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Background: The short arm of chromosome 16 consists of several copy number variants (CNVs) that are crucial in neurodevelopmental disorders; however, incomplete penetrance and diverse phenotypes after birth aggravate the difficulty of prenatal genetic counseling., Methods: We screened 15,051 pregnant women who underwent prenatal chromosomal microarray analysis between July 2012 and December 2017. Patients with positive array results were divided into four subgroups based on the type of mutation identified on screening (16p13.3, 16p13.11, 16p12.2, and 16p11.2), and the maternal characteristics, prenatal examinations, and postnatal outcomes of different cases were reviewed., Results: Chromosome 16 CNVs were identified in 34 fetuses, including four with 16p13.3 CNVs, 22 with 16p13.11 CNVs, two with 16p12.2 microdeletions, and six with 16p11.2 CNVs. Of the 34 fetuses, 17 delivered without early childhood neurodevelopmental disorders, three developed neurodevelopmental disorders during childhood, and 10 were terminated., Conclusion: Incomplete penetrance and variable expressivity make prenatal counseling challenging. Most cases with inherited 16p13.11 microduplication were reported to have normal development in early childhood, and we also report a few cases of de novo 16p CNVs without further neurodevelopmental disorders., (© 2023 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)

Paternal uniparental disomy 14 (UDP(14)pat) is a rare imprinting disorder with a set of unique neonatal clinical features documented, including craniofacial abnormalities, thoracic and abdominal wall defects, and polyhydraminos. To date, no studies focus on prenatal diagnosis of uniparental disomy have been published. We report a case of a fetus with abnormal ultrasound features at 18 weeks of gestation and normal karyotype result. Subsequent Single nucleotide polymorphism (SNP)-based Affymetrix 750K Microarray analysis revealed the complete loss of heterozygosity for chromosome 14, identifying a case of uniparental disomy. Postmortem examination of the aborted fetus at 21 weeks, coupled with further Affymetrix 750K microarray analysis on the parents, confirmed the diagnosis of parental uniparental disomy for chromosome 14., (Copyright © 2019. Published by Elsevier B.V.)

In this first Asian study, the decision outcomes (decision conflict, decision regret, and anxiety) of 262 pregnant women offered noninvasive prenatal test (NIPT) for high-risk Down screening results were assessed. Decision conflict was experienced by 3.5% and level of decisional regret low (mean score 15.7, 95%CI 13.2-18.3). All 13 cases of decisional regret were NIPT acceptors. Elevated anxiety was experienced by 55.9% at the time of decision making about NIPT and persistent in 30.3%. Insufficient knowledge about NIPT was associated with elevated anxiety at decision making (p = .011) and with decisional regret (p = .016). Decisional regret was associated with prolonged anxiety (p = .010).

We present a rare male fetus with karyotype of mosaic 45,X that comprises two types of aberrant Y chromosomes arising de novo (Yq12 deletion and isodicentric Yq11.22). Both types of the aberrant Y chromosomes lack the AZFc region which are expected to result in oligospermia but unaffected male external genitalia. Genetic analyses by karyotyping, chromosome microarray (CMA), and multiplex ligation-dependent probe amplification (MLPA) for the fetus revealed conflicting results. Additional molecular cytogenetics tools including fluorescence in situ hybridization (FISH) and multicolor banding (mBAND) were performed, which help resolving the discrepancy and delineated the composition of the aberrant Y chromosomes. This report highlighted the importance of incorporating multiple genetic technologies for accurate characterization of complex chromosomal rearrangements, which aid in the prenatal diagnosis and genetic counseling., (Copyright © 2018. Published by Elsevier B.V.)

