RESUMEN
Dyssegmental dysplasia (DD) is a severe skeletal dysplasia comprised of two subtypes: lethal Silverman-Handmaker type (DDSH) and nonlethal Rolland-Desbuquois type (DDRD). DDSH is caused by biallelic pathogenic variants in HSPG2 encoding perlecan, whereas the genetic cause of DDRD remains undetermined. Schwartz-Jampel syndrome (SJS) is also caused by biallelic pathogenic variants in HSPG2 and is an allelic disorder of DDSH. In SJS and DDSH, 44 and 8 pathogenic variants have been reported in HSPG2, respectively. Here, we report that five patients with DDRD carried four pathogenic variants in HSPG2: c.9970 G > A (p.G3324R), c.559 C > T (p.R187X), c7006 + 1 G > A, and c.11562 + 2 T > G. Two patients were homozygous for p.G3324R, and three patients were heterozygous for p.G3324R. Haplotype analysis revealed a founder haplotype spanning 85,973 bp shared in the five patients. SJS, DDRD, and DDSH are allelic disorders with pathogenic variants in HSPG2.
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Haplotipos , Proteoglicanos de Heparán Sulfato , Osteocondrodisplasias , Femenino , Humanos , Masculino , Alelos , Enfermedades del Desarrollo Óseo/genética , Enfermedades del Desarrollo Óseo/patología , Efecto Fundador , Proteoglicanos de Heparán Sulfato/genética , Mutación , Osteocondrodisplasias/genética , Osteocondrodisplasias/patología , Enfermedades FetalesRESUMEN
Constitutional complex chromosomal rearrangements (CCRs) are rare cytogenetic aberrations arising in the germline via an unknown mechanism. Here we analyzed the breakpoint junctions of microscopically three-way or more complex translocations using comprehensive genomic and epigenomic analyses. All of these translocation junctions showed submicroscopic genomic complexity reminiscent of chromothripsis. The breakpoints were clustered within small genomic domains with junctions showing microhomology or microinsertions. Notably, all of the de novo cases were of paternal origin. The breakpoint distributions corresponded specifically to the ATAC-seq (assay for transposase-accessible chromatin with sequencing) read data peak of mature sperm and not to other chromatin markers or tissues. We propose that DNA breaks in CCRs may develop in an accessible region of densely packaged chromatin during post-meiotic spermiogenesis.
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ADN , Semen , Masculino , Humanos , Aberraciones Cromosómicas , Cromatina/genética , Espermatozoides , Translocación GenéticaRESUMEN
OBJECTIVES: To evaluate neonatal outcomes after the use of a cervical pessary in Japanese women with short cervical length (CL) less than 25 mm. METHODS: This multicenter study involved women with singleton pregnancies between 20 and 29+6 gestational weeks and a CL of less than 25 mm. The primary outcome was preterm birth (PTB) before 34 weeks of gestation. This study was registered in the Japan Registry of Clinical Trials (JRCT: jRCTs042180102). RESULTS: Two hundred pregnant women were enrolled; 114 in the pessary group and 86 in the expectant management group as controls. In the pessary group, all 114 neonates were investigated for perinatal outcomes, and 112 pregnant women were investigated for primary, and secondary outcomes. In the control group, 86 pregnant women were investigated for primary and secondary outcomes and 86 neonates were investigated for neonatal outcomes. There were no significant differences in PTB in ≤34, ≤37, and ≤28 weeks of gestation or in preterm rupture of membranes (PROM) ≤34 weeks between the groups. The gestational weeks at birth and birth weight were significantly higher in the pessary group. Regression analysis demonstrated that the CL decreased without a pessary, whereas the shortening rate was suppressed during the intervention. No significant differences were observed in adverse neonatal outcomes, chorioamnionitis, or preterm PROM. CONCLUSIONS: The cervical pessary effectively reduced CL shortening during pregnancy resulting in an average increased gestational age, however, did not reduced the rates of preterm birth.
