[Prenatal diagnosis of a fetus with 1p36 deletion syndrome and 3p26.3p25.2 duplication].

OBJECTIVE: To explore the characteristics of a fetus with chromosome 1p36 deletion syndrome and 3p26.3p25.2 duplication. METHODS: A pregnant woman who had attended the Genetic Counseling Clinic of Linyi People's Hospital on February 22, 2022 and her fetus were selected as the study subjects. Clinical data were collected. Chromosomal karyotyping, fluorescence in situ hybridization (FISH) and chromosomal microarray analysis (CMA) were carried out for the prenatal diagnosis. RESULTS: Ultrasonography at 24th gestational week revealed that the fetus had ventricular septal defect, single umbilical artery, and slight widening of left lateral ventricle (12 mm). The woman was found to have a karyotype of 46,XX,t(1;3)(p36.22;p25.2), and the result of FISH was t(1;3)(3pter+,1qter+;1pter+,3qter+). The fetus was found to have a karyotype of 46,X?,add(1)(p36), and CMA confirmed that it has a 9.0 Mb deletion at 1p36.33p36.22 and a 12.6 Mb duplication at 3p26.3p25.2. Combining the maternal karyotype, the molecular karyotype of the fetus was determined as 46,X?,der(1)t(1;3)(p36.22;p25.2)mat.arr[hg19]1p36.33p36.22(849467_9882666)×1, 3p26.3p25.2(61892_12699607)×3, with the former known to be associated with 1p36 deletion syndrome. CONCLUSION: The fetus was diagnosed with 1p36 deletion syndrome, and its 1p36.33p36.22 deletion and 3p26.3p25.2 duplication had both derived from the balanced translocation carried by its mother.

Atypicality index as an add-on to combined first-trimester screening for chromosomal aberrations.

OBJECTIVES: To compute a set of atypicality indices based on combined first-trimester screening (cFTS) markers and second-trimester estimated fetal weight (EFW), and to demonstrate their potential in identifying pregnancies at reduced or increased risk of chromosomal aberrations following a low-risk cFTS result. METHODS: The atypicality index quantifies the unusualness of an individual set of measurements relative to a reference distribution and can be computed from any variables or measurements available. A score of 0% on the atypicality index represents the most typical profiles, while a score of 100% indicates the highest level of atypicality. From the Danish Fetal Medicine Database, we retrieved data on all pregnant women seen for cFTS in the Central Denmark Region between January 2008 and December 2018. All pregnancies with a cytogenetic or molecular analysis obtained prenatally, postnatally or following pregnancy loss or termination were identified. A first-trimester atypicality index (AcFTS) was computed based on nuchal translucency (NT) thickness, maternal serum free ß-human chorionic gonadotropin (ß-hCG) and pregnancy-associated plasma protein-A (PAPP-A). Furthermore, a second-trimester index (AcFTS + EFW) was computed from cFTS markers and EFW from a routine second-trimester anomaly scan. All pregnancies were stratified into subgroups based on their atypicality levels and their cFTS risk estimates. The risk of chromosomal aberrations in each subgroup was then compared with the overall prevalence, and a graphical presentation of the multivariate measurement profiles was developed. RESULTS: We retrieved data on 145 955 singleton pregnancies, of which 9824 (6.7%) were genetically examined. Overall, 1 in 122 (0.82% (95% CI, 0.77-0.87%)) of all pregnancies seen for cFTS were affected by a fetal chromosomal aberration, and in screen-negative pregnancies (cFTS trisomy 21 risk < 1 in 100 and/or trisomy 18/13 risk < 1 in 50), 0.41% (95% CI, 0.38-0.44%) were affected. In screen-negative pregnancies with a typical first-trimester profile (AcFTS < 80%), the risk of chromosomal aberrations was significantly reduced (0.28%) compared with the overall risk. The risk of chromosomal aberrations increased with higher atypicality index to 0.49% (AcFTS [80-90%)), 1.52% (AcFTS [90-99%)) and 4.44% (AcFTS ≥ 99%) and was significantly increased in the two most atypical subgroups. The same applied for the second-trimester atypicality index, with risks of chromosomal aberrations of 0.76% and 4.16% in the two most atypical subgroups (AcFTS + EFW [90-99%) and AcFTS + EFW ≥ 99%, respectively). CONCLUSIONS: As an add-on to cFTS, the atypicality index identifies women with typical measurement profiles, which may provide reassurance, whereas atypical profiles may warrant specialist referral and further investigation. In pregnancies identified as low risk on cFTS but with a highly atypical distribution of NT, PAPP-A and ß-hCG, the risk of a chromosomal aberration is substantially increased. The atypicality index optimizes the interpretation of pre-existing prenatal screening profiles and is not limited to cFTS markers or EFW. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.

