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. 2022 Nov;269(11):6086-6093.
doi: 10.1007/s00415-022-11275-9. Epub 2022 Jul 21.

Prevalence of intronic repeat expansions in RFC1 in Dutch patients with CANVAS and adult-onset ataxia

Fatemeh Ghorbani  1 , Jelkje de Boer-Bergsma  1 , Corien C Verschuuren-Bemelmans  1   2 , Maartje Pennings  3 , Eddy N de Boer  1 , Berry Kremer  4   2 , Els K Vanhoutte  5 , Jeroen J de Vries  4   2 , Raymond van de Berg  6 , Erik-Jan Kamsteeg  3 , Cleo C van Diemen #  1 , Helga Westers #  1 , Bart P van de Warrenburg #  7 , Dineke S Verbeek  8   9
Affiliations

Prevalence of intronic repeat expansions in RFC1 in Dutch patients with CANVAS and adult-onset ataxia

Fatemeh Ghorbani et al. J Neurol. 2022 Nov.

Abstract

Recently, an intronic biallelic (AAGGG)n repeat expansion in RFC1 was shown to be a cause of CANVAS and adult-onset ataxia in multiple populations. As the prevalence of the RFC1 repeat expansion in Dutch cases was unknown, we retrospectively tested 9 putative CANVAS cases and two independent cohorts (A and B) of 395 and 222 adult-onset ataxia cases, respectively, using the previously published protocol and, for the first time optical genome mapping to determine the size of the expanded RFC1 repeat. We identified the biallelic (AAGGG)n repeat expansion in 5/9 (55%) putative CANVAS patients and in 10/617 (1.6%; cohorts A + B) adult-onset ataxia patients. In addition to the AAGGG repeat motif, we observed a putative GAAGG repeat motif in the repeat expansion with unknown significance in two adult-onset ataxia patients. All the expanded (AAGGG)n repeats identified were in the range of 800-1299 repeat units. The intronic biallelic RFC1 repeat expansion thus explains a number of the Dutch adult-onset ataxia cases that display the main clinical features of CANVAS, and particularly when ataxia is combined with neuropathy. The yield of screening for RFC1 expansions in unselected cohorts is relatively low. To increase the current diagnostic yield in ataxia patients, we suggest adding RFC1 screening to the genetic diagnostic workflow by using advanced techniques that attain long fragments.

Keywords: Adult-onset ataxia; CANVAS; Optical genome mapping; RFC1; Repeat expansion.

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Conflict of interest statement

The authors report no conflict of interest.

Figures

Fig. 1
Fig. 1
Diagram showing the workflow and the number of patients from each cohort at the start of the study to identify patients with RFC1 (AAGGG)n expanded alleles. The study started with 3 cohorts including a putative CANVAS cohort consisting of nine cases, and cohorts A and B with 395 and 222 adult-onset ataxia cases, respectively. The subsequent steps included: (1) RFC1-flanking PCR to identify cases with a non-amplifiable RFC1 region, (2) repeat primed-PCR (RP–PCR) to identify patients suspected of carrying biallelic (AAGGG)n  expansions, (3) Sanger sequencing (Sanger-Seq) to read the repeat motifs and (4) collect fresh blood and (5) optical genome mapping to determine the size of the repeat expansion
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