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

Abstract

Background and ObjectivesTo 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.MethodsA 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 theNOP56gene.ResultsCES 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 wasSPG7(n = 15), followed bySETX(n = 6),CACNA1A(n = 5),POLR3A(n = 4), andSYNE1(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), andTPP1(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.DiscussionOur 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.

Spinocerebellar Ataxia 36 is a Frequent Cause of Hereditary Ataxia in Eastern Spain

“…Patients were enrolled from the Ataxia Clinic at Hospital Universitari i Politècnic La Fe, a national referral center for Hereditary Cerebellar Ataxia and Spastic Paraplegia. The inclusion criteria were: (1) patients with a progressive cerebellar ataxia with negative studies for acquired etiologies; (2) sporadic or AD presentation; and (3) negative genetic studies including analysis of trinucleotide repeat expansion ataxias (SCA1, SCA2, SCA3, SCA6, SCA7, SCA8, SCA12, SCA17, DRPLA and Friedreich ataxia) and/or clinical exome sequencing 8 . Ultimately, SCA36 was screened in 84 index patients from 297 pedigrees.…”

“…Screening of the hexanucleotide repeat was ruled out with both conventional PCR and Repeat-Primed PCR (RP-PCR) as previously described. 1,8 The number of repeats in non-expanded alleles was calculated according to an amplicon of 174pb with a static region of 132 pb.…”

Spinocerebellar ataxia type 19: a series of patients from Latin America. Phenotypic spectrum from early-onset to late-onset slowly progressive ataxia

“…Spinocerebellar ataxia (SCA) 19 is a rare autosomal dominant genetic disorder that leads to progressive ataxia and cerebellar atrophy [1]. It is caused by mutations in KCND3, which encodes a voltage-gated potassium channel subunit that plays a crucial role in the function of cerebellar Purkinje cells.…”