Bioinformatics Seminars

Bioinformatics Seminar

Time: 10:45am Tuesdays.
Level 7 Seminar Room 2, WEHI1

30 April 2019

Homozygous inheritance of AAGGG RE in RFC1 causes CANVAS

Haloom Rafehi
WEHI Population Health & Immunity

Cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome (CANVAS) is an inherited cerebellar ataxia with no known genetic risk factors. Linkage analysis on four families affected with CANVAS identified a shared linkage region on chromosome 4. Whole exome sequencing of 25 affected individuals from 15 families did not identify plausible candidate variants with standard analysis pipelines. Subsequent analysis of whole genome sequencing (WGS) using two unrelated CANVAS individuals identified a recessively inherited intronic AAGGG RE in the gene Replication Factor C1 (RFC1), within the chr4 linkage region. This motif localised to the 3' end of an alu element and completely replaced the AAAAG motif present in the reference genome. This previously uncharacterised AAGGG RE has an estimated allele frequency of 0.03 (in-house controls). Repeat primed PCR confirmed the homozygous inheritance of the RE in 16 CANVAS families, but was negative for five CANVAS patients. WGS of these patients identified mutations that lead to genomic re-diagnosis with spastic ataxia of Charlevoix-Saguenay (SACS), SCA3 (ATXN3 expansion), SCA45 (FAT2) and a variant of unknown significance in ATXN7. The AAGGG RE shared a core ancestral haplotype in all but one patient and was estimated to have arisen in Europe over 25,000 years ago. This study identified the genetic basis of CANVAS and demonstrated that improved bioinformatics tools increase the diagnostic utility of WGS to determine the genetic basis of a heterogeneous group of clinically overlapping neurogenetic disorders.

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