Minkyeong Kim1, Ah Reum Kim2, Ji Sun Kim3, Jongkyu Park4, Jinyoung Youn5, Jong Hyeon Ahn3, Jun Kyu Mun3, Chung Lee6, Nam-Soon Kim7, Nayoung K D Kim6, Woong-Yang Park8, Jin Whan Cho9. 1. Department of Neurology, Gyeongsang National University Hospital, Jinju, South Korea. 2. Genomics Core Facility, Biomedical Research Institute, Seoul National University Hospital, Seoul, South Korea. 3. Department of Neurology, Samsung Medical Center, Seoul, South Korea; Neuroscience Center, Samsung Medical Center, Seoul, South Korea. 4. Department of Neurology, Soonchunhyang University Hospital, Soonchunhyang University School of Medicine, Cheonan, South Korea. 5. Department of Neurology, Samsung Medical Center, Seoul, South Korea; Neuroscience Center, Samsung Medical Center, Seoul, South Korea; Department of Neurology, Sungkyunkwan University School of Medicine, Suwon, South Korea. 6. GENINUS Inc., Seoul, 05836 South Korea. 7. Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, South Korea; Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology (UST), Daejeon, South Korea. 8. GENINUS Inc., Seoul, 05836 South Korea; Samsung Genome Institute, Samsung Medical Center, Seoul, South Korea; Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon, South Korea. 9. Department of Neurology, Samsung Medical Center, Seoul, South Korea; Neuroscience Center, Samsung Medical Center, Seoul, South Korea; Department of Neurology, Sungkyunkwan University School of Medicine, Suwon, South Korea. Electronic address: jinwhan.cho@samsung.com.
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.
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 ataxiapatients 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.