Etablissement Français du Sang (EFS) - Bretagne, Brest, France.
Clin Genet. 2010 Oct;78(4):310-20. doi: 10.1111/j.1399-0004.2010.01474.x.
The number of known mutations in human nuclear genes, underlying or associated with human inherited disease, has now exceeded 100,000 in more than 3700 different genes (Human Gene Mutation Database). However, for a variety of reasons, this figure is likely to represent only a small proportion of the clinically relevant genetic variants that remain to be identified in the human genome (the 'mutome'). With the advent of next-generation sequencing, we are currently witnessing a revolution in medical genetics. In particular, whole-genome sequencing (WGS) has the potential to identify all disease-causing or disease-associated DNA variants in a given individual. Here, we use examples of recent advances in our understanding of mutational/pathogenic mechanisms to guide our thinking about possible locations outwith gene-coding sequences for those disease-causing or disease-associated variants that are likely so often to have been overlooked because of the inadequacy of current mutation screening protocols. Such considerations are important not only for improving mutation-screening strategies but also for enhancing the interpretation of findings derived from genome-wide association studies, whole-exome sequencing and WGS. An improved understanding of the human mutome will not only lead to the development of improved diagnostic testing procedures but should also improve our understanding of human genome biology.
已知与人类遗传疾病相关或与之相关的人类核基因突变的数量，现在已经在 3700 多个不同的基因中超过了 100,000 个（人类基因突变数据库）。然而，由于各种原因，这个数字可能只是人类基因组中尚未确定的具有临床相关性的遗传变异的一小部分（“突变组”）。随着下一代测序技术的出现，我们目前正在见证医学遗传学的革命。特别是全基因组测序（WGS）有可能在给定个体中识别所有致病或与疾病相关的 DNA 变异。在这里，我们使用我们对突变/发病机制的理解的最新进展的例子，来指导我们思考那些可能因现有突变筛选方案不足而经常被忽视的致病或与疾病相关的变异的基因编码序列之外的可能位置。这些考虑不仅对于改进突变筛选策略很重要，而且对于增强从全基因组关联研究、外显子组测序和 WGS 中得出的发现的解释也很重要。对人类突变组的更好理解不仅将导致开发出改进的诊断测试程序，而且还应提高我们对人类基因组生物学的理解。