Objective: To evaluate the clinical value of prenatal array comparative genomic hybridisation (CGH) in screening for submicroscopic genomic imbalances., Design: Cross-sectional study., Setting: Tertiary referral centre., Population: From June 2008 to February 2011, 3171 fetuses underwent prenatal array CGH testing and karyotyping at the National Taiwan University Hospital. Indications for invasive prenatal diagnosis included abnormal karyotype, abnormal ultrasound, advanced maternal age and parental anxiety., Methods: In all, 2497 fetuses were screened with 1-Mb resolution bacterial artificial chromosome array-based CGH, and 674 fetuses with 60-K oligonucleotide array-based CGH. Multiplex ligation-dependent probe amplification, fluorescence in situ hybridization, or 105-K oligonucleotide array CGH provided further confirmation., Main Outcome Measure: Copy number variations identified by array CGH., Results: Array CGH detected numerical chromosome anomalies in 37 (1.2%) fetuses, microdeletion/duplication in 34 (1.1%) fetuses, large deletion/duplication in 13 (0.4%) fetuses, benign copy number changes in 13 (0.4%) fetuses and variation of unknown clinical significance in five (0.2%) fetuses. Array CGH was effective in identifying submicroscopic genomic imbalance in fetuses with de novo balance translocations (2/17, 1.8%), supernumerary marker chromosomes (3/6, 50%), and abnormal prenatal ultrasound findings (33/194, 17.0%). Array CGH detected microdeletions/duplications in 12 fetuses with normal karyotype., Conclusion: Prenatal array CGH is effective in screening for submicroscopic genomic imbalance. Array CGH may add 8.2% to the diagnostic field, compared with conventional karyotyping, for fetuses with abnormal ultrasound results, and is particularly useful in fetuses with karyotypic balanced translocation or marker chromosomes. There is a 0.52% baseline risk of submicroscopic genomic imbalance, even in women with an uneventful prenatal examination., (© 2012 The Authors BJOG An International Journal of Obstetrics and Gynaecology © 2012 RCOG.)

Background: Spinal muscular atrophy (SMA) is the most common neuromuscular autosomal recessive disorder. The American College of Medical Genetics has recently recommended routine carrier screening for SMA because of the high carrier frequency (1 in 25-50) as well as the severity of that genetic disease. Large studies are needed to determine the feasibility, benefits, and costs of such a program., Methods and Findings: This is a prospective population-based cohort study of 107,611 pregnant women from 25 counties in Taiwan conducted during the period January 2005 to June 2009. A three-stage screening program was used: (1) pregnant women were tested for SMA heterozygosity; (2) if the mother was determined to be heterozygous for SMA (carrier status), the paternal partner was then tested; (3) if both partners were SMA carriers, prenatal diagnostic testing was performed. During the study period, a total of 2,262 SMA carriers with one copy of the SMN1 gene were identified among the 107,611 pregnant women that were screened. The carrier rate was approximately 1 in 48 (2.10%). The negative predictive value of DHPLC coupled with MLPA was 99.87%. The combined method could detect approximately 94% of carriers because most of the cases resulted from a common single deletion event. In addition, 2,038 spouses were determined to be SMA carriers. Among those individuals, 47 couples were determined to be at high risk for having offspring with SMA. Prenatal diagnostic testing was performed in 43 pregnant women (91.49%) and SMA was diagnosed in 12 (27.91%) fetuses. The prevalence of SMA in our population was 1 in 8,968., Conclusion: The main benefit of SMA carrier screening is to reduce the burden associated with giving birth to an affected child. In this study, we determined the carrier frequency and genetic risk and provided carrier couples with genetic services, knowledge, and genetic counseling.

Objective: To assess the usefulness of quadruple test screening for Down syndrome in Taiwan., Materials and Methods: Maternal serum concentrations of alpha-fetoprotein, human chorionic gonadotropin, unconjugated estriol, and inhibin A were measured in 21,481 pregnant women from 15 to 20 weeks of gestation., Results: Of the 21,481 women, 977 returned values greater than the high-risk cut-off value (1 in 270). Most of these women (86.2%) decided to have an invasive procedure for genetic diagnosis. Nine cases of Down syndrome and 19 cases of other chromosomal anomalies were detected prenatally. Two children with Down syndrome were diagnosed after delivery even though a low estimated risk was determined following the quadruple test. The detection rate was 81.8% (nine out of 11 cases), with a 4.4% false-positive rate. The median multiple of the median value for a-fetoprotein, human chorionic gonadotropin, unconjugated estriol and inhibin A were 0.87, 2.34, 0.77 and 2.16, respectively, in affected cases., Conclusion: This is the first study of the quadruple test for Down syndrome in a Chinese population. Our findings suggested that the second-trimester quadruple test provides an effective screening tool for Down syndrome in Taiwan.

