RESUMEN

BACKGROUND: Whole exome sequencing (WES) has been recommended to investigate the genetic cause of fetal structural anomalies. In this retrospective study, we aimed to evaluate the diagnostic yield of WES in our cohort of families with pregnancy loss or termination of pregnancy due to structural anomalies. METHODS: As aneuploidy, triploidy and copy number variations (CNVs) could be detected by exome-based CNV analysis, only WES is performed in this study. And the results of 375 cases assessed by WES were analyzed. RESULTS: The overall detection rate was 32.3% (121/375), including aneuploidy and triploidy (7.5%, 28/375), CNVs (5.1%, 19/375) and single-nucleotide variants (SNVs) /insertions or deletions (Indels) (19.7%, 74/375). Among these, the diagnostic yield for likely pathogenic (LP) or pathogenic (P) CNVs is 4.8% (18/375), and the diagnostic yield for LP or P SNVs/Indels is 15.2% (57/375). And an additional 4.8% (18/375) of cases had CNVs or SNVs/Indels classified as variants of uncertain significance (VUS) with potential clinical significance. CONCLUSIONS: Our findings expand the known mutation spectrum of genetic variants related to fetal abnormalities, increase our understanding of prenatal phenotypes, and enable more accurate counseling of recurrence risk for future pregnancies.

Asunto(s)

RESUMEN

OBJECTIVES: The identification of structural variants and single-nucleotide variants is essential in finding molecular etiologies of monogenic genetic disorders. Whole-genome sequencing (WGS) is becoming more widespread in genetic disease diagnosis. However, data on its clinical utility remain limited in prenatal practice. We aimed to expand our understanding of implementing WGS in the genetic diagnosis of fetal structural anomalies. METHODS: We employed trio WGS with a minimum coverage of 40× on the MGI DNBSEQ-T7 platform in a cohort of 17 fetuses presenting with aberrations detected by ultrasound, but uninformative findings of standard chromosomal microarray analysis (CMA) and exome sequencing (ES). RESULTS: Causative genetic variants were identified in two families, with an increased diagnostic yield of 11.8% (2/17). Both were exon-level copy-number variants of small size (3.03 kb and 5.16 kb) and beyond the detection thresholds of CMA and ES. Moreover, to the best of our knowledge, we have described the first prenatal instance of the association of FGF8 with holoprosencephaly and facial deformities. CONCLUSIONS: Our analysis demonstrates the clinical value of WGS in the diagnosis of the underlying etiology of fetuses with structural abnormalities, where routine genetic tests have failed to diagnose. Additionally, the novel variants and new fetal manifestations have expanded the mutational and phenotypic spectrums of BBS9 and FGF8. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.

RESUMEN

INTRODUCTION: Food insecurity represents a public health issue that has been associated with poor birth outcomes. We describe the methodological steps followed to structure and validate a questionnaire, which has the potential to contribute to the planning and conduction of future studies investigating the possible association between maternal food insecurity and fetal structural anomalies. METHODS: We first conducted a literature review to structure and validate the questionnaire. Subsequently, we drafted the questionnaire based on the results of this review, further refined through two focus groups. Afterward, the questionnaire was submitted using the Delphi Method to a panel of experts for validation. We conducted a pilot study prior to recruiting the final sample. RESULTS: The questionnaire consisted of sections covering information about socio-demographic characteristics, women's health and lifestyle, pregnancy, and food security status. After the first Delphi round, the Content Validity Index (CVI) for each section ranged 0.81-0.85, while after the second round all items had a CVI of 1. The final version of the questionnaire, consisting of 87 items, was pilot tested among 20 participants. Cronbach's Alpha for each section resulted in values higher than 0.6. The response rate ranged from 78 to 100%. A situation of food security was present in 85% of the participants, while 5% were in a situation of mild food insecurity and 10% of moderate food insecurity. CONCLUSION: The questionnaire has appropriate measurement properties, and is an adequate instrument to evaluate the association between maternal food insecurity and fetal structural anomalies.

