Fetal Karyotype Research Articles

First-Trimester Crown-Rump Length and Risk of Chromosomal Aberrations-A Systematic Review and Meta-analysis.

Lower than expected first-trimester crown-rump length (CRL) is a common sonographic finding, usually leading to reassessment of gestational age. The aim of this study was to perform a meta-analysis defining the risk of chromosomal aberrations in pregnancies with decreased first-trimester CRL. A search was conducted by a research librarian in 5 databases, with no time or language restrictions. Original researches examining the risk of chromosomal aberrations in pregnancies with low CRL were selected. The effect estimates were presented as odds ratios with 95% confidence intervals). Following screening of 3894 references, 12 articles were selected. Only 2 articles directly fulfilled the review goals, comparing the rates of chromosomal aberrations in small-CRL versus normal-CRL fetuses. Combined analysis of these 2 studies, encompassing a total of 403 fetuses with small CRL and 4047 control pregnancies, yielded an odds ratio of 5.54 (95% confidence interval, 1.2-26.1) for abnormal karyotype in small-CRL fetuses. Ten studies compared CRL in fetuses with specific chromosomal aberrations to pregnancies with normal karyotype, yielding a significant growth delay in fetuses with trisomy 18 (6 of 7 articles) and triploidy, but not in fetuses with trisomy 21. Overall quality of evidence was rated as "very low" using Grading of Recommendations Assessment, Development and Evaluation criteria. Our review results indicate that low first-trimester CRL might be associated with a significantly increased risk of chromosomal anomalies. Thus, invasive prenatal testing or cell-free DNA screening might be offered in such pregnancies, particularly if dating is certain.

The Incidence of Chromosomal Aberrations in Prenatally Diagnosed Isolated Agenesis of the Corpus Callosum.

To establish the prevalence of chromosomal aberrations in fetuses with an apparently isolated agenesis of the corpus callosum (ACC) on prenatal ultrasound. This was a retrospective study of complete isolated ACC at the time of ultrasound evaluation with respect to karyotype information. Within this group, a subgroup with non-malformation minor abnormalities, such as a single umbilical artery (SUA), polyhydramnios or fetal growth restriction (FGR), was investigated. Complete ACC was diagnosed in 343 cases. Of them, 143 (41.6 %) were isolated, with 16 fetuses showing additional minor findings. In 76.2 % (109/143) karyotyping was performed. Additional array CGH analysis was performed in 7.7 % (11/143). Chromosomal aberrations were found in 4.6 % (5/109) overall, in 3.1 % (3/98) of those without any additional sonographic findings (all represented mosaic trisomy 8) and in 18.2 % (2/11) of those with minor abnormalities. The prevalence of pathogenic submicroscopic copy number variant (CNV) was 9 % (1/11). Fetal karyotyping is recommended in ACC, as trisomy 8 mosaicism should be considered despite otherwise unremarkable ultrasound. The role of novel techniques such as array CGH and its implication has to be explored in prospective studies.

Cytogenetic analysis in fetuses with late onset abnormal sonographic findings.

To determine the rate of chromosomal cytogenetic abnormalities in fetuses with late onset abnormal sonographic findings. Retrospective cohort of women who underwent amniocentesis at or beyond 23 weeks of gestation, for fetal karyotype and chromosomal microarray analysis, indicated due to late onset abnormal sonographic findings. All 103 fetuses had a normal karyotype. Ninety-five women also had chromosomal microarray analysis (CMA) performed. The detection rate of abnormal CMA (5/95, 5.3%) was similar to that of women who underwent amniocentesis due to abnormal early onset ultrasound findings detected at routine prenatal screening tests during the first or early second trimester (7.3%, P=0.46) and significantly higher than that for women who underwent amniocentesis and CMA upon request, without a medical indication for CMA (0.99%, P<0.0001). Late onset sonographic findings are an indication for amniocentesis, and if performed, CMA should be applied to evaluate fetuses with late onset abnormal sonographic findings.

Prenatal Diagnosis of Choroid Plexus Cyst: What Next?