Influence of fibroids on cell-free DNA screening accuracy.

OBJECTIVE: Cell-free DNA (cfDNA) screening assesses both maternal and placental cfDNA. Fibroids are common and release cfDNA into maternal serum. Genetic abnormality is seen in 50% of fibroids. We aimed to assess the impact of fibroids on the accuracy of genome-wide cfDNA screening. METHODS: This was a prospective cohort study of singleton pregnancies examined at one of two centers in Melbourne and Sydney, Australia, between 1 November 2019 and 31 December 2020. All cases underwent pretest ultrasound examination to confirm an ongoing pregnancy of at least 10 weeks' gestation, and, at this stage, the number and volume of any uterine fibroid were documented. Genome-wide cfDNA screening was performed to detect all copy-number variants (CNV) > 7 megabases. The incidence of a false-positive result was compared between cases with and those without fibroids. RESULTS: Over the 14-month study period, 13 184 patients underwent cfDNA screening, of whom 1017 (7.7%) had fibroids. Fibroids were not identified in any of the 17 participants who had a false-positive result for chromosomes 13, 18, 21, X or Y. Ninety-five (0.7%) cases were screen-positive for subchromosomal aberration (SA), rare autosomal trisomy (RAT) or multiple abnormalities (MA), with 10 of these cases having a fetal genetic abnormality. The incidence of a false-positive RAT, MA or SA result was significantly higher in participants with fibroids (20/1017 (2.0%)) than in those without fibroids (64/12 167 (0.5%)). Women with fibroids were approximately six times as likely to have a false-positive result for SA, and this was associated positively with both fibroid number and volume. CONCLUSIONS: Most women with fibroids do not have an abnormal result on genome-wide cfDNA screening. However, CNVs due to fibroids are associated with false-positive SA findings, although fibroids do not appear to influence cfDNA screening accuracy for the common autosomal trisomies or sex-chromosomal abnormalities. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Prenatal diagnosis of recurrent mosaic ring chromosome 13 of maternal origin.

OBJECTIVE: We present prenatal diagnosis of recurrent mosaic ring chromosome 13 [r(13)] of maternal origin. CASE REPORT: A 27-year-old woman underwent amniocentesis at 17 weeks of gestation because of a past history of fetal abnormality caused by mosaic r(13) in the previous fetus associated with fetal intrauterine growth restriction (IUGR), a karyotype of 46,XY,r(13)[23]/45,XY,-13[10]/46,XY,idic r(13)[2] and a maternal origin of abnormal r(13). The parental karyotypes were normal. During this pregnancy, amniocentesis revealed a karyotype of 46,XX,r(13)[12]/45,XX,-13[8] and a 22.80-Mb deletion of chromosome 13q31.3-q34. The pregnancy was subsequently terminated, and a malformed fetus was delivered with craniofacial dysmorphism. Repeat amniocentesis revealed a karyotype of 46,XX,r(13)(p11.1q31)[18]/45,XX,-13[12]. The placenta had a karyotype of 46,XX,r(13)(p11.1q31)[27]/45,XY,-13[13]. Polymorphic DNA marker analysis using the DNA derived from the parental bloods and umbilical cord confirmed a maternal origin of the abnormal r(13). CONCLUSION: Prenatal diagnosis of mosaic r(13) in consecutive pregnancies should raise a suspicion of parental gonadal mosaicism, and polymorphic DNA marker analysis is useful for determination of the parental origin of recurrent aneuploidy under such a circumstance.

Investigation on combined copy number variation sequencing and cytogenetic karyotyping for prenatal diagnosis.

