Long-Read Sequencing in Isolated Dystonia
Abstract
Dystonia is defined as a movement disorder characterized by sustained or intermittent muscle contractions causing abnormal, often repetitive, movements, postures, or both. Dystonic movements are typically patterned and twisting and may be tremulous. Dystonia is often initiated or worsened by voluntary action and associated with overflow muscle activation. In isolated dystonia, dystonia is the only motor feature except for tremor. In isolated dystonia, patients have no other neurological abnormalities. Most patients with isolated dystonia have late-onset adult-onset disease beginning in the fourth and fifth decades of life. Even though late-onset isolated dystonia has a considerable heritable component, large pedigrees are rare. Conversely, small multiplex pedigrees with two or three affected individuals are not uncommon. To date, only a small number of genes have been linked to adult-onset isolated dystonia and explain only a very small percentage of cases. Currently, almost 95% of patients with sporadic and familial adult-onset isolated dystonia are lacking a genetic diagnosis. Traditional short-read sequencing methods, which have been used over the past 20 years, are unable to detect several specific types of mutations. Recently, PACBIO has developed high-fidelity long read (HiFi-LR) technology that permits virtual detection types of genetic abnormalities. PACBIO HiFi-LR sequencing will be performed in multiplex pedigrees with adult-onset isolated dystonia. Based on discovery rates in other adult-onset neurological disorders and recent successes with HiFi-LR, we anticipate discovering novel causes of isolated adult-onset dystonia and expose complex structural and/or non-coding genetic abnormalities in established dystonia-associated genes. Most importantly, these pilot experiments will serve as a platform for more expansive studies of adult-onset isolated dystonia using modern LR technologies. To our knowledge, HiFi-LR technology has not been applied to the study of adult-onset isolated dystonia. HiFi-LR sequencing opens the possibility of exposing the undiscovered heritability of adult-onset isolated dystonia and pinpointing targets for pharmacological intervention.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210215
Entities
People
- Mark S LeDoux
Organizations
- United States Army
- University of Memphis