Dataset Information

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.

SUBMITTER: Galatolo D

PROVIDER: S-EPMC8395181 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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NGS in Hereditary Ataxia: When Rare Becomes Frequent.

Galatolo Daniele D De Michele Giovanna G Silvestri Gabriella G Leuzzi Vincenzo V Casali Carlo C Musumeci Olimpia O Antenora Antonella A Astrea Guja G Barghigiani Melissa M Battini Roberta R Battisti Carla C Caputi Caterina C Cioffi Ettore E De Michele Giuseppe G Dotti Maria Teresa MT Fico Tommasina T Fiorillo Chiara C Galosi Serena S Lieto Maria M Malandrini Alessandro A Melone Marina A B MAB Mignarri Andrea A Natale Gemma G Pegoraro Elena E Petrucci Antonio A Ricca Ivana I Riso Vittorio V Rossi Salvatore S Rubegni Anna A Scarlatti Arianna A Tinelli Francesca F Trovato Rosanna R Tedeschi Gioacchino G Tessa Alessandra A Filla Alessandro A Santorelli Filippo Maria FM

International journal of molecular sciences 20210806 16

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 diagn ...[more]

PMID: 34445196

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Project description:BackgroundThe genetics of cerebellar ataxia is complex. Hundreds of causative genes have been identified, but only a few cause more than single cases. The spectrum of ataxia-causing genes differs considerably between populations. The aim of the study was to investigate the molecular epidemiology of ataxia in the Finnish population.Patients and methodsAll patients in hospital database were reviewed for the diagnosis of unspecified ataxia. Acquired ataxias and nongenetic ataxias such as those related to infection, trauma or stroke were excluded. Sixty patients with sporadic ataxia with unknown etiology and 36 patients with familial ataxia of unknown etiology were recruited in the study. Repeat expansions in the SCA genes (ATXN1, 2, 3, 7, 8/OS, CACNA1A, TBP), FXN, and RFC1 were determined. Point mutations in POLG, SPG7 and in mitochondrial DNA (mtDNA) were investigated. In addition, DNA from 8 patients was exome sequenced.ResultsA genetic cause of ataxia was found in 33 patients (34.4%). Seven patients had a dominantly inherited repeat expansion in ATXN8/OS. Ten patients had mitochondrial ataxia resulting from mutations in nuclear mitochondrial genes POLG or RARS2, or from a point mutation m.8561C > G or a single deletion in mtDNA. Interestingly, five patients were biallelic for the recently identified pathogenic repeat expansion in RFC1. All the five patients presented with the phenotype of cerebellar ataxia, neuropathy, and vestibular areflexia (CANVAS). Moreover, screening of 54 patients with Charcot-Marie-Tooth neuropathy revealed four additional patients with biallelic repeat expansion in RFC1, but none of them had cerebellar symptoms.ConclusionsExpansion in ATXN8/OS results in the majority of dominant ataxias in Finland, while mutations in RFC1 and POLG are the most common cause of recessive ataxias. Our results suggest that analysis of RFC1 should be included in the routine diagnostics of idiopathic ataxia and Charcot-Marie-Tooth polyneuropathy.

Dataset Information

NGS in Hereditary Ataxia: When Rare Becomes Frequent.

Publications

NGS in Hereditary Ataxia: When Rare Becomes Frequent.

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