NGS in Hereditary Ataxia: When Rare Becomes Frequent

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.

Keywords: Genesis; HA; TRP; cohort; diagnostic yield; exome sequencing; mutation; next-generation sequencing; targeted resequencing panel; variant.

Figure 1

Features of the initial cohort, including the possibility of performing segregation studies (violet).

Figure 2

(A) Overall diagnostic yield achieved in this study compared with average results of TRP and ES approaches as described in the literature; (B) Diagnostic yield presented by specific features.

Figure 3

Comparison of molecular findings between this study (black) and literature (green) in terms of (A) mutation types and patterns of inheritance, (B) most common disease-causing genes, and (C) pathways involved.