Journal article
Truncating Variants in RFC1 in Cerebellar Ataxia, Neuropathy, and Vestibular Areflexia Syndrome
Neurology, Vol.100(5), pp.e543-E554
01/31/2023
DOI: 10.1212/WNL.0000000000201486
PMCID: PMC9931080
PMID: 36289003
Abstract
Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS) is an autosomal recessive neurodegenerative disease characterized by adult-onset and slowly progressive sensory neuropathy, cerebellar dysfunction, and vestibular impairment. In most cases, the disease is caused by biallelic (AAGGG)
repeat expansions in the second intron of the replication factor complex subunit 1 (
). However, a small number of cases with typical CANVAS do not carry the common biallelic repeat expansion. The objective of this study was to expand the genotypic spectrum of CANVAS by identifying sequence variants in
-coding region associated with this condition.
Fifteen individuals diagnosed with CANVAS and carrying only 1 heterozygous (AAGGG)
expansion in
underwent whole-genome sequencing or whole-exome sequencing to test for the presence of a second variant in
or other unrelated gene. To assess the effect of truncating variants on
expression, we tested the level of RFC1 transcript and protein on patients' derived cell lines.
We identified 7 patients from 5 unrelated families with clinically defined CANVAS carrying a heterozygous (AAGGG)
expansion together with a second truncating variant
in
, which included the following: c.1267C>T (p.Arg423Ter), c.1739_1740del (p.Lys580SerfsTer9), c.2191del (p.Gly731GlufsTer6), and c.2876del (p.Pro959GlnfsTer24). Patient fibroblasts containing the c.1267C>T (p.Arg423Ter) or c.2876del (p.Pro959GlnfsTer24) variants demonstrated nonsense-mediated mRNA decay and reduced RFC1 transcript and protein.
Our report expands the genotype spectrum of RFC1 disease. Full
sequencing is recommended in cases affected by typical CANVAS and carrying monoallelic (AAGGG)
expansions. In addition, it sheds further light on the pathogenesis of RFC1 CANVAS because it supports the existence of a loss-of-function mechanism underlying this complex neurodegenerative condition.
Details
- Title: Subtitle
- Truncating Variants in RFC1 in Cerebellar Ataxia, Neuropathy, and Vestibular Areflexia Syndrome
- Creators
- Riccardo Ronco - National Hospital for Neurology and NeurosurgeryCecilia Perini - National Hospital for Neurology and NeurosurgeryRiccardo Currò - National Hospital for Neurology and NeurosurgeryNatalia Dominik - National Hospital for Neurology and NeurosurgeryStefano Facchini - National Hospital for Neurology and NeurosurgeryAlice Gennari - National Hospital for Neurology and NeurosurgeryRoberto Simone - National Hospital for Neurology and NeurosurgerySkye Stuart - National Hospital for Neurology and NeurosurgerySara Nagy - National Hospital for Neurology and NeurosurgeryElisa Vegezzi - National Hospital for Neurology and NeurosurgeryIlaria Quartesan - National Hospital for Neurology and NeurosurgeryAmar El-Saddig - National Hospital for Neurology and NeurosurgeryTimothy Lavin - National Hospital for Neurology and NeurosurgeryArianna Tucci - National Hospital for Neurology and NeurosurgeryAgnieszka Szymura - National Hospital for Neurology and NeurosurgeryLuiz Eduardo Novis De FariasAlexander Gary - National Hospital for Neurology and NeurosurgeryMegan Delfeld - National Hospital for Neurology and NeurosurgeryPriscilla Kandikatla - National Hospital for Neurology and NeurosurgeryNifang Niu - National Hospital for Neurology and NeurosurgerySanjukta Tawde - National Hospital for Neurology and NeurosurgeryJoseph Shaw - National Hospital for Neurology and NeurosurgeryJames Polke - National Hospital for Neurology and NeurosurgeryMary M Reilly - National Hospital for Neurology and NeurosurgeryNick W WoodEmmanuele Crespan - National Hospital for Neurology and NeurosurgeryChristopher Gomez - National Hospital for Neurology and NeurosurgeryJin Yun Helen Chen - National Hospital for Neurology and NeurosurgeryJeremy Dan Schmahmann - National Hospital for Neurology and NeurosurgeryDavid Gosal - National Hospital for Neurology and NeurosurgeryHenry Houlden - National Hospital for Neurology and NeurosurgerySoma Das - National Hospital for Neurology and NeurosurgeryAndrea Cortese - National Hospital for Neurology and Neurosurgery
- Resource Type
- Journal article
- Publication Details
- Neurology, Vol.100(5), pp.e543-E554
- DOI
- 10.1212/WNL.0000000000201486
- PMID
- 36289003
- PMCID
- PMC9931080
- ISSN
- 0028-3878
- eISSN
- 1526-632X
- Grant note
- MR/S01165X/1 / Medical Research Council Wellcome Trust MR/T001712/1 / Medical Research Council
- Language
- English
- Date published
- 01/31/2023
- Academic Unit
- Stead Family Department of Pediatrics; Medical Genetics and Genomics
- Record Identifier
- 9984701550202771
Metrics
6 Record Views