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.

A new genetic cause of spastic ataxia: the p.Glu415Lys variant in TUBA4A

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Autosomal recessive cerebellar ataxias: a diagnostic classification approach according to ocular features

“…This genetic pleiotropy is further augmented by the growing number of genes associated with both autosomal dominant ataxias and severe early-onset autosomal recessive ataxia syndromes (e.g., AFG3L2/SCA 28, SPTBN2/SCA5, ITPR1/SCA29, OPA1; Rossi et al, 2018 ). The advent of Next-Generation Sequencing (NGS) techniques has raised the diagnostic capacities and, at the same time, it has amplified the diagnostic complexity with ever-expanding pleiotropy of ARCAs genes ( Galatolo et al, 2021 ). However, the wide used NGS approaches have the limitation of being unavailable in detecting pathological noncoding triplet expansions, such those occurring in FRDA or CANVAS, which are common ARCAs types.…”

Sleep Disorders Associated with Neurodegenerative Diseases

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