Fetal choroid plexus cysts (CPC) are often detected on prenatal ultrasounds and pose a need to formulate protocol for management and counseling. A total of 1024 unselected cases between gestational ages 11 and 20 weeks were sonologically screened for CPC in 1-year period. On ultrasound, CPC are seen as sonolucent spaces in the echogenic choroid plexus of lateral ventricles of brain measuring at least 2-3 mm in diameter. Those diagnosed with CPC were subjected to thorough anomaly scan. Prenatal karyotype was offered in cases of associated anomalies. The incidence of CPC is 1% (10/1024) in this study. Associated anomalies were found in 20% (2/10) of cases, which were offered invasive testing for fetal karyotype. All the cases with isolated CPC had good outcome. Isolated CPC with low-risk biochemical screening for aneuploidies are now considered normal variants rather than a pathology, need no invasive testing and carry a good prognosis. CPC associated with other anomalies warrant invasive testing and are more likely to be associated with Trisomy 18.

Chromosomal Microarray Analysis in Fetuses with Growth Restriction and Normal Karyotype: A Systematic Review and Meta-Analysis

Objective: To perform a systematic review of the literature and a meta-analysis to estimate the incremental yield of chromosomal microarray analysis (CMA) over karyotyping in fetal growth restriction (FGR). Methods: This was a systematic review conducted in accordance with the PRISMA criteria. All articles identified in PubMed, Ovid Medline, and ISI Web of Knowledge (Web of Science) from January 2009 to November 2016 describing pathogenic copy number variants (CNVs) in fetuses with growth restriction were included. Case reports were excluded. Risk differences were pooled to estimate the overall and stratified CMA incremental yield. Results: Ten studies with full data available met the inclusion criteria for analysis. Combined data from these studies revealed a 4% (95% confidence interval [CI] 1-6%) incremental yield of CMA over karyotyping in nonmalformed growth-restricted fetuses, and a 10% (95% CI 6-14%) incremental yield in FGR when associated with fetal malformations. The most frequently found pathogenic CNVs were 22q11.2 duplication, Xp22.3 deletion, and 7q11.23 deletion (Williams-Beuren syndrome), particularly in isolated FGR. Conclusion: The use of genomic CMA provides a 4% incremental yield of detecting pathogenic CNVs in fetuses with isolated growth restriction and normal karyotype.

Detection of fetal duplication 16p11.2q12.1 by next-generation sequencing of maternal plasma and invasive diagnosis

Objective: The objective of study is to report the feasibility of non-invasive prenatal screening (NIPS) combined with invasive detection by chromosomal analysis in identifying fetal duplication, providing clinical performance of NIPS on copy number variations (CNVs) detection. Material and methods: NIPS was offered to a 35-year-old pregnant woman. Amniocentesis was performed to confirm the positive screening result. Fetal sample was detected by karyotyping, fluorescence in situ hybridization (FISH), and chromosomal microarray (CMA). Parental karyotyping was also conducted. Results: NIPS result was positive for chromosome 16, indicating an extra copy of chromosome 16. FISH and chromosomal karyotyping revealed that the fetus had a marker chromosome derived from chromosome 16. CMA further demonstrated an approximately 19-Mb duplication in chromosome 16. The final fetal karyotype was 47,XY,+mar. ish der (16)(D16Z3+).arr 16p11.2q12.1 (30 624 186–49 696 337 × 3). Ultrasound scan and MRI showed some structure malformations. Conclusions: A protocol for CNVs detection by combining a series of genetic methods was presented in this study and a novel marker duplication 16p11.2q12.1 was reported. With the ability to identify subchromosomal deletions and duplications in fetus, NIPS could reduce the possibility of invasive diagnosis. The followed confirmation test for positive sample is necessary and ensures the accuracy of the diagnosis.

