Special issue on “Feto-Maternal Genomic Medicine”: a decade of incredible advances

Gray, Kathryn J.; Wilkins‐Haug, Louise

doi:10.1007/s00439-020-02217-4

Cited by 5 publications

(7 citation statements)

References 8 publications

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“…Previous genetic studies of pregnancy losses are limited for several reasons, including (1) lack of access to paternal DNA samples, which would make interpretations difficult without distinguishing inherited form from de novo variants, 30 (2) unavailability of pedigrees with products of conception from chromosomally normal losses and live-births, or (3) unavailability of high-quality data and protocols for DNA restoration and variant detection. [31][32][33] Loss-of-function risk variants and inherited variants in intolerant genes (i.e., genes that are critical for human development, conditions incompatible with life resulting in fetal demise) 16,23,34 were not identified, possibly due to limited sample size and focus on families with recurrent, rather than sporadic losses.…”

Section: Discussionmentioning

confidence: 99%

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: 99%

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

Workalemahu

Avery

Lopez

et al. 2022

Preprint

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“…For studies that did not report specific pathways, we conducted an Online Mendelian Inheritance in Man (OMIM) search to identify the roles of the reported genes in disease or functional pathways. Finally, we focused our discussion toward studies that report findings based on genetic factors that are likely causal (e.g., single-gene, autosomal and/or recessive de novo or inherited mutations, "intolerome, " copy number variations [CNVs], single nucleotide polymorphisms [SNPs]) (13). We summarized multiomic studies, e.g., studies based on proteins and methylated genes that have different mechanisms than single-gene mutations or CNVs.…”

Section: Study Summarizationmentioning

confidence: 99%

“…In these databases, lethal phenotypes are especially poorly represented. Other strategies for gene discovery, including determination of the "intolerome" are likely to reveal new genotype-phenotype correlations and shed light on the human "intolerome, " conditions incompatible with life resulting in fetal demise (11,13). Studies that incorporate DNA sequencing in affected and unaffected families, designed as case-control trio studies, will help in determination of the "intolerome" by identifying novel embryonic-lethal or fetal-lethal variants that are not seen in unaffected families.…”

Section: Guide To Next Steps In Determining Genetic Factors Associated With Pregnancy Lossmentioning

confidence: 99%

“…With the advent of next-generation sequencing (NGS), studies in the past 20 years have identified genetic pathways that are essential for in utero survival. In particular, some studies have shown increased likelihood of a genetic cause in early pregnancy (13), while challenges (e.g., accessibility, maternal cell contamination) remain when assessing biospecimen in products of conception from early losses. Furthermore, inconsistencies in categorizing pregnancy loss by gestational age have been noted by others (14).…”

Section: Introductionmentioning

confidence: 99%

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A Systematic Review to Guide Future Efforts in the Determination of Genetic Causes of Pregnancy Loss

Carey

Blue

Pagé

et al. 2021

Front. Reprod. Health

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Background: Pregnancy loss is the most common obstetric complication occurring in almost 30% of conceptions overall and in 12–14% of clinically recognized pregnancies. Pregnancy loss has strong genetic underpinnings, and despite this consensus, our understanding of its genetic causes remains limited. We conducted a systematic review of genetic factors in pregnancy loss to identify strategies to guide future research.Methods: To synthesize data from population-based association studies on genetics of pregnancy loss, we searched PubMed for relevant articles published between 01/01/2000-01/01/2020. We excluded review articles, case studies, studies with limited sample sizes to detect associations (N < 4), descriptive studies, commentaries, and studies with non-genetic etiologies. Studies were classified based on developmental periods in gestation to synthesize data across various developmental epochs.Results: Our search yielded 580 potential titles with 107 (18%) eligible after title/abstract review. Of these, 54 (50%) were selected for systematic review after full-text review. These studies examined either early pregnancy loss (n = 9 [17%]), pregnancy loss >20 weeks' gestation (n = 10 [18%]), recurrent pregnancy loss (n = 32 [59%]), unclassified pregnancy loss (n = 3 [4%]) as their primary outcomes. Multiple genetic pathways that are essential for embryonic/fetal survival as well as human development were identified.Conclusion: Several genetic pathways may play a role in pregnancy loss across developmental periods in gestation. Systematic evaluation of pregnancy loss across developmental epochs, utilizing whole genome sequencing in families may further elucidate causal genetic mechanisms and identify other pathways critical for embryonic/fetal survival.

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“…For example, detection rate for all congenital cardiac malformations using ultrasound is only a 36 to 39%. 8 As chromosomal microarray assessments aid standard genetic testing for perinatal diagnoses, 9 identifying pathogenic CNVs associated with fetal structural malformations can guide the management and counseling of families at risk for stillbirth. As such, information about the likelihood of associated anomalies that are not apparent in the second trimester may inform important medical decisions.…”

Section: Introductionmentioning

confidence: 99%

Copy number variants and fetal structural abnormalities in stillborn fetuses: a secondary analysis of the Stillbirth Collaborative Research Network study

Workalemahu

Dalton

Son

et al. 2022

Preprint

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Objective To examine the association of placental and fetal DNA copy number variants (CNVs) with fetal structural malformations (FSMs) in stillborn fetuses. Design A secondary analysis of stillbirth cases in the Stillbirth Collaborative Research Network (SCRN) study. Setting Multicenter, 59 hospitals in 5 geographic regions in the USA. Population 384 stillbirth cases of the SCRN study (2006-2008). Methods FSMs were grouped by anatomic system and specific malformation type (e.g., central nervous system, thoracic, cardiac, gastrointestinal, skeletal, umbilical cord and craniofacial defects). Single-nucleotide polymorphism array detected CNVs of at least 500kb. CNVs were classified into two groups: normal, defined as no CNVs>500kb or benign CNVs, and abnormal, defined as pathogenic or variants of unknown clinical significance. Main outcome measures The proportions of abnormal CNVs and normal CNVs were compared between stillbirth cases with and without FSMs using the Wald Chi-squared test. Results The proportion of stillbirth cases with any FSMs was higher among those with abnormal CNVs compared with those with normal CNVs (46.7% vs. 19.6%; p-value<0.001). The most common organ system-specific FSMs associated with abnormal CNVs were cardiac defects, followed by craniofacial and skeletal defects. A pathogenic deletion of 1q21.1 involving 46 genes (e.g., CHD1L) and a duplication of 21q22.13 involving 4 genes (SIM2, CLDN14, CHAF1B, HLCS) were associated with a skeletal and cardiac defect, respectively. Conclusion Specific CNVs involving several genes were associated with FSMs in stillborn fetuses. The findings warrant further investigation and may inform counseling and care surrounding pregnancies affected by FSMs at risk for stillbirth.

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Special issue on “Feto-Maternal Genomic Medicine”: a decade of incredible advances

Cited by 5 publications

References 8 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

A Systematic Review to Guide Future Efforts in the Determination of Genetic Causes of Pregnancy Loss

Copy number variants and fetal structural abnormalities in stillborn fetuses: a secondary analysis of the Stillbirth Collaborative Research Network study

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