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Discovery of rare ancestry-specific variants in the fetal genome that confer risk of preterm premature rupture of membranes (PPROM) and preterm birth.

ABSTRACT: BACKGROUND:Preterm premature rupture of membranes (PPROM) is the leading identifiable cause of preterm birth, a complication that is more common in African Americans. Attempts to identify genetic loci associated with preterm birth using genome-wide association studies (GWAS) have only been successful with large numbers of cases and controls, and there has yet to be a convincing genetic association to explain racial/ethnic disparities. Indeed, the search for ancestry-specific variants associated with preterm birth has led to the conclusion that spontaneous preterm birth could be the consequence of multiple rare variants. The hypothesis that preterm birth is due to rare genetic variants that would go undetected in standard GWAS has been explored in the present study. The detection and validation of these rare variants present challenges because of the low allele frequency. However, some success in the identification of fetal loci/genes associated with preterm birth using whole genome sequencing and whole exome sequencing (WES) has recently been reported. While encouraging, this is currently an expensive technology, and methods to leverage the sequencing data to quickly identify and cost-effectively validate variants are needed. METHODS:We developed a WES data analysis strategy based on neonatal genomic DNA from PPROM cases and term controls that was unencumbered by preselection of candidate genes, and capable of identifying variants in African Americans worthy of focused evaluation to establish statistically significant associations. RESULTS:We describe this approach and the identification of damaging nonsense variants of African ancestry in the DEFB1 and MBL2 genes that encode anti-microbial proteins that presumably defend the fetal membranes from infectious agents. Our approach also enabled us to rule out a likely contribution of a predicted damaging nonsense variant in the METTL7B gene. CONCLUSIONS:Our findings support the notion that multiple rare population-specific variants in the fetal genome contribute to preterm birth associated with PPROM.

SUBMITTER: Modi BP

PROVIDER: S-EPMC6173941 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Discovery of rare ancestry-specific variants in the fetal genome that confer risk of preterm premature rupture of membranes (PPROM) and preterm birth.

Modi Bhavi P BP Parikh Hardik I HI Teves Maria E ME Kulkarni Rewa R Liyu Jiang J Romero Roberto R York Timothy P TP Strauss Jerome F JF

BMC medical genetics 20181005 1

<h4>Background</h4>Preterm premature rupture of membranes (PPROM) is the leading identifiable cause of preterm birth, a complication that is more common in African Americans. Attempts to identify genetic loci associated with preterm birth using genome-wide association studies (GWAS) have only been successful with large numbers of cases and controls, and there has yet to be a convincing genetic association to explain racial/ethnic disparities. Indeed, the search for ancestry-specific variants ass ...[more]

PMID: 30290772

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Project description:BackgroundEstimation of fetal weight (EFW) by ultrasound is useful in clinical decision-making. Numerous formulas for EFW have been published but have not been validated in pregnancies complicated by preterm premature rupture of membranes (PPROM). The purpose of this study is to compare the accuracy of EFW formulas in patients with PPROM, and to further evaluate the performance of the most commonly used formula - Hadlock IV.MethodsA retrospective cohort study of women with singleton gestations and PPROM, admitted to a single tertiary center between 2005 and 2017 from 220/7-330/7 (n = 565). All women had an EFW within 14 days of delivery by standard biometry (biparietal diameter, head circumference, abdominal circumference and femur length). The accuracy of previously published 21 estimated EFW formulas was assessed by comparing the Pearson correlation with actual birth weight, and calculating the random error, systematic error, proportion of estimates within 10% of birth weight, and Euclidean distance.ResultsThe mean gestational was 26.8 ± 2.4 weeks at admission, and 28.2 ± 2.6 weeks at delivery. Most formulas were strongly correlated with actual birth weight (r > 0.9 for 19/21 formulas). Mean systematic error was - 4.30% and mean random error was 14.5%. The highest performing formula, by the highest proportion of estimates and lowest Euclidean distance was Ott (1986), which uses abdominal and head circumferences, and femur length. However, there were minimal difference with all of the first 10 ranking formulas. The Pearson correlation coefficient for the Hadlock IV formula was strong at r = 0.935 (p < 0.001), with 319 (56.5%) of measurements falling within 10%, 408 (72.2%) within 15% and 455 (80.5%) within 20% of actual birth weight. This correlation was unaffected by gender (r = 0.936 for males, r = 0.932 for females, p < 0.001 for both) or by amniotic fluid level (r = 0.935 for mean vertical pocket < 2 cm, r = 0.943 for mean vertical pocket ≥2 cm, p < 0.001 for both).ConclusionsIn women with singleton gestation and PPROM, the Ott (1986) formula for EFW was the most accurate, yet all of the top ten ranking formulas performed quite well. The commonly used Hadlock IV performed quite similarly to Ott's formula, and is acceptable to use in this specific setting.

Dataset Information

Discovery of rare ancestry-specific variants in the fetal genome that confer risk of preterm premature rupture of membranes (PPROM) and preterm birth.

Publications

Discovery of rare ancestry-specific variants in the fetal genome that confer risk of preterm premature rupture of membranes (PPROM) and preterm birth.

Similar Datasets

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