BACKGROUND: We aimed to evaluate the clinical value of copy number variation-sequencing (CNV-Seq) in combination with cytogenetic karyotyping in prenatal diagnosis. METHODS: CNV-Seq and cytogenetic karyotyping were performed in parallel for 9452 prenatal samples for comparison of the diagnostic performance of the two methods, and to evaluate the screening performance of maternal age, maternal serum screening, fetal ultrasound scanning and noninvasive prenatal testing (NIPT) for fetal pathogenic copy number variation (CNV). RESULTS: Among the 9452 prenatal samples, traditional karyotyping detected 704 cases (7.5%) of abnormal cytogenetic karyotypes, 171 (1.8%) chromosome polymorphism, 20 (0.2%) subtle structural variations, 74 (0.7%) mutual translocation (possibly balanced), 52 (0.6%) without karyotyping results, and 8431 (89.2%) normal cytogenetic karyotypes. Among the 8705 cases with normal karyotype, polymorphism, mutual translocation, or marker chromosome, CNV-Seq detected 63 cases (0.7%) of pathogenic chromosome microdeletion/duplication. Retrospectively, noninvasive prenatal testing (NIPT) had high sensitivity and specificity for the screening of fetal pathogenic CNV, and NIPT combining with maternal age, maternal serum screening or fetal ultrasound scanning, which improved the screening performance. CONCLUSION: The combined application of cytogenetic karyotyping and CNV-Seq significantly improved the detection rate of fetal pathogenic chromosome microdeletion/duplication. NIPT was recommended for the screening of pathogenic chromosome microdeletion/duplication, and NIPT combining with other screening methods further improved the screening performance for pathogenic fetal CNV.

Prenatal diagnosis of a fetus with mosaic ring chromosome 13: Case report and review of the literature.

OBJECTIVE: To diagnose the ring chromosome 13 (r(13)) in a fetus, and analyze the genotype-phenotype correlation. CASE REPORT: A 26-year-old woman who was second pregnancy, underwent amniocentesis at 18 weeks of gestation because of the increased nuchal translucency (NT). Prenatal ultrasound showed the NT thickness was 3.5 mm at 12+1 weeks of gestation and nuchal fold (NF) was 6.1 mm at 18 weeks of gestation, and amniotic fluid karyotype analysis revealed mosaic r(13). CMA detected a 16.293 Mb duplication at 13q21.32q31.1 and 31.303 Mb deletion at 13q31.1q34. CONCLUSION: R(13) is a very rare chromosomal abnormality. Cytogenetic examination combined with CMA can provide accurate diagnosis and effective information for genetic counseling.

Chromosomal analysis for embryos from balanced chromosomal rearrangement carriers using next generation sequencing.

We aimed to use next generation sequencing (NGS) to investigate chromosomal abnormalities in blastocyst trophectoderm (TE) samples, and reproductive outcomes with the different types of chromosomal rearrangements (CR) and for each sex of CR carrier. A total of 1189 blastocyst TE samples were evaluated using NGS to detect chromosomal unbalanced translocations as well as aneuploidy, including blastocytes from 637 blastocysts from carriers of balanced CR and 552 blastocysts from carriers of normal chromosomes. The optimal embryos had lower chromosomal abnormality rates compared to the poor-quality embryos. The experimental group had significantly reduced rates of normal embryos and euploidy, and higher rates of total abnormalities, aneuploidy and unbalanced chromosomal aberrations. Carriers of reciprocal translocations had a reduced rate of normal embryos and an increased percentage of embryos with total abnormalities and unbalanced chromosomal aberrations compared with carriers of Robertsonian translocations. Couples with female carriers of chromosomal abnormalities had significantly reduced rates of normal embryos and euploidy, and a higher percentage of embryos with total abnormalities, aneuploidy, and unbalanced chromosomal aberrations compared with couples of male carriers. Our preimplantation genetic testing (PGT) study identified higher rates of chromosomal abnormalities, including chromosomal unbalanced translocations and aneuploidy, in blastocysts from CR carriers, especially from the female carriers, in a Chinese population. The PGT cycles successfully improved clinical outcomes by increasing the fertilization rate and reducing the early spontaneous abortion rate compared with the in vitro fertilization and intracytoplasmic sperm injection cycles, especially for CR carriers.

Chromosomal mosaicism: Origins and clinical implications in preimplantation and prenatal diagnosis.