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Rotura Prematura de Membranas Fetales , Nacimiento Prematuro , Medición de Longitud Cervical , Cuello del Útero/diagnóstico por imagen , Femenino , Edad Gestacional , Humanos , Recién Nacido , Pesarios , Embarazo , Nacimiento Prematuro/prevención & controlRESUMEN
AIM: The present study investigated the current situation regarding intrauterine blood transfusion (IUT) for fetal anemia in Japan. METHODS: We conducted a nationwide, multicenter, retrospective cohort questionnaire survey for cases that underwent IUT from 2011 to 2015. The questionnaire required perioperative information, indications, details of the procedure, procedure-related complications, and neonatal morbidity. RESULTS: A total of 100 IUT procedures were performed in 66 cases at 19 institutions during the study period. The most frequent indication of IUT was complicated monochorionic diamniotic (MCDA) twins in 28 (42.4%) cases, followed by 16 (24.2%) cases of red-cell alloimmunization, and 10 (15.2%) cases of parvovirus B19 infection. IUT was performed through the umbilical cord in the vast of majority cases (92%). Bleeding from the IUT site was the most common adverse event (40%). Two cases (2%) underwent emergency cesarean section after the procedure. There were no cases of rupture of membrane or intrauterine infection after IUT. The neonatal survival rate was 77.3% in the 66 total cases and 64% in the hydrops cases. The neonatal survival rates in MCDA twins, red-cell alloimmunization, and parvovirus B19 infection were 75%, 93.8%, and 70%, respectively. CONCLUSIONS: IUT was performed for mainly three indications in Japan: MCDA twins, red-cell alloimmunization, and parvovirus B19 infection. The incidences of severe adverse events seemed very low. The outcomes after IUT were favorable with variations in survival rates according to indications. However, further studies with long-term follow-up will be required to assess the effectiveness of IUT, especially for complicated MCDA twins.
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Anemia , Parvovirus B19 Humano , Anemia/epidemiología , Anemia/terapia , Transfusión de Sangre Intrauterina , Cesárea , Femenino , Humanos , Recién Nacido , Japón/epidemiología , Embarazo , Estudios Retrospectivos , Encuestas y CuestionariosRESUMEN
AIM: We aimed to evaluate the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of noninvasive prenatal testing (NIPT) in high-risk pregnant women. METHODS: Pregnant women who underwent GeneTech NIPT, the most commonly used NIPT in Japan, between January 2015 and March 2019, at Japan NIPT Consortium medical sites were recruited for this study. The exclusion criteria were as follows: pregnant women with missing survey items, multiple pregnancy/vanishing twins, chromosomal abnormalities in the fetus other than the NIPT target disease, and nonreportable NIPT results. Sensitivity and specificity were calculated from the obtained data, and maternal age-specific PPV and NPV were estimated. RESULTS: Of the 45 504 cases, 44 263 cases fulfilling the study criteria were included. The mean maternal age and gestational weeks at the time of procedure were 38.5 years and 13.1 weeks, respectively. Sensitivities were 99.78% (95% confidence interval [95% CI]: 98.78-99.96), 99.12% (95% CI: 96.83-99.76), and 100% (95% CI: 88.30-100) for trisomies 21, 18, and 13, respectively. Specificities were more than 99.9% for trisomies 21, 18, and 13, respectively. Maternal age-specific PPVs were more than 93%, 77%, and 43% at the age of 35 years for trisomies 21, 18, and 13, respectively. CONCLUSION: The GeneTech NIPT data showed high sensitivity and specificity in the detection of fetal trisomies 21, 18, and 13 in high-risk pregnant women, and maternal age-specific PPVs were obtained. These results could provide more accurate and improved information regarding NIPT for genetic counseling in Japan.
