A novel RFC1 repeat motif (ACAGG) in two Asia-Pacific CANVAS families.

Cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS) is a progressive late-onset, neurological disease. Recently, a pentanucleotide expansion in intron 2 of RFC1 was identified as the genetic cause of CANVAS. We screened an Asian-Pacific cohort for CANVAS and identified a novel RFC1 repeat expansion motif, (ACAGG)exp, in three affected individuals. This motif was associated with additional clinical features including fasciculations and elevated serum creatine kinase. These features have not previously been described in individuals with genetically-confirmed CANVAS. Haplotype analysis showed our patients shared the same core haplotype as previously published, supporting the possibility of a single origin of the RFC1 disease allele. We analysed data from >26 000 genetically diverse individuals in gnomAD to show enrichment of (ACAGG) in non-European populations.

Scriba CK ，Beecroft SJ ，Clayton JS ，Cortese A ，Sullivan R ，Yau WY ，Dominik N ，Rodrigues M ，Walker E ，Dyer Z ，Wu TY ，Davis MR ，Chandler DC ，Weisburd B ，Houlden H ，Reilly MM ，Laing NG ，Lamont PJ ，Roxburgh RH ，Ravenscroft G ... -  《-》

A Māori specific RFC1 pathogenic repeat configuration in CANVAS, likely due to a founder allele.

Cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome (CANVAS) is a recently recognized neurodegenerative disease with onset in mid- to late adulthood. The genetic basis for a large proportion of Caucasian patients was recently shown to be the biallelic expansion of a pentanucleotide (AAGGG)n repeat in RFC1. Here, we describe the first instance of CANVAS genetic testing in New Zealand Māori and Cook Island Māori individuals. We show a novel, possibly population-specific CANVAS configuration (AAAGG)10-25(AAGGG)exp, which was the cause of CANVAS in all patients. There were no apparent phenotypic differences compared with European CANVAS patients. Presence of a common disease haplotype among this cohort suggests this novel repeat expansion configuration is a founder effect in this population, which may indicate that CANVAS will be especially prevalent in this group. Haplotype dating estimated the most recent common ancestor at ∼1430 ce. We also show the same core haplotype as previously described, supporting a single origin of the CANVAS mutation.

Beecroft SJ ，Cortese A ，Sullivan R ，Yau WY ，Dyer Z ，Wu TY ，Mulroy E ，Pelosi L ，Rodrigues M ，Taylor R ，Mossman S ，Leadbetter R ，Cleland J ，Anderson T ，Ravenscroft G ，Laing NG ，Houlden H ，Reilly MM ，Roxburgh RH ... -  《-》

Repeat conformation heterogeneity in cerebellar ataxia, neuropathy, vestibular areflexia syndrome.

Cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS) is a late-onset, slow-progressing multisystem neurodegenerative disorder. Biallelic AAGGG repeat expansion in RFC1 has been identified as causative of this disease, and repeat conformation heterogeneity (ACAGG repeat) was also recently implied. To molecularly characterize this disease in Japanese patients with adult-onset ataxia, we accumulated and screened 212 candidate families by an integrated approach consisting of flanking PCR, repeat-primed PCR, Southern blotting and long-read sequencing using Sequel II, GridION or PromethION. We identified 16 patients from 11 families, of whom seven had ACAGG expansions [(ACAGG)exp/(ACAGG)exp] (ACAGG homozygotes), two had ACAGG and AAGGG expansions [(ACAGG)exp/(AAGGG)exp] (ACAGG/AAGGG compound heterozygotes) and seven had AAGGG expansions [(AAGGG)exp/(AAGGG)exp] (AAGGG homozygotes). The overall detection rate was 5.2% (11/212 families including one family having two expansion genotypes). Long-read sequencers revealed the entire sequence of both AAGGG and ACAGG repeat expansions at the nucleotide level of resolution. Clinical assessment and neuropathology results suggested that patients with ACAGG expansions have similar clinical features to previously reported patients with homozygous AAGGG expansions, although motor neuron involvement was more notable in patients with ACAGG expansions (even if one allele was involved). Furthermore, a later age of onset and slower clinical progression were implied in patients with ACAGG/AAGGG compound heterozygous expansions compared with either ACAGG or AAGGG homozygotes in our very limited cohort. Our study clearly shows the occurrence of repeat conformation heterogeneity, with possible different impacts on the affected nervous systems. The difference in disease onset and progression between compound heterozygotes and homozygotes might also be suspected but with very limited certainty due to the small sample number of cases in our study. Studies of additional patients are needed to confirm this.

Miyatake S ，Yoshida K ，Koshimizu E ，Doi H ，Yamada M ，Miyaji Y ，Ueda N ，Tsuyuzaki J ，Kodaira M ，Onoue H ，Taguri M ，Imamura S ，Fukuda H ，Hamanaka K ，Fujita A ，Satoh M ，Miyama T ，Watanabe N ，Kurita Y ，Okubo M ，Tanaka K ，Kishida H ，Koyano S ，Takahashi T ，Ono Y ，Higashida K ，Yoshikura N ，Ogata K ，Kato R ，Tsuchida N ，Uchiyama Y ，Miyake N ，Shimohata T ，Tanaka F ，Mizuguchi T ，Matsumoto N ... -  《-》

Biallelic RFC1 pentanucleotide repeat expansions in Greek patients with late-onset ataxia.

Cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS) has been recently linked to biallelic expansions of a pentanucleotide repeat in the replication factor C subunit 1 (RFC1) gene. Herein, we sought to investigate the presence of pathological RFC1 expansions in selected Greek patients with late-onset ataxia and delineate the phenotypic spectrum of genetically confirmed CANVAS in the Greek population. We screened genetically a total of 77 selected index patients, 67 originating from a cerebellar ataxia cohort and 10 from a hereditary neuropathy cohort. We identified five index cases (6.5%) with biallelic pathological RFC1 expansions, two in the cerebellar ataxia cohort (3%) and three in the neuropathy cohort (30%). Overall, four out of five of cases with full-blown CANVAS and one case with sensory ataxic neuropathy had biallelic pathological expansions. The phenotypic spectrum of positive cases (including two affected siblings) was consistent with previous reports and implied that the sensory neuropathy may be the earliest feature in genetically confirmed CANVAS. Screening for biallelic RFC1 expansions is recommended in all cases with late-onset ataxia of unknown cause, particularly when a sensory neuropathy is present.

Kontogeorgiou Z ，Kartanou C ，Tsirligkani C ，Anagnostou E ，Rentzos M ，Stefanis L ，Karadima G ，Koutsis G ... -  《-》

Long-read sequencing identifies the pathogenic nucleotide repeat expansion in RFC1 in a Japanese case of CANVAS.

Nakamura H ，Doi H ，Mitsuhashi S ，Miyatake S ，Katoh K ，Frith MC ，Asano T ，Kudo Y ，Ikeda T ，Kubota S ，Kunii M ，Kitazawa Y ，Tada M ，Okamoto M ，Joki H ，Takeuchi H ，Matsumoto N ，Tanaka F ... -  《-》