PT  - JOURNAL ARTICLE
AU  - Baviera-Muñoz, Raquel
AU  - Carretero-Vilarroig, Lidón
AU  - Vázquez-Costa, Juan Francisco
AU  - Morata-Martínez, Carlos
AU  - Campins-Romeu, Marina
AU  - Muelas, Nuria
AU  - Sastre-Bataller, Isabel
AU  - Martínez-Torres, Irene
AU  - Pérez-García, Julia
AU  - Sivera, Rafael
AU  - Sevilla, Teresa
AU  - Vilchez, Juan J.
AU  - Jaijo, Teresa
AU  - Espinós, Carmen
AU  - Millán, Jose M.
AU  - Bataller, Luis
AU  - Aller, Elena
TI  - Diagnostic Efficacy of Genetic Studies in a Series of Hereditary Cerebellar Ataxias in Eastern Spain
AID  - 10.1212/NXG.0000000000200038
DP  - 2022 Dec 01
TA  - Neurology Genetics
PG  - e200038
VI  - 8
IP  - 6
4099  - http://ng.neurology.org/content/8/6/e200038.short
4100  - http://ng.neurology.org/content/8/6/e200038.full
SO  - Neurol Genet2022 Dec 01; 8
AB  - 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.aCGH=arrayCGH; AD=autosomal dominant; AOA2=ataxia with oculomotor apraxia type 2; AR=autosomal recessive; CA=cerebellar ataxia; CES=clinical exome-targeted sequencing; CNV=copy number variant; MLPA=multiple ligation-dependent probe amplification analysis; NGS=next-generation sequencing; RP-PCR=repeat primed PCR; SCA=spinocerebellar ataxia