Rapid diagnosis of SCA36 in a three-generation family using short-read whole genome sequencing data

Abstract

Background: Spinocerebellar ataxias (SCA) are often caused by expansions of short tandem repeats (STRs). Recent methodological advances have made repeat expansion (RE) detection with whole genome sequencing (WGS) feasible. Objectives: To determine the genetic basis of ataxia in a large, multigenerational Australian pedigree, with autosomal dominant inheritance and possible anticipation. Methods and Results: WGS was performed on three affected relatives. The sequence data was screened for known pathogenic REs using three repeat expansion detection tools: exSTRa, ExpansionHunter and GangSTR. This screen provided a clear and rapid diagnosis (<5 days from receiving the sequencing data) of SCA36, a very rare form of ataxia which is caused by an intronic hexanucleotide GGCCTG RE in NOP56. Conclusions:We have demonstrated that diagnosis of rare ataxias caused by REs is highly feasible and cost effective with WGS. We propose a change in current clinical practice, such that WGS be implemented as the frontline, cost effective methodology for molecular testing of individuals with a clinical diagnosis of ataxia.

A Diagnostic Ceiling for Exome Sequencing in Cerebellar Ataxia and Related Neurological Disorders (2006)

“…The development of collaborative resources to merge data and analysis from large cohorts of patients with ataxic phenotypes may aid in the discovery of such genes (Fogel, 2018a), as will a focus on mutation types not typically detected by exome sequencing. For example, novel disease-causing repeat expansion disorders continue to be described and subsequently identified in undiagnosed patients (Cortese et al, 2019;Ishikawa et al, 2011;Kobayashi et al, 2011;Rafehi et al, 2019;Seixas et al, 2017;Valera et al, 2017). Furthermore, variants whose effect is determined in combination with additional genes (digenic, polygenic), epigenetic, or environmental factors, or causal mutations in the noncoding genome that affect gene regulation would be difficult to detect by current DNAonly methods.…”

“…Coupling next-generation sequencing methods with transcriptome analysis has already shown diagnostic utility in other rare diseases (Lee et al, 2019). In addition to WGS, new sequencing platforms and analysis strategies are in various stages of development that could facilitate the identification of rare or novel repeat expansions (Gymrek, Golan, Rosset, & Erlich, 2012;Rafehi et al, 2019), or smaller or more complex CNV or CNV mediated by difficult to map repeat elements (SINEs, LINEs, etc. ;Turner et al, 2016).…”