Getting to the point (mutation)

Abstract

Pregnancy loss is, by far, the most common complication of pregnancy and affects roughly 1 in 5 clinically recognized pregnancies. Although there are many etiologies for pregnancy losses, the majority are due to chromosomal abnormalities such as aneuploidy (1Maisenbacher M.K. Merrion K. Levy B. Kutteh W.H. Single nucleotide polymorphism (SNP) array analysis of 63,277 products of conception (POC) samples: a 10-year laboratory experience.Fertil Steril. 2020; 114: e47Abstract Full Text Full Text PDF Google Scholar). For those who experience a pregnancy loss, one of the most difficult things to hear is that the workup came back normal. Identifying the cause of the loss helps alleviate feelings of guilt, shame, and depression, often experienced after a pregnancy loss, and helps inform future treatment to mitigate the risk of subsequent losses (2Bardos J. Hercz D. Friedenthal J. Missmer S.A. Williams Z. A national survey on public perceptions of miscarriage.Obstet Gynecol. 2015; 125: 1313-1320Crossref PubMed Scopus (70) Google Scholar). The typical human genome contains approximately 5 million variations compared with the human reference genome, but a vast majority of these are shared by more than 0.5% of the population. The de novo mutation rate in humans appears to be approximately 1 × 10−8 per nucleotide per genome or approximately 50 de novo single nucleotide mutations in the genome of the average person, with 1–2 affecting coding sequences (3Francioli L.C. Polak P.P. Koren A. Menelaou A. Chun S. Renkens I. et al.Genome-wide patterns and properties of de novo mutations in humans.Nat Genet. 2015; 47: 822-826Crossref PubMed Scopus (203) Google Scholar). Point mutations in critical genes result in a pathology ranging from gametogenesis to congenital anomalies across the reproductive spectrum (4Petrovski S. Aggarwal V. Giordano J.L. Stosic M. Wou K. Bier L. et al.Whole-exome sequencing in the evaluation of fetal structural anomalies: a prospective cohort study.Lancet. 2019; 393: 758-767Abstract Full Text Full Text PDF PubMed Scopus (158) Google Scholar). Genes and chromosome regions that are critical for early human development and whose loss is incompatible with life are referred to as the “intolerome.” In the current issue of Fertility and Sterility, Kline et al. (5Kline J. Vardarajan B. Abhyankar A. Kytömaa S. Levin B. Sobreira N. et al.Embryonic lethal genetic variants and chromosomally normal pregnancy loss.Fertil Steril. 2021; 116: 1351-1358Abstract Full Text Full Text PDF Scopus (1) Google Scholar) add to the growing list of lethal embryonic variants that constitute the intolerome and highlight a powerful approach to further characterize it. In an elegant study, the investigators used whole-exome sequencing to compared the frequency and types of rare and damaging single gene variants in 19 trios comprising parents and products of conception due to euploid losses at <18 weeks of gestational age, with 547 unaffected controls from a large dataset. Although the rates of synonymous missense variants and loss-of-function and damaging de novo or recessive variants were similar in the cases and controls, damaging variants classified as “possibly” embryonic lethal were present in genes in 3 (15.8%) cases. The variants were present in BAZ1A, FBN2, and TIMP2, which might plausibly play a role in embryogenesis, as reported in the existing literature. The most notable limitation of the study, as the investigators themselves pointed out, is the small sample size, making it difficult to extrapolate the frequency at which single point mutations may cause euploid pregnancy losses. In addition, the genes were defined as being damaging because they were variants with a predicted loss of function, but no functional studies were performed. Highlighting the challenge of interpreting variant data, 7 (1.3%) of the “healthy” controls were also identified as having damaging variants classified as “possibly” embryonic lethal. Finally, different platforms were used for the cases and controls, although the investigators tried to adjust for this by restricting the analysis to regions covered by both the platforms. Collectively, this study adds to our understanding of the intolerome and serves as a model for using whole-exome sequencing to further characterize and help us identify lethal variants that have previously been missed. It is a promising starting point that can hopefully continue to reveal additional causes of pregnancy loss. Embryonic lethal genetic variants and chromosomally normal pregnancy lossFertility and SterilityVol. 116Issue 5PreviewTo examine whether rare damaging genetic variants are associated with chromosomally normal pregnancy loss and estimate the magnitude of the association. Full-Text PDF