Pathogenic expansions of tandem repeat sequences underlie a diverse set of neurological conditions. To assess frequencies of repeat expansion mutations in the general population, Ibañez et al. analyzed whole-genome sequencing data from two large population-based studies comprising 82,176 individuals of diverse ancestries, focusing on 16 repeat expansion disorder loci for which they could accuracy classify allele sizes as normal, premutation or full expansion. In the combined cohort, they found that the number of individuals harboring full-expansion alleles was two- to three-fold higher than the estimated prevalence of these repeat expansion disorders based on clinical observation, consistent with incomplete penetrance or underdiagnosis. Although they observed some variability in the frequencies of specific repeat expansions and in the distributions of repeat lengths across different ancestry groups, they found that most repeat expansion mutations were detected across all ancestry groups. Collectively, these population-based estimates of repeat expansion carrier allele frequencies suggest that the number of individuals who could benefit from genetic testing and counseling for these disorders — and from future therapies — is higher than previously suspected.

Original reference: Nat. Med. https://doi.org/10.1038/s41591-024-03190-5 (2024)

串联重复序列的致病性扩增是多种神经系统疾病的基础。为了评估一般人群中重复扩增突变的频率，Ibañez 等人分析了来自两项大型人群研究的全基因组测序数据，该研究包括 82,176 个不同血统的个体，重点关注 16 个重复扩增障碍位点，他们可以准确地将等位基因大小分类为正常、前突变或完全扩增。在联合队列中，他们发现携带完全扩增等位基因的个体数量比根据临床观察估计的这些重复扩增障碍的患病率高出 2 到 3 倍，这与不完全外显率或诊断不足一致。尽管他们观察到特定重复扩增的频率和不同祖先群体中重复长度的分布存在一些变化，但他们发现在所有祖先群体中都检测到了大多数重复扩增突变。总的来说，这些基于人群的重复扩增携带者等位基因频率估计表明，可以从这些疾病的基因检测和咨询以及未来疗法中受益的个体数量高于以前怀疑的。

原始参考：Nat. Med.https://doi.org/10.1038/s41591-024-03190-5 （2024）