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This article belongs to the Special Issue Novel Insights into Prenatal Genetic Testing. Background: Despite advances in routine prenatal cytogenetic testing, most anomalous fetuses remain without a genetic diagnosis. Exome sequencing (ES) is a molecular technique that identifies sequence variants across protein-coding regions and is now increasingly used in clinical practice. Fetal phenotypes differ from postnatal and, therefore, prenatal ES interpretation requires a large amount of data deriving from prenatal testing. The aim of our study was to present initial results of the implementation of ES to prenatal diagnosis in Polish patients and to discuss its possible clinical impact on genetic counseling. Methods: In this study we performed a retrospective review of all fetal samples referred to our laboratory for ES from cooperating centers between January 2017 and June 2021. Results: During the study period 122 fetuses were subjected to ES at our institution. There were 52 abnormal ES results: 31 in the group of fetuses with a single organ system anomaly and 21 in the group of fetuses with multisystem anomalies. The difference between groups was not statistically significant. There were 57 different pathogenic or likely pathogenic variants reported in 33 different genes. The most common were missense variants. In 17 cases the molecular diagnosis had an actual clinical impact on subsequent pregnancies or other family members. Conclusions: Exome sequencing increases the detection rate in fetuses with structural anomalies and improves genetic counseling for both the affected couple and their relatives. This research was funded by the Ministry of Health, granted to the Center of Postgradu- ate Medical Education, Poland, grant number Minigrant-501-1-106-44-20/MG4 to J.B., and by the National Science Centre, Poland, grant number Miniatura 2—Dec2018/02/X/NZ2/00709 to D.M. info:eu-repo/semantics/publishedVersion

BACKGROUND Both gestational and chronological age of the neonate may influence and impair the function of the delicate and immature myocardium. However, the transition from fetal to neonatal circulation in preterm neonates is poorly understood. AIMS This study aimed to compare left ventricular (LV) systolic and diastolic function between premature neonates at expected term and term neonates during the postnatal cardiovascular transitional period. METHODS Using echocardiography, we assessed systolic and diastolic function of the LV in 89 preterm neonates at week 40 of postconceptional age and 29 term neonates after closure of the patent ductus arteriosus (PDA) and on the 28th day of life. Based on M‑mode images, we measured myocardial thickness and fractional shortening (FS%). Using pulsed‑wave Doppler echocardiography, we estimated cardiac output, myocardial performance index (MPI), and LV diastolic function (E and A waves, E/A ratio). Systolic and diastolic function was also assessed by tissue Doppler imaging. RESULTS Compared with term neonates on the 28th day of life, preterm neonates had reduced myocardial thickness (P ≤0.04), FS% (P = 0.002), and cardiac output (P = 0.01). However, preterm neonates had a lower MPI than term neonates after PDA closure (P0.001) and on the 28th day of life (P = 0.02). The E/A ratio and S' wave values were similar in preterm and term neonates (P0.05). CONCLUSIONS Preterm neonates at 40 weeks of postconceptional age have preserved systolic and diastolic function of the LV.

The Mediator complex subunit 13-like is a part of the large Mediator complex. Recently, a large number of patients were diagnosed with mutations in this gene, which makes it one of the most frequent causes of syndromic intellectual disability. In this work, we report a patient with a novel de novo likely pathogenic variant c.5941C>T, p.(Gln1981*) in the MED13L gene with severe intellectual disability and facial dysmorphism. Uncommon findings like lack of speech, strabismus and self-destructive behaviour present in our patient allowed us to further define the phenotypic spectrum of mental retardation and distinctive facial features with or without cardiac defects syndrome.

Congenital heart defects (CHDs) appear in 8–10 out of 1000 live born newborns and are one of the most common causes of deaths. In fetuses, the congenital heart defects are found even 3–5 times more often. Currently, microarray comparative genomic hybridization (array CGH) is recommended by worldwide scientific organizations as a first-line test in the prenatal diagnosis of fetuses with sonographic abnormalities, especially cardiac defects. We present the results of the application of array CGH in 484 cases with prenatally diagnosed congenital heart diseases by fetal ultrasound scanning (256 isolated CHD and 228 CHD coexisting with other malformations). We identified pathogenic aberrations and likely pathogenic genetic loci for CHD in 165 fetuses and 9 copy number variants (CNVs) of unknown clinical significance. Prenatal array-CGH is a useful method allowing the identification of all unbalanced aberrations (number and structure) with a much higher resolution than the currently applied traditional assessment techniques karyotype. Due to this ability, we identified the etiology of heart defects in 37% of cases.