P12.04: Congenital megalourethra: a rare form of obstructive uropathy

Introduction: Congenital megalourethra is a rare form of functional lower urinary tract obstruction (LUTO) caused by primary or secondary agenesis/hypoplasia of the penile corporal tissues. In primary absence/hypoplasia of the corpora spongiosa and cavernosa the amniotic fluid volume is usually normal, the renal function is preserved and the outcome is commonly good. In obstructive (secondary) megalourethra there is higher incidence of renal failure leading to oligohydramnios and pulmonary hypoplasia, thus higher perinatal mortality rates are observed. The prenatal diagnosis of LUTO is suspected when distended bladder with or without hydroureter and hydronephrosis is detected on ultrasound. In addition, in megalourethra a cystic structure in the perineal region is usually found. The thin-walled distended urethra can be relatively easy mistaken with a loop of umbilical cord. The differential diagnosis is made by colour Doppler. In all cases of LUTO oligohydramnios is associated with poor prognosis. Case report: A 19-year-old primigravida was referred at 20+2 w.g. for a routine second trimester fetal morphology survey. The scan revealed a male fetus with dilated penile portion of the urethra, distended bladder, empty left renal fossa and right moderate pyelectasia. The amniotic fluid was reduced. Megalourethra and unilateral left renal agenesis was suspected. After extensive counselling the parents opted for termination of pregnancy. Post-abortem autopsy confirmed the prenatal diagnosis. No other associated structural abnormalities were found. The fetal karyotype was normal, 46 XY. Conclusion: Congenital megalourethra is a rare form of LUTO that should be always suspected in cases of urinal retention. Early prenatal diagnosis and extensive evaluation of all prognostic factors allow adequate obstetrical management.

EP24.01: The evolution and significance of enlarged nuchal translucency detected before 11 weeks of pregnancy

The embryology and pathophysiology of nuchal translucency (NT) are still not entirely known. Current guidelines recommend measuring NT in fetuses with a Crown–rump length (CRL) of 45-84 mm. The aim of this study was to assess the significance and the evolution of enlarged NT if detected before the CRL of 45 mm. Retrospective observational study. Information about NT measurements performed at our centre in 2005-2016 was retrieved from the database. We searched for cases of singleton pregnancies with viable fetuses and with NT above the 95th centile observed before the CRL of 45 mm, and for which a second NT measurement was performed in the recommended CRL of 45-84 mm. The information about a fetal karyotype, a result of first-trimester combined test, ultrasound scan at 20 weeks and pregnancy outcome was recorded. In total, 44067 women had the NT scans during the period. Of these, 17 cases with paired measurements were eligible for the analysis. The average CRL of the first NT measurement was 38 mm (range 31-44 mm), the average of the second measurement was 57 mm (range 45-73 mm). In 8 (47%) fetuses the NT measurement was found to be below the 95th centile at the second measurement. The risks from combined test were low (range 1/440-1/25000), CVS was performed in one case with normal karyotype and in all these cases ultrasound scans at 20 weeks were normal and healthy neonate were born. However, NT remained enlarged at the second measurement in 9 (53%) cases. Of these, an abnormal karyotype was found in 4 (44%) cases, one (12%) fetus had a complex cardiac anomaly, and in 4 (44%) cases the karyotype was normal and a healthy neonate was born. The results of our study suggest that the significance of enlarged NT detected before the CRL of 45 mm is questionable. The second evaluation with the recommended CRL of 45-84 mm is warranted and the NT thickness falls below the 95th centile in 47% of cases. If the enlargement disappears and the risk from combined test is low, the pregnancy outcome is excellent.

OP22.07: Validation of NIPT as a screening test for Trisomy 21, 18, 13 and fetal sex performed at Hvidovre Hospitals NIPT Centre, Copenhagen, Denmark

The objective of this study was to establish an open source platform for NIPT based on Massive Parallel whole-genome Sequencing (MPS) in a public setting. MPS was performed on circulating cell-free DNA from 205 selected pregnant women with known fetal karyotypes. The pipeline included automated library preparation and sequencing on a HiSeq1500 (Illumina). WISECONDOR and SeqFF were used for data analysis of aneuploidies, fetal sex and fetal fraction (FF). Data analysis for aneuploidy and fetal sex were accepted in samples with FF above 0.02 and 0.025, respectively. Samples with FF below cut-off were described as 'no-calls'. The NIPT results were positive for T21 in 44 of 46 T21 cases. The two negative T21 cases were 'no-calls' due to low FF. Among 19 T18 cases 14 were NIPT positive of which two cases were identified even though FF were too low. Two samples were 'no-calls' and three samples were false negative, which could be explained by a vanished twin or IVF treatment. Finally, seven out of eight T13 cases were positive, though one case had a low FF. The false negative T13 sample is probably explained by a vanished twin. Among normal karyotypes we found four false positive cases. Fetal sex was analysed in 189 samples (FF<0.025 excluded) and was correctly identified in all 94 females. Fetal sex was correctly identified in 92 out of 95 male fetuses. Two of the incorrectly results might be due to a vanished twin and a very high maternal BMI. Our study shows that screening for fetal aneuploidy and sex can be done by our fully automated NIPT pipeline. The sensitivity for T21 was 100% but lower for T18 and T13. This study demonstrates that FF, a vanished twin, BMI and perhaps IVF are important factors that should be taken into consideration in the interpretation of NIPT results.

