frameshift, and canonical splicesite variants that were absent from public datasets, including dbSNP137 [6], the 1000 Genomes Project [7], and the NHLBI Exome Sequencing Project (ESP) Exome Variant Server database [8]
Summary
Spinocerebellar ataxias (SСAs) are a highly heterogeneous group of inherited neurological disorders. A study of a fourgeneration family with autosomal dominant (AD) non-progressive SCA with mild symptoms was conducted. The genotyping of this family revealed no frequent pathogenic mutations. They are characterized by significant clinical polymorphism resulting from combination of cerebellar ataxia with additional non-cerebellar symptoms, which seriously complicates clinical differentiation [1]. Neuronal loss is observed predominantly in the cerebellum and the brainstem, and neuroimaging (CT or MRI) demonstrates the atrophy of those regions These pathologies can be caused by autosomal dominant (AD), autosomal recessive, and X-linked mutations
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