Milestones in genetics of cerebellar ataxias

Abstract

Cerebellar ataxias (CAs) comprise a group of rare, neurological disorders characterized by extensive phenotypic and genetic heterogeneity. The core clinical feature is the cerebellar syndrome, which is often accompanied by other neurological or non-neurological signs. In the last 30 years, our understanding of the CA etiology has increased significantly, and numerous ataxia-associated genes have been discovered. Conventional variants or tandem repeat expansions, localized in the coding or non-coding DNA sequences, lead to hereditary ataxia, which can display different patterns of inheritance. Advances in molecular techniques have enabled a rapid and cost-effective detection of causative variants in a significant number of CA patients. However, despite performing extensive investigations, a definite diagnosis is still unknown in the majority of affected individuals. In this review, we discuss the major advances in the genetics of CAs over the last 30 years, focusing on the impact of next-generation sequencing on the genetic landscape of childhood- and adult-onset CAs. Additionally, we outline possible directions for further genetic research in hereditary and sporadic CAs in the era of increasing application of whole-genome sequencing and genome-wide association studies in various neurological disorders.

Dystonia, Chorea, and Ataxia: Three Challenging Cases

“…It is important to bear in mind, however, that the most common types of SCAs result from expansions of trinucleotide CAG repeats which are not reliably detected by NGS. 17 In this case, the clue for the diagnosis of SCA7 was the visual loss due to the retinopathy. Considering all SCA subtypes, SCA7 is the classic form that presents with marked retinal dystrophy.…”

“…The term sporadic is also commonly used in cases where there is no relevant family history. 16,17 Spinocerebellar ataxias (SCAs) are the most common group of ADCAs. More than 40 genetically distinct subtypes of SCA have been described.…”

“…It is important to bear in mind, however, that the most common types of SCAs result from expansions of trinucleotide CAG repeats which are not reliably detected by NGS. 17…”

A Novel SPG7 Gene Pathogenic Variant in a Cypriot Family With Autosomal Recessive Spastic Ataxia

“…It is widely accepted that the advent of NGS strategies, including the targeted sequencing panels, the WES and the whole-genome sequencing (WGS), improved dramatically the genetic diagnosis of clinically and genetically heterogeneous diseases such as the HCAs and HSP. NGS has also enabled the identification of many novel genes and variants ( Coutelier et al, 2018 ; Elert-Dobkowska et al, 2019 ; Krygier and Mazurkiewicz-Bełdzińska, 2021 ; Sahin and Saat, 2021 ). Through a WES approach followed by in silico targeted gene analysis, the present study describes the first identification of a pathogenic variant in the SPG7 gene in the Cypriot population.…”

“…However, it might be more expensive than a targeted panel analysis with a relatively lower coverage provided. The major limitation of both the targeted panel and WES compared to the WGS approach, which provides longer reads, has been their inability to detect repeat expansions, deep intronic variants or CNVs ( Coutelier et al, 2018 ; Krygier and Mazurkiewicz-Bełdzińska, 2021 ; Saputra and Kumar, 2021 ). Therefore, for undiagnosed patients excluded from small scale variants through gene panel analysis or WES, the use of WGS could be a promising option.…”