Down syndrome (DS) is the most common human disease caused by a structural chromosome defect. The original screening test for DS was maternal age or a history of a previously affected infant. Maternal serum screening has been incorporated into routine prenatal checkup in Taiwan since 1994. We used free beta-human chorionic gonadotropin and alpha-fetoprotein (double test) as the serum markers, and this was carried out between the 15th to 20th week of gestation. The overall detection rate was 56% and was compatible with studies of Caucasian populations. The impact of double tests in Taiwan has shown itself by a dramatic lowering of the rate of DS live birth from 0.63 before screening to 0.16 per 1,000 live births at present. However, because of its relatively low detection rate and poor cost-effectiveness, the double test is not justified as a routine screening tool currently. First-trimester combined test is now becoming more widely available and provides increased sensitivity when detecting DS; it has a detection rate of approximately 85% with a false-positive rate of 5%. Nuchal translucency measurement requires ongoing quality control and sufficient certified obstetricians; therefore, first-trimester ultrasound is limited only in designated centers. The quadruple test, having comparable detection rate, should be considered for incorporation into second-trimester screening in Taiwan in the near future. Other screening approaches and combinations have also been utilized in the Western countries. In this review, we outline the various options with respect to DS screening and hope that this will provide practical information for physicians offering such screenings.

Objective: The purpose of this study was to compare the effectiveness between total human chorionic gonadotropin (hCG) and free beta-hCG in two-marker Down syndrome screening programs during the second trimester in a Taiwanese population., Materials and Methods: From a multicenter collaborative study, we investigated the second-trimester maternal serum levels of total hCG from 67 data, free beta-hCG from 72 and alpha-fetoprotein (AFP) from 96 obtained from Taiwanese pregnant women carrying fetuses with Down syndrome., Results: High total hCG and free beta-hCG, as well as low AFP levels, were found with median values of 2.06, 2.49 and 0.77 multiples of the median (MoM), respectively. At a 5% false-positive rate, total hCG and free beta-hCG could detect 31% and 43% of Down syndrome pregnancies, respectively, whilst AFP alone could detect only 15% of affected cases. When combined with maternal age-specific risk, total hCG could achieve a 52% detection rate, free beta-hCG a 54% and AFP a 39%. Combined total hCG and AFP achieved a detection rate of 55%, and combined free beta-hCG and AFP achieved a rate of 60%., Conclusion: The measurement of free beta-hCG is more beneficial than total hCG in serum screening for Down syndrome during the second trimester of pregnancy.

Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are caused by various mutations in the dystrophin gene. Rapid prenatal diagnosis of DMD with gene duplications is difficult due to limitation in gene dosage determination and the requirement for a known disease-causing mutation in the pedigree to achieve a rapid and accurate diagnosis. We report, here, a case with rapid prenatal diagnosis of DMD-affected male with gene duplications in the absence of a known disease-causing variation in the pedigree by using ion-pair reversed-phase high-performance liquid chromatography (IP-RP-HPLC) coupled with competitive multiplex polymerase chain reaction (PCR) protocol. In cases with clinical diagnosis of DMD/BMD, this test should identify greater than 92% of disease-causing DNA variants. The postnatal genetic diagnosis of this case and the same disease-causing mutations subsequently identified in other members of the pedigree confirmed the accuracy of competitive multiplex PCR/IP-RP-HPLC assay in direct prenatal diagnosis of DMD.

Diaphragmatic eventration is the upward displacement of the abdominal viscera secondary to a thin or paralytic diaphragm. Its clinical presentations and radiographic pictures are similar to those of diaphragmatic hernia. Prenatal diagnosis of diaphragmatic eventration is extremely rare. A pregnant woman was referred to us because of abnormal cardiac findings noted at 20 weeks of gestation. A diagnosis of partial anomalous pulmonary venous connection was made on the basis of our findings of right atrial enlargement with an abnormal vascular channel drainage to it. The infant was born via cesarean section at 40 weeks and developed complications of cyanosis immediately after birth. Postnatal imaging studies and surgical findings disclosed right side diaphragmatic eventration with liver and associated vasculature upward displacement into the right pleural cavity. The cardiac structure was otherwise normal. We conclude that when an abnormal vessel tracing and unexplainable cardiac chamber asymmetry is encountered, diaphragmatic eventration should be considered as one of the differential diagnoses. Correct recognition and transferral to the hospital for neonatal assistance may lead to timely and appropriate management of these fetuses., (Copyright 2005 John Wiley & Sons, Ltd.)

