Validation of a clinical practice-based algorithm for the diagnosis of autosomal recessive cerebellar ataxias based on NGS identified cases

Abstract

Establishing a molecular diagnosis of autosomal recessive cerebellar ataxias (ARCA) is challenging due to phenotype and genotype heterogeneity. We report the validation of a previously published clinical practice-based algorithm to diagnose ARCA. Two assessors performed a blind analysis to determine the most probable mutated gene based on comprehensive clinical and paraclinical data, without knowing the molecular diagnosis of 23 patients diagnosed by targeted capture of 57 ataxia genes and high-throughput sequencing coming from a 145 patients series. The correct gene was predicted in 61 and 78 % of the cases by the two assessors, respectively. There was a high inter-rater agreement [K = 0.85 (0.55-0.98) p < 0.001] confirming the algorithm's reproducibility. Phenotyping patients with proper clinical examination, imaging, biochemical investigations and nerve conduction studies remain crucial for the guidance of molecular analysis and to interpret next generation sequencing results. The proposed algorithm should be helpful for diagnosing ARCA in clinical practice.

Genetic and phenotypic features of patients with childhood ataxias diagnosed by next-generation sequencing gene panel

“…In conclusion, the diagnostic efficacy of NGS in non-FRDA autosomal recessive ataxias in our study was 25%, a figure compatible with previous studies [1][2][3][4]. Even if comparisons are difficult with such a limited number of diseases, considering the rarity of the diseases and the patient population, we think that our results are nevertheless highly conclusive.…”

“…NGS technologies are spreading rapidly. NGS technologies are spreading rapidly, resulting in a number of publications on the subject of gene panels in ataxia [1][2][3][4]. We think that our study is important for determining the characteristics of these diseases, particularly in our geographical region, in which the number of studies on ataxia is limited.…”

“…The content of panels and the characteristics of the patients accepted for investigation affect the diagnosis rates. The study involving 57 target ataxia genes in a 145patient series reported a positive detection rate of 19% with NGS [4]. A rate of 46/146 (32%) was reported in another, more heterogeneous cohort in which 42 target genes were screened [3].…”

“…Many patients may be undiagnosed for years, thus being deprived of genetic counselling and of support among the available therapeutic options. The analysis of wide panels with next-generation sequencing (NGS) and exome sequencing has finally yielded advances in the diagnosis of genetic ataxias [1][2][3][4].…”

Diagnosis and management of progressive ataxia in adults

“…The presence of a demyelinating neuropathy (autosomal recessive spastic ataxia of Charlevoix-Saguenay) 10…”