Short tandem repeat expansions in sporadic amyotrophic lateral sclerosis and frontotemporal dementia

Abstract

Pathogenic short tandem repeat (STR) expansions cause over 20 neurodegenerative diseases. To determine the contribution of STRs in sporadic amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), we used ExpansionHunter, REviewer, and polymerase chain reaction validation to assess 21 neurodegenerative disease-associated STRs in whole-genome sequencing data from 608 patients with sporadic ALS, 68 patients with sporadic FTD, and 4703 matched controls. We also propose a data-derived outlier detection method for defining allele thresholds in rare STRs. Excluding C9orf72 repeat expansions, 17.6% of clinically diagnosed ALS and FTD cases had at least one expanded STR allele reported to be pathogenic or intermediate for another neurodegenerative disease. We identified and validated 162 disease-relevant STR expansions in C9orf72 (ALS/FTD), ATXN1 [spinal cerebellar ataxia type 1 (SCA1)], ATXN2 (SCA2), ATXN8 (SCA8), TBP (SCA17), HTT (Huntington's disease), DMPK [myotonic dystrophy type 1 (DM1)], CNBP (DM2), and FMR1 (fragile-X disorders). Our findings suggest clinical and pathological pleiotropy of neurodegenerative disease genes and highlight their importance in ALS and FTD.

Fig. 1.. Statistical analysis of clinical variables in sALS cohort (n = 608).

Significant associations are denoted by red P values. (A) There was a significant difference in the site of onset between males and females with ALS, with more males presenting with spinal onset ALS. (B) The age of onset was significantly older in females with ALS. (C) Males with ALS tended to have a longer disease duration, although not statistically significant. (D) Patients diagnosed with ALS at a younger age lived significantly longer than those diagnosed later in life. (E) Patients with bulbar onset ALS typically presented with disease at an older age. (F) A significant difference in ALS disease duration was observed between the site of onset, with bulbar onset having a worse prognosis.

Fig. 2.. Statistical analysis of clinical variables in sFTD cohort (n = 68).

Significant associations are denoted by red P values. (A) There was no significant difference in the age of onset between males and females with FTD. (B) Females with FTD have a significantly worse prognosis compared to male with FTD. (C) No associations were found between the age of onset and the disease duration in patients with FTD.

Fig. 3.. ExpansionHunter STR expansion size estimates (number of repeats) for the long allele and PCR validation results for 608 patients with sALS and 68 patients with sFTD.

C9orf72 has been graphed separately to allow for a larger expansion range. The color of each point is reflective of the PCR validation results. Note that only intermediate and pathogenic expansions identified by ExpansionHunter were PCR-validated.

Fig. 4.. ExpansionHunter STR length frequency distributions in 608 patients with sALS and 4703 control participants for 19 neurodegenerative disease loci.

The y axis is the square root of the total number of alleles for each repeat length to allow better depiction of frequency variations.

Fig. 5.. Outlier alleles in 608 patients with sALS using 99.9th percentile data-derived thresholds.

Distributions of repeat lengths in patients with sALS (dark blue) and controls (light blue) are shown for diseases inherited in a dominant pattern (either autosomal dominant, X-linked dominant, or male carriers of X-linked recessive STRs). Two recessive disorders [spinal bulbar muscular atrophy (SBMA), an X-linked STR; and Friedreich’s ataxia (FRDA), an autosomal recessive STR] are shown in scatter plots of patient allele lengths with control distributions rendered as contours at the quartiles of the distribution. Allele lengths detected as outliers in patients with sALS are indicated by green points. For recessive disorders, patients with only one allele detected as an outlier are indicated by orange points (i.e., carriers).