Increased frequency of repeat expansion mutations across different populations.

Abstract

Repeat expansion disorders (REDs) are a devastating group of predominantly neurological diseases. Together they are common, affecting 1 in 3,000 people worldwide with population-specific differences. However, prevalence estimates of REDs are hampered by heterogeneous clinical presentation, variable geographic distributions, and technological limitations leading to under-ascertainment. Here, leveraging whole genome sequencing data from 82,176 individuals from different populations, we found an overall disease allele frequency of REDs of 1 in 283 individuals. Modelling disease prevalence using genetic data, age at onset and survival, we show that the expected number of people with REDs would be two to three times higher than currently reported figures, indicating under-diagnosis and/or incomplete penetrance. While some REDs are population-specific, e.g. Huntington disease-like 2 in Africans, most REDs are represented in all broad genetic ancestries (i.e. Europeans, Africans, Americans, East Asians, and South Asians), challenging the notion that some REDs are found only in specific populations. These results have worldwide implications for local and global health communities in the diagnosis and counselling of REDs.