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

Raquel Baviera-Muñoz; Lidón Carretero-Vilarroig; Juan Francisco Vázquez-Costa; Carlos Morata-Martínez; Marina Campins-Romeu; Nuria Muelas; Isabel Sastre-Bataller; Irene Martínez-Torres; Julia Pérez-García; Rafael Sivera; Teresa Sevilla; Juan J Vilchez; Teresa Jaijo; Carmen Espinós; Jose M Millán; Luis Bataller; Elena Aller

doi:10.1212/NXG.0000000000200038

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

Neurol Genet. 2022 Nov 14;8(6):e200038. doi: 10.1212/NXG.0000000000200038. eCollection 2022 Dec.

Authors

Raquel Baviera-Muñoz¹, Lidón Carretero-Vilarroig¹, Juan Francisco Vázquez-Costa¹, Carlos Morata-Martínez¹, Marina Campins-Romeu¹, Nuria Muelas¹, Isabel Sastre-Bataller¹, Irene Martínez-Torres¹, Julia Pérez-García¹, Rafael Sivera¹, Teresa Sevilla¹, Juan J Vilchez¹, Teresa Jaijo¹, Carmen Espinós¹, Jose M Millán¹, Luis Bataller¹, Elena Aller¹

Affiliation

¹ Neuromuscular Diseases Unit (R.B.-M., J.F.V.-C., C.M.-M., M.C.-R., N.M., I.S.-B., I.M.-T., J.P.-G., R.S., T.S., L.B.), Neurology Department, Hospital Universitari I Politècnic La Fe and Neuromuscular Reference Centre, ERN-EURO-NMD; Neuromuscular and Ataxias Research Group. Instituto de Investigación Sanitaria La Fe (R.B.-M., L.C.-V., J.F.V.-C., N.M., R.S., T.S., J.J.V., L.B.); Rare Diseases Joint Unit (R.B.-M., L.C.-V., J.F.V.-C., N.M., I.S.-B., I.M.-T., T.S., J.J.V., T.J., C.E., J.M.M., L.B., E.A.), CIPF-IIS La Fe; Cell Biology Department (L.C.-V.), University of Valencia; Department of Medicine (J.F.V.-C., N.M., T.S., L.B.), University of Valencia; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER) (J.F.V.-C., N.M., R.S., T.S., J.J.V., T.J., J.M.M., L.B., E.A.); Department of Medicine (R.S.), University CEU Cardenal Herrera; Department of Genetics (T.J., E.A.), Hospital Universitari I Politècnic La Fe; Cellular (T.J., J.M.M., E.A.), Molecular and Genomics Biomedicine Group, Instituto de Investigación Sanitaria La Fe; and Laboratory of Rare Neurodegenerative Diseases (C.E.), Centro de Investigación Príncipe Felipe (CIPF), Valencia, Spain.

Abstract

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.