Aim Echocardiographic evaluation of left ventricular function in preterm infants with and without bronchopulmonary dysplasia. Methods In 82 preterm infants (32 in no-bronchopulmonary-dysplasia group, 35 in mild-bronchopulmonary-dysplasia group, and 15 in severe-bronchopulmonary-dysplasia group), echocardiography was performed on the first day of life, at 28 days of life, and at 36 weeks postconceptional age. Results The mean E/A ratio at 36 PCA was 0.94±0.31 and 0.73±0.12 in the mild- and severe-bronchopulmonary-dysplasia groups, respectively (P=.037). The mean E′-wave velocity was 5.62±1.61 cm/s vs 4.32±1.11 cm/s at 1 day of life (P=.006) and 6.40±1.39 cm/s vs 5.34±1.37 cm/s at 28 days of life (P=.030) in the no-bronchopulmonary-dysplasia and mild-bronchopulmonary-dysplasia groups, respectively. This measure tended to be lower in the severe-bronchopulmonary-dysplasia group compared to the no-bronchopulmonary-dysplasia group (5.25±1.29 cm/s at 28 days of life; P=.081). The E/E′ ratio differed between the no-bronchopulmonary-dysplasia (7.21±1.85) and mild-bronchopulmonary-dysplasia groups (9.03±2.56; P=.019) at 1 day of life. The left ventricle myocardial performance index decreased between 1 day of life and 36 postconceptional age in infants without bronchopulmonary dysplasia and those with mild bronchopulmonary dysplasia, but not in those with severe bronchopulmonary dysplasia. Conclusion E/A and E/E′ ratios are the most sensitive indicators of impaired left ventricle diastolic function in preterm infants with bronchopulmonary dysplasia.

Aim To evaluate right ventricular function in preterm infants with and without bronchopulmonary dysplasia. Methods Eighty-nine preterm infants (

Background: The myocardial performance index (MPI) is a noninvasive method to measure global systolic and diastolic myocardial function. In both term and premature neonates, changes in the systolic and diastolic function of the left ventricle (LV) and right ventricle (RV) reflect the degree of neonatal myocardial immaturity and the co-existence of foetal circulation. Aim: To assess MPI (or Tei indices) of both ventricles in term and preterm newborns, and to observe MPI trends throughout the neonatal period. Methods: Heart ultrasound imaging was performed on the first day of life (DOL), after patent ductus arteriosus (PDA) closure, and on the 28th DOL, in 29 term and 29 preterm newborns. RVMPI and LVMPI were measured within the preterm group at 40 weeks of post-conception age (PCA). Results: A statistically significant reduction in RVMPI was observed in both term and preterm newborns. In term newborns, the RVMPI value on the first DOL was 0.42 ± 14, dropping to 0.29 ± 0.09 after PDA closure, and finally reaching 0.22 ± 0.09 on the 28th DOL. The respective RVMPI values for the preterm newborns were 0.44 ± 0.15, 0.30 ± 0.12, and 0.21 ± 0.08. Little variability in the mean values of LVMPI was observed in both groups throughout the neonatal period. The LVMPI for term neonates in successive measurements was 0.37 ± 0.10, 0.39 ± 0.07, and 0.37 ± 0.11, respectively, and for the preterm neonates it was 0.37 ± 0.10, 0.35 ± 0.09, and 0.36 ± 0.10, respectively. The MPI values from preterm newborns taken at 40 weeks PCA (RVMPI = 0.28 ± 0.09; LVMPI = 0.37 ± 0.05) were comparable to those measured in term newborns after PDA closure. Conclusions: Observed postnatal changes in RVMPI correspond to changes in ventricular function, reflecting the haemodynamic changes of the transitional circulation. The relatively small postnatal changes in LVMPI in term and preterm newborns may reflect an immature myocardium. The RVMPI and LVMPI values at 40 weeks PCA in preterm newborns correlate best with MPI values in term newborns just after PDA closure.