Asunto(s)

RESUMEN

Background: More than half of the cases of fetal structural anomalies have no known cause with standard investigations like karyotype testing and chromosomal microarray. The differential metabolic profiles of amniotic fluid (AF) and maternal blood may reveal valuable information about the physiological processes of fetal development, which may provide valuable biomarkers for fetal health diagnostics. Methods: This cohort study of singleton-pregnant women had indications for amniocentesis, including structural anomalies and a positive result from maternal serum screening or non-invasive prenatal testing, but did not have any positive abnormal karyotype or chromosomal microarray analysis results. A total of 1580 participants were enrolled between June 2021 and March 2022. Of the 1580 pregnant women who underwent amniocentesis, 294 were included in the analysis. There were 137 pregnant women in the discovery cohort and 157 in the validation cohort. Results: High-coverage untargeted metabolomic analysis of AF revealed distinct metabolic signatures with 321 of the 602 metabolites measured (53%) (false discovery rate, q < 0.005), among which amino acids predominantly changed in structural anomalies. Targeted metabolomics identified glutamate and glutamine as novel predictive markers for structural anomalies, their vital role was also confirmed in the validation cohort with great predictive ability, and the area under the receiver operating characteristic curves (AUCs) were 0.862 and 0.894 respectively. And AUCs for glutamine/glutamate were 0.913 and 0.903 among the two cohorts. Conclusions: Our results suggested that the aberrant glutamine/glutamate metabolism in AF is associated with nonchromosomal modificantions fetal structural anomalies. Based on our findings, a novel screening method could be established for the nonchromosomal modificantions fetal structural anomalies. And the results also indicate that monitoring fetal metabolic conditions (especially glutamine and glutamine metabolism) may be helpful for antenatal diagnosis and therapy.

Asunto(s)

RESUMEN

BACKGROUND: Emerging studies suggest that whole genome sequencing provides additional diagnostic yield of genomic variants when compared with chromosomal microarray analysis in the etiologic diagnosis of infants and children with suspected genetic diseases. However, the application and evaluation of whole genome sequencing in prenatal diagnosis remain limited. OBJECTIVE: This study aimed to evaluate the accuracy, efficacy, and incremental yield of whole genome sequencing in comparison with chromosomal microarray analysis for routine prenatal diagnosis. STUDY DESIGN: In this prospective study, a total of 185 unselected singleton fetuses with ultrasound-detected structural anomalies were enrolled. In parallel, each sample was subjected to whole genome sequencing and chromosomal microarray analysis. Aneuploidies and copy number variations were detected and analyzed in a blinded fashion. Single nucleotide variations and insertions and deletions were confirmed by Sanger sequencing, and trinucleotide repeats expansion variants were verified using polymerase chain reaction plus fragment-length analysis. RESULTS: Overall, genetic diagnoses using whole genome sequencing were obtained for 28 (15.1%) cases. Whole genome sequencing not only detected all these aneuploidies and copy number variations in the 20 (10.8%) diagnosed cases identified by chromosomal microarray analysis, but also detected 1 case with an exonic deletion of COL4A2 and 7 (3.8%) cases with single nucleotide variations or insertions and deletions. In addition, 3 incidental findings were detected including an expansion of the trinucleotide repeat in ATXN3, a splice-sites variant in ATRX, and an ANXA11 missense mutation in a case of trisomy 21. CONCLUSION: Compared with chromosomal microarray analysis, whole genome sequencing increased the additional detection rate by 5.9% (11/185). Using whole genome sequencing, we detected not only aneuploidies and copy number variations, but also single nucleotide variations and insertions and deletions, trinucleotide repeat expansions, and exonic copy number variations with high accuracy in an acceptable turnaround time (3-4 weeks). Our results suggest that whole genome sequencing has the potential to be a new promising prenatal diagnostic test for fetal structural anomalies.