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Síndrome de Down , Pruebas Prenatales no Invasivas , Adulto , Femenino , Humanos , Japón , Laboratorios , Embarazo , Diagnóstico Prenatal , TrisomíaRESUMEN
BACKGROUND: Women who receive negative results from non-invasive prenatal genetic testing (NIPT) may find that they later have mixed or ambivalent feelings, for example, feelings of accepting NIPT and regretting undergoing the test. This study aimed to investigate the factors generating ambivalent feelings among women who gave birth after having received negative results from NIPT. METHODS: A questionnaire was sent to women who received a negative NIPT result, and a contents analysis was conducted focusing on ambivalent expressions for those 1562 women who responded the questionnaire. The qualitative data gathered from the questionnaire were analyzed using the N-Vivo software package. RESULTS: Environmental factors, genetic counseling-related factors, and increased anticipatory anxiety, affected the feeling of ambivalence among pregnant women. Furthermore, pregnant women desired more information regarding the detailed prognosis for individuals with Down syndrome and living with them and/or termination, assuming the possibility that they were positive. CONCLUSIONS: Three major interrelated factors affected the feeling of ambivalence in women. Highlighting and discussing such factors during genetic counseling may resolve some of these ambivalences, thereby enhancing the quality of decisions made by pregnant women.
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Emociones , Resultados Negativos , Pruebas Prenatales no Invasivas , Parto/psicología , Mujeres Embarazadas/psicología , Toma de Decisiones , Femenino , Asesoramiento Genético/psicología , Humanos , Japón/epidemiología , Embarazo , Investigación Cualitativa , Medio Social , Encuestas y CuestionariosRESUMEN
AIM: This study aimed to compare the accuracy of fetal pulse pressure estimated with a vascular simulator with that obtained by a manometer (reference) and evaluate the pulse pressure in normal human fetuses and fetuses whose mothers received corticosteroids. METHODS: Fetal pulse pressure was estimated as the product of blood flow velocity and pulse wave velocity, based on the water hammer equation. Ultrasonic raw radiofrequency signals for blood flow velocity were captured from the fetal descending aortas at the diaphragm level, and pulse wave velocity was simultaneously measured from different directions using the phased-tracking method. First, the precision and accuracy of pulse pressure in the estimated method were verified by a circulatory phantom simulator, which reproduced fetal blood flow using a pulsating pump. Then, the pulse pressure of 98 normal human fetuses after 17 weeks of gestation and the fetal pulse pressure in 21 mothers who received antenatal corticosteroids for fetal maturation were measured. RESULTS: A significant correlation between the estimated pulse pressure values and the actual values was found in the phantom simulation (r = 0.99, P < 0.01). The estimated pulse pressure was significantly correlated with gestational age in normal fetuses (r = 0.74, P < 0.01). In steroid-treated pregnant women, fetal pulse pressure was observed to increase significantly on the second day of administration (P < 0.01). CONCLUSION: A noninvasive and accurate estimation model of fetal pulse pressure could be established using phased-tracking method, and this method has the potential to improve the assessment of human fetal hemodynamics.
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Análisis de la Onda del Pulso , Ultrasonografía Prenatal , Corticoesteroides , Velocidad del Flujo Sanguíneo , Presión Sanguínea , Femenino , Feto , Humanos , EmbarazoRESUMEN
OBJECTIVE: To evaluate the reasons for nonreportable cell-free DNA (cfDNA) results in noninvasive prenatal testing (NIPT), we retrospectively studied maternal characteristics and other details associated with the results. METHODS: A multicenter retrospective cohort study in pregnant women undergoing NIPT by massively parallel sequencing (MPS) with failed cfDNA tests was performed between April 2013 and March 2017. The women's data and MPS results were analyzed in terms of maternal characteristics, test performance, fetal fraction (FF), z scores, anticoagulation therapy, and other details of the nonreportable cases. RESULTS: Overall, 110 (0.32%) of 34 626 pregnant women had nonreportable cfDNA test results after an initial blood sampling; 22 (20.0%) cases had a low FF (<4%), and 18 (16.4%) cases including those with a maternal malignancy, were found to have altered genomic profile. Approximately half of the cases with nonreportable results had borderline z score. Among the women with nonreportable results because of altered genomic profile, the success rate of retesting using a second blood sampling was relatively low (25.0%-33.3%). Thirteen (11.8%) of the women with nonreportable results had required hypodermic heparin injection. CONCLUSIONS: The classification of nonreportable results using cfDNA analysis is important to provide women with precise information and to reduce anxiety during pregnancy.