Congenital Diaphragmatic Hernia (CDH) occurs with an estimated incidence of 1 to 2500 live births. Even though the exact etiology is still unknown, more and more often current research points out genetic factors as the possible cause of the defect. According to the latest data and the own experience 50-60% of CDH cases are isolated. The rest forms a group of CDH complicated by an additional anatomic defect or a genetic syndrome caused by a mutation of a single gene or the whole chromosome. We have presented a case study of a 32 years-old multigravida para 3, who has been referred to the Reference Centre of Prenatal Cardiology in 30 weeks of gestation due to the diagnosis of acrania with exencephaly, spina bifida and suspicion for CDH in a fetus. Although the patient's first child died due to CDH, the patient neither before nor during the pregnancy was getting a folic acid supplementation. Moreover, she has not agreed on a further cytogenetic testing or an advanced consultation with a clinical geneticist. The child died after delivery in a local hospital. The case was described to indicate the problem that the CDH diagnostic procedure is still missing a molecular genetic analysis especially in the cases of recurrent CDH. By saying that in the cases of CDH we should always strive to complete the molecular testing having in mind that by discovering pathogenesis and genes responsible for the formation of CDH we not only might improve the therapeutic methods but also find a way to prevent its development.

Intellectual disability (ID)/Developmental delay (DD), which occurs in 1-3% of the population, accounts for a large number of cases regularly seen in genetics clinics. Currently, Array Comparative Genomic Hybridization (array CGH) is recommended by the International Standards for Cytogenomic Arrays (ISCA) Consortium as a first line test in the diagnostics of ID/DD, replacing G-banded chromosome analysis.Application of array CGH in clinical diagnostics of developmental delay/ intellectual disability in children.We present the results of 8x60K oligonucleotide array application that was successfully implemented in a cohort of 112 patients with the clinical diagnosis of intellectual disability and accompanying dysmorphic features and/or congenital malformations.We have identified 37 copy number variants (CNVs) with the size ranging from 40 kb to numerical chromosomal aberrations, including unbalanced translocations and chromosome Y disomy, receiving an overall diagnostic yield of 33%. Known pathogenic changes were identified in 21.4% of the cases. Among patients with pathogenic CNVs identified by array CGH, 41.7% had a previously normal karyotype analysis.Our studies provide more insights into the benefits derived by using chromosomal microarray analysis and demonstrate the usefulness of array CGH as a first-tier clinical setting test in patients with intellectual disability.

Wstep i cel: Przy uzyciu echokardiograficznej metody doplera tkankowego oceniono zmiany ruchu miokardium dla leweji prawej komory oraz czasy przewodzenia przedsionkowo-komorowego u noworodkow donoszonych w pierwszym miesiącu zycia. Metody: Badania wykonano u 20 zdrowych noworodkow urodzonych miedzy 37.–41. tygodniem ciązy. Pomiar predkości miokardium wykonywano w projekcji koniuszkowej, w osi dlugiej serca, jako obraz 4 jam serca kodowany kolorowym doplerem tkankowym. Odczytywano zapis cyklu serca przedstawionego za pomocą trzech fal: fala skurczowa (Sm; kiedy platki zastawki wedrują w kierunku koniuszka serca), fala wczesnej fazy rozkurczowej (Em; kiedy pierścien zastawki oddala sie od koniuszka serca) oraz fala związana z fazą skurczu przedsionkow (Am). Ponadto wykonano pomiary nastepujących czasow: czas Am-IV (od początku fali Am do początku fali IV); czas Am-Sm (od początku fali Am do początku fali Sm); czas IV-Am (odpoczątku fali IV do początku kolejnej fali Am); czas Sm-Am (od początku fali Sm do początku nastepnej fali Am). Zmierzono tez czas skurczu izowolumetrycznego (IVCT) i czas rozkurczu izowolumetrycznego (IVRT). Wszystkie pomiary wykonano u kazdego noworodka 3-krotnie: 1. pomiar — bezpośrednio po urodzeniu w 1. dobie zycia, 2. pomiar — w 3. dobie zycia oraz 3. pomiar — na koniec okresu noworodkowego w 28. dobie zycia. Wyniki: We wszystkich pomiarach wartości średniej predkości ruchu miokardium w zakresie fal Em, Am i Sm byly wyzszedla komory prawej niz dla komory lewej. Zmiane istotną statystycznie odnotowano dla komory prawej w zakresie czasow: Am-IV i Am-Sm (miedzy dobą 1. a 3.), p < 0,02; IV-Am (miedzy dobą 1. a 28.), p < 0,005; Sm-Am (miedzy dobą 1. a 28.), p < 0,01. Dla komory lewej zmiane istotną statycznie wykazano w zakresie czasow: Am-IV (miedzy dobą 1. a 28.), p < 0,05 oraz Sm-Am (miedzy dobą 1. a 28.) p < 0,01. Średnie wartości IVCT i IVRT pozostawaly stale we wszystkich pomiarach dla komory prawej. Natomiast dla komory lewej zarowno w zakresie IVCT i IVRT wykazano roznice istotną statycznie miedzy1. i 28. dobą zycia (p < 0,01). Wnioski: Zaobserwowane roznice w średnich wartościach predkości miokardium i w średnich wartościach czasow przewodzenia odzwierciedlają zmiany w hemodynamice ukladu sercowo-naczyniowego charakterystyczne dla okresu noworodkowego.

