Objective: To evaluate the utility of gene panel testing in a population of patients with genetically undetermined ataxia attending the Irish National Ataxia clinic.

Background: The inherited ataxias are a group of clinically and genetically heterogeneous neurodegenerative disorders. The diagnostic evaluation of patients with progressive cerebellar ataxia is often challenging. The success in obtaining a diagnosis in individuals and families with rare ataxias increases with evaluation at dedicated Ataxia Clinics with comprehensive clinical assessment and appropriate genetic evaluation and the use of recently available next generation sequencing (NGS) techniques.

Methods: 47 previously undiagnosed patients with early or late onset sporadic or familial cerebellar ataxias were tested using commercially available NGS gene panels, 39 patients with the Oxford Ataxia gene panel and 8 patients with the Sheffield or Liverpool Hereditary Spastic Paraplegia panel.   

Results: 47% of the cohort were male (22/47), average age was 59.7 years (range 23 – 79). Most of the patients (64%) were sporadic cases, half of them adult onset.  Of the familial cases (17/47), most had late symptom onset (59%). Following NGS testing, definitive genetic diagnosis was obtained in 17 patients (36 %), an impressive yield given clinical and genetic heterogeneity of cerebellar ataxias. Genetic diagnosis was achieved in 50% of patients tested with the HSP panel and in 33% tested with ataxia panel. In addition, potentially pathogenic compound heterozygous variants were found in one case (SPG7) and a novel variant in a dominant gene was found in two cases (AFG3L2, CACNA1A). Single heterozygous variants in a recessive gene that could potentially explain the phenotype were found in 7 cases (SPG7, ANO10, POLG, ZFYVE26).

Conclusions: A commercial panel approach using NGS has increased the rate of positive genetic results where traditional methods were unsuccessful in many familial and sporadic cases. NGS in ataxia patients with unknown underlying genetic cause has delivered new diagnostic potential, providing a diagnosis in more than one-third of patients in our cohort; higher than has been found in other published cohorts.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/utility-of-ataxia-gene-panel-testing-in-diagnosing-inherited-ataxia-evaluation-of-an-irish-cohort/