Bioinformatics-Based Identification of Expanded Repeats: A Non-reference Intronic Pentamer Expansion in RFC1 Causes CANVAS.

TitleBioinformatics-Based Identification of Expanded Repeats: A Non-reference Intronic Pentamer Expansion in RFC1 Causes CANVAS.
Publication TypeJournal Article
Year of Publication2019
AuthorsRafehi, H, Szmulewicz, DJ, Bennett, MF, Sobreira, NLM, Pope, K, Smith, KR, Gillies, G, Diakumis, P, Dolzhenko, E, Eberle, MA, Barcina, MGarcía, Breen, DP, Chancellor, AM, Cremer, PD, Delatycki, MB, Fogel, BL, Hackett, A, G Halmagyi, M, Kapetanovic, S, Lang, A, Mossman, S, Mu, W, Patrikios, P, Perlman, SL, Rosemergy, I, Storey, E, Watson, SRD, Wilson, MA, Zee, DS, Valle, D, Amor, DJ, Bahlo, M, Lockhart, PJ
JournalAm J Hum Genet
Date Published2019 Jul 03

Genomic technologies such as next-generation sequencing (NGS) are revolutionizing molecular diagnostics and clinical medicine. However, these approaches have proven inefficient at identifying pathogenic repeat expansions. Here, we apply a collection of bioinformatics tools that can be utilized to identify either known or novel expanded repeat sequences in NGS data. We performed genetic studies of a cohort of 35 individuals from 22 families with a clinical diagnosis of cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome (CANVAS). Analysis of whole-genome sequence (WGS) data with five independent algorithms identified a recessively inherited intronic repeat expansion [(AAGGG)] in the gene encoding Replication Factor C1 (RFC1). This motif, not reported in the reference sequence, localized to an Alu element and replaced the reference (AAAAG) short tandem repeat. Genetic analyses confirmed the pathogenic expansion in 18 of 22 CANVAS-affected families and identified a core ancestral haplotype, estimated to have arisen in Europe more than twenty-five thousand years ago. WGS of the four RFC1-negative CANVAS-affected families identified plausible variants in three, with genomic re-diagnosis of SCA3, spastic ataxia of the Charlevoix-Saguenay type, and SCA45. This study identified the genetic basis of CANVAS and demonstrated that these improved bioinformatics tools increase the diagnostic utility of WGS to determine the genetic basis of a heterogeneous group of clinically overlapping neurogenetic disorders.

Alternate JournalAm. J. Hum. Genet.
PubMed ID31230722
PubMed Central IDPMC6612533
Grant List / / Wellcome Trust / United Kingdom
R01 NS082094 / NS / NINDS NIH HHS / United States
U54 HG006542 / HG / NHGRI NIH HHS / United States