Repeat expansions in AR, ATXN1, ATXN2 and HTT in Norwegian patients diagnosed with amyotrophic lateral sclerosis

Abstract

Genetic repeat expansions cause neuronal degeneration in amyotrophic lateral sclerosis as well as other neurodegenerative disorders such as spinocerebellar ataxia, Huntington's disease and Kennedy's disease. Repeat expansions in the same gene can cause multiple clinical phenotypes. We aimed to characterize repeat expansions in a Norwegian amyotrophic lateral sclerosis cohort. Norwegian amyotrophic lateral sclerosis patients (n = 414) and neurologically healthy controls adjusted for age and gender (n = 713) were investigated for repeat expansions in AR, ATXN1, ATXN2 and HTT using short read exome sequencing and the ExpansionHunter software. Five amyotrophic lateral sclerosis patients (1.2%) and two controls (0.3%) carried ≥36 repeats in HTT (P = 0.032), and seven amyotrophic lateral sclerosis patients (1.7%) and three controls (0.4%) carried ≥29 repeats in ATXN2 (P = 0.038). One male diagnosed with amyotrophic lateral sclerosis carried a pathogenic repeat expansion in AR, and his diagnosis was revised to Kennedy's disease. In ATXN1, 50 amyotrophic lateral sclerosis patients (12.1%) and 96 controls (13.5%) carried ≥33 repeats (P = 0.753). None of the patients with repeat expansions in ATXN2 or HTT had signs of Huntington's disease or spinocerebellar ataxia type 2, based on a re-evaluation of medical records. The diagnosis of amyotrophic lateral sclerosis was confirmed in all patients, with the exception of one patient who had primary lateral sclerosis. Our findings indicate that repeat expansions in HTT and ATXN2 are associated with increased likelihood of developing amyotrophic lateral sclerosis. Further studies are required to investigate the potential relationship between HTT repeat expansions and amyotrophic lateral sclerosis.

Keywords: Norway; amyotrophic lateral sclerosis; genetic risk factor; population-based study.

Graphical Abstract

Figure 1

Repeat expansions detection workflow. ExpansionHunter software is performed on exome sequencing data. Low coverage samples can be investigated for visual confirmation. Expanded repeats in HTT and ATXN2 were found in 13 amyotrophic lateral sclerosis patients. Created with BioRender.com.

Figure 2

Distribution of allele frequency and allele sizes in amyotrophic lateral sclerosis patients and controls. (A) HTT repeat expansions in 391 amyotrophic lateral sclerosis patients and 695 controls. (B) ATXN2 repeat expansions in 414 amyotrophic lateral sclerosis patients and 712 controls. (C) AR repeat expansions in 414 amyotrophic lateral sclerosis patients and 712 controls and (D) ATXN1 repeat expansions in 414 amyotrophic lateral sclerosis patients and 713 controls. The number of amyotrophic lateral sclerosis patients and controls differs since samples with low coverage for a specific repeat were removed from the analysis. The dashed black line represents the thresholds of which the number of repeats is considered to be associated with amyotrophic lateral sclerosis risk, and the black line represents the thresholds of which the number of repeats is considered to be pathogenic for each locus (Supplementary Table 3). Created with BioRender.com.