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Pruebas Genéticas/métodos , Secuenciación de Nucleótidos de Alto Rendimiento , Diagnóstico Prenatal/métodos , Proyectos de Investigación , Trisomía/diagnóstico , Adulto , Reacciones Falso Negativas , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Secuenciación de Nucleótidos de Alto Rendimiento/normas , Secuenciación de Nucleótidos de Alto Rendimiento/estadística & datos numéricos , Humanos , Valor Predictivo de las Pruebas , Embarazo , Primer Trimestre del Embarazo/sangre , Primer Trimestre del Embarazo/genética , Segundo Trimestre del Embarazo/sangre , Segundo Trimestre del Embarazo/genética , Reproducibilidad de los Resultados , Proyectos de Investigación/normas , Proyectos de Investigación/estadística & datos numéricos , Estudios Retrospectivos , Factores de Riesgo , Trisomía/genéticaRESUMEN
Perinatal hypophosphatasia (HPP) is a rare, potentially life-threatening, inherited, systemic metabolic bone disease that can be difficult to recognize in utero and postnatally. Diagnosis is challenging because of the large number of skeletal dysplasias with overlapping clinical features. This review focuses on the role of fetal and neonatal imaging modalities in the differential diagnosis of perinatal HPP from other skeletal dysplasias (e.g., osteogenesis imperfecta, campomelic dysplasia, achondrogenesis subtypes, hypochondrogenesis, cleidocranial dysplasia). Perinatal HPP is associated with a broad spectrum of imaging findings that are characteristic of but do not occur in all cases of HPP and are not unique to HPP, such as shortening, bowing and angulation of the long bones, and slender, poorly ossified ribs and metaphyseal lucencies. Conversely, absent ossification of whole bones is characteristic of severe lethal HPP and is associated with very few other conditions. Certain features may help distinguish HPP from other skeletal dysplasias, such as sites of angulation of long bones, patterns of hypomineralization, and metaphyseal characteristics. In utero recognition of HPP allows for the assembly and preparation of a multidisciplinary care team before delivery and provides additional time to devise treatment strategies.
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Hipofosfatasia/diagnóstico por imagen , Diagnóstico Prenatal/métodos , Diagnóstico Diferencial , Femenino , Humanos , Recién Nacido , EmbarazoRESUMEN
AIM: Perimortem cesarean section (PCS) is a procedure performed as part of cardiopulmonary resuscitation (CPR). This study aims to clarify maternal and neonatal prognosis and establish PCS's utility and limitations. METHODS: We sent structured questionnaires to obstetrics facilities regarding the cases of PCS performed in Japan between April 2010 and April 2015. Receiver operating characteristic (ROC) curve was used to determine the optimal cut-off values of the time from cardiopulmonary arrest (CPA) to return of spontaneous circulation to predict the onset of disseminated intravascular coagulation (DIC). RESULTS: PCS was performed for 18 patients. Out of 18 patients, 12 were resuscitated. The women who were discharged without major sequelae (n = 6) were compared with the non-discharged women who were dead or in persistent vegetative state (n = 12), and median interval time from arrest to PCS was significantly shorter in the former group (P = 0.002). Median interval time from CPA to PCS in the cases in which the neonates survived without major morbidities was significantly shorter than that in the cases of neonatal death and hypoxic encephalopathy (P = 0.01). DIC was observed in 8/9 (89%) patients whose resuscitation took more than 20 min from the diagnosis of CPA. Percutaneous cardiopulmonary support (PCPS) was introduced in 4/9 patients. However, more cases with uncontrolled bleeding, possibly caused by a sudden increase in blood flow and DIC after resuscitation, were observed in the PCPS group compared to the non-PCPS group. CONCLUSION: PCS can be an effective CPR procedure. However, if PCS is not performed within 20 min from CPA, starting PCPS before PCS is an option.