The diagnosis of chromosomal mosaicism in the preimplantation and prenatal stage is fraught with uncertainty and multiple factors need to be considered in order to gauge the likely impact. The clinical effects of chromosomal mosaicism are directly linked to the type of the imbalance (size, gene content, and copy number), the timing of the initial event leading to mosaicism during embryogenesis/fetal development, the distribution of the abnormal cells throughout the various tissues within the body as well as the ratio of normal/abnormal cells within each of those tissues. Additional factors such as assay noise and culture artifacts also have an impact on the significance and management of mosaic cases. Genetic counseling is an important part of educating patients about the likelihood of having a liveborn with a chromosome abnormality and these risks differ according to the time of ascertainment and the tissue where the mosaic cells were initially discovered. Each situation needs to be assessed on a case-by-case basis and counseled accordingly. This review will discuss the clinical impact of finding mosaicism through: embryo biopsy, chorionic villus sampling, amniocentesis, and noninvasive prenatal testing using cell-free DNA.

Chromosomal microarray analysis in fetuses with high-risk prenatal indications: A retrospective study in China.

OBJECTIVE: The present study aimed to determine the diagnostic value of prenatal chromosomal microarray analysis (CMA) for fetuses with several indications of being at high risk for various conditions. MATERIALS AND METHODS: This retrospective analysis included 1256 pregnancies that were prenatally evaluated due to high-risk indications using invasive CMA. The indications for invasive prenatal diagnosis mainly included ultrasound anomalies, high-risk for maternal serum screening (MSS), high-risk for non-invasive prenatal tests (NIPT), family history of genetic disorders or birth defects, and advanced maternal age (AMA). The rate of clinically significant genomic imbalances between the different groups was compared. RESULTS: The overall prenatal diagnostic yield was 98 (7.8%) of 1256 pregnancies. Clinically significant genomic aberrations were identified in 2 (1.5%) of 132 patients with non-structural ultrasound anomalies, 36 (12.7%) of 283 with structural ultrasound anomalies, 2 (4.5%) of 44 at high-risk for MSS, 38 (26.6%) of 143 at high-risk for NIPT, 11 (3.8%) of 288 with a family history, and 7 (2.1%) of 328 with AMA. Submicroscopic findings were identified in 29 fetuses, 19 of whom showed structural ultrasound anomalies. CONCLUSION: The diagnostic yields of CMA for pregnancies with different indications greatly varied. CMA could serve as a first-tier test for structural anomalies, especially multiple anomalies, craniofacial dysplasia, urinary defects, and cardiac dysplasia. Our results have important implications for genetic counseling.

Prenatal diagnosis of Cri-du-Chat syndrome with concomitant distal trisomy 10q syndrome in one fetus with ultrasound anomalies.

OBJECTIVE: The aim of this work was to characterize the genetic abnormalities and prenatal diagnosis indications in one fetus with Cri-du-Chat syndrome with codependent 10q24.2-q26.3 duplication in prenatal screening. MATERIALS AND METHODS: A 31-year-old woman had a second trimester serum screening that indicated the fetus was at low risk. During this pregnancy, the woman underwent amniocentesis at 18+4 weeks' gestation because of adverse fertility history and nuchal fold thickening. Cytogenetic analysis and next-generation sequencing analysis were simultaneously performed to provide genetic analysis of fetal amniotic fluid. According to abnormal results, parental chromosome karyotype of peripheral blood was performed to analysis. RESULTS: CNV-seq detected a 14.00 Mb deletion at 5p15.33-p15.2 and a 34.06 Mb duplication at 10q24.2-q26.3 in the fetus. Cytogenetic analysis of the fetus revealed a karyotype of 46, XY, der(5) t(5;10) (p15.2;q26.3). The karyotype of pregnant women was 46,XX,t(5;10) (p15.2;q24.2). The pregnancy was subsequently terminated after sufficient informed consent. CONCLUSION: This is the first study that reports prenatal diagnosis of a Cri-du-Chat syndrome with concomitant 10 q24.2-q26.3 duplication. Adverse pregnancy history has to be as an important indicator for prenatal diagnosis, and the genetic factors of abnormal pregnancy should be identified before next pregnancy. Nuchal fold thickening is closely related to fetal abnormalities. Combined with ultrasonography, the use of CNV-seq will improve the diagnosis of submicroscopic chromosomal aberrations in fetuses with congenital anomalies.