EP01.06: Isolated absence of septum pellucidum: a report of two cases

Agenesis of the septum pellucidum (ASP) is a rare cerebral anomaly which can appear in a partial or a complete form and agenesis may occur in an isolated or in an association with various congenital brain malformations. We report two cases with isolated agenesis of septum pellucidum which were suspected prenatally with 2D ultrasound and fetal MRI. A-32-year-old G1P0 woman first visited Cheil General Hospital at 12weeks of gestation. During routine antenatal examination in 28 gestational weeks, CSP was not seen and the fusion between the frontal horns of lateral ventricle in fetal brain was found. Cerebral developmental anomalies related to the ASP were suspected. Fetal MRI was performed at 29 weeks and 4 days of gestation. Septum pellucidum was still not seen but the corpus callosum and the fornix were intact and no definite fusion in brain parenchyme was found. Due to fetal movement, measurement of the optic nerves were not possible. As a result, isolated ASP was suspected with possibility of septo-optic dysplasia. A full-term 3,245 gram female was born after a normal delivery. Postnatal evaluation with brain ultrasound was performed 3 days after birth and isolated ASP was suspected. The newborn was discharged afterward and no definite sign of focal neurologic deficit was found by this time. A-37-year-old G1P0 woman was referred at 17 weeks and 6 days of gestation due to increased risk of Trisomy 21 and neural tube defect in Quad test. Fetal karyotype was normal. In the mid-trimester ultrasound, estimated fetal weight was 3 percentile and small cystic lesion in fetal head posterior fossa was noted. She was hospitalised at 27 weeks due to symptoms of pre-eclampsia. In follow up ultrasound at 32 weeks and 1 day of gestation, estimated fetal weight was below 1 percentile and cystic lesion in posterior fetal head was still seen. The day after Caesarean section was performed due to fetal distress. A preterm 1,220 gram male was born. Brain ultrasound and MRI was performed 48 days after birth and isolated ASP with well visualised both optic nerves were noticed.

EP21.02: Intrauterine open fetal surgery for cervical spina bifida correction: case report

Spina bifida is characterised by the incomplete formation of structures that protect the spinal cord and the inappropriate closure of the spinal bones. It presented a high rate of associated comorbidities (hydrocephalus, neurological deficits, motor deficiency in the lower limbs, vesical e and intestinal dysfunctions) secondary to the herniation of the structures of the posterior fossa by the foramen magno (Arnold-Chiari II malformation) and spinal cord injury and anchorage. Currently, there is the possibility of intrauterine open fetal surgery for correction of spina bifida lumbosacral which showed benefits in relation to the postnatal treatment according to MOMS clinical trial. Spina bifida in cervical topography is rare (3.5% of cases) and may be associated with Chiari II, hydrocephalus and cognitive deficits. Although it does not meet the criteria for intrauterine correction, we present a case with an isolated diagnosis of cervical myelomeningocele submitted to open fetal surgery for correction of spinal dysraphism. Pregnant LMOC, 37 years old, primigravida, no comordidades, ultrasound showing cervical myelomeningocele (C5-C7), no ventriculomegaly, chiari II (with anchoring of the cervical spine), no other malformations in the central nervous system. Fetal magnetic resonance imaging confirming findings of the ultrasound. Normal fetal karyotype. After clarification and consent of the couple and approval of our institution's ethics committee, patient underwent open fetal surgery at 26 weeks. Post-surgical ultrasound showed complete reversal of cerebellar herniation and absence of ventriculomegaly. Caesarean delivery at 37 weeks, newborn weight 3035g, female, apgar 9/10. Postnatal exams normal. Immediate postnatal follow-up adequate for the age. Cervical spina bifida is rare, but may present sequelae such as hydrocephalus and cognitive deficits. In carefully-selected cases, intrauterine surgery may be considered as therapeutic option.

