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Bioinformatics-Based Identification of Expanded Repeats: A Non-reference Intronic Pentamer Expansion in RFC1 Causes
Haloom Rafehi1, David J Szmulewicz2, Mark F Bennett3
1Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, 1G Royal Parade, Parkville, VIC 3052, Australia.
American Journal of Human Genetics
|June 25, 2019
Summary
Researchers identified a repeat expansion in the RFC1 gene as the cause of cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome (CANVAS). This discovery advances genomic diagnostics for neurogenetic disorders.
Area of Science:
- Genomics
- Neurogenetics
- Bioinformatics
Background:
- Next-generation sequencing (NGS) revolutionizes diagnostics but struggles with repeat expansions.
- Cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome (CANVAS) is a neurodegenerative disorder with an unknown genetic cause.
Purpose of the Study:
- To identify the genetic basis of CANVAS using advanced bioinformatics tools.
- To improve the diagnostic utility of whole-genome sequencing (WGS) for repeat expansion disorders.
Main Methods:
- Applied multiple bioinformatics algorithms to analyze whole-genome sequencing (WGS) data from CANVAS patients.
- Investigated a cohort of 35 individuals from 22 families with a clinical diagnosis of CANVAS.
- Performed genetic analyses to confirm pathogenic repeat expansions and identify ancestral haplotypes.
Main Results:
- Identified a novel intronic repeat expansion [(AAGGG)exp] in the Replication Factor C1 (RFC1) gene in 18 of 22 CANVAS families.
- The RFC1 repeat expansion replaced a reference short tandem repeat and localized to an Alu element.
- Re-diagnosed four RFC1-negative families with other spinocerebellar ataxias (SCAs), including SCA3, spastic ataxia of Charlevoix-Saguenay, and SCA45.
Conclusions:
- The intronic repeat expansion in RFC1 is the primary genetic cause of CANVAS.
- Developed and validated bioinformatics tools for detecting pathogenic repeat expansions in WGS data.
- Enhanced WGS utility for diagnosing heterogeneous neurogenetic disorders.
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