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Reanimación Cardiopulmonar/métodos , Cesárea/métodos , Paro Cardíaco/terapia , Complicaciones Cardiovasculares del Embarazo/terapia , Resultado del Embarazo , Adulto , Reanimación Cardiopulmonar/estadística & datos numéricos , Cesárea/estadística & datos numéricos , Femenino , Paro Cardíaco/epidemiología , Humanos , Japón , Embarazo , Complicaciones Cardiovasculares del Embarazo/epidemiología , Resultado del Embarazo/epidemiología , Estudios RetrospectivosRESUMEN
AIM: Since fetal therapy has been newly developed, objective evaluation of adverse events (AE), all harmful events that are not always related to the procedures, has not yet been adequately reported. We established new terminology and tried to re-evaluate it based on the Japanese prospective thoraco-amniotic shunting (TAS) study. METHODS: From the literature, all complications that occurred with all fetal therapies were identified as a basis for developing the terminology. Grading was set from 0 to 5. Grade 3 was defined as the need for invasive treatment, such as surgery. Grade 4 was defined as life-threatening, and Grade 5 was defined as death of the mother or fetus. Then, one series of TAS that we had already reported was re-evaluated, including 24 cases with 37 procedures and 200 opportunities those could be evaluated AE after procedures. RESULTS: Grade 4 preterm rupture of the membranes was reported in only 1 of 24 cases. Catheter displacement was reported in 7, 2 and 11 cases, of Grades 1, 2 and 3, respectively. It was found that the double-basket catheter had some association with catheter displacement, but it was clear that there were no life-threatening AE. CONCLUSION: Newly developed AE criteria are now available for fetal therapy. They will contribute to the objective evaluation of AE of new fetal therapies in the future.
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Cateterismo/efectos adversos , Drenaje/efectos adversos , Terapias Fetales/efectos adversos , Derrame Pleural/cirugía , Complicaciones Posoperatorias , Complicaciones del Embarazo , Terminología como Asunto , Amnios/cirugía , Femenino , Enfermedades Fetales/cirugía , Humanos , Japón , Complicaciones Posoperatorias/etiología , Embarazo , Complicaciones del Embarazo/etiología , Complicaciones del Embarazo/cirugía , Procedimientos Quirúrgicos Torácicos/efectos adversosRESUMEN
The data collected by nation-wide study of noninvasive prenatal genetic testing (NIPT) for trisomy 21 from 21,610 pregnant women with advanced maternal age in Japan were reported. Among 188 NIPT-positive cases, 180 cases were true positive. The incidence of aneuploidy according to maternal age was estimated using a state-space model. Although, the frequency of trisomy increased exponentially with maternal age as previously reported, the maternal age-specific risk for trisomy 21 that was based on the clinical performance of NIPT was lower than the predicted risk in previous Western cohorts based on the data from invasive prenatal testing (Bayesian two-sided tail-area probability P = 0.0156). The empirical positive predictive value (PPV) of NIPT is likely to turn out higher than that of the theoretical PPV calculated from the sensitivity/specificity of the test and the incidence of trisomy 21 from this study.
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Síndrome de Down/epidemiología , Síndrome de Down/genética , Edad Gestacional , Edad Materna , Adulto , Femenino , Humanos , Incidencia , Japón/epidemiología , Persona de Mediana Edad , Embarazo , Estudios Prospectivos , Factores de RiesgoRESUMEN
Since the advance online publication of this article, the authors of the above paper have noticed errors in the list of authors and affiliations. The article with correct author information now appears in this issue.