Prenatal diagnosis of 20p13 microdeletion syndrome.

OBJECTIVE: The objective of this study was to report the first case of prenatal diagnosis of the fetal 20p13 microdeletion syndrome in the literature. CASE REPORT: The mother was 31 years old and had a first trimester serum screening that indicated the fetus was at low risk. The prenatal ultrasound at 23 weeks of gestation showed mild ventriculomegaly (10.2 mm) and absent septum pellucidum. She underwent amniocentesis because of the abnormal imaging results. Karyotype analysis revealed normal results. Chromosome microarray analysis (CMA) was then performed to provide genetic analysis of the fetus and parents. CMA detected 317.902 kb deletion of 20p13 in fetus. Finally, pregnancy was terminated at 32 weeks of gestation. CONCLUSION: This study is the first to report the prenatal diagnosis of a 20p13 microdeletion syndrome. Our results further confirmed that genes in this region, including SOX12, NRSN2 are essential for normal fetal growth and TBC1D20 for normal brain development.

Genome-wide abnormalities in embryos: Origins and clinical consequences.

Ploidy or genome-wide chromosomal anomalies such as triploidy, diploid/triploid mixoploidy, chimerism, and genome-wide uniparental disomy are the cause of molar pregnancies, embryonic lethality, and developmental disorders. While triploidy and genome-wide uniparental disomy can be ascribed to fertilization or meiotic errors, the mechanisms causing mixoploidy and chimerism remain shrouded in mystery. Different models have been proposed, but all remain hypothetical and controversial, are deduced from the developmental persistent genomic constitutions present in the sample studied and lack direct evidence. New single-cell genomic methodologies, such as single-cell genome-wide haplotyping, provide an extended view of the constitution of normal and abnormal embryos and have further pinpointed the existence of mixoploidy in cleavage-stage embryos. Based on those recent findings, we suggest that genome-wide anomalies, which persist in fetuses and patients, can for a large majority be explained by a noncanonical first zygotic cleavage event, during which maternal and paternal genomes in a single zygote, segregate to different blastomeres. This process, termed heterogoneic division, provides an overarching theoretical basis for the different presentations of mixoploidy and chimerism.

Prenatal diagnosis and molecular cytogenetic characterization of a pure ring chromosome 21 with a 4.657-Mb 21q22.3 deletion.

OBJECTIVE: We present diagnosis and molecular cytogenetic characterization of a pure ring chromosome [r(21)] with a 4.657-Mb 21q22.3 deletion. CASE REPORT: A 44-year-old woman underwent amniocentesis at 18 weeks of gestation because of advanced maternal age. Amniocentesis revealed a karyotype 46,XX,r(21)(p11.2q22.3). Prenatal ultrasound findings were unremarkable. Simultaneous array comparative genomic hybridization (aCGH) analysis on uncultured amniocytes revealed a 4.657-Mb deletion at 21q22.3. The parental karyotypes were normal. The pregnancy was subsequently terminated, and a malformed fetus was delivered with facial dysmorphism and clinodactyly. Postnatal cytogenetic analysis of umbilical cord revealed a karyotype of 46,XX,r(21)(p11.2q22.3). aCGH analysis of umbilical cord revealed the result of arr 21q22.3 (43,427,188-48,084,156) × 1.0 with a 4.657-Mb 21q22.3 deletion encompassing 57 Online Mendelian Inheritance in Man (OMIM) genes including TRPM2, TSPEAR, COL18A1, COL6A1, COL6A2, LSS, PCNT, DIP2A, S100B and PRMT2. Metaphase fluorescence in situ hybridization (FISH) analysis of the umbilical cord fibroblasts confirmed a 21q22.3 deletion. CONCLUSION: Prenatal diagnosis of an r(21) should include molecular cytogenetic characterization such as aCGH and FISH to determine the extent of the 21q22.3 deletion.

Prenatal diagnosis and ultrasonographic findings of partial trisomy of chromosome 6q: A case report and review of the literature.

