Sequencing and de novo assembly of seven wild relatives of soybean yields insights relevant to crop domestication and improvement.

Objectives: Embryonic numerical and structural chromosomal abnormalities are the most common cause of early pregnancy loss. However, the role of submicroscopic copy‐number variations (CNVs) in early pregnancy loss is unclear, and little is known about the critical regions and candidate genes for miscarriage, because of the large size of structural chromosomal abnormalities. The aim of this study was to identify potential miscarriage‐associated submicroscopic CNVs and critical regions of large CNVs as well as candidate genes for miscarriage.Methods: Over a 5‐year period, 5180 fresh miscarriage specimens were investigated using quantitative fluorescent polymerase chain reaction/CNV sequencing or chromosomal microarray analysis. Statistically significant submicroscopic CNVs were identified by comparing the frequency of recurrent submicroscopic CNVs between cases and a published control cohort. Furthermore, genes within critical regions of miscarriage‐associated CNVs were prioritized by integrating the Residual Variation Intolerance Score and the human gene expression dataset for identification of potential miscarriage candidate genes.Results: Results without significant maternal‐cell contamination were obtained in 5003 of the 5180 (96.6%) cases. Clinically significant chromosomal abnormalities were identified in 59.1% (2955/5003) of these cases. Three recurrent submicroscopic CNVs (microdeletions in 22q11.21, 2q37.3 and 9p24.3p24.2) were significantly more frequent in miscarriage cases, and were considered to be associated with miscarriage. Moreover, 44 critical regions of large CNVs were observed, including 14 deletions and 30 duplications. There were 309 genes identified as potential miscarriage candidate genes through gene‐prioritization analysis.Conclusions: We identified potential miscarriage candidate CNVs and genes. These data demonstrate the importance of CNVs in the etiology of miscarriage and highlight the importance of ongoing analysis of CNVs in the study of miscarriage. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Whole genome sequencing (WGS) is a powerful tool for postnatal genetic diagnosis, but relevant clinical studies in the field of prenatal diagnosis are limited. The present study aimed to prospectively evaluate the utility of WGS compared with chromosomal microarray (CMA) and whole exome sequencing (WES) in the prenatal diagnosis of fetal structural anomalies. We performed trio WGS (≈40-fold) in parallel with CMA in 111 fetuses with structural or growth anomalies, and sequentially performed WES when CMA was negative (CMA plus WES). In comparison, WGS not only detected all pathogenic genetic variants in 22 diagnosed cases identified by CMA plus WES, yielding a diagnostic rate of 19.8% (22/110), but also provided additional and clinically significant information, including a case of balanced translocations and a case of intrauterine infection, which might not be detectable by CMA or WES. WGS also required less DNA (100 ng) as input and could provide a rapid turnaround time (TAT, 18 ± 6 days) compared with that (31 ± 8 days) of the CMA plus WES. Our results showed that WGS provided more comprehensive and precise genetic information with a rapid TAT and less DNA required than CMA plus WES, which enables it as an alternative prenatal diagnosis test for fetal structural anomalies.

Expanded carrier screening (ECS) has been demonstrated to increase the detection rate of carriers compared with traditional tests. The aim of this study was to assess the potential value of ECS for clinical application in Southern China, a region with high prevalence of thalassemia and with diverse ethnic groups, and to provide a reference for future implementations in areas with similar population characteristics. A total of 10,476 prenatal/preconception couples from 34 self-reported ethnic groups were simultaneously tested and analyzed anonymously for 11 Mendelian disorders using targeted next-generation sequencing. Overall, 27.49% of individuals without self-reported family history of disorders were found to be carriers of at least 1 of the 11 conditions, and the carrier frequency varied greatly between ethnic groups, ranging from 4.15% to 81.35%. Furthermore, 255 couples (2.43%) were identified as carrier couples at an elevated risk having an affected baby, sixty-five of which would not have been identified through the existing screening strategy, which only detects thalassemia. The modeled risk of fetuses being affected by any of the selected disorders was 531 per 100,000 (95% CI, 497–567 per 100,000). Our data demonstrate the feasibility of ECS, and provide evidence that ECS is a promising alternative to traditional one-condition screening strategies. The lessons learned from this experience should be applicable for other countries or regions with diverse ethnic groups.

Here, we aimed to validate a noninvasive method using capture sequencing for prenatal diagnosis of congenital adrenal hyperplasia due to 21-Hydroxylase deficiency (21-OHD). Noninvasive prenatal diagnosis (NIPD) of 21-OHD was based on 14 plasma samples collected from 12 families, including four plasma sample collected during the first trimester. Targeted capture sequencing was performed using genomic DNA from the parents and child trios to determine the pathogenic and wild-type alleles associated with the haplotypes. Maternal plasma DNA was also sequenced to determine the fetal inheritance of the allele using hidden Markov model-based haplotype linkage analysis. The effect of fetal DNA fraction and sequencing depth on the accuracy of NIPD was investigated. The lower limit of fetal DNA fraction was 2% and the threshold mean sequence depth was 38, suggesting potential advantage if used in early gestation. The CYP21A2 genotype of the fetus was accurately determined in all the 14 plasma samples as early as day 1 and 8 weeks of gestation. Results suggest the accuracy and feasibility of NIPD of 21-OHD using a small target capture region with a low threshold for fetal DNA fraction and sequence depth. Our method is cost-effective and suggests diagnostic applications in clinical practice.