Embryonic lethal genetic variants and chromosomally normal pregnancy loss

Kline, Jennie; Vardarajan, Badri N.; Abhyankar, Avinash; Kytömaa, Sonja; Levin, Bruce; Sobreira, Nara; Tang, Andrew; Thomas‐Wilson, Amanda; Zhang, Ruiwei; Jobanputra, Vaidehi

doi:10.1016/j.fertnstert.2021.06.039

Cited by 11 publications

(15 citation statements)

References 34 publications

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“…Although we demonstrated some sharing of SNVs across families (e.g., compound heterozygous SNVs in four TM2D1 , MUC16 ,VWA5B2 were shared across two families), losses may not have common etiologies. 22,37 As such, this finding suggests that different genes may play a role at different developmental epochs and across families. 16 Second, we explored validation of VWA5B2 gene by Sanger sequencing and confirmed that WGS in our sample confidently called its compound heterozygous SNV (chr3:184236380:T:C).…”

Section: Discussionmentioning

confidence: 78%

“…similarly hypothesized that chromosomally normal losses are caused by rare variants in several different genes, some of which are incompatible with development to the fetal stage. 22 The authors reported damaging variants in several genes that are relevant to recurrent pregnancy loss, including FBN2 (Fibrillin 2). Notably, we identified a de novo in-frame deletion involving FBN2 in fetal death in Family 4 that was not identified in any of the live births across families.…”

Section: Discussionmentioning

confidence: 99%

“…Third, among SNVs that were identified in any of the pregnancy losses, we selected pathogenic SNVs (SNVs with pLI>0.90 and LOEUF<0.36) to highlight potentially damaging variants in candidate genes. Finally, we selected SNVs in genes that were involved in pregnancy loss-relevant phenotypes/diseases (e.g., embryonic/fetal death and developmental abnormalities [22][23][24] ) to interpret candidate genes. Analyses were performed using Slivar and R, utilizing resources and support from the Center for High Performance Computing at the University of Utah.…”

Section: Variant Prioritization and Selection Of Candidate Genes Rele...mentioning

confidence: 99%

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Whole-genome sequencing analysis in families with recurrent pregnancy loss: A pilot study

Workalemahu

Avery

Lopez

et al. 2022

Preprint

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Objective To conduct a feasibility whole-genome sequencing (WGS) study in families to identify genetic variants relevant to unexplained pregnancy loss. Methods We conducted a pilot WGS study of four families with recurrent pregnancy loss, including parents, healthy live births, and losses, which included an embryonic loss (<10 weeks’ gestation), fetal deaths (10-20 weeks’ gestation) and stillbirths (≥ 20 weeks’ gestation). We used the Illumina platform for WGS and state-of-the-art protocols to identify single nucleotide variants (SNVs) following various modes of inheritance. Results We identified 87 SNVs involving 75 genes in embryonic loss (n=1), 370 SNVs involving 228 genes in fetal death (n=3), and 122 SNVs involving 122 genes in stillbirth (n=2). Of these, 22 de novo, 6 autosomal dominant and an X-linked recessive SNVs were pathogenic (probability of being loss-of-function intolerant >0.9), impacting known genes (e.g., DICER1, FBN2, FLT4, HERC1, and TAOK1) involved in embryonic/fetal development and congenital abnormalities. Further, we identified missense compound heterozygous SNVs impacting genes (e.g., VWA5B2) in two fetal death samples that were absent from live births and population controls, providing evidence for haplosufficient genes relevant to pregnancy loss. Conclusions In this pilot study, we provide evidence for de novo and inherited SNVs relevant to pregnancy loss. Our findings provide justification for conducting WGS using larger numbers of families and warrant validation by targeted sequencing to ascertain causal variants. Elucidating genes causing pregnancy loss may facilitate the development of risk stratification strategies and novel therapeutics.

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Section: Discussionmentioning

confidence: 78%

Section: Discussionmentioning

confidence: 99%

Section: Variant Prioritization and Selection Of Candidate Genes Rele...mentioning

confidence: 99%

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Whole-genome sequencing analysis in families with recurrent pregnancy loss: A pilot study

Workalemahu

Avery

Lopez

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…Third, among SNVs that were identified in any of the pregnancy losses, we selected pathogenic SNVs (SNVs with pLI>0.90 and LOEUF<0.36) to highlight potentially damaging variants in candidate genes. Finally, we selected SNVs in genes that were involved in pregnancy loss-relevant phenotypes/diseases (e.g., embryonic/fetal death and developmental abnormalities [22][23][24]) to interpret candidate genes. Analyses were performed using Slivar and R, utilizing resources and support from the Center for High Performance Computing at the University of Utah.…”