RESUMEN
Type II collagen is a major component of cartilage. Heterozygous mutations in the type II collagen gene (COL2A1) result in a group of skeletal dysplasias known as Type II collagenopathy (COL2pathy). The understanding of COL2pathy is limited by difficulties in obtaining live chondrocytes. In the present study, we converted COL2pathy patients' fibroblasts directly into induced chondrogenic (iChon) cells. The COL2pathy-iChon cells showed suppressed expression of COL2A1 and significant apoptosis. A distended endoplasmic reticulum (ER) was detected, thus suggesting the adaptation of gene expression and cell death caused by excess ER stress. Chondrogenic supplementation adversely affected the chondrogenesis due to forced elevation of COL2A1 expression, suggesting that the application of chondrogenic drugs would worsen the disease condition. The application of a chemical chaperone increased the secretion of type II collagen, and partially rescued COL2pathy-iChon cells from apoptosis, suggesting that molecular chaperons serve as therapeutic drug candidates. We next generated induced pluripotent stem cells from COL2pathy fibroblasts. Chondrogenically differentiated COL2pathy-iPS cells showed apoptosis and increased expression of ER stress-markers. Finally, we generated teratomas by transplanting COL2pathy iPS cells into immunodeficient mice. The cartilage in the teratomas showed accumulation of type II collagen within cells, a distended ER, and sparse matrix, recapitulating the patient's cartilage. These COL2pathy models will be useful for pathophysiological studies and drug screening.
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Diferenciación Celular , Células Madre Pluripotentes Inducidas/citología , Osteocondrodisplasias/fisiopatología , Animales , Apoptosis , Células Cultivadas , Condrocitos/citología , Condrocitos/metabolismo , Colágeno Tipo II/genética , Colágeno Tipo II/metabolismo , Fibroblastos/citología , Fibroblastos/metabolismo , Humanos , Células Madre Pluripotentes Inducidas/metabolismo , Ratones , Osteocondrodisplasias/genética , Osteocondrodisplasias/metabolismoRESUMEN
OBJECTIVE: In 2011, we collected data on fetal CT radiation dose to determine the diagnostic reference level (DRL); however, continuous evaluation of the DRL is necessary. The hypothesis of this study is that the fetal CT radiation dose has decreased, and we predict a widespread use of iterative reconstruction (IR). We also predict that the national decrease in exposure is because of the DRL reported as a result of the previous national study. MATERIALS AND METHODS: Various testing protocols from each site were summarized as part of the study results. The minimum, one-fourth (25th percentile), median, three-fourths (75th percentile), and maximum values were obtained for volume CT dose index (CTDIvol), dose-length product (DLP), and scan length of 120 fetal CT examinations. The trends for IR usage and tube voltage were also investigated. RESULTS: Compared to the results of the 2011 study (n = 119), the minimum, 25th percentile, median, and 75th percentile values for CTDIvol and DLP have decreased for the tabulated results in 2015 (n = 120). The 75th percentile value for CTDIvol was 4.9 mGy, which is 43% of the previous value. IR was used in 70% of the sites. The radiation dose was significantly lower among groups that used IR. CONCLUSION: Four years passed between our initial survey on DRL and the present follow-up survey, and it appears that the previous report sufficiently fulfilled its objective and role in contributing to the decrease in DRL observed in this follow-up study.
