Krude Heiko, Mundlos Stefan, Øien Nancy Christine, Opitz Robert, Schuelke Markus
Institute of Experimental Pediatric Endocrinology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
Institute for Medical and Human Genetics, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
Med Genet. 2021 Aug 14;33(2):121-131. doi: 10.1515/medgen-2021-2071. eCollection 2021 Jun.
Whole exome sequencing discovers causative mutations in less than 50 % of rare disease patients, suggesting the presence of additional mutations in the non-coding genome. So far, non-coding mutations have been identified in less than 0.2 % of individuals with genetic diseases listed in the ClinVar database and exhibit highly diverse molecular mechanisms. In contrast to our capability to sequence the whole genome, our ability to discover and functionally confirm such non-coding mutations is lagging behind severely. We discuss the problems and present examples of confirmed mutations in deep intronic sequences, non-coding triplet repeats, enhancers, and larger structural variants and highlight their proposed disease mechanisms. Finally, we discuss the type of data that would be required to establish non-coding mutation detection in routine diagnostics.
全外显子组测序在不到50%的罕见病患者中发现致病突变，这表明非编码基因组中存在其他突变。到目前为止，在ClinVar数据库列出的遗传病患者中，不到0.2%的个体被鉴定出非编码突变，并且这些突变表现出高度多样的分子机制。与我们对全基因组进行测序的能力相比，我们发现并在功能上确认此类非编码突变的能力严重滞后。我们讨论了相关问题，并给出了在深度内含子序列、非编码三联体重复序列、增强子和较大结构变异中已确认突变的实例，并强调了它们可能的疾病机制。最后，我们讨论了在常规诊断中建立非编码突变检测所需的数据类型。