RATIONALE: Partial trisomy of the long arm of chromosome 6 syndrome is a rare chromosomal disorder with distinctive phenotypic expressivity, in which cytogenetic abnormalities are usually reported in infancy and childhood. Ultrasonographic findings on trisomy of the distal long arm of chromosome 6 in previous studies are limited. PATIENT CONCERNS: A 32-year-old, gravida 6, para 1, pregnant woman who had 4 spontaneous abortions underwent a clinical ultrasound examination at 26 weeks of gestation. DIAGNOSES: Ultrasonographic findings were microcephaly, an acoustic image of a transparent septum, a flat nasal bridge, right pulmonary artery stenosis, and a single umbilical artery. Cytogenetic and single-nucleotide polymorphism array analyses were performed to estimate genetic factors of this diagnosis by amniocentesis. INTERVENTIONS: After genetic counseling, the patient and her husband opted to terminate the pregnancy. OUTCOMES: Cytogenetic examination of the fetus showed the karyotype 46,XX,der(20)t(6;20)(q24;p13). The single-nucleotide polymorphism (SNP) array showed a 22.104-Mb duplication of 6q24.3q27 and a 0.784-Mb deletion of 20p13. LESSONS: Ultrasonographic findings of fetal abnormalities, including microcephaly, an acoustic image of a transparent septum, a flat nasal bridge, right pulmonary artery stenosis, and a single umbilical artery, may be related to a 22.104-Mb duplication of 6q24.3q27 and a 0.784-Mb deletion of 20p13. More ultrasonographic and genotype studies are required to extend the phenotypic characterization of partial trisomy 6q syndrome.

Clinical utility of expanded non-invasive prenatal screening and chromosomal microarray analysis in high-risk pregnancy.

OBJECTIVE: To evaluate the utility of expanded non-invasive prenatal screening (NIPS), compared with chromosomal microarray analysis (CMA), for the detection of chromosomal abnormalities in high-risk pregnancies. METHODS: This was a multicenter retrospective study of singleton pregnancies at high risk for chromosomal abnormality. Patients who underwent expanded NIPS and CMA sequentially during pregnancy from 2015 to 2019 were included in the analysis. Pregnancies with a positive result for sex chromosome aneuploidy were excluded as the full details could not be retrieved. The utility of expanded NIPS and CMA for detection of chromosomal abnormalities in this cohort was compared by assessing the concordance between the results. RESULTS: Of the 774 included high-risk pregnancies, 550 (71.1%) had a positive NIPS result, while a positive CMA result was detected in 308 (39.8%) cases. The rate of full or partial concordance between NIPS and CMA was 82.2%, 59.6% and 25.0% for trisomies 21, 18 and 13, respectively. For rare aneuploidies and segmental imbalances, NIPS and CMA results were fully or partially concordant in 7.5% and 33.3% of cases, respectively. Copy-number variants < 5 Mb were detected more often by CMA, with an incidence of 7.9% (61/774) compared with 3.1% (24/774) by NIPS. A genetic aberration was detected by CMA in 1 in 17 (5.8%) high-risk pregnancies that had a negative or non-reportable NIPS result. CONCLUSION: CMA allows for comprehensive detection of genome-wide chromosomal abnormalities in high-risk pregnancies. CMA should be offered instead of expanded NIPS for high-risk pregnancies. Copyright © 2020 ISUOG. Published by John Wiley & Sons Ltd.

Universal chromosomal microarray analysis reveals high proportion of copy-number variants in low-risk pregnancies.

