Diagnostic Efficacy of Genetic Studies in a Series of Hereditary Cerebellar Ataxias in Eastern Spain

Background and Objectives To determine the diagnostic efficacy of clinical exome-targeted sequencing (CES) and spinocerebellar ataxia 36 (SCA36) screening in a real-life cohort of patients with cerebellar ataxia (CA) from Eastern Spain. Methods A total of 130 unrelated patients with CA, negative for common trinucleotide repeat expansions (SCA1, SCA2, SCA3, SCA6, SCA7, SCA8, SCA12, SCA17, dentatorubral pallidoluysian atrophy [DRPLA], and Friedreich ataxia), were studied with CES. Bioinformatic and genotype-phenotype analyses were performed to assess the pathogenicity of the variants encountered. Copy number variants were analyzed when appropriate. In undiagnosed dominant and sporadic cases, repeat primed PCR was used to screen for the presence of a repeat expansion in the NOP56 gene. Results CES identified pathogenic or likely pathogenic variants in 50 families (39%), including 23 novel variants. Overall, there was a high genetic heterogeneity, and the most frequent genetic diagnosis was SPG7 (n = 15), followed by SETX (n = 6), CACNA1A (n = 5), POLR3A (n = 4), and SYNE1 (n = 3). In addition, 17 families displayed likely pathogenic/pathogenic variants in 14 different genes: KCND3 (n = 2), KIF1C (n = 2), CYP27A1A (n = 2), AFG3L2 (n = 1), ANO10 (n = 1), CAPN1 (n = 1), CWF19L1 (n = 1), ITPR1 (n = 1), KCNA1 (n = 1), OPA1 (n = 1), PNPLA6 (n = 1), SPG11 (n = 1), SPTBN2 (n = 1), and TPP1 (n = 1). Twenty-two novel variants were characterized. SCA36 was diagnosed in 11 families, all with autosomal dominant (AD) presentation. SCA36 screening increased the total diagnostic rate to 47% (n = 61/130). Ultimately, undiagnosed patients showed delayed age at onset (p < 0.05) and were more frequently sporadic. Discussion Our study provides insight into the genetic landscape of CA in Eastern Spain. Although CES was an effective approach to capture genetic heterogeneity, most patients remained undiagnosed. SCA36 was found to be a relatively frequent form and, therefore, should be tested prior to CES in familial AD presentations in particular geographical regions.

Automated summary

This study aimed to determine the diagnostic efficacy of clinical exome-targeted sequencing (CES) and spinocerebellar ataxia 36 (SCA36) screening in a real-life cohort of patients with cerebellar ataxia (CA) from Eastern Spain. The results showed that CES identified different pathogenic variants in a majority of the patients, but many cases remained undiagnosed.