分子尸检是指基于DNA的死因鉴定。尽管最近试图扩大其范围,该术语通常保留给年轻人不明原因的猝死。在这项研究中,我们的目的是展示分子尸检在定义人类致命变异中的实用性。
我们描述了我们对481例病例的经验,其中使用来自索引或亲属的DNA(通过代理进行分子尸检)调查了过早死亡的原因。分子尸检工具通常是外显子组测序,尽管在研究的早期阶段使用靶向方法进行了研究;这些包括位置映射,靶向基因测序,染色体微阵列,和基因面板。
该研究包括来自近亲家庭的449例病例和141例缺乏家族史(单纯性)。胚胎的年龄范围是18岁。在63.8%(307/481)中发现了可能的因果变异(致病性/可能致病性),与同一人群的一般诊断产量(43%)相比,产量要高得多。隐性致死等位基因的优势使我们能够通过代理对55对夫妇进行分子尸检,产率同样高(63.6%)。我们还注意到典型的非致死性显性疾病的双等位基因致死形式的发生,有时代表一种新的真正的双等位基因隐性疾病特征。在本研究过程中鉴定了46个无OMIM表型的疾病基因。提供的数据支持另外两个先前报道的新疾病基因(FAAH2和MSN)的候选资格。对致死表型的关注揭示了许多有趣的表型扩展以及临床表现中的显着变异性的例子。此外,根据结果,强调了对群体遗传学和变异解释的重要见解。
分子尸检,广义定义,被证明是一种有用的临床方法,可提供对致命变异和人类基因组临床注释的独特见解。
Molecular autopsy refers to DNA-based identification of the cause of death. Despite recent attempts to broaden its scope, the term remains typically reserved to sudden unexplained death in young adults. In this study, we aim to showcase the utility of molecular autopsy in defining lethal variants in humans.
We describe our experience with a cohort of 481 cases in whom the cause of premature death was investigated using DNA from the index or relatives (molecular autopsy by proxy). Molecular autopsy tool was typically exome sequencing although some were investigated using targeted approaches in the earlier stages of the study; these include positional mapping, targeted gene sequencing, chromosomal microarray, and gene panels.
The study includes 449 cases from consanguineous families and 141 lacked family history (simplex). The age range was embryos to 18 years. A likely causal variant (pathogenic/likely pathogenic) was identified in 63.8% (307/481), a much higher yield compared to the general diagnostic yield (43%) from the same population. The predominance of recessive lethal alleles allowed us to implement molecular autopsy by proxy in 55 couples, and the yield was similarly high (63.6%). We also note the occurrence of biallelic lethal forms of typically non-lethal dominant disorders, sometimes representing a novel bona fide biallelic recessive disease trait. Forty-six disease genes with no OMIM phenotype were identified in the course of this study. The presented data support the candidacy of two other previously reported novel disease genes (FAAH2 and MSN). The focus on lethal phenotypes revealed many examples of interesting phenotypic expansion as well as remarkable variability in clinical presentation. Furthermore, important insights into population genetics and variant interpretation are highlighted based on the results.
Molecular autopsy, broadly defined, proved to be a helpful clinical approach that provides unique insights into lethal variants and the clinical annotation of the human genome.