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Clarification of undiagnosed ataxia using whole-exome sequencing with clinical implications

Authors :
Jinyoung Youn
Jun Kyu Mun
Minkyeong Kim
Woong-Yang Park
Jin Whan Cho
Nam-Soon Kim
Ji Sun Kim
Jongkyu Park
Jong Hyeon Ahn
Ah Reum Kim
Nayoung Kim
Chung Lee
Source :
Parkinsonism & Related Disorders. 80:58-64
Publication Year :
2020
Publisher :
Elsevier BV, 2020.

Abstract

Background Hereditary cerebellar ataxias exhibit heterogeneous phenotypes and genotypes. To date, advancement of next-generation sequencing technologies have identified many causative genes for ataxia in various population. In this study, whole-exome sequencing (WES) was utilized to explore the genetic cause of ataxia among Korean patients who remained undiagnosed following routine investigation. Methods Patients with ataxia were enrolled in this study. We excluded patients with acquired, degenerative, and trinucleotide repeat ataxias, such as spinocerebellar ataxia 1 (SCA1), SCA2, SCA3, SCA6, SCA7, SCA8, SCA17, Dentatorubral-pallidoluysian atrophy, and Friedreich ataxia. WES was performed. After basic filtering based on population databases, we then performed primary filtering to screen for known ataxia-associated genes, followed by expanded filtering customized for individual patients. Results We enrolled 77 ataxia patients from 68 families. Eighteen families had pathogenic or likely pathogenic variants in 14 different genes, including NEU1, APTX, SPG7, HTRA1, POLG2, SYNE1, CACNA1G, CACNA1A, ITPR1, AHI1, SPG11, ANO10, ATM, and C5orf42, resulting in a diagnostic yield of 26.5%. Hereditary spastic paraplegia was the most common diagnosis. Adult-onset ataxias and those without family history were frequently encountered. Variants of unknown significance were found in 14 (20.6%) families, some of which were highly probable from the clinical perspective. Conclusion Using WES, we explored the molecular etiology of ataxia in patients whom were not diagnosed through routine clinical investigation. This study revealed unexpected rare disorders as well as the known ataxia-associated genes in a Korean population.

Details

ISSN :
13538020
Volume :
80
Database :
OpenAIRE
Journal :
Parkinsonism & Related Disorders
Accession number :
edsair.doi.dedup.....c8cb81f61b2175c3ae168668a5314c71
Full Text :
https://doi.org/10.1016/j.parkreldis.2020.08.040