Gando Ivan, Yang Hua-Qian, Coetzee William A
Pediatrics, NYU School of Medicine, 450 E 29th Street, ACLS 824, New York, NY, 10016, USA.
Physiology & Neuroscience, NYU School of Medicine, 450 E 29th Street, ACLS 824, New York, NY, 10016, USA.
Forensic Sci Med Pathol. 2019 Sep;15(3):437-444. doi: 10.1007/s12024-018-0063-y. Epub 2018 Dec 13.
Determining the cause of unexplained death in all age groups, including infants, is a priority in forensic medicine. The triple risk model proposed for sudden infant death syndrome involves the intersection of three risks: (1) a critical developmental period in homeostatic control (2), exogenous stressors, and (3) a vulnerable infant. Even though sex and age factor into some forms of inherited arrhythmogenic deaths in young individuals and adults, more appropriate a dual-risk disease model for adults involves exogenous stressors and a vulnerable individual. The vulnerability aspect clearly has a genetic component as underscored by a number of recent large-scale and high-throughput genetic testing studies performed in attempt to define the causes of sudden unexplained death. These studies often focus on 'cardiac' and channelopathy genes. Genetic testing often identify lists of rare or ultra-rare nonsynonymous variants, classified according to the ACMG guidelines as 'pathogenic' or 'likely pathogenic', which may form the basis of diagnostic decisions and/or family counseling. However, computer algorithms used to categorize gene variants are not completely accurate and these variants are often not functionally tested to determine their pathogenicity. Due to conflicting computational predictions, a large number of variants are labeled as 'variants of uncertain significance' or VUS. Functional testing of these VUS can greatly assist to reclassify these VUS as 'likely benign' or 'likely pathogenic'. However, functional testing has its limits and by itself cannot be used to determine cause of death. Going forward, computer algorithms must be improved to take account of variants across multiple genes and efforts must be expanded to obtain clinical, familial and segregation data. Forensic genetic testing needs to be held to the same rigorous standards as defined by the NIH Clinical Genome Resource Consortium, where functional evaluation of a channelopathy variant is only one (but important) aspect of the overall picture.
确定包括婴儿在内的所有年龄组不明原因死亡的原因是法医学的一个优先事项。为婴儿猝死综合征提出的三重风险模型涉及三种风险的交集：（1）稳态控制中的关键发育阶段；（2）外源性应激源；（3）易损婴儿。尽管性别和年龄在年轻人和成年人某些形式的遗传性心律失常性死亡中起作用，但更适合成年人的双风险疾病模型涉及外源性应激源和易损个体。正如最近一些为确定不明原因猝死原因而进行的大规模高通量基因检测研究所强调的那样，易损性方面显然有遗传成分。这些研究通常集中在“心脏”和通道病基因上。基因检测通常会识别出一系列罕见或超罕见的非同义变异，根据美国医学遗传学与基因组学学会（ACMG）的指南分类为“致病性”或“可能致病性”，这可能构成诊断决策和/或家族咨询的基础。然而，用于对基因变异进行分类的计算机算法并不完全准确，而且这些变异通常没有经过功能测试以确定其致病性。由于计算预测相互矛盾，大量变异被标记为“意义未明的变异”（VUS）。对这些VUS进行功能测试可以极大地帮助将这些VUS重新分类为“可能良性”或“可能致病性”。然而，功能测试有其局限性，仅凭它不能用于确定死亡原因。展望未来，必须改进计算机算法以考虑多个基因的变异，并且必须扩大努力以获取临床、家族和分离数据。法医基因检测需要遵循与美国国立卫生研究院临床基因组资源联盟所定义的相同严格标准，其中通道病变异的功能评估只是整体情况的一个（但很重要）方面。
