DOI: 10.5061/dryad.1vhhmgqrd
title: Natural history, phenotypic spectrum, and discriminative features of multisystemic RFC1-disease

description: Objective: To delineate the full phenotypic spectrum, discriminative
 features, piloting longitudinal progression data, and sample size
 calculations of RFC1-repeat expansions, recently identified as causing
 cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS).
 Methods: Multimodal RFC1 repeat screening (PCR, southern blot,
 whole-exome/genome (WES/WGS)-based approaches) combined with
 cross-sectional and longitudinal deep-phenotyping in (i) cross-European
 cohort A (70 families) with ≥2 features of CANVAS and/or
 ataxia-with-chronic-cough (ACC); and (ii) Turkish cohort B (105 families)
 with unselected late-onset ataxia. Results: Prevalence of RFC1-disease was
 67% in cohort A, 14% in unselected cohort B, 68% in clinical CANVAS, and
 100% in ACC. RFC1-disease was also identified in Western and Eastern
 Asians, and even by WES. Visual compensation, sensory symptoms, and cough
 were strong positive discriminative predictors (&gt;90%) against
 RFC1-negative patients. The phenotype across 70 RFC1-positive patients was
 mostly multisystemic (69%), including dysautonomia (62%) and bradykinesia
 (28%) (=overlap with cerebellar-type multiple system atrophy [MSA-C]),
 postural instability (49%), slow vertical saccades (17%), and chorea
 and/or dystonia (11%). Ataxia progression was ~1.3 SARA points/year (32
 cross-sectional, 17 longitudinal assessments, follow-up ≤9 years [mean
 3.1]), but also included early falls, variable non-linear phases of
 MSA-C-like progression (SARA 2.5-5.5/year), and premature death. Treatment
 trials require 330 (1-year-trial) and 132 (2-year-trial) patients in total
 to detect 50% reduced progression. Conclusions: RFC1-disease is frequent
 and occurs across continents, with CANVAS and ACC as highly diagnostic
 phenotypes, yet as variable, overlapping clusters along a continuous
 multisystemic disease spectrum, including MSA-C-overlap. Our natural
 history data help to inform future RFC1-treatment trials.
description: All patients and/or records
 were systematically re-assessed by the local physician according to a
 common comprehensive standardized data sheet developed by our RFC1 study
 group. All patients had at least one neurological examination;
 longitudinal data with ≥2 prospective examinations were available from 31
 patients. Classification as CANVAS required clinical evidence of
 cerebellar, neuropathic (abnormal vibration sense with or without abnormal
 ankle reflex) and bilateral vestibular (vestibulo-ocular reflex by
 head-impulse test or video-oculography) damage to increase the sensitivity
 of our screening and to allow capturing patients from various centers
 across Europe (rather than electrophysiological evidence of e.g. sensory
 neuropathy, as required by the proposed diagnostic criteria of CANVAS).
 The phenotype was classified as “multisystemic” if any additional feature
 was present in addition to the CANVAS systems’ features: e.g. hypokinetic
 or hyperkinetic movement disorders, pyramidal signs , slow saccades,
 cognitive impairment, and/or signs of autonomic dysfunction. Ataxia
 severity was assessed by the Scale for the Assessment and Rating of Ataxia
 (SARA). Functional impairment was rated with the Spinocerebellar
 Degeneration Functional Score (SDFS) based on patient history and clinical
 examinations. In a small
 independent exploratory analysis, we aimed to investigate whether the
 intronic AAGGG repeat motif can also be detected in WGS and in particular
 even WES datasets. We developed a data screening algorithm that first
 searched for sequence reads mapping within the chromosomal position of the
 RFC1 repeat expansion and then displayed the AAGGG motif in soft-clipped
 reads, in WES leveraging unintended off-target reads incidentally
 overlapping the repeat locus.
description: Missing values in Excel sheet reflect missing clinical data that
 could not be extracted from the records, probably indicating that the
 corresponding feature had not been asked or clinically examined.