OBJECTIVES: To evaluate the yield and utility of the routine use of chromosomal microarray analysis (CMA) for prenatal genetic diagnosis in a large cohort of pregnancies with normal ultrasound (US) at the time of genetic testing, compared with pregnancies with abnormal US findings. METHODS: We reviewed all prenatal CMA results in our center between November 2013 and December 2018. The prevalence of different CMA results in pregnancies with normal US at the time of genetic testing ('low-risk pregnancies'), was compared with that in pregnancies with abnormal US findings ('high-risk pregnancies'). Medical records were searched in order to evaluate subsequent US follow-up and the outcome of pregnancies with a clinically relevant copy-number variant (CNV), i.e. a pathogenic or likely pathogenic CNV or a susceptibility locus for disease with > 10% penetrance, related to early-onset disease in the low-risk group. RESULTS: In a cohort of 6431 low-risk pregnancies that underwent CMA, the prevalence of a clinically significant CNV related to early-onset disease was 1.1% (72/6431), which was significantly lower than the prevalence in high-risk pregnancies (4.9% (65/1326)). Of the low-risk pregnancies, 0.4% (27/6431) had a pathogenic or likely pathogenic CNV, and another 0.7% (45/6431) had a susceptibility locus with more than 10% penetrance. Follow-up of the low-risk pregnancies with a clinically significant early-onset CNV revealed that 31.9% (23/72) were terminated, while outcome data were missing in 26.4% (19/72). In 16.7% (12/72) of low-risk pregnancies, an US abnormality was discovered later on in gestation, after genetic testing had been performed. CONCLUSION: Although the background risk of identifying a clinically significant early-onset abnormal CMA result in pregnancies with a low a-priori risk is lower than that observed in high-risk pregnancies, the risk is substantial and should be conveyed to all pregnant women. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.

Prenatal diagnosis and molecular cytogenetic characterization of a chromosome 15q24 microdeletion.

OBJECTIVE: We present prenatal diagnosis, molecular cytogenetic characterization and genetic counseling of a chromosome 15q24 microdeletion of paternal origin. CASE REPORT: A 34-year-old primigravid woman underwent amniocentesis at 17 weeks of gestation because of advanced maternal age. Amniocentesis revealed a karyotype of 46,XY. Simultaneous array comparative genomic hybridization (aCGH) analysis on amniotic fluid revealed a de novo 2.571-Mb microdeletion of 15q24.1-q24.2. Prenatal ultrasound findings were unremarkable except persistent left superior vena cava and enlarged coronary sinus. The woman requested repeat amniocentesis at 22 weeks of gestation, and aCGH analysis confirmed the result of arr 15q24.1q24.2 (72,963,970-75,535,330) × 1.0 [GRCh37 (hg19)] and a 15q24 microdeletion encompassing the genes of STRA6, CYP11A1, SEMA7A, ARID3B, CYP1A1, CYP1A2, CSK and CPLX3. The parents did not have such a deletion, and polymorphic DNA marker analysis confirmed a paternal origin of the de novo deletion. Metaphase fluorescence in situ hybridization analysis confirmed a 15q24 deletion. The parents elected to terminate the pregnancy, and a malformed fetus was delivered with characteristic facial dysmorphism. CONCLUSION: Simultaneous aCGH analysis of uncultured amniocytes at amniocentesis may help to detect rare de novo microdeletion disorders.

Prenatal diagnosis and molecular cytogenetic characterization of a de novo interchromosomal insertion of ins(1;8)(p22.1;q22q23).

OBJECTIVE: We present prenatal diagnosis and molecular cytogenetic characterization of a de novo interchromosomal insertion of ins(1; 8)(p22.1; q22q23) at amniocentesis. CASE REPORT: A 34-year-old woman underwent amniocentesis at 18 weeks of gestation because of advanced maternal age. Conventional cytogenetic analysis revealed a chromosome 1p22.1 interstitial duplication and a chromosome 8q22-q23 interstitial deletion. The parental karyotypes were normal. Array comparative genomic hybridization (aCGH) analysis using the DNA extracted from cultured amniocytes revealed no genomic imbalance. Metaphase fluorescence in situ hybridization (FISH) analysis on cultured amniocytes showed an interchromosomal insertion of ins(1; 8)(p22.1; q22q23) or ins(1; 8) (1pter→1p22.1::8q23→8q22::1p22.1→1qter; 8pter→8q22::8q23→8qter). The long arm of chromosome 8 between bands 8q22 and 8q23 had been directly inserted into the short arm of chromosome 1 at band 1p22.1. The karyotype was 46,XY,ins(1; 8)(p22.1; q22q23) or 46,XY,ins(1; 8)(1pter→1p22.1::8q23→8q22::1p22.1→1qter; 8pter→8q22::8q23→8qter). After genetic counseling, the parents decided to continue the pregnancy. A phenotypically normal male baby was delivered at term. CONCLUSION: FISH and aCGH are useful for genetic counseling and molecular cytogenetic characterization of a de novo interchromosomal insertion detected by amniocentesis.