Mok Jung-Wan, Gibson Shelley B, Dostalik Haley A, Yamamoto Shinya
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, Texas 77030, USA.
Genome Res. 2025 Jul 1;35(7):1473-1484. doi: 10.1101/gr.278291.123.
Individuals living with rare diseases often undergo a frustrating and expensive diagnostic odyssey. Clinical geneticists who analyze exome or genome sequencing data from rare disease patients often encounter a list of variants of uncertain significance (VUS) in known disease-causing genes or rare variants in genes of uncertain significance (GUS) that are difficult to interpret, even with the integration of the latest bioinformatic tools. In this Perspective, we review how studies using the fruit fly have facilitated rare disease diagnosis by uncovering the clinical relevance of GUS and classifying rare variants into specific allelic categories (loss-of-function or gain-of-function, Muller's morphs). We showcase how fly researchers have been collaboratively studying the loss-of-function of orthologous fly genes, assessing the ability of the human genes to rescue the fly mutant phenotypes, determining the effect of overexpressing human proteins, and testing functional consequences of rare variants of interest by generating analogous fly mutants to contribute to rare disease diagnosis. We argue that data obtained using can be leveraged to design effective multiplexed assays for variant effects (MAVEs) to decipher the vast human variome.
患有罕见病的个体常常要经历一段令人沮丧且费用高昂的诊断历程。分析罕见病患者外显子组或基因组测序数据的临床遗传学家，即便整合了最新的生物信息学工具，也常常会在已知致病基因中遇到一系列意义未明的变异（VUS），或是在意义未明的基因（GUS）中遇到难以解释的罕见变异。在这篇观点文章中，我们回顾了利用果蝇开展的研究如何通过揭示GUS的临床相关性并将罕见变异分类到特定的等位基因类别（功能丧失或功能获得，穆勒形态）来推动罕见病诊断。我们展示了果蝇研究人员如何通过合作研究直系同源果蝇基因的功能丧失、评估人类基因拯救果蝇突变体表型的能力、确定人类蛋白质过表达的影响，以及通过生成类似的果蝇突变体来测试感兴趣的罕见变异的功能后果，从而为罕见病诊断做出贡献。我们认为，利用果蝇获得的数据可用于设计有效的变异效应多重检测（MAVE），以解读庞大的人类变异组。
