Genetic profiles of multiple system atrophy revealed by exome sequencing, long-read sequencing and spinocerebellar ataxia repeat expansion analysis

Abstract

Background and purpose: Multiple system atrophy (MSA) is a progressive, adult-onset neurodegenerative disorder clinically characterized by combinations of autonomic failure, parkinsonism, cerebellar ataxia and pyramidal signs. Although a few genetic factors have been reported to contribute to the disease, its mutational profiles have not been systemically studied.

Methods: To address the genetic profiles of clinically diagnosed MSA patients, exome sequencing and triplet repeat detection was conducted in 205 MSA patients, including one familial case. The pathogenicity of variants was determined according to the American College of Medical Genetics and Genomics and the Association for Molecular Pathology guidelines.

Results: In the familial patient, a novel heterozygous COQ2 pathogenic variant (p.Ala351Thr) was identified in the MSA pedigree. In the sporadic patients, 29 pathogenic variants were revealed in 21 genes, and the PARK7 p.Ala104Thr variant was significantly associated with MSA (p = 0.0018). Moreover, burden tests demonstrated that the pathogenic variants were enriched in cerebellar ataxia-related genes in patients. Furthermore, repeat expansion analyses revealed that two patients carried the pathogenic CAG repeat expansion in the CACNA1A gene (SCA6), one patient carried the (ACAGG)exp/(ACAGG)exp expansion in RFC1 and one carried the GAA-pure expansion in FGF14 gene.

Conclusion: In conclusion, a novel COQ2 pathogenic variant was identified in a familial MSA patient, and repeat expansions in CACNA1A, RFC1 and FGF14 gene were detected in four sporadic patients. Moreover, a PARK7 variant and the burden of pathogenic variants in cerebellar ataxia-related genes were associated with MSA.

Keywords: COQ2; PARK7; RFC1 and FGF14 repeats; multiple system atrophy; spinocerebellar ataxia repeat 6.

FIGURE 1

The genetic and clinical characteristics of the family with clinically diagnosed MSA. (a) The pedigree chart and Sanger sequencing. (b) The brain MRI of III‐4 and III‐5. (c) The demographic features, motor and non‐motor symptoms and medication condition of four symptomatic patients and one pre‐symptomatic subject in the family. (d) Structure of the COQ2. AAO, age at onset; MRI, magnetic resonance imaging; MSA, multiple system atrophy; RBD, rapid eye movement sleep behaviour disorder.

FIGURE 2

The clinical characteristics of two patients with SCA6, RFC1 and FGF14 abnormal expanded repeat alleles. (a) The clinical scale scores and genetic data. MRI, magnetic resonance imaging. (b), (c) Routine brain MRI of the two patients with SCA6: (b) patient M034; (c) patient M126. (d) The sequencing data and brain MRI of patient M132. (e) The sequencing data and brain MRI of patient M084. MSA‐P, MSA with predominant parkinsonism; MSA‐C, MSA with predominant cerebellar ataxia; MSA‐C + P, MSA with predominant cerebellar ataxia and parkinsonism; MoCA, Montreal Cognitive Assessment; NMSS, Non‐Motor Symptoms Scale; RBDQ‐HK, Rapid Eye Movement Sleep Behaviour Disorder Questionnaire—Hong Kong; UMSARS, Unified Multiple System Atrophy Rating Scale.