Asunto(s)

RESUMEN

With the advancements in prenatal diagnostics, genome sequencing is now incorporated into clinical use to maximize the diagnostic yield following uninformative conventional tests (karyotype and chromosomal microarray analysis). Hong Kong started publicly funded prenatal genomic sequencing as a sequential test in the investigation of fetal structural anomalies in April 2021. The objective of the study was to evaluate the clinical performance and usefulness of this new service over one year. We established a web-based multidisciplinary team to facilitate case selection among the expert members. We retrospectively analyzed the fetal phenotypes, test results, turnaround time and clinical impact in the first 15 whole exome sequencing and 14 whole genome sequencing. Overall, the molecular diagnostic rate was 37.9% (11/29). De novo autosomal dominant disorders accounted for 72.7% (8/11), inherited autosomal recessive disorders for 18.2% (2/11), and inherited X-linked disorders for 9.1% (1/11). The median turnaround time for ongoing pregnancy was 19.5 days (range, 13-31 days). Our study showed an overall clinical impact of 55.2% (16/29), which influenced reproductive decision-making in four cases, guided perinatal management in two cases and helped future family planning in ten cases. In conclusion, our findings support the important role of genome sequencing services in the prenatal diagnosis of fetal structural anomalies in a population setting. It is important to adopt a multidisciplinary team approach to support the comprehensive genetic service.

Asunto(s)

RESUMEN

OBJECTIVE: To evaluate the efficacy of the first-trimester ultrasound scan in the detection of fetal structural anomalies in twin pregnancies. To examine the association between increased nuchal translucency (NT) thickness, crown-rump length (CRL) or NT discordance, and detection of structural anomalies in a large twin series in China. METHODS: We performed retrospective analysis of twin pregnancies who underwent 11-13+6 -week and second-trimester anomaly scan and booked at Beijing Obstetrics and Gynecology Hospital between January 2012 and December 2016. Measurement of fetal CRL/NT and assessment of fetal anatomic structures were based on standard (not detailed) protocols. Conjoined twins and twin-reversed arterial perfusion sequence (TRAPS) were excluded from structural anomalies. The diagnostic performance of first-trimester ultrasound in detection of fetal structural anomalies in twins was determined and compared with that of second trimester. The accuracy of independent variates associated with structural anomaly detection was calculated. RESULTS: A total of 1442 women with twin pregnancies were included. In 40 women and 45 fetuses, structural anomalies were found. Fetal structural anomalies verified at delivery were detected in 42.5% (17/40) of affected pregnancies in the first trimester and 92.5% (37/40) of affected pregnancies when added second trimester (P = .13). The survival rate of pregnancies detected in second trimester was higher than that of pregnancies detected in first trimester (11.8% vs 65.2%). The mean value of intertwin CRL/NT discordance in cases with fetal structural anomalies was larger in monochorionic twins than dichorionic twins, but monochorionicity was not associated with structural anomalies. CRL discordance ≥10% (OR 3.1, 95%CI 1.5-6.3) and NT ≥95th centile (OR 20.0, 95%CI 9.0-44.2) were associated with fetal structural anomalies. In both dichorionic (DC) and monochorionic (MC) twins, the percentages of CRL discordance ≥10% was larger in twins with structural anomalies than those without structural anomalies (37.5% vs 13.4% in DC twins and 50.0% vs 12.5% in MC twins), and this was also true for NT ≥95th centile (31.3% vs 1.7% in DC twins and 37.5% vs 2.2% in MC twins). In the setting of CRL discordance ≥10%, 40.0% (16/40) of twins with structural anomalies were found, in which the predominant fetal structural anomalies were cardiovascular defects, abdominal wall defects, and central nervous system defects. The AUC for detecting structural anomalies by CRL discordance ≥10% was 0.63. In the setting of NT ≥95th centile, 32.5% (13/40) of twins with structural anomalies were found, in which the predominant fetal structural anomalies were cardiovascular defects, cystic hygroma, and abdominal wall defects. The AUC for detecting structural anomalies by NT ≥95th centile was 0.65. CONCLUSIONS: The detection rate of twins with fetal structural anomalies was 42.5% per pregnancy in the first trimester. CRL discordance ≥10% and NT ≥95th centile may indicate higher risk of fetal structural anomalies in twins, but their efficacy was limited.

