Increased frequency of repeat expansion mutations across different populations

Area of Science:

• Genetics
• Neurology
• Genomic Medicine

Background:

• Repeat expansion disorders (REDs) are a group of neurological diseases with significant global health impact.
• Current prevalence estimates for REDs are likely underestimated due to diagnostic challenges and population-specific data limitations.

Purpose of the Study:

• To determine the actual disease allele frequency of REDs across diverse populations.
• To re-evaluate the global prevalence and diagnostic landscape of REDs using large-scale genomic data.

Main Methods:

• Whole-genome sequencing data from 82,176 individuals from various global populations were analyzed.
• Disease allele frequencies for REDs were calculated.
• Disease prevalence was modeled using genetic data, age at onset, and survival statistics.

Main Results:

• An overall disease allele frequency of 1 in 283 individuals for REDs was identified, significantly higher than previously reported.
• Modeled prevalence suggests REDs affect two to three times more people than currently diagnosed.
• Most REDs were found across all major genetic ancestries, challenging previous assumptions of population specificity.

Conclusions:

• REDs are substantially underdiagnosed globally, with incomplete penetrance potentially contributing to ascertainment bias.
• The widespread distribution of REDs across ancestries necessitates a global approach to diagnosis and genetic counseling.
• These findings have critical implications for healthcare providers in improving REDs diagnosis and patient management worldwide.