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

Abstract

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.

An update on the neurological short tandem repeat expansion disorders and the emergence of long-read sequencing diagnostics

“…The mechanism of disease caused by these interruptions is difficult to discern; further genotyping of these regions is first required. This complex motif structure is commonly seen in several newly discovered pentanucleotide repeat expansions such as RFC1 or SAMD12 , which show that pathogenic sequences are often extremely dynamic in nature [ 3 , 107 , 138 ].…”

“…Recently, more novel pathogenic RFC1 conformations have been implicated with CANVAS. ‘ACAGG’ was found to have expanded in two Asia–Pacific families [ 138 ] who demonstrated additional clinical features, namely fasciculations and elevated serum kinase. Another study showed a ‘(AAAGG) 10–25 (AAGGG) exp ’ allele was the predominant pathogenic allele found in Māori populations, with no apparent phenotypic differences when compared to the European populations [ 11 ].…”

Molecular Mechanisms in Pentanucleotide Repeat Diseases

“…The size of the repeat is much larger in (AAGGG) exp alleles, which can reach more than 1,000 units than in (AAAGG) n alleles in the expansion range, that are below 1,000 repeats; most of the (AAAAG) n large alleles have less than 200 units [ 32 ]. Three additional repeat structures, AGAGG, AAGAG, and ACAGG have been observed in adult-onset ataxia cases [ 129 , 130 ], as well as a new allele with an (AAAGG) 10-25 tract preceding the (AAGGG) n [ 131 ] further showing the unstable nature of this repeat, being advisable to give careful attention to its sequence and size before releasing a molecular diagnosis.…”

Cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS): genetic and clinical aspects

“…More recently, novel pathogenic (AAAGG)10-25(AAGGG)exp(AAAGG)4-6 and (ACAGG)exp configurations were identified individual from Oceania and East Asia (15)(16)(17).…”