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About 3% of newborns show malformations, with about 20% of the affected having genetic causes. Clarification of genetic diseases in postnatal diagnostics was significantly improved with high-throughput sequencing, in particular through whole exome sequencing covering all protein-coding regions. Here, we aim to extend the use of this technology to prenatal diagnostics.Between 07/2018 and 10/2020, 500 pregnancies with fetal ultrasound abnormalities were analyzed after genetic counseling as part of prenatal diagnostics using WES of the fetus and parents.Molecular genetic findings could explain ultrasound abnormalities in 38% of affected fetuses. In 47% of these, disease-causing de novo variants were found. Pathogenic variants in genes with autosomal recessive or X-linked inheritance were detected in more than one-third (70/189 = 37%). The latter are associated with increased probability of recurrence, making their detection important for further pregnancies. Average time from sample receipt to report was 12 days in the recent cases.Trio exome sequencing is a useful addition to prenatal diagnostics due to its high diagnostic yield and short processing time (comparable to chromosome analysis). It covers a wide spectrum of genetic changes. Comprehensive interdisciplinary counseling before and after diagnostics is indispensable.

Objective The objective of this study is to validate the diagnostic accuracy of a non-invasive prenatal test for detecting trisomies 13, 18, and 21 for a population in Germany and Switzerland. Methods Random massively parallel sequencing was applied using Illumina sequencing platform HiSeq2000. Fetal aneuploidies were identified using a median absolute deviation based z-score equation. A bioinformatics algorithm based on guanine-cytosine normalization was applied after the data were unblinded. Results of massively parallel sequencing and invasive procedures were compared. Results Overall, 40/42 samples were correctly classified as trisomy 21-positive, including a translocation trisomy 21 [46,XY,der(13;21),+21] and a structural aberration of chromosome 21 [46,XX,rec(21)dup(21q)inv(21)(p12q21.1)] but not including a low percentage mosaic trisomy 21 [47,XY,+21/46,XY], [sensitivity: 95.2%; one-sided lower confidence limit: 85.8%]; 430/430 samples were correctly classified as trisomy 21-negative (specificity: 100%; one-sided lower CL: 99.3%). Using a new bioinformatics algorithm with guanine-cytosine normalization, detection of trisomy 21 was facilitated, and five of five trisomy 13 cases and eight of eight trisomy 18 cases were correctly identified. Conclusion Our newly established non-invasive prenatal test allows detection of fetal trisomies 13, 18, and 21 with high accuracy in a population in Germany and Switzerland. © 2013 John Wiley & Sons, Ltd.

The individual risk assessment of fetal Down's syndrome based on measurement of nuchal translucency (NT) according to Nicolaides, optionally complemented by the determination of PAPP-A and free beta HCG has progressively supplanted other search strategies for fetal aneuploidies. It could be shown that this diagnostic strategy equally detects other numeric aneuploidies at a comparable rate. A positive test result is also predictive for the presence of a fetal malformation. In this field, several computer programs are available for clinical use. The objective of our study was to re-evaluate the first consecutive 1463 NT-risk calculations determined by Nicolaides' method and to compare the risk calculation to the JOY software (NT-risk calculation module, JOY Patient Database) introduced in 2002.At the Department of Obstetrics and Gynecology, Hannover Medical School, 1463 consecutive complete data sets comprising first trimester screening performed between May 2, 2000 and June 26, 2003 and corresponding fetal outcome were analysed using risk assessment based on the Nicolaides method (PIA Fetal Database NT-Module) and compared with the risk evaluation as determined by the JOY software (JOY Patient Database NT module). A risk exceeding 1:300 was considered to indicate the need for further invasive testing. In a first step, only cytogenetically detectable chromosomal aberrations were analysed. Then, a second evaluation including fetal malformations was performed.Among the 1463 cases, 1445 (98.77%) fetuses revealed to be cytogenetically healthy. Both softwares showed identical detection rates at the genetic and somatic level:13 cases of Down-Syndrome (0.89%), 2 cases of trisomy 18 (0.14%), one case of triploidy, one Turner-Syndrome, one Klinefelter-Syndrome (0.07% each) were detected. A positive test result was found in 15 cases ending in a spontaneous abortion, intrauterine death or peripartum death (1.03%) and in 22 cases of fetal malformation (1.50%). At the level of genetic detection the test positive rate dropped from 92 (PIA) to 71 (JOY) (-22.8%). At the level of combined adverse outcome the test positive rate was reduced from 100 (PIA) to 76 (JOY) (-22.0%), thus yielding in a marked improvement of the characteristic test performance parameters.The novel, recently developed JOY software package allowed reliable evaluation of the risk for aneuploidy with increased specificity whereas sensitivity was unchanged. Our data suggest an improvement of the screening for aneuploidy when using this novel software: With an identical detection rate, the number of unnecessary invasive measures may be reduced.

The objective of this study is to validate the diagnostic accuracy of a non-invasive prenatal test for detecting trisomies 13, 18, and 21 for a population in Germany and Switzerland.Random massively parallel sequencing was applied using Illumina sequencing platform HiSeq2000. Fetal aneuploidies were identified using a median absolute deviation based z-score equation. A bioinformatics algorithm based on guanine-cytosine normalization was applied after the data were unblinded. Results of massively parallel sequencing and invasive procedures were compared.Overall, 40/42 samples were correctly classified as trisomy 21-positive, including a translocation trisomy 21 [46,XY,der(13;21),+21] and a structural aberration of chromosome 21 [46,XX,rec(21)dup(21q)inv(21)(p12q21.1)] but not including a low percentage mosaic trisomy 21 [47,XY,+21/46,XY], [sensitivity: 95.2%; one-sided lower confidence limit: 85.8%]; 430/430 samples were correctly classified as trisomy 21-negative (specificity: 100%; one-sided lower CL: 99.3%). Using a new bioinformatics algorithm with guanine-cytosine normalization, detection of trisomy 21 was facilitated, and five of five trisomy 13 cases and eight of eight trisomy 18 cases were correctly identified.Our newly established non-invasive prenatal test allows detection of fetal trisomies 13, 18, and 21 with high accuracy in a population in Germany and Switzerland.

Sonographic training in obstetrics differs broadly in Germany, although there are clearly defined quality-oriented requirements. In order to improve professional education, a training concept was devised utilizing an ultrasound simulator system.Between October 2004 and May 2006, 100 obstetric ultrasound training courses were held in 12 federal states of Germany. In these daily courses, doctors were trained in the detection of the most common malformations.One hundred training courses with a total of 1,266 participants.As a measure of quality assurance, a standardized questionnaire focusing on testing sonographic proficiency before and after the courses was issued in order to analyze the effect of these simulator-based ultrasound courses.Effectiveness of the method with reference to its potential role in structured sonographic training.The concept found prevailing approval (90%) at the level of principle, practical implementation, and clinical usefulness. Of the participants, 91% estimated their subjective training effect as good. The questionnaire analysis showed significant improvement. On average, 75.3% of the questions relating to sonographic proficiency were answered correctly at the end of the course as opposed to 48.6% at the beginning.Structured ultrasound training courses based on an ultrasound simulator system seem to be useful for defining a basic standardized quality of training and significantly improving examiners' skills. This is a suitable additional instrument to improve the education in obstetric ultrasound.