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Diagnóstico Prenatal/estadística & datos numéricos , Dosis de Radiación , Exposición a la Radiación/prevención & control , Exposición a la Radiación/estadística & datos numéricos , Protección Radiológica/estadística & datos numéricos , Tomografía Computarizada por Rayos X/estadística & datos numéricos , Femenino , Estudios de Seguimiento , Humanos , Japón/epidemiología , Estudios Longitudinales , Masculino , Diagnóstico Prenatal/tendencias , Tomografía Computarizada por Rayos X/tendenciasRESUMEN
OBJECTIVE: The objective of this study is to clarify the usefulness of parental alkaline phosphatase (ALP) for prenatal diagnosis of hypophosphatasia (HPP). METHODS: Maternal (m) and paternal (p) ALP values were measured in 77 cases from a multicenter cohort (fetal skeletal dysplasia forum in Japan) of cases with short limbs on ultrasonography during pregnancy. After birth, X-rays, cord blood ALP, and gene analysis were evaluated to achieve an exact diagnosis. The screening usefulness of ALP was examined retrospectively. RESULTS: Seventeen cases were eventually diagnosed as HPP and 60 as not HPP; the overall mean m-ALP and p-ALP (standard deviation) values were 133.4 (53) versus 197 (69) IU/L and 149.6 (71.8) versus 231 (61.4) IU/L (p < 0.001). Receiver operating characteristic curve analysis showed that the optimal m-ALP and p-ALP cutoff values were 123 and 165 IU/L, respectively. Presence of at least one of the m-ALP or p-ALP values abnormally low had a sensitivity, specificity, and positive predictive values of 82% (14/17), 93%, and 78%, respectively, for the diagnosis of HPP. CONCLUSION: Parental ALP measurement might be an auxiliary tool to hone in the prenatal diagnosis of fetal HPP. © 2017 John Wiley & Sons, Ltd.
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Fosfatasa Alcalina/sangre , Hipofosfatasia/diagnóstico , Padres , Diagnóstico Prenatal/métodos , Estudios de Cohortes , Análisis Mutacional de ADN/métodos , Femenino , Sangre Fetal/química , Pruebas Genéticas , Edad Gestacional , Humanos , Hipofosfatasia/sangre , Hipofosfatasia/genética , Masculino , Embarazo , Estudios RetrospectivosRESUMEN
AIM: The purpose of this study was to report the 3-year experience of a nationwide demonstration project to introduce non-invasive prenatal testing (NIPT) of maternal plasma for aneuploidy, and review the current status of NIPT in Japan. METHODS: Tests were conducted to detect aneuploidy in high-risk pregnant women, and adequate genetic counseling was provided. The clinical data, test results, and pregnancy outcomes were recorded. We discuss the problems of NIPT on the basis of published reports and meta-analyses. RESULTS: From April 2013 to March 2016, 30 613 tests were conducted at 55 medical sites participating in a multicenter clinical study. Among the 30 613 women tested, 554 were positive (1.81%) and 30 021 were negative (98.1%) for aneuploidy. Of the 289, 128, and 44 women who tested positive for trisomies 21, 18, and 13, respectively, and underwent definitive testing, 279 (96.5%), 106 (82.8%), and 28 (63.6%) were determined to have a true-positive result. For the 13 481 women with negative result and whose progress could be traced, two had a false-negative result (0.02%). The tests were performed on the condition that a standard level of genetic counseling be provided at hospitals. CONCLUSION: Here, we report on the 3-year nationwide experience with NIPT in Japan. It is important to establish a genetic counseling system to enable women to make informed decisions regarding prenatal testing. Moreover, a welfare system is warranted to support women who decide to give birth to and raise children with chromosomal diseases.
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Aneuploidia , Pruebas de Detección del Suero Materno/tendencias , Femenino , Asesoramiento Genético , Humanos , Japón , Pruebas de Detección del Suero Materno/ética , Pruebas de Detección del Suero Materno/métodos , EmbarazoRESUMEN
The purpose of this noninvasive prenatal testing (NIPT) study was to compare the fetal fraction of singleton gestations by gestational age, maternal characteristics and chromosome-specific aneuploidies as indicated by z-scores. This study was a multicenter prospective cohort study. Test data were collected from women who underwent NIPT by the massively parallel sequencing method. We used sequencing-based fetal fraction calculations in which we estimated fetal DNA fraction by simply counting the number of reads aligned within specific autosomal regions and applying a weighting scheme derived from a multivariate model. Relationships between fetal fractions and gestational age, maternal weight and height, and z-scores for chromosomes 21, 18 and 13 were assessed. A total of 7740 pregnant women enrolled in the study, of which 6993 met the study criteria. As expected, fetal fraction was inversely correlated with maternal weight (P<0.001). The median fetal fraction of samples with euploid result (n=6850) and trisomy 21 (n=70) were 13.7% and 13.6%, respectively. In contrast, the median fetal fraction values for samples with trisomies 18 (n=35) and 13 (n=9) were 11.0% and 8.0%, respectively. The fetal fraction of samples with trisomy 21 NIPT result is comparable to that of samples with euploid result. However, the fetal fractions of samples with trisomies 13 and 18 are significantly lower compared with that of euploid result. We conclude that it may make detecting these two trisomies more challenging.