To assess the possibility of foetal circulatory system evaluation between 11+0 to 13+6 weeks of gestation in a reference perinatal cardiology centre.A prospective study was conducted between January 2004 and June 2008 in patients admitted to the reference perinatal cardiology centre for a foetal echocardiographic examination. 1170 foetuses were examined: 31 in 2004, 167 in 2005, 310 in 2006, 406 in 2007 and 262 in the first half of 2008. All foetuses had early echocardiography performed during 11-13+6 weeks of gestation, following the Foetal Medicine Foundation guidelines. The examination included: position and size of the heart, 4-chamber view and outflow tracts evaluation. The flow through ductus venosus, atrio-ventricular and arterial valves were assessed with colour and pulsed Doppler. 982 patients with confirmed normal heart anatomy in the second trimester were further analysed.Mean maternal age was 30 years. 237 (20%) patients were35 years old. Mean CRL (crown rump length) was 65 mm. 4-chamber view was obtained in 933 foetuses (95%) and outflow tracts in 813 (83%) cases. Diagnostic flow through the tricuspid valve was detected in 894 (91%) foetuses.Early foetal echocardiography is available in a reference perinatal cardiology centre since 11th week of gestation, in most cases with transabdominal probe. Possibility of the foetal heart anatomy evaluation increases with gestational age. Only patients from the high risk group (i.e. previous child with a major cardiac defect, diabetes mellitus, monochorionic pregnancy) and foetuses with increased NT should be examined. In every case, a control echocardiographic examination in the second trimester must be performed.

To assess myocardial performance index (Tei index) for left and right ventricle in fetuses at 11.0 to 13.6 week of gestation.Flow velocity waveforms of mitral, tricuspid, aortic and pulmonary valves were obtained. The Tei index for the left ventricle (Tei LV) was calculated in 55, and for the right ventricle (Tei RV) in 27 fetuses.The value of Tei LV ranged from 0.28 to 0.59, mean 0.41 +/- 0.08, and for Tei RV from 0.23 to 0.56, mean 0.37 +/- 0.11. There was no statistically important correlation either between Tei index and both ventricles or gestational age and fetal heart rate. The possibility to measure Tei index increased with the progress of the pregnancy. There remains a significant correlation between Tei LV and Tei RV values.Tei index may be useful for the assessment of fetal myocardial performance in the first trimester of pregnancy. Tei index is independent of gestational age and fetal heart rate. It is easier to measure the Tei index for the left ventricle than for the right one.

Due to the rapid advances in medical technology, medical students are now being faced with increasingly complex and unparalleled ethical and practical dilemmas during their training. The new and future challenges of high-tech medicine demand improvements in current medical education, not only by meeting the needs of students through humanized training programs, but also by involving them in finding solutions to the ethical and legal quandaries they encounter. Today's students of medical universities must acquire knowledge and understanding of the ethical and legal issues relevant to the practice of medicine, and we have to do everything possible to introduce these students to the current discussions on more or less controversial ethical and legal topics. Although final answers may not be found, the very discussion, argumentation, and awakening of students' interest should become an essential part of the core curriculum of every doctor.