Background: A heart rate <100 beats/min may be present in 5% of fetuses with arrhythmia. In this study, we sought to define the feasibility of in utero diagnosis of the underlying mechanisms and the postnatal outcome., Methods: The types of fetal bradycardia were defined by fetal echocardiogram. Fetuses with transient sinus bradycardia were excluded., Results: From 1995-2000, a total of 18 fetuses were found to have bradycardia. Postnatal 12-lead electrocardiograms made at least 3 times during follow-up confirmed the cardiac rhythm in all except those terminated during pregnancy. Sick sinus bradycardia was noted in 4 patients (22 %), of whom 1 had a positive family history and 2 received permanent pacemakers at age 4 and 5 years. Frequent nonconducted atrial premature beats or nonconducted atrial bigeminy or trigeminy were noted in 5 (28%). All of them revealed normal sinus rhythm after birth. Atrioventricular (AV) block was noted in 6 (33%), of whom 3 were terminated due to severe heart failure, and another 2 fetuses received permanent pacemaker implantation soon after birth. Only 1 fetus whose mother showed normal levels of C3 and C4 recovered at late gestation. Most importantly, 3 patients (17%) developed intermittent bradycardia (AV block) and ventricular tachycardia during the fetal stage. They were found to have long QT syndrome. Two of them died during early infancy. One received in utero propranolol and postnatal propranolol and nicorandil with satisfactory control., Conclusion: The mechanisms responsible for fetal bradycardia were diverse and could be characterized by fetal echocardiography. The prognosis was poor in those with long QT syndrome manifested as intermittent fetal bradycardia and tachycardia with AV dissociation.

The association of rare chromosomal rearrangements involving a specific 10q breakpoint with a single umbilical artery (SUA) and sex reversal has never been reported. This report describes the case of a fetus with prenatal ultrasound features of severe intrauterine growth retardation (IUGR), congenital heart disease, and SUA. Fetal blood study revealed de novo deletion of 10q25 and a 46,XY karyotype, while ultrasound demonstrated female genitalia. Based on these findings, sex reversal was diagnosed. Polymerase chain reaction (PCR) amplification revealed the presence of the sex-determining region of the Y (SRY) gene. The pregnancy was terminated at 36 weeks and the newborn weighed 1908 g with marked facial dysmorphism and abnormal genitalia. Because the parents refused autopsy for this case, histopathological examination of gonads was not performed. Breakpoint of the long arm of chromosome 10 may be responsible for sex reversal in the present case and it could thus confirm the concept of autosomal sex reversal proposed in previous reports.

Objective: To determine the frequency of intrauterine rubella infection in Taiwan., Methods: One hundred three pregnant women with evidence of rubella infection were enrolled. Congenital rubella infection was diagnosed by testing specific immunoglobulin (Ig) M in fetal cord serum obtained from funipuncture or amniotic fluid culture. The fetal outcomes were evaluated by ultrasonic examination, specific antibody detection in cord blood at birth, and complete physical examination during early childhood., Results: Prenatal diagnosis was possible in 95 of 103 fetuses, 93 by funipuncture and two by amniocentesis. Five intrauterine rubella infections were detected prenatally, and another one was diagnosed after birth. The intrauterine infection rates were 10.0, 11.8, 2.9, and 6.5% after maternal infection at 1-10, 11-14, 15-19, and 20-29 gestational weeks, respectively. Among the six fetuses with serologic evidence of congenital infection, one had congenital rubella syndrome with sensorineural deafness, two were terminated during the second trimester, two others were normal, and one was lost to follow-up. With the exception of the infant with clinical congenital rubella syndrome, no evidence of rubella defects was found in the other 81 children who received follow-up to 2-4 years old., Conclusion: The risk of congenital rubella infection in seropositive pregnant women is relatively low in Taiwan.