Abstract
The term hereditary ataxia (HA) refers to a heterogeneous group of neurological disorders with multiple genetic etiologies and a wide spectrum of ataxia-dominated phenotypes. Massive gene analysis in next-generation sequencing has entered the HA scenario, broadening our genetic and clinical knowledge of these conditions. In this study, we employed a targeted resequencing panel (TRP) in a large and highly heterogeneous cohort of 377 patients with a clinical diagnosis of HA, but no molecular diagnosis on routine genetic tests. We obtained a positive result (genetic diagnosis) in 33.2% of the patients, a rate significantly higher than those reported in similar studies employing TRP (average 19.4%), and in line with those performed using exome sequencing (ES, average 34.6%). Moreover, 15.6% of the patients had an uncertain molecular diagnosis. STUB1, PRKCG, and SPG7 were the most common causative genes. A comparison with published literature data showed that our panel would have identified 97% of the positive cases reported in previous TRP-based studies and 92% of those diagnosed by ES. Proper use of multigene panels, when combined with detailed phenotypic data, seems to be even more efficient than ES in clinical practice.
Highlights
The term hereditary ataxia (HA) refers to a heterogeneous group of rare neurodegenerative disorders with a wide spectrum of ataxia-dominated phenotypes
Considering the high coverage reached with multigene panels, and the easier and faster analysis of their results compared with the more commonly used ES method, it can be argued—as others have done [93]—that multigene panels are still worth using for quick screening of large cohorts
Our results indicate that the large multigene panel we designed would have intercepted
Summary
The term hereditary ataxia (HA) refers to a heterogeneous group of rare neurodegenerative disorders with a wide spectrum of ataxia-dominated phenotypes. Lack of coordination, dysarthria, and dysmetria are the most common clinical traits, associated with degeneration of Purkinje cells and/or spinocerebellar connections, often combined with atrophy of other regions of both the central and peripheral nervous systems [1]. These conditions have been formally classified on the basis of patterns of transmission and disease–gene relationships, different examples of commonalities with a range of clinical syndromes are rapidly emerging. The forms collectively termed autosomal recessive spinocerebellar ataxia (SCAR, prevalence: 1.8–4.9 × 10−5 [3]) are caused by mutations in more than 100 genes. Changes in a similar number of genes are responsible for recessive forms in which ataxia is only part of the clinical picture
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