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. 2021 Aug 6;22(16):8490.
doi: 10.3390/ijms22168490.

NGS in Hereditary Ataxia: When Rare Becomes Frequent

Daniele Galatolo  1 , Giovanna De Michele  2 , Gabriella Silvestri  3   4 , Vincenzo Leuzzi  5 , Carlo Casali  6 , Olimpia Musumeci  7 , Antonella Antenora  2 , Guja Astrea  1 , Melissa Barghigiani  1 , Roberta Battini  1 , Carla Battisti  8 , Caterina Caputi  5 , Ettore Cioffi  6 , Giuseppe De Michele  2 , Maria Teresa Dotti  8 , Tommasina Fico  2 , Chiara Fiorillo  9 , Serena Galosi  5 , Maria Lieto  2 , Alessandro Malandrini  8 , Marina A B Melone  10 , Andrea Mignarri  8 , Gemma Natale  1 , Elena Pegoraro  11 , Antonio Petrucci  12 , Ivana Ricca  1 , Vittorio Riso  3   4 , Salvatore Rossi  3   4 , Anna Rubegni  1 , Arianna Scarlatti  1 , Francesca Tinelli  1 , Rosanna Trovato  1 , Gioacchino Tedeschi  10 , Alessandra Tessa  1 , Alessandro Filla  2 , Filippo Maria Santorelli  1
Affiliations

NGS in Hereditary Ataxia: When Rare Becomes Frequent

Daniele Galatolo et al. Int J Mol Sci. .

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.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Features of the initial cohort, including the possibility of performing segregation studies (violet).
Figure 2
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
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.
See this image and copyright information in PMC

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