Genomic Medicine Center, Children's Mercy Kansas City, Kansas City, MO, 64108, USA.
Children's Mercy Research Institute, Children's Mercy Kansas City, Kansas City, MO, 64108, USA.
Sci Rep. 2022 May 9;12(1):7576. doi: 10.1038/s41598-022-11589-8.
Clinical whole genome sequencing has enabled the discovery of potentially pathogenic noncoding variants in the genomes of rare disease patients with a prior history of negative genetic testing. However, interpreting the functional consequences of noncoding variants and distinguishing those that contribute to disease etiology remains a challenge. Here we address this challenge by experimentally profiling the functional consequences of rare noncoding variants detected in a cohort of undiagnosed rare disease patients at scale using a massively parallel reporter assay. We demonstrate that this approach successfully identifies rare noncoding variants that alter the regulatory capacity of genomic sequences. In addition, we describe an integrative analysis that utilizes genomic features alongside patient clinical data to further prioritize candidate variants with an increased likelihood of pathogenicity. This work represents an important step towards establishing a framework for the functional interpretation of clinically detected noncoding variants.
临床全基因组测序使得能够在先前遗传检测阴性的罕见病患者的基因组中发现潜在致病的非编码变异。然而，解释非编码变异的功能后果并区分那些导致疾病病因的变异仍然是一个挑战。在这里，我们通过使用大规模平行报告基因检测在一个未确诊的罕见病患者队列中对罕见非编码变异的功能后果进行了规模化的实验分析，从而解决了这一挑战。我们证明，这种方法可以成功地识别出改变基因组序列调控能力的罕见非编码变异。此外，我们还描述了一种综合分析方法，该方法利用基因组特征以及患者临床数据，进一步优先考虑具有更高致病性可能性的候选变异。这项工作是朝着建立临床检测到的非编码变异的功能解释框架迈出的重要一步。
