Shin-Yu Lin

Role of three‐dimensional power Doppler in the antenatal diagnosis of placenta accreta: comparison with gray‐scale and color Doppler techniques

To assess the role of three‐dimensional (3D) power Doppler in the antenatal diagnosis of placenta accreta and compare its diagnostic performance with gray‐scale and color Doppler ultrasonography.

A whole genome methylation analysis of systemic lupus erythematosus: hypomethylation of the IL10 and IL1R2 promoters is associated with disease activity

The etiology of systemic lupus erythematosus (SLE) involves a complex interaction of genetic and environmental factors. Investigations have shown that environmentally driven epigenetic changes contribute to the etiology of SLE. Here, we hypothesize that aberrant DNA methylation may contribute to the activation of the immune machinery and trigger lupus disease activity. A whole genome methylation array was applied to investigate the DNA methylation changes between 12 pairs of active SLE patients and healthy controls. The results were further confirmed in 66 SLE patients, 102 healthy controls. The methylation statuses of the IL10 and IL1R2 genes were significantly reduced in the SLE patient samples relative to the healthy controls (age-adjusted odds ratios, 64.2 and 16.9, respectively, P<0.0001). There was a trend toward SLE patients having hypomethylated IL10 and IL1R2 genes accompanied by greater disease activity. We observed that the methylation degree of IL10 and IL1R2 genes were reduced in the rheumatoid arthritis (RA) patients as well but the hypomethylation change was more significant in IL1R2 genes than in the IL10 genes in RA patients. This study demonstrated that DNA hypomethylation might be associated with SLE. Hypomethylated IL10 and IL1R2 genes may provide potential epigenetic markers as clinical predictors for autoimmune diseases.

Carrier Screening for Spinal Muscular Atrophy (SMA) in 107,611 Pregnant Women during the Period 2005–2009: A Prospective Population-Based Cohort Study

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.

Mutation spectrum of 122 hemophilia A families from Taiwanese population by LD-PCR, DHPLC, multiplex PCR and evaluating the clinical application of HRM

BackgroundHemophilia A represents the most common and severe inherited hemorrhagic disorder. It is caused by mutations in the F8 gene, which leads to a deficiency or dysfunctional factor VIII protein, an essential cofactor in the factor X activation complex.MethodsWe used long-distance polymerase chain reaction and denaturing high performance liquid chromatography for mutation scanning of the F8 gene. We designed the competitive multiplex PCR to identify the carrier with exonal deletions. In order to facilitate throughput and minimize the cost of mutation scanning, we also evaluated a new mutation scanning technique, high resolution melting analysis (HRM), as an alternative screening method.ResultsWe presented the results of detailed screening of 122 Taiwanese families with hemophilia A and reported twenty-nine novel mutations. There was one family identified with whole exons deletion, and the carriers were successfully recognized by multiplex PCR. By HRM, the different melting curve patterns were easily identified in 25 out of 28 cases (89%) and 15 out of 15 (100%) carriers. The sensitivity was 93 % (40/43). The overall mutation detection rate of hemophilia A was 100% in this study.ConclusionWe proposed a diagnostic strategy for hemophilia A genetic diagnosis. We consider HRM as a powerful screening tool that would provide us with a more cost-effective protocol for hemophilia A mutation identification.

AdimFlu-S® influenza A (H1N1) vaccine during pregnancy: The Taiwanese Pharmacovigilance Survey

BACKGROUND This study evaluated the incidence, nature, and seriousness of adverse drug reactions (ADRs) occurring after AdimFlu-S(®) influenza A (H1N1) vaccination in pregnant women was administered. METHODS This is a retrospective cohort study. Between October 2009 and February 2010, 198 pregnant women who had received the AdimFlu-S(®) influenza A (H1N1) vaccine during pregnancy and 198 age-matched pregnant women who had not received influenza vaccine were included and recorded. The pregnancy outcome and maternal adverse effects were extracted from chart reviews. Infant health status data were followed up until 8 weeks post-partum. RESULTS During the observation period of each cohort, four subjects (2.0%) in the exposed group experienced vaccine-related adverse events that were mild in severity. A total of 17 women (8.6%) in the vaccine exposed group and 40 women (20.2%) in the unexposed group underwent at least one adverse effect during their pregnancy. A total of 72 infants (35.6%) in the exposed group and 101 infants (49%) in the unexposed group had at least one adverse event within 8 weeks after they were born (p<0.05). The adverse events experienced by the women and their infants were not increased when the vaccine was administered during the first trimester. There were no significant differences between these two groups with regard to preterm delivery rate and stillbirth rate. CONCLUSION AdimFlu-S (®) influenza A (H1N1) vaccine is safe for pregnant women and their infants.

