Exome Sequencing Improves Clinical Diagnosis of Sporadic or Familial Cerebellar Ataxia (S32.003)

Objective: To investigate the contribution of genetic disease in a population of predominantly adult- and sporadic-onset cerebellar ataxia patients. Background: The cerebellar ataxias are a diverse collection of neurological disorders with causes ranging from common acquired etiologies to rare genetic conditions. Numerous genetic disorders have been associated with chronic progressive ataxia and this consequently presents a diagnostic challenge for the clinician regarding how to approach and prioritize genetic testing in patients with such clinically heterogeneous phenotypes. Additionally, while the value of genetic testing in early-onset and/or familial cases seems clear, many ataxia patients present sporadically with adult-onset of symptoms and the contribution of genetic variation to the phenotype of these patients has not yet been established. Design/Methods: We examined a consecutive series of 76 patients presenting to a tertiary referral center for evaluation of chronic progressive cerebellar ataxia. Results: We performed next-generation exome sequencing coupled with comprehensive bioinformatic analysis, phenotypic analysis, and clinical correlation. Results: We identified clinically relevant genetic information in over 60[percnt] of patients studied (n=46), including diagnostic pathogenic gene variants in 21[percnt] (n=16), a remarkable yield result given the diverse genetics and clinical heterogeneity of the cerebellar ataxias. Conclusions: This study demonstrates that clinical exome sequencing in patients with adult-onset and sporadic presentations of ataxia is a high yield test, providing a definitive diagnosis in over one-fifth of patients, and suggesting a potential diagnosis in more than one-third to guide additional phenotyping and diagnostic evaluation. Clinical exome sequencing is therefore an appropriate consideration in the routine genetic evaluation of all patients presenting with chronic progressive cerebellar ataxia. Study Supported By: The National Institute of Mental Health, the National Institute for Neurological Disorders and Stroke, and the National Ataxia Foundation Disclosure: Dr. Fogel has received personal compensation for activities with the American Physician Institute for Advanced Professional Studies. Dr. Fogel has received personal compensation in an editorial capacity for Neurologic Clinics. Dr. Lee has nothing to disclose. Dr. Deignan has nothing to disclose. Dr. Strom has nothing to disclose. Dr. Kantarci has nothing to disclose. Dr. Wang has nothing to disclose. Dr. Quintero-Rivera has nothing to disclose. Dr. Vilain has nothing to disclose. Dr. Grody has nothing to disclose. Dr. Perlman has received research support from Santhera Pharmaceuticals. Dr. Geschwind has received personal compensation for activities with SynapDX, Allen Brain Institute, and Vanderbilt Kennedy Center. Dr. Nelson has nothing to disclose.