Rapid Diagnosis of Spinocerebellar Ataxia 36 in a Three‐Generation Family Using Short‐Read Whole‐Genome Sequencing Data

Abstract

Background Spinocerebellar ataxias are often caused by expansions of short tandem repeats. Recent methodological advances have made repeat expansion (RE) detection with whole‐genome sequencing (WGS) feasible. Objectives The objective of this study was to determine the genetic basis of ataxia in a multigenerational Australian pedigree with autosomal‐dominant inheritance. Methods and Results WGS was performed on 3 affected relatives. The sequence data were screened for known pathogenic REs using 2 RE detection tools: exSTRa and ExpansionHunter. This screen provided a clear and rapid diagnosis (<5 days from receiving the sequencing data) of spinocerebellar ataxia 36, a rare form of ataxia caused by an intronic GGCCTG RE in NOP56. Conclusions The diagnosis of rare ataxias caused by REs is highly feasible and cost‐effective with WGS. We propose that WGS could potentially be implemented as the frontline, cost‐effective methodology for the molecular testing of individuals with a clinical diagnosis of ataxia. © 2020 International Parkinson and Movement Disorder Society

Low Prevalence of NOTCH2NLC GGC Repeat Expansion in White Patients with Movement Disorders

“…In addition, we successfully detected the pathogenic expansion in NOTCH2NLC in a patient using the computational tool ExpansionHunter, corroborating the utility of WGS data for screening repeat expansion disorders. 20 We leveraged the WGS data in a large population cohort to demonstrate that the background repeat structure and allelic frequency of the GGC repeat in NOTCH2NLC between Whites and East Asians are comparable and do not explain the ethnic difference in NIID prevalence. The difference in prevalence may be a result of a founder effect in East Asian populations.…”

The clinical utility of exome sequencing and extended bioinformatic analyses in adolescents and adults with a broad range of neurological phenotypes: an Australian perspective

“…The repeat expansion detection tools, exSTRa and ExpansionHunter, were used with default parameters, but with additional parameters for ExpansionHunter: inclusion of off-target reads and read-depth of 30 and min-anchor-mapq of 20; applications of these methods have been published where they have been used to detect a variety of repeat expansions. [1][2][3]12,20] An up to date list of known repeat expansions for all currently used bioinformatic repeat expansion detection tools can be obtained from https://github.com/bahlol ab/Bio-STR-exSTRa.…”

Unexpected diagnosis of myotonic dystrophy type 2 repeat expansion by genome sequencing

“…Alignment was performed based on the GATK best practice pipeline. Fastq files aligned to the hg19 reference genome using BWAmem, then duplicate marking, local realignment, and recalibration were performed with GATK and analyzed for REs of STRs known to cause neurological disorders using RE detection tools exSTRa [6] and Expansion-Hunter [7], as previously described [2]. A database of pre-defined pathogenic REs was used: https://github.com/bahlolab/exSTRa/blob/ master/inst/extdata/repeat_expansion_disorders_hg19.txt (file version committed on Nov 21, 2019).…”

“…More recently, there have been significant advances in the development of bioinformatic methods for the detection of repeat expansions (REs) of short tandem repeats (STRs) in short-read sequencing datasets, such as exSTRa and ExpansionHunter [1]. These tools have proven successful for the diagnosis of conditions caused by known REs, and in the discovery of new REs [2,3]. In this study, we recruited a multigenerational family (Family A) with multiple incidences of autism spectrum disorder (ASD), in order to study generic determinates of ASD, including REs.…”