EP15.11: Partial hydatiform mole: a case report

Partial hydatidiform mole is a histopathologic entity characterised by focal trophoblastic hyperplasia with villous hydrops together with identifiable fetal tissue. 90% of partial moles are due to diandric triploidy. In Type I placenta is modified; in type II placenta is normal. We report a case of PHM type I with increased fetal NT and other fetal anomalies (Dandy-Walker complex and tetralogy of Fallot). A 32 year old woman (gravida 2, para 0 with a miscarriage) was referred to Fetal Medicine AOUI Verona Centre for an increased fetal NT (4.6 mm) and vacuole formations in the placenta diagnosed at I trimester US scan. An expert US scan which reported nuchal edema (5.2 mm), vacuole formations in the placenta and heart anomalies was performed at 15+2 weeks. Amniocentesis showed a 69 XXY fetal karyotype. US scan at 18 weeks showed a IUGR, Dandy-Walker Complex, Tetralogy of Fallot, molar changes of placenta and ovaries enlarged with multiple bilateral theca lutein cysts. The patient had no clinical symptoms of molar pregnancy. BHCG was 1.255.660 UI/L. Pregnancy was terminated at 19+4 weeks by induction of labour with intravaginal Gemeprost. A fetus with molar placenta was delivered; suction and curettage were performed. Histopathologic analysis and immunohistochemistry confirmed the diagnosis of partial hydatiform mole. Cytogenetic analysis showed a triploid kariotype. Fetal autopsy wasn't done under request of the patient. Chest-X- ray was negative. BHCG levels were checked every 2 weeks until the values were within the normal range. A closed follow up is still being performed. Definitive diagnosis of partial mole by ultrasound is often difficult especially in the early scan. It might be confused with missed abortions or blighted ovum. Triploidy is usually incompatible with life. In this case the fetus survived up to the second trimester with IUGR and a major anomaly of the heart. Molar pregnancies generally have severe outcomes. Serial follow up of HCG levels after termination of pregnancy is necessary. Cytogenetic pattern has to be correlated with histopathological diagnosis.

EP06.08: First trimester prenatal diagnosis of aberrant right subclavian artery

To assess the possibilities of first trimester prenatal diagnosis of aberrant right subclavian artery (ARSA). A prospective study of 283 singleton pregnancies scanned between 11-13+6 weeks of gestation (w.g.) was performed in MC “Markovs”, Sofia between Jun 2015 and Feb 2016. All cases were examined in B-mode and ultrasound screening for fetal abnormalities was performed according to standard published guidelines. In addition, the natural course of the right subclavian artery (RSA) was also identified by Colour Doppler. All continuing pregnancies were followed-up by ultrasound in the second trimester. No false-positive or false-negative cases of ARSA were found. Overall 5 cases of ARSA were detected in the first trimester throughout the study period. In 4 of them ARSA was an isolated finding. In the last case the nuchal translucency was also increased. Fetal karyotyping revealed an associated Trisomy 21 and the parents opted for termination of pregnancy. Visualisation of RSA is relatively easy during the 11-13+6 w.g. scan. Since the association between ARSA and chromosomal fetal abnormalities is well established, the implementation of its sonographic evaluation might improve the sensitivity of the first trimester screening.