Background: To define age-related changes in left and right ventricular function using myocardial performance index (Tei Index) in healthy term newborn infants. Materials and Methods: 9 newborn infants were selected from normal full-term healthy neonates with gestational age 38-42 weeks, mean birth weight 3572 g (min. 2870, max. 4160 g). The Tei Index is a Doppler myocardial performance tool which can be used to evaluate of systolic and diastolic function. The first measurement was taken as soon as possible after birth, the second one was taken on day 3 of life. Results: The higher Tei index were obtained in the right ventricle (mean value - 0,44; SD +/-;0,11) then the left ventricle (mean value - 0,31; SD +/-;0,07) in the first day of life. In the left ventricle the Tei index were converted during the first three days of life (from mean value 0,31 to 0,37), and we observed the convertion in the right ventricle too between the first and the third day of life (mean value 0,44- day 1 to 0,26 -day 3). Conclusion: In neonates, the diastolic and systolic fuction of the right ventricle were higher then those measured in the left ventricle during the first day of life and this ratio changing in the third day of life. Higher mean value Tei index in the right ventricle might be reflecting the “persistent” fetal status of this ventricle in the first day of life. Further investigations are needed in a greater population of neonates. (granted MZiNSW nr NN407414336).

Background To define age-related changes in left (LV) and right (RV) ventricular function by using myocardial performance index (Tei Index) in preterm neonates. Materials and Methods 18 newborn infants were selected from preterm neonates with the gestational age of 24–32 weeks, mean birth weight 917.5 g (min. 520, max. 1920 g). The Tei Index is a Doppler-derived myocardial performance tool which can be used to evaluate the systolic and diastolic function. The first measurement was taken as soon as possible after birth, the second one was taken on day 3 of life, the third one at the 40 th wk post-conceptional age (pca). Results The higher Tei index was obtained in the RV (mean value - 0.39; SD +/–0.15) then the LV (mean value - 0.36; SD +/–0.10) in the first day of life. In the LV the Tei index was constant during the neonatal period and at 40 wks pca (from mean value 0.36-day 1, 0.35 day 3 and at 40 wks pca.), and we observed the conversion in the RV between the first and the third day of life and at 40 wks pca (mean value 0.39- day 1 to 0.30 -day 3 and to 0.28 at 40 wks pca). Conclusion The higher mean value of the Tei index in the RV might be reflecting the “persistent” fetal status of this ventricle in the first day of life. Although constant value of the Tei index in the LV reflect the degree of neonatal myocardial immaturity. Grant- MNiSW No. 407414336.

report series of 4 cases of termination of pregnancy done on the basis of ultrasound diagnosis of bilateral renal agenesis and ahydramnios during the period of 365 days. We describe interesting epidemiology of two variants of these cases and difficult early prenatal diagnosis in the first trimester anomaly scan which should be the aim to minimize the trauma related to the termination of pregnancy at advanced gestation.

Results: In normal fetuses, it was possible to identify the respective position of the inferior vena cava and the descending aorta in all cases. In the 3 cases with left atrial isomerism, it was possible to identify the azygos continuation adjacent to the descending aorta and the abnormal stomach position. In no case could the multiple spleens be identified. In the 3 cases with right atrial isomerism, it was possible to identify the abnormal central position of the inferior vena cava and the displacement of the stomach to the left. The abnormal liver morphology consistent with left and right isomerism could be identified in 5/6 cases. Discussion: Identification of fetal situs has so far been carried out by assessing the position of the abdominal vessels on an axial view of the fetal abdomen. Using the coronal plane of the fetal trunk from three-dimensional volumes, it was possible to identify visceral anatomic patterns consistent with a diagnosis of situs solitus or ambiguous (left or right isomerim) independently from the type of congenital heart disease present. This may be of help in difficult cases to tag the type of cardiosplenic syndrome.

described and the frequency with which muscular VSDs resolve in utero has also not been extensively reported. Methods: We investigated the perinatal course of isolated muscular VSDs diagnosed and followed between 1 January 2005 and 31 December 2006. Results: We performed a total of 2583 fetal echocardiograms on 2410 fetuses during 2328 pregnanies. The study group included 78 twin gestations (3.4%) and seven triplet gestations (0.3%). There were 16 diagnoses of isolated muscular VSD (6.6/1000). Mean ± SD gestational age at diagnosis was 24.5 ± 4.9 weeks. Two of the isolated muscular VSDs (12.5%) spontaneously resolved prenatally. One fetus had trisomy 21. Conclusions: Isolated VSD is a common congenital heart defect. Resolution of prenatally diagnosed isolated muscular VSDs is less frequent than reported in the past. Trisomy 21 risk may be increased in isolated muscular VSDs even in the absence of other ultrasound markers. A larger cohort is needed to provide a better risk estimate for aneuploidy in the presence of an isolated VSD.