Abstract
Previous studies using whole exome sequencing (WES) have shown that a significant proportion of adult patients with undiagnosed ataxia in European and North American cohorts have a known genetic cause. Little is known about the diagnostic yield of WES in non-Caucasian ataxic populations. Herein, we used WES to investigate a Brazilian cohort of 76 adult patients with idiopathic ataxia previously screened for trinucleotide expansions in known ataxia genes. We collected clinical and radiological data from each patient. WES was performed following standard procedures. Only variants labeled as pathogenic or likely pathogenic according to American college of medical genetics and genomics (ACMG) criteria were retrieved. We determined the diagnostic yield of WES for the whole cohort and also for subgroups defined according to presence or not of pyramidal signs, peripheral neuropathy, and cerebellar atrophy. There were 41 women and 35 men. Mean age at testing was 48 years. Pyramidal signs, peripheral neuropathy, tremor, and cerebellar atrophy were found in 38.1%, 13.1%, 10.5%, and 68.3% of all subjects, respectively. Diagnostic yield of WES was 35.5%. Thirty-six distinct mutations were found in 20 different genes, determining the diagnosis of 18 autosomal recessive and 9 autosomal dominant ataxias. SACS and SPG7 were the most frequently found underlying genes. WES performed better in the subgroup with vs the subgroup without spasticity (p = 0.005). WES was diagnostic in 35.5% of cases of the Brazilian cohort of ataxia cases. These results have implications for diagnosis, genetic counseling and eventually treatment.
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Retterer K, Juusola J, Cho MT, et al. Clinical application of whole-exome sequencing across clinical indications. Genet Med. 2016;18:696–704.
Fogel BL, Satya-Murti S, Cohen BH. Clinical exome sequencing in neurologic disease. Neurol Clin Pract. 2016;6:164–76.
Farwell KD, Shahmirzadi L, El-Khechen D, et al. Enhanced utility of family-centered diagnostic exome sequencing with inheritance model-based analysis: results from 500 unselected families with undiagnosed genetic conditions. Genet Med. 2015;17:578–86.
Matos CM, Alonso I, Leão M. Diagnostic yield of next-generation sequencing applied to neurological disorders. J Clin Neurosci. 2019;67:14–8.
Bamshad MJ, Ng SB, Bigham AW, Tabor HK, Emond MJ, Nickerson DA, et al. Exome sequencing as a tool for Mendelian disease gene discovery. Nat Rev Genet. 2011;12:745–55.
Pyle A, Smertenko T, Bargiela D, Griffin H, Duff J, Appleton M, et al. Exome sequencing in undiagnosed inherited and sporadic ataxias. Brain. 2014;138:276–83.
Fogel BL, Lee H, Deignan JL, Strom SP, Kantarci S, Wang X, et al. Exome sequencing in the clinical diagnosis of sporadic or familial cerebellar ataxia. JAMA Neurol. 2014;71:1237–46.
Fogel BL, Lee JY, Lane J, et al. Mutations in rare ataxia genes are uncommon causes of sporadic cerebellar ataxia. Mov Disord. 2012;27:442–6.
Perez Maturo J, Zavala L, Vega P, González-Morón D, Medina N, Salinas V, Rosales J, Córdoba M, Arakaki T, Garretto N, Rodríguez-Quiroga S, Kauffman MA. Overwhelming genetic heterogeneity and exhausting molecular diagnostic process in chronic and progressive ataxias: facing it up with an algorithm, a gene, a panel at a time. J Hum Genet. 2020;65:895–902.
Rodríguez-Quiroga SA, Cordoba M, González-Morón D, Medina N, Vega P, Dusefante CV, Arakaki T, Garretto NS, Kauffman MA. Neurogenetics in Argentina: diagnostic yield in a personalized research based clinic. Genet Res (Camb). 2015;97:e10.
Pena SD, Bastos-Rodrigues L, Pimenta JR, Bydlowski SP. DNA tests probe the genomic ancestry of Brazilians. Braz J Med Biol Res. 2009;42:870–6.
Barsottini OGP, Albuquerque MVCD, Neto PB, Pedroso JL. Adult onset sporadic ataxias: a diagnostic challenge. Arq Neuropsiquiatr. 2014;72:232–40.
Sambrook J, Fritsch EF, Maniatis T. Molecular cloning: a laboratory manual. 2nd ed. New York: Cold Spring Harbor Laboratory Press; 1989. p. 3–4.
Richards S, Aziz N, Bale S, et al. ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405–24.
Marelli C, Guissart C, Hubsch C, et al. Mini-Exome coupled to read-depth based copy number variation analysis in patients with inherited ataxias. Hum Mutat. 2016;37:1340–53.
Németh AH, Kwasniewska AC, Lise S, et al. Next generation sequencing for molecular diagnosis of neurological disorders using ataxias as a model. Brain. 2013;136:3106–18.
van de Warrenburg BP, Schouten MI, de Bot ST, et al. Clinical exome sequencing for cerebellar ataxia and spastic paraplegia uncovers novel gene-disease associations and unanticipated rare disorders. Eur J Hum Genet. 2016;24:1460–6.
Ferreira LB, Mendes CT, Wiezel CEV, Luizon MR, Simões AL. Genomic ancestry of a sample population from the state of São Paulo. Brazil Am J Hum Biol. 2006;18:702–5.
Véliz-Otani D, Inca-Martinez M, Bampi GB, et al. ATXN10 microsatellite distribution in a Peruvian Amerindian population. Cerebellum. 2019;18:841–8.
Cintra VP, Bonadia LC, Andrade HMT, et al. The frequency of the C9orf72 expansion in a Brazilian population. Neurobiol Aging. 2018;66:179.e1-179.e4.
Cortese A, Simone R, Sullivan R, et al. Biallelic expansion of an intronic repeat in RFC1 is a common cause of late-onset ataxia. Nat Genet. 2019;51:649–58.
Galatolo D, Tessa A, Filla A, Santorelli FM. Clinical application of next generation sequencing in hereditary spinocerebellar ataxia: increasing the diagnostic yield and broadening the ataxia-spasticity spectrum. A retrospective analysis. Neurogenetics. 2018;19:1–8.
Mariotti C, Gellera C, Rimoldi M, et al. Ataxia with isolated vitamin E deficiency: neurological phenotype, clinical follow-up and novel mutations in TTPA gene in Italian families. Neurol Sci. 2004;25:130–7.
Traschütz A, Schirinzi T, Laugwitz L, et al. Clinico-genetic, imaging and molecular delineation of COQ8A-ataxia: a multicenter study of 59 patients [published online ahead of print, 2020 Apr 26]. Ann Neurol 2020;https://doi.org/10.1002/ana.25751. doi:https://doi.org/10.1002/ana.25751
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This work was supported by Fundação de Amaro à Pesquisa do Estado de São Paulo (FAPESP) Grant # 2013/07559–3.
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All authors contributed to the study conception and design. Material preparation, data collection, and analysis were performed by all authors. The first draft of the manuscript was written by Felipe Franco da Graça and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
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da Graça, F.F., Peluzzo, T.M., Bonadia, L.C. et al. Diagnostic Yield of Whole Exome Sequencing for Adults with Ataxia: a Brazilian Perspective. Cerebellum 21, 49–54 (2022). https://doi.org/10.1007/s12311-021-01268-1
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DOI: https://doi.org/10.1007/s12311-021-01268-1