Asunto(s)

RESUMEN

To determine the diagnostic yield of exome sequencing (ES), a microarray analysis was carried out of fetuses with recurrent fetal structural anomalies (with similar anomalies in consecutive pregnancies). This is a systematic review conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria. The selected studies describing ES in fetuses with recurrent fetal malformation were assessed using the Standards for Reporting of Diagnostic Accuracy Studies (STARD) criteria for risk of bias. Incidence was used as the pooled effect size by single-proportion analysis using random-effects modeling (weighted by inverse of variance). We identified nine studies on ES diagnostic yield that included 140 fetuses with recurrent structural anomalies. A pathogenic or likely pathogenic variant was found in 57 fetuses, resulting in a 40% (95%CI: 26% to 54%) incremental performance pool of ES. As expected, the vast majority (86%: 36/42) of the newly identified diseases had a recessive inheritance pattern, and among these, 42% (15/36) of variants were found in homozygosity. Meckel syndrome was the monogenic disease most frequently found, although the genes involved were diverse. The ES diagnostic yield in pregnancies with recurrent fetal structural anomalies was 40% (57/140). Homozygous disease-causing variants were found in 36% (15/57) of the newly identified monogenic disorders.

RESUMEN

BACKGROUND: Prenatal whole-exome sequencing (WES) is becoming increasingly used when karyotype and microarray tests are not diagnostic of fetal malformations. Although the value of WES clearly emerges in terms of higher diagnostic rates, the limitations of prenatal phenotyping together with the counseling challenges for variants of uncertain significance and incidental results suggest that the routine application of prenatal WES is not yet easy. METHODS: Structurally abnormal fetuses with a mean gestational age of 24 weeks (range 13-38 weeks) were recruited from the Chong Qing Health Center for Women and Children. We performed a retrospective WES investigation in 85 fetuses, using DNA from amniotic fluid (66 samples, 77.6%), umbilical cord blood (10 samples, 11.8%), and fetal tissues (9 samples, 10.6%). Parental DNA was extracted from peripheral blood. RESULTS: Molecular diagnosis was obtained in 16 of the 85 fetuses (18.8%). According to the variant segregation mode and family history, 7 fetuses (43.75%) were affected by an autosomal dominant condition (6 variants were de novo and 1 variant was inherited from an unknowingly affected father), 7 fetuses (43.75%) had an autosomal recessive syndrome always associated with compound heterozygosity, and 2 fetuses (12.5%) had an X-linked condition (one mother was a carrier). In addition, the highest diagnostic rate was observed in fetuses with multisystem abnormalities (38.9%, 7/18). A variant of uncertain significance was detected in 16 samples (18.8%, 16/85). CONCLUSION: Our study confirms that prenatal WES is an efficient tool for studying fetal abnormalities, although further improvements are needed to establish stronger fetal genotype-phenotype correlations.

Asunto(s)

RESUMEN

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.

Asunto(s)

