Exome sequencing in the clinical diagnosis of sporadic or familial cerebellar ataxia

Abstract

Importance: Cerebellar ataxias are a diverse collection of neurologic 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 patients with ataxia present sporadically with adult onset of symptoms and the contribution of genetic variation to the phenotype of these patients has not yet been established.

Objective: To investigate the contribution of genetic disease in a population of patients with predominantly adult- and sporadic-onset cerebellar ataxia.

Design, setting, and participants: We examined a consecutive series of 76 patients presenting to a tertiary referral center for evaluation of chronic progressive cerebellar ataxia.

Main outcomes and measures: Next-generation exome sequencing coupled with comprehensive bioinformatic analysis, phenotypic analysis, and clinical correlation.

Results: We identified clinically relevant genetic information in more than 60% of patients studied (n = 46), including diagnostic pathogenic gene variants in 21% (n = 16), a notable yield given the diverse genetics and clinical heterogeneity of the cerebellar ataxias.

Conclusions and relevance: This study demonstrated that clinical exome sequencing in patients with adult-onset and sporadic presentations of ataxia is a high-yield test, providing a definitive diagnosis in more than one-fifth of patients and suggesting a potential diagnosis in more than one-third to guide additional phenotyping and diagnostic evaluation. Therefore, clinical exome sequencing is an appropriate consideration in the routine genetic evaluation of all patients presenting with chronic progressive cerebellar ataxia.

Figure 1. Neuroimaging and Pathology From Selected Cases With Pathogenic Variants

A, Case ATX1. T2 fluid-attenuated inversion recovery axial imaging shows diffuse white matter hyperintensities in a patient with disease due to POLR3A mutation. B, Case ATX48. T1 sagittal imaging shows severe cerebellar atrophy in a patient with disease due to POLR3B mutation. C, Case ATX67. T1 sagittal imaging shows cerebellar atrophy in a patient with disease due to a de novo mutation in ITPR1. Mitochondrial disease due to NDUFS7 mutation in case ATX58 (D and E). D, Subsarcolemmal linear aggregates are seen with the oxidative enzyme SDH (original magnification ×20, arrowheads). Occasional small ragged blue fibers are also seen (asterisks). E, Electron microscopy demonstrates aggregates of subsarcolemmal mitochondrial hyperplasia with pleioconia, occasional megaconial forms, abnormal cristae architecture, and crystalline inclusions (original magnification ×25 000, arrowheads).

Figure 2. Diagnostic Evaluation for Patients Presenting With Chronic Progressive Cerebellar Ataxia

A general flowchart for the clinical evaluation of a patient presenting with chronic progressive cerebellar ataxia. Initial diagnostic testing should address acquired etiologies because these are more common than genetic causes and often treatable or modifiable. Once acquired conditions are ruled out, a more formal genetic evaluation would include basic testing for either high-yield single genes or, if presentation is sporadic, the most common genetic causes worldwide. If nondiagnostic, a more detailed genetic evaluation is recommended using clinical exome sequencing for rare genetic causes or variant presentations of other disorders. Trio testing of parents and probands may be useful in cases of early-onset (at or before age 20 years) or suspected recessive inheritance to evaluate allelic segregation or de novo mutation. ^aSingle-gene testing for high-yield disorders based on clinical phenotype or family history. If initial differential includes strong consideration of multiple single genes, exome sequencing is likely preferable because of cost. SCA indicates spinocerebellar ataxia.