OP14.02: Cystic abnormalities of fetal posterior fossa at 11–13+6 weeks scan

To study the diagnostic value of cystic abnormalities of the posterior fossa in the first trimester as a marker for chromosomal diseases and to assess how often it is associated with other anatomical defects. This was a retrospective analysis of data from 15778 pregnant women sent to two referral fetal medicine centres for detailed ultrasound examination of fetal anatomy at 11 to 13+6 gestational weeks. All scans included extended systematical transabdominal and/or transvaginal examination of the fetal brain. In case of suspicion for brain anomaly 3D volumes were routinely acquired and analysed offline by 3D multiplanar reconstruction tool. Overall we diagnosed 50 fetuses with cystic abnormalities of the posterior fossa. In 43 cases (86%) it was associated with defects in other anatomical structures, in 7 fetuses (14%) posterior fossa abnormalities were isolated. 27 out of 50 pregnant women with fetal posterior fossa abnormalities opted for fetal karyotyping. In 20 of them (40%) various chromosomal abnormalities were found and the pregnancy was terminated. 23 women with multiple fetal abnormalities decided to terminate the pregnancy without further prenatal invasive tests. In 7 cases with isolated fetal anomaly the karyotype was normal. All 7 women in this group opted to continue with the pregnancy. At 20 weeks ultrasound scan 3 fetuses were diagnosed with Dandy Walker anomaly, 1 had an arachnoid cyst of the posterior fossa, 2 had Blake's pouch cyst and in 1 case the posterior fossa had normal appearance. Two women with Dandy Walker anomaly decided to terminate the pregnancy at 20 weeks, the others continued and the sonographic diagnosis was confirmed in all of them after birth. Cystic abnormalities of the posterior fossa in the first trimester of pregnancy is a strong marker for fetal chromosomal abnormalities. In most cases cystic abnormalities of the posterior fossa are associated with multiple malformations of other fetal structures. The prognosis of posterior fossa cystic abnormalities diagnosed in the first trimester of pregnancy is generally poor.

OP08.01: Cytogenetic analysis in fetuses with late onset abnormal sonographic findings

We studied the rate of chromosomal cytogenetic abnormalities of fetuses with abnormal sonographic findings detected in the late second or third trimester. Retrospective analysis of all women at or beyond 23 gestational weeks at a single medical centre, who underwent amniocentesis during January 2012 to December 2015, indicated for abnormal sonographic findings that first appeared and were diagnosed at late second or third trimester. Primary endpoints were the results of fetal karyotype and chromosomal microarray analysis (CMA). 102 women with 103 fetuses underwent amniocentesis due to late onset abnormal sonographic findings. All fetuses had a normal karyotype. Ninety-five women also had CMA performed. The detection rate of abnormal CMA (5/95, 5.3%) was similar to that of women who underwent amniocentesis due to abnormal early onset ultrasound findings detected at routine prenatal screening tests during the 1st or early 2nd trimester (7.3%, p=.46) and significantly higher than that for women who performed amniocentesis and CMA upon request, without having any fetal abnormal sonographic findings or medical indication for CMA (0.99%, p<.0001). Late onset sonographic findings are an indication for amniocentesis. We suggest that if amniocentesis is performed, CMA should be applied to evaluate fetuses with late onset abnormal sonographic findings.

Prenatal Diagnosis of Clubfoot: A Review of Current Available Methodology

Clubfoot is one of the most common congenital limb deformities. Prenatal diagnosis of the condition is essential as it can help treat the malformation as early as possible. We reviewed the recent available literature concerning the current methods for prenatal diagnosis of clubfoot. The following databases were searched from 1966 to 2015: PubMed, OVID, Cochrane, CINAHL, Google scholar and Embase. Out of a total number of 197 retrieved articles, after abstract or title page evaluation, 158 articles not matching the inclusion criteria were excluded. The full text versions of the remaining 39 articles were obtained, and their reference lists screened, with the addition of another 5 full-text articles. Currently, ultrasonography is considered the most reliable method of prenatal diagnosis of clubfoot. Ultrasonographic diagnosis of clubfoot appears more likely between the 18th and the 24th week of pregnancy. Alternative imaging is not indicated. There is no agreement whether to propose foetal karyotyping when isolated clubfoot is diagnosed by prenatal ultrasonography. Early detection of clubfoot should prompt a careful surveillance during pregnancy in order to detect any possible additional abnormalities and, if any of these are detected, invasive testing should be offered.

