Analysis and occurrence of biallelic pathogenic repeat expansions in RFC1 in a German cohort of patients with a main clinical phenotype of motor neuron disease

Biallelic pathogenic repeat expansions in RFC1 were recently identified as molecular origin of cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS) as well as of one of the most common causes of adult-onset ataxia.

In the meantime, the phenotypic spectrum has expanded massively and now includes mimics of multiple system atrophy or parkinsonism.

After identifying a patient with a clinical diagnosis of amyotrophic lateral sclerosis (ALS) as a carrier of biallelic pathogenic repeat expansions in RFC1 , we studied a cohort of 106 additional patients with a clinical main phenotype of motor neuron disease (MND) to analyze whether such repeat expansions are more common in MND patients.

Indeed, two additional MND patients (one also with ALS and one with primary lateral sclerosis/PLS) have been identified as carrier of biallelic pathogenic repeat expansions in RFC1 in the absence of another genetic alteration explaining the phenotype, suggesting motor neuron disease as another extreme phenotype of RFC1 spectrum disorder.

Therefore, MND might belong to the expanding phenotypic spectrum of pathogenic RFC1 repeat expansions, particularly in those MND patients with additional features such as sensory and/or autonomic neuropathy, vestibular deficits, or cerebellar signs.

By systematically analyzing the RFC1 repeat array using Oxford nanopore technology long-read sequencing, our study highlights the high intra- and interallelic heterogeneity of this locus and allows the identification of the novel repeat motif ‘ACAAG’.