美国哥伦比亚大学欧文医学中心David B. Goldstein团队分析了死产中基因变异的因果关系。2020年8月12日，《新英格兰医学杂志》发表了该项成果。

在大多数情况下，尽管进行了详细的临床和实验室评估，死产的原因仍然未知。死产中约有10％到20％归因于染色体异常。然而，单核苷酸变异和外显子中微小插入和缺失的因果性质尚未得到充分研究。

研究组生成了246个死胎病例的外显子组测序数据，并遵循已建立的指导方针来鉴定疾病相关基因中的因果变异。这些基因包括那些与死产有关的基因和强候选基因。研究组还根据功能变异的缺失程度，分层评估了18653个基因在病例对照分析中的贡献。

研究组对246例死产病例中的15例（6.1%）进行了分子诊断，涉及7个与死产有关的基因和6个表型扩展的疾病基因。在评估的病例中，研究组还发现人类群体对这种变异不耐受的基因中功能缺失变异很丰富，优势比为2.15。不耐受基因的功能缺失变异集中在与人类疾病无关的基因上，优势比为2.22，这与该研究中评估的两个产后临床人群的结果有所不同。

研究组的发现建立了临床外显子组测序的诊断效用，以评估死胎中微小基因组变化的作用。新危险信号的强度与已知疾病基因相似，这表明死产的遗传原因在很大程度上仍然未知。

附：英文原文

Title: Causal Genetic Variants in Stillbirth

Author: Kate E. Stanley, B.A.,, Jessica Giordano, M.S., C.G.C.,, Vanessa Thorsten, M.P.H.,, Christie Buchovecky, Ph.D.,, Amanda Thomas, Ph.D.,, Mythily Ganapathi, Ph.D.,, Jun Liao, Ph.D.,, Avinash V. Dharmadhikari, Ph.D.,, Anya Revah-Politi, M.S., C.G.C.,, Michelle Ernst, M.S., C.G.C.,, Natalie Lippa, M.S., C.G.C.,, Halie Holmes, M.S., C.G.C.,, Gundula Povysil, M.D., Ph.D.,, Joseph Hostyk, B.S.,, Corette B. Parker, Dr.P.H.,, Robert Goldenberg, M.D.,, George R. Saade, M.D.,, Donald J. Dudley, M.D.,, Halit Pinar, M.D.,, Carol Hogue, Ph.D., M.P.H.,, Uma M. Reddy, M.D., M.P.H.,, Robert M. Silver, M.D.,, Vimla Aggarwal, M.B., B.S.,, Andrew S. Allen, Ph.D.,, Ronald J. Wapner, M.D.,, and David B. Goldstein, Ph.D.

Issue&Volume: 2020-08-12

Abstract:

BACKGROUND

In the majority of cases, the cause of stillbirth remains unknown despite detailed clinical and laboratory evaluation. Approximately 10 to 20% of stillbirths are attributed to chromosomal abnormalities. However, the causal nature of single-nucleotide variants and small insertions and deletions in exomes has been understudied.

METHODS

We generated exome sequencing data for 246 stillborn cases and followed established guidelines to identify causal variants in disease-associated genes. These genes included those that have been associated with stillbirth and strong candidate genes. We also evaluated the contribution of 18,653 genes in case–control analyses stratified according to the degree of depletion of functional variation (described here as “intolerance” to variation).

RESULTS

We identified molecular diagnoses in 15 of 246 cases of stillbirth (6.1%) involving seven genes that have been implicated in stillbirth and in six disease genes that are good candidates for phenotypic expansion. Among the cases we evaluated, we also found an enrichment of loss-of-function variants in genes that are intolerant to such variation in the human population (odds ratio, 2.15; 95% confidence interval [CI], 1.46 to 3.06). Loss-of-function variants in intolerant genes were concentrated in genes that have not been associated with human disease (odds ratio, 2.22; 95% CI, 1.41 to 3.34), findings that differ from those in two postnatal clinical populations that were also evaluated in this study.

CONCLUSIONS

Our findings establish the diagnostic utility of clinical exome sequencing to evaluate the role of small genomic changes in stillbirth. The strength of the novel risk signal (as generated through the stratified analysis) was similar to that in known disease genes, which indicates that the genetic cause of stillbirth remains largely unknown.

DOI: 10.1056/NEJMoa1908753

Source: https://www.nejm.org/doi/full/10.1056/NEJMoa1908753