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ADN/genética , Marcadores Genéticos , Diagnóstico Prenatal , Trisomía/genética , Adulto , Peso Corporal , ADN/sangre , Femenino , Pruebas Genéticas/métodos , Edad Gestacional , Humanos , Embarazo , Diagnóstico Prenatal/métodos , Reproducibilidad de los ResultadosRESUMEN
The purpose of this study is to summarize the results from a survey on awareness of genetic counseling for pregnant women who wish to receive non-invasive prenatal testing (NIPT) in Japan. As a component of a clinical study by the Japan NIPT Consortium, genetic counseling was conducted for women who wished to receive NIPT, and a questionnaire concerning both NIPT and genetic counseling was given twice: once after pre-test counseling and again when test results were reported. The responses of 7292 women were analyzed. They expressed high satisfaction with the genetic counseling system of the NIPT Consortium (94%). The number of respondents who indicated that genetic counseling is necessary for NIPT increased over time. Furthermore, they highly valued genetic counseling provided by skilled clinicians, such as clinical geneticists or genetic counselors. The vast majority (90%) responded that there was sufficient opportunity to consider the test ahead of time. Meanwhile, women who received positive test results had a poor opinion and expressed a low-degree satisfaction. We confirmed that the pre-test genetic counseling that we conducted creates an opportunity for pregnant women to sufficiently consider prenatal testing, promotes its understanding and has possibilities to effectively facilitate informed decision making after adequate consideration. A more careful and thorough approach is considered to be necessary for women who received positive test results.
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Asesoramiento Genético , Conocimientos, Actitudes y Práctica en Salud , Diagnóstico Prenatal , Encuestas y Cuestionarios , Adulto , Concienciación , Comprensión , Femenino , Humanos , Japón , Persona de Mediana Edad , Satisfacción del Paciente , Embarazo , Diagnóstico Prenatal/métodos , Adulto JovenRESUMEN
OBJECTIVES: This study aimed to assess the perinatal outcome in monochorionic diamniotic (MD) twin pregnancies complicated by amniotic fluid discordance (AFD) adjoining twin-twin transfusion syndrome (TTTS). METHODS: An observational study of 84 consecutive MD twin pregnancies complicated by AFD that resembled TTTS was conducted. AFD adjoining TTTS was defined by a maximal vertical pocket of amniotic fluid ≤3 cm in one twin and ≥7 cm in the other excluding TTTS. The study population was divided into two groups, group 1 and group 2, according to positive and absent or reversed end-diastolic flow (AREDF) in the umbilical artery, respectively. RESULTS: Fifteen of the 35 (42.9%) group 1 cases and 30 of the 49 (61.2%) group 2 cases progressed to TTTS. The overall survival and intact survival rate in constant AFD that never progressed to TTTS in group 1 was 100% (40/40) and 90% (36/40), respectively. The overall survival and intact survival rate of constant AFD in group 2 with selective intrauterine growth restriction (sIUGR) was 54.2% (13/24) and 41.7% (10/24), respectively, and for those without sIUGR was 64.3% (9/14) and 57.1% (8/14), respectively. CONCLUSIONS: Constant AFD with AREDF in the umbilical artery represents an extremely high risk for adverse outcomes regardless of the presence of sIUGR.