Causal Genetic Variants in Stillbirth

Stanley, Kate E.; Giordano, Jessica L.; Thorsten, Vanessa; Buchovecky, Christie; Adejoh, Thomas; Ganapathi, Mythily; Liao, Jun; Dharmadhikari, Avinash V.; Revah‐Politi, Anya; Ernst, Michelle; Lippa, Natalie; Holmes, Helen; Povysil, Gundula; Hostyk, Joseph; Parker, Cora; Goldenberg, R.L.; Saade, George R.; Dudley, Donald J.; Pınar, Halit; Hogue, Carol J.; Reddy, Uma M.; Silver, R.M.; Aggarwal, Vimla S.; Allen, Andrew S.; Wapner, R. J.; Goldstein, DB

doi:10.1097/01.aoa.0000732532.96202.8a

Cited by 15 publications

(31 citation statements)

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“…31 Stanley and colleagues performed whole exome sequencing in a large stillbirth case cohort and identified previously unknown genetic variants leading to a suspected genetic cause of death in 18% of the stillbirths in the study cohort. 4 They found variants in genes that are known to be pathogenic in postnatal life but also variants that are critical for in utero survival that had not yet been reported in association with stillbirth. 4 Our study contributes new data as the largest and most comprehensive intergenerational study of stillbirth.…”

Section: Discussionmentioning

confidence: 99%

“…4 They found variants in genes that are known to be pathogenic in postnatal life but also variants that are critical for in utero survival that had not yet been reported in association with stillbirth. 4 Our study contributes new data as the largest and most comprehensive intergenerational study of stillbirth. It is the first to identify familial aggregation of stillbirth and quantifies stillbirth risk based on an individual's family history.…”

Section: Discussionmentioning

confidence: 99%

“…2 Birth/death year of the founder 3 Familial Standardized Incidence Ratio, comparing the incidence of stillbirth in a family to its expected incidence in the population 4 The observed and expected counts of stillbirth between pedigrees may overlap…”

Section: Discussionmentioning

confidence: 99%

“…The accepted range for birth weights of live births are 500-6000g. 4 Difference in education status is due to a reduced rate of maternal form completion in fetal death cases as compared to controls.…”

Section: Disclosure Of Interestsmentioning

confidence: 99%

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Familial aggregation of stillbirth: a pedigree analysis of a matched case control study

Workalemahu

Pagé

Meeks

et al. 2022

Preprint

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Objective To determine if stillbirth aggregates in families and quantify its familial risk using extended pedigrees. Design State-wide matched case-control study. Setting Utah, United States. Population Stillbirth cases (n=9 404) and live-birth controls (18 808) between 1978 and 2019. Methods Using the Utah Population Database, a population‐based genealogical resource linked with state fetal death and birth records, we identified high-risk pedigrees with excess familial aggregation of stillbirth using the Familial Standardized Incidence Ratio (FSIR). Stillbirth odds ratio (OR) for first-degree relatives (FDR), second-degree relatives (SDR), and third-degree relatives (TDR) of parents with a stillbirth and live-birth were estimated using logistic regression models. Results We identified 390 high-risk pedigrees with evidence for excess familial aggregation (FSIR≥2.00 and P-value<0.05). FDRs, SDRs and TDRs of affected parents had 1.14-fold (95% confidence interval [CI]: 1.04-1.26), 1.22-fold (95% CI: 1.11-1.33), and 1.15-fold (95% CI: 1.08-1.21) higher stillbirth odds compared to FDRs, SDRs and TDRs of unaffected parents, respectively. Parental sex-specific analyses showed male FDRs, SDRs and TDRs of affected fathers had 1.22-fold (95% CI: 1.02-1.47), 1.38-fold (95% CI: 1.17-1.62), 1.17-fold (95% CI: 1.05-1.30) higher stillbirth odds compared to those of unaffected fathers, respectively. FDRs, SDRs and TDRs of affected mothers had 1.12-fold (95% CI: 0.98-1.28), 1.09-fold (95% CI: 0.96-1.24), and 1.15-fold (95% CI: 1.06-1.24) higher stillbirth odds compared with those of unaffected mothers, respectively. Conclusions We provide evidence for familial aggregation of stillbirth. Our findings warrant investigation into genes associated with stillbirth and underscore the need to design large-scale studies to determine its genetic architecture.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Disclosure Of Interestsmentioning

confidence: 99%

See 2 more Smart Citations

Familial aggregation of stillbirth: a pedigree analysis of a matched case control study

Workalemahu

Pagé

Meeks

et al. 2022

Preprint

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“…3 In stillbirths, you are probably familiar with a recent paper from New York where nearly every variant was dominant, again the complete opposite of the pattern we had observed in our consanguineous population, which is in a way a silver lining because we are able to trace the cause of death in the DNA of the parents when we have no DNA left from the stillbirth (molecular autopsy by proxy). 4,5 In male infertility, we have conducted the largest genomic investigation into azoospermia and found that >80% of hits are recessive, and it will be interesting to see what similar studies in outbred populations will show as these become available. 6 In consanguineous unions, not only do you get enrichment for even the rarest of autosomal recessive traits, but you also get to map the causal variant readily even when you have no clue what the gene's function is thanks to the autozygome.…”

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confidence: 99%

2020 Curt Stern Award address: a more perfect clinical genome—how consanguineous populations contribute to the medical annotation of the human genome

Alkuraya

2021

The American Journal of Human Genetics

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Impact of parental relatedness on reproductive outcomes among the Old Order Amish of Lancaster County

Lynch,

Maloney,

Pollin

et al. 2022

American J of Med Genetics Pt A

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Genetically isolated populations that arise due to recent bottleneck events have reduced genetic variation reflecting the common set of founders. Increased genetic relatedness among members of isolated populations puts them at increased risk for some recessive disorders that are rare in outbred populations. To assess the burden on reproductive health, we compared frequencies of adverse reproductive outcomes between Amish couples who were both heterozygous carriers of a highly penetrant pathogenic or likely pathogenic variant and noncarrier couples from the same Amish community. In addition, we evaluated whether overall genetic relatedness of parents was associated with reproductive outcomes. Of the 1824 couples included in our study, 11.1% were at risk of producing a child with an autosomal recessive disorder. Carrier couples reported a lower number of miscarriages compared to noncarrier couples (p = 0.02), although the number of stillbirths (p = 0.3), live births (p = 0.9), and number of pregnancies (p = 0.9) did not differ significantly between groups. In contrast, higher overall relatedness between spouses was positively correlated with number of live births (p < 0.0001), pregnancies (p < 0.0001), and stillbirths (p = 0.03), although not with the number of miscarriages (p = 0.4). These results highlight a complex association between relatedness of parents and reproductive health outcomes in this community.

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Causal Genetic Variants in Stillbirth

Cited by 15 publications

References 0 publications

Familial aggregation of stillbirth: a pedigree analysis of a matched case control study

Familial aggregation of stillbirth: a pedigree analysis of a matched case control study

2020 Curt Stern Award address: a more perfect clinical genome—how consanguineous populations contribute to the medical annotation of the human genome

Impact of parental relatedness on reproductive outcomes among the Old Order Amish of Lancaster County

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