Rapid aneuploidy diagnosis by multiplex ligation-dependent probe amplification and array comparative genomic hybridization in pregnancy with major congenital malformations

OBJECTIVE To report five cases of major congenital malformations associated with common aneuploidies detected by rapid aneuploidy diagnosis. CASE REPORTS The fetus in the first case presented cebocephaly, semilobar holoprosencephaly, and tetralogy of Fallot on ultrasound at 25 gestational weeks. Cordocentesis using multiplex ligation-dependent probe amplification to detect aneuploidies of chromosomes X, Y, 13, 18, and 21 in uncultured cord blood revealed three copies of all targets on chromosome 13 consistent with the diagnosis of trisomy 13. The fetus in the second case presented bilateral choroid plexus cysts, congenital diaphragmatic hernia, and club foot on ultrasound at 18 gestational weeks. Amniocentesis using array-based comparative genomic hybridization (aCGH) in uncultured amniocytes revealed a gain in the DNA dosage of chromosome 18 consistent with the diagnosis of trisomy 18. The fetus in the third case presented aortic stenosis and nuchal edema on ultrasound at 22 gestational weeks. Amniocentesis using aCGH in uncultured amniocytes revealed a result of monosomy X and Turner syndrome. The fetus in the fourth case presented nuchal cystic hygroma and ventriculomegaly on ultrasound at 17 gestational weeks. Amniocentesis using aCGH in uncultured amniocytes revealed a gain in the DNA dosage of chromosome 21 consistent with the diagnosis of trisomy 21. The fetus in the fifth case presented holoprosencephaly, omphalocele, and hydronephrosis on ultrasound at 17 gestational weeks. Amniocentesis using aCGH in uncultured amniocytes revealed a gain in the DNA dosage of chromosome 13 consistent with the diagnosis of trisomy 13. CONCLUSIONS Prenatal diagnosis of major congenital malformations should alert one to the possibility of chromosomal abnormalities. Multiplex ligation-dependent probe amplification and aCGH have the advantage of rapid aneuploidy diagnosis of common aneuploidies in cases with major congenital malformations.

Prenatal diagnosis of mosaic trisomy 2: discrepancy between molecular cytogenetic analyses of uncultured amniocytes and karyotyping of cultured amniocytes in a pregnancy with severe fetal intrauterine growth restriction.

Department of Obstetrics and Gynecology, Mackay Memorial Hospital, Taipei, Taiwan Department of Medical Research, Mackay Memorial Hospital, Taipei, Taiwan Department of Biotechnology, Asia University, Taichung, Taiwan d School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung, Taiwan e Institute of Clinical and Community Health Nursing, National Yang-Ming University, Taipei, Taiwan Department of Obstetrics and Gynecology, School of Medicine, National Yang-Ming University, Taipei, Taiwan Department of Medical Genetics, National Taiwan University Hospital, Taipei, Taiwan Department of Obstetrics and Gynecology, National Taiwan University Hospital, Taipei, Taiwan Department of Bioengineering, Tatung University, Taipei, Taiwan

Newborn genetic screening for hearing impairment: a preliminary study at a tertiary center.

