Department of Biology, Lund University, 22362 Lund, Sweden.
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA.
Genes (Basel). 2021 Feb 2;12(2):216. doi: 10.3390/genes12020216.
Sudden infant death syndrome (SIDS) is the unexpected death of an infant under one year of age that remains unexplained after a thorough investigation. Despite SIDS remaining a diagnosis of exclusion with an unexplained etiology, it is widely accepted that SIDS can be caused by environmental and/or biological factors, with multiple underlying candidate genes. However, the lack of biomarkers raises questions as to why genetic studies on SIDS to date are unable to provide a clearer understanding of the disease etiology. We sought to improve the identification of SIDS-associated genes by reviewing the SIDS genetic literature and objectively categorizing and scoring the reported genes based on the strength of evidence (from C1 (high) to C5 (low)). This was followed by analyses of function, associations between genes, the enrichment of gene ontology (GO) terms, and pathways and gender difference in tissue gene expression. We constructed a curated database for SIDS gene candidates consisting of 109 genes, 14 of which received a category 4 (C4) and 95 genes received the lowest category of C5. That none of the genes was classified into the higher categories indicates the low level of supporting evidence. We found that genes of both scoring categories show distinct networks and are highly diverse in function and involved in many GO terms and pathways, in agreement with the perception of SIDS as a heterogeneous syndrome. Genes of both scoring categories are part of the cardiac system, muscle, and ion channels, whereas immune-related functions showed enrichment for C4 genes. A limited association was found with neural development. Overall, inconsistent reports and missing metadata contribute to the ambiguity of genetic studies. Considering those parameters could help improve the identification of at-risk SIDS genes. However, the field is still far from offering a full-pledged genetic test to identify at-risk infants and is still hampered with methodological challenges and misunderstandings of the vulnerabilities of vital biological mechanisms.
婴儿猝死综合征（SIDS）是指一岁以下婴儿在经过彻底调查后仍无法解释的意外死亡。尽管 SIDS 仍然是一种排除性诊断，其病因尚不清楚，但人们普遍认为 SIDS 可能由环境和/或生物因素引起，并有多个潜在的候选基因。然而，由于缺乏生物标志物，人们不禁要问，为什么迄今为止针对 SIDS 的遗传研究仍无法更清楚地了解疾病的病因。我们通过回顾 SIDS 遗传文献，对报告的基因进行客观分类和评分（从 C1（高）到 C5（低）），以提高 SIDS 相关基因的识别能力。然后对基因功能、基因之间的关联、基因本体论（GO）术语和途径的富集以及组织基因表达的性别差异进行分析。我们构建了一个 SIDS 候选基因的精选数据库，其中包含 109 个基因，其中 14 个基因被归类为 4 类（C4），95 个基因被归类为最低的 5 类（C5）。没有一个基因被归类为更高的类别，这表明支持证据的水平很低。我们发现，两个评分类别的基因都显示出明显的网络，在功能上高度多样化，涉及许多 GO 术语和途径，这与 SIDS 作为一种异质性综合征的认识一致。两个评分类别的基因都属于心脏系统、肌肉和离子通道，而免疫相关功能则富集了 C4 基因。与神经发育有一定的关联。总的来说，不一致的报告和缺失的元数据导致了遗传研究的模糊性。考虑到这些参数可以帮助提高对高危 SIDS 基因的识别。然而，该领域仍远未提供全面的遗传测试来识别高危婴儿，并且仍然受到方法学挑战和对生命生物学机制脆弱性的误解的阻碍。
