Evidence and practices of the use of next generation sequencing in patients with undiagnosed autosomal dominant cerebellar ataxias: a review.

Luiz Eduardo Novis,Salmo Raskin,Hélio A G Teive,Marcia Jardim,Mariana Spitz

doi:10.1590/0004-282x20200017

Abstract

Autosomal dominant cerebellar ataxias (ADCA) are heterogeneous diseases with a highly variable phenotype and genotype. They can be divided into episodic ataxia and spinocerebellar ataxia (SCA); the latter is considered the prototype of the ADCA. Most of the ADCA are caused by polyglutamine expansions, mainly SCA 1, 2, 3, 6, 7, 17 and Dentatorubral-pallidoluysian atrophy (DRPLA). However, 30% of patients remain undiagnosed after testing for these most common SCA. Recently, several studies have demonstrated that the new generation of sequencing methods are useful for the diagnose of these patients. This review focus on searching evidence on the literature, its usefulness in clinical practice and future perspectives.

Highlights

Autosomal dominant cerebellar ataxias (ADCA) comprise a group of inherited cerebellar ataxias that are clinically and genetically heterogeneous[1]
When one suspects of spinocerebellar ataxias (SCA) and performs a DNA test such as Whole Exome Sequencing (WES), about 64% of the diagnoses made by this method are from mutations traditionally known to be responsible for causing hereditary ataxias, while 30% are from newly discovered genes and 6% from genes that were not typically considered to cause ataxia[35]
Larger sequencing of the genome is the likely explanation for the superior results of the study by Pyle et al Since it allowed the detection of mutations in genes that, known to cause ataxia, are not considered “ataxia genes” and are not usually included in the gene panels[39,41]

Summary

Introduction

Autosomal dominant cerebellar ataxias (ADCA) comprise a group of inherited cerebellar ataxias that are clinically and genetically heterogeneous[1]. When one suspects of SCA and performs a DNA test such as Whole Exome Sequencing (WES), about 64% of the diagnoses made by this method are from mutations traditionally known to be responsible for causing hereditary ataxias, while 30% are from newly discovered genes and 6% from genes that were not typically considered to cause ataxia[35].

Results

Conclusion