Universal newborn hearing screening (UNHS) is of paramount importance for early identification and management of hearing impairment in children. However, infants with slight/mild, progressive, or late-onset hearing impairment might be missed in conventional UNHS. To investigate whether genetic screening for common deafness-associated mutations could assist in identifying these infants, 1017 consecutive newborns in a tertiary hospital were subjected to both newborn hearing screening using a two-step distortion-product otoacoustic emissions (DPOAE) screening and newborn genetic screening (NGS) for deafness. The NGS targeted 4 deafness-associated mutations commonly found in the Taiwanese population, including p.V37I (c.109G>A) and c.235delC of the GJB2 gene, c.919-2A>G of the SLC26A4 gene, and mitochondrial m.1555A>G of the 12S rRNA gene. The results of the NGS were then correlated to the results of the NHS. Of the 1017 newborns, 16 (1.6%) had unilateral DPOAE screening failure, and 22 (2.2%) had bilateral DPOAE screening failure. A total of 199 (19.6%) babies were found to have at least 1 mutated allele on the NGS for deafness, 11 (1.1%) of whom were homozygous for GJB2 p.V37I, 6 (0.6%) compound heterozygous for GJB2 p.V37I and c.235delC, and 1 (0.1%) homoplasmic for m.1555A>G, who may potentially have hearing loss. Among them, 3 babies, 5 babies, and 1 baby, respectively, passed the NHS at birth. Comprehensive audiological assessments in the 9 babies at 3 months identified 1 with slight hearing loss and 2 with mild hearing loss. NGS for common deafness-associated mutations may identify infants with slight/mild or potentially progressive hearing impairment, thus compensating for the inherent limitations of the conventional UNHS.

Mutation spectrum of the fibrillin‐1 (FBN1) gene in Taiwanese patients with Marfan syndrome

The aim of this study was to establish a national database of mutations in the fibrillin‐1 (FBN1) gene that cause Marfan syndrome (MFS) in the Taiwanese population. In this study, we screened 294 patients from 157 families for the presence of FBN1 mutations using polymerase chain reaction/ denaturing high performance liquid chromatography (PCR/DHPLC). We identified 56 mutations in 62 of the 157 (40%) families including 49 single‐base substitutions (36 missense mutations, seven nonsense mutations, and six splicing sites), one small insertion, four small deletions, one small indel (insertion and deletion), and one exonic deletion (Exon 36). When family history was taken into consideration, the mutation detection rate rose to 91% (29 of 32). We further investigated the phenotypic data and found that one third (47 of 157) of the families fit the Ghent criteria for MFS. Based on that data, the mutation rate was 98% (46/47). That finding implies that family history and the Ghent criteria play a more important role than clinical manifestations in establishing a clinical diagnosis of Marfan syndrome. Among the 56 mutations found in this study, 40 (71%) have not been registered in the Human Gene Mutation Database (HGMD) or in the Universal Mutation Database (UMD). This is the first study of the mutation spectrum of MFS in a cohort of patients in Taiwan. The database is expected to considerably improve genetic counseling for and medical care of MFS families.

The Safety and Immunogenicity of Trivalent Inactivated Influenza Vaccination: A Study of Maternal-Cord Blood Pairs in Taiwan

Background There are little data about adverse effects and immunogenicity of flu vaccine in Asian pregnant women. Methods This prospective trial (NCT01514708) enrolled 46 pregnant women who received a single intramuscular dose of trivalent flu vaccine (AdimFlu-S®) containing 15 mcg of hemagglutinin for each strain/0.5 mL from influenza A (H1N1), influenza A (H3N2), and influenza B after the first trimester. Blood samples were collected at day 0 and 28 after vaccination, and at delivery. Cord blood was also collected. Hemagglutination inhibition (HAI) assays were performed to determine seroprotection and seroconversion rates and fold increase in the HAI geometric mean titer (GMT). Results Twenty-eight days after vaccination the seroprotection rate against H1N1, H3N2, and influenza B was 91.3%, 84.8% and 56.5%, respectively. The GMT fold increase was 12.8, 8.4, and 4.6 for H1N1, H3N2, and influenza B, respectively. At delivery, both the seroprotection rate (86.4%, 68.2%, and 47.7%) and GMT fold increase (9.4, 5.7 and 3.8) were slightly lower than day 28. The seroprotection rate and GMT fold increase in maternal and cord blood samples were comparable. No significant adverse effects were detected. Conclusions Trivalent flu vaccine induces a strong immune response in pregnant women and their infants without adverse effects. Trial Registration Clinical Trials. gov NCT01514708