Section: Plos Onementioning

confidence: 99%

Whole-genome sequencing analysis in families with recurrent pregnancy loss: A pilot study

Workalemahu

Avery²,

Lopez³

et al. 2023

PLoS ONE

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One to two percent of couples suffer recurrent pregnancy loss and over 50% of the cases are unexplained. Whole genome sequencing (WGS) analysis has the potential to identify previously unrecognized causes of pregnancy loss, but few studies have been performed, and none have included DNA from families including parents, losses, and live births. We conducted a pilot WGS study in three families with unexplained recurrent pregnancy loss, including parents, healthy live births, and losses, which included an embryonic loss (<10 weeks’ gestation), fetal deaths (10–20 weeks’ gestation) and stillbirths (≥ 20 weeks’ gestation). We used the Illumina platform for WGS and state-of-the-art protocols to identify single nucleotide variants (SNVs) following various modes of inheritance. We identified 87 SNVs involving 75 genes in embryonic loss (n = 1), 370 SNVs involving 228 genes in fetal death (n = 3), and 122 SNVs involving 122 genes in stillbirth (n = 2). Of these, 22 de novo, 6 inherited autosomal dominant and an X-linked recessive SNVs were pathogenic (probability of being loss-of-function intolerant >0.9), impacting known genes (e.g., DICER1, FBN2, FLT4, HERC1, and TAOK1) involved in embryonic/fetal development and congenital abnormalities. Further, we identified inherited missense compound heterozygous SNVs impacting genes (e.g., VWA5B2) in two fetal death samples. The variants were not identified as compound heterozygous SNVs in live births and population controls, providing evidence for haplosufficient genes relevant to pregnancy loss. In this pilot study, we provide evidence for de novo and inherited SNVs relevant to pregnancy loss. Our findings provide justification for conducting WGS using larger numbers of families and warrant validation by targeted sequencing to ascertain causal variants. Elucidating genes causing pregnancy loss may facilitate the development of risk stratification strategies and novel therapeutics.

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“…In euploid abortions, using molecular techniques such as aCGH, SNP array, and NGS, the possible candidate genes associated with RPL have been revealed, including genes involved in the immune response, coagulation, metabolism, angiogenesis, cell division, cilial function, and fetal movement [ 51 , 52 , 53 ]. The identification of genes that are causative of or predisposing to pregnancy loss is of significant impact for patient counselling and treatment, though most of these genes show moderate associations with RPL and have been described in only small case–control studies, as reviewed by [ 54 , 55 , 56 ].…”

Section: Genetic Causes Of Miscarriagementioning

confidence: 99%

Stem Cell-Based Trophoblast Models to Unravel the Genetic Causes of Human Miscarriages

Nikitina

Lebedev

2022

Cells

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Miscarriage affects approximately 15% of clinically recognized pregnancies, and 1–3% of couples experience pregnancy loss recurrently. Approximately 50–60% of miscarriages result from chromosomal abnormalities, whereas up to 60% of euploid recurrent abortions harbor variants in candidate genes. The growing number of detected genetic variants requires an investigation into their role in adverse pregnancy outcomes. Since placental defects are the main cause of first-trimester miscarriages, the purpose of this review is to provide a survey of state-of-the-art human in vitro trophoblast models that can be used for the functional assessment of specific abnormalities/variants implicated in pregnancy loss. Since 2018, when primary human trophoblast stem cells were first derived, there has been rapid growth in models of trophoblast lineage. It has been found that a proper balance between self-renewal and differentiation in trophoblast progenitors is crucial for the maintenance of pregnancy. Different responses to aneuploidy have been shown in human embryonic and extra-embryonic lineages. Stem cell-based models provide a powerful tool to explore the effect of a specific aneuploidy/variant on the fetus through placental development, which is important, from a clinical point of view, for deciding on the suitability of embryos for transfer after preimplantation genetic testing for aneuploidy.

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Embryonic lethal genetic variants and chromosomally normal pregnancy loss

Cited by 11 publications

References 34 publications

Whole-genome sequencing analysis in families with recurrent pregnancy loss: A pilot study

Whole-genome sequencing analysis in families with recurrent pregnancy loss: A pilot study

Whole-genome sequencing analysis in families with recurrent pregnancy loss: A pilot study

Stem Cell-Based Trophoblast Models to Unravel the Genetic Causes of Human Miscarriages

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