RESUMEN

BACKGROUND: Food insecurity, an issue also affecting developed countries, is associated with different negative outcomes. Particularly in pregnant women, a vulnerable population group, it has a double burden, as it affects both the woman and her child. Food insecurity has been associated with low birth weight and shorter gestational age, but there is less evidence on the association with fetal structural anomalies. AIM: To fill this gap, a study will be conducted to examine if pregnant women in a condition of food insecurity have a higher risk for fetal structural anomalies. METHODS: A case-control study will be conducted in three centers. Cases will be pregnant women (>18 years old) diagnosed with a fetal structural anomaly during the prenatal ultrasound examination of the II-III trimester, while controls will be pregnant women (>18 years old) with a negative result for fetal structural anomaly at the II-III trimester prenatal ultrasound examination. The exposure of interest will be food insecurity during the last 12 months, measured using the validated Household Food Insecurity Access Scale. A dedicated questionnaire will be given to women after they sign the informed consent form. SUMMARY: Finding a positive association between food insecurity in pregnant women and fetal structural anomalies could be the first step towards screening for it among pregnant women and designing policies that could mitigate this condition. Lowering food insecurity could prevent a certain number of fetal structural anomalies, leading to fewer negative pregnancy outcomes and health problems during childhood and adulthood.

Asunto(s)

RESUMEN

OBJECTIVE: To evaluate the clinical application of medical exome sequencing (MES) for prenatal diagnosis of genetic diseases related to fetal structural anomalies detected by prenatal ultrasound examination. STUDY DESIGN: A total of 105 fetuses with structural anomalies were negative results in both Quantitative fluorescent polymerase chain reaction (QF-PCR) and chromosomal microarray analysis (CMA). Then trio-based MES was further used for identifying the potential monogenic diseases in these fetuses. Coding regions and known pathogenic non-coding regions of over 4000 disease-related genes were interrogated, and variants were classified following the guidelines of American College of Medical Genetics (ACMG). RESULTS: The 105 fetuses with structural anomalies were categorized into 12 phenotypic groups. A definitive diagnosis was achieved in 19% (20/105) of the cases, with the identification of 21 pathogenic or likely pathogenic variants in 14 genes. The proportion of patients with diagnostic genetic variants varied between the phenotypic groups, with the highest diagnostic yield in the cardiovascular abnormalities (44%), followed by the skeletal and limb abnormalities (38%) and brain structural abnormalities (25%). In addition, 12 fetuses were detected variants of unknown significance (VOUS), while the relevance of phenotypes and variants would further evaluated. CONCLUSION: MES can identify the underlying genetic cause in fetal structural anomalies. It can further assist the management of pregnancy and genetic counseling. It was demonstrated the importance of translating prenatal MES into clinical practice.

Asunto(s)

RESUMEN

OBJECTIVES: To evaluate the diagnostic yield of prenatal whole exome sequencing (WES) for monogenic disorders in fetuses with structural malformations and normal results on cytogenetic testing, and to describe information on pathogenic variants that is provided by WES. METHODS: Karyotyping, chromosomal microarray analysis (CMA) and WES were performed sequentially on stored samples from a cohort of 3949 pregnancies with fetal structural abnormalities detected on ultrasound and/or magnetic resonance imaging, referred between January 2011 and December 2015. Diagnostic rates of the three techniques were investigated overall, for phenotypic subgroups and for proband-only vs fetus-mother-father samples. Information on pathogenic variants was identified by WES. RESULTS: Overall, 18.2% (720/3949) of fetuses had an abnormal karyotype. Pathogenic copy number variants were detected on CMA in 8.2% (138/1680) of fetuses that had a normal karyotype result. WES performed on a subgroup of 196 fetuses with normal CMA and karyotype results revealed the putative genetic variants responsible for the abnormal phenotypes in 47 cases (24%). The molecular diagnosis rates for fetus-mother-father and proband-only samples were 26.5% (13/49) and 23.1% (34/147), respectively. Variants of uncertain significance were detected in 12.8% (25/196) of fetuses, of which 22 were identified in the fetal proband-only group (15%; 22/147) and three in the fetus-mother-father group (6.1%; 3/49). The incidental finding rate was 6.1% (12/196). CONCLUSIONS: WES is a promising method for the identification of genetic variants that cause structural abnormalities in fetuses with normal results on karyotyping and CMA. This enhanced diagnostic yield has the potential to improve the clinical management of pregnancies and to inform better the reproductive decisions of affected families. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Asunto(s)