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Clarification of undiagnosed ataxia using whole-exome sequencing with clinical implications
- 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.
- Subjects :
- Adult
Male
0301 basic medicine
congenital, hereditary, and neonatal diseases and abnormalities
Pediatrics
medicine.medical_specialty
Ataxia
Adolescent
Cerebellar Ataxia
Hereditary spastic paraplegia
Population
Young Adult
03 medical and health sciences
0302 clinical medicine
Republic of Korea
Exome Sequencing
medicine
Humans
Family history
education
Exome sequencing
education.field_of_study
Cerebellar ataxia
Spastic Paraplegia, Hereditary
business.industry
Middle Aged
medicine.disease
030104 developmental biology
Neurology
Etiology
Female
Neurology (clinical)
Geriatrics and Gerontology
medicine.symptom
business
Trinucleotide repeat expansion
030217 neurology & neurosurgery
Subjects
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