P16.03: Alterations in placental development in Down's syndrome fetuses mirror differences of miRNA profiles

Epigenetic mechanisms might play a role in Down's syndrome (DS), which is the most common aneuploidy in man. In our previous work, we studied miRNA expressions in normal and trisomic placentas. We have found seven miRNAs significantly upregulated in DS placentas. We would expect, according to biological functions of miRNA, that similar findings could be present in maternal plasma of affected pregnancies. A total of 26 plasma samples from pregnant women - 13 bearing DS fetuses and 13 normal karyotype fetuses, were included. Genome-wide miRNA expressions were profiled using Affymetrix miRNA 4.1 array strips. Results were evaluated using Partek Genomics Suite. The one-way ANOVA with a cut-off p-value < 0.05 and Benjamini-Hochberg correction for multiple testing was used for detection of differentially expressed miRNAs. We identified 61 human miRNAs as being significantly dysregulated between compared groups of samples. Unlike the placenta, most of these miRNAs (44) were down-regulated in plasma of women bearing the DS fetus. Many biological pathways were identified as being potentially influenced by altered miRNA levels. Cell communication and signalling pathways were between the most enriched ones. Seven miRNAs, previously determined as upregulated in DS placentas, did not differ on the plasma level. Our study shows that differences of miRNA profiles between normal and DS fetuses are detectable even on the level of maternal plasma. Such differences could mirror alterations in placental development and they deserve further study. Supported by the Ministry of Health of the Czech Republic RVO VFN64165.

Screening for Sex Chromosome Aneuploidy by Cell-Free DNA Testing: Patient Choice and Performance

Objective: To study patient choice regarding testing for sex chromosome aneuploidy (SCA) and the performance of cell-free DNA (cfDNA) screening for SCA. Methods: Patient choice regarding screening for SCA and factors influencing this choice were evaluated in a single center. In a subsequent two-center study, cases that screened positive for SCA were analyzed to determine the positive predictive value (PPV) for each SCA. Results: In all, 1,957 (61.9%) of the 3,162 patients undergoing cfDNA testing opted for SCA screening. Regression analysis demonstrated that independent predictors of a patient's decision for SCA were earlier gestational age, spontaneous conception, and cfDNA chosen as a primary method of screening. A total of 161 cases screened positive for SCA and follow-up data were available for 118 (73.3%). Forty-six of the 61 cases of 45,X were false-positive results and 15 were concordant with the fetal karyotype (PPV = 24.6%). Seventeen of the 22 cases of 47,XXX were false positive and 5 concordant (PPV = 22.7%). Eleven of the 30 cases of 47,XXY were false positive and 19 concordant (PPV = 63.3%). All 5 cases of 47,XYY were correctly identified, thus yielding a PPV of 100%. Conclusion: More than half of the patients undergoing cfDNA aneuploidy screening also opted for SCA testing, but they were less likely to do so in the presence of an increased risk of trisomy. SCAs involving the X chromosome had a lower PPV than those involving the Y chromosome.

Maternal iAMP21 acute lymphoblastic leukemia detected on prenatal cell-free DNA genetic screening.

cfDNA sequencing for fetal aneuploidy may detect chromosomal abnormalities representative of maternal malignancy.Maternal malignancy must be considered when abnormal cfDNA sequencing for fetal aneuploidy is associated with normal fetal karyotype.

Prenatal diagnosis of holoprosencephaly associated with Smith–Lemli–Opitz syndrome (SLOS) in a 46,XX fetus

ObjectiveTo show the importance of measuring cholesterol precursor levels in amniotic fluid in all pregnancies with ultrasound features (such as holoprosencephaly) suggestive of Smith–Lemli–Opitz syndrome (SLOS), after exclusion of chromosomal anomalies. Case reportA 28-year-old woman, gravida 1 para 0, performed chorionic villus sampling for fetal karyotyping at 13 weeks of gestation due to positive combined first trimester screening in a fetus with increased nuchal translucency and suspected holoprosencephaly. The result was normal – 46,XX. The diagnosis of alobar holoprosencephaly was confirmed at 15 weeks of gestation, and cardiac and limb defects were also identified. Thus, a syndromic cause was considered, specifically a chromosomal microdeletion syndrome or a monogenic entity such as SLOS. The latter was confirmed by measuring 7-dehydrocholesterol (7DHC) and 8-dehydrocholesterol (8DHC) in amniotic fluid. Molecular analysis of DHCR7 gene identified a homozygous mutation in intron 8, c.964-1G>C, providing molecular confirmation for this diagnosis. ConclusionThe differential diagnosis of holoprosencephaly is broad. Identification of the cause of holoprosencephaly aids in establishing the prognosis and is essential to ascertain the mode of inheritance for adequate genetic counseling.