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IntroductionNeonatal haemochromatosis, considered to be a gestational alloimmune liver disease (NH-GALD), is a rare but serious disease that results in fulminant hepatic failure. The recurrence rate of NH-GALD in a subsequent infant of a mother with an affected infant is 70%–90%. Recently, antenatal maternal high-dose intravenous immunoglobulin (IVIG) therapy has been reported as being effective for preventing recurrence of NH-GALD in a subsequent infant. However, no clinical trial has been conducted to date.Methods and analysisThis is a multicentre open-label, single-arm study of antenatal maternal high-dose IVIG therapy in pregnant women with a history of documented NH in a previous offspring. The objective of this study is to evaluate the efficacy and safety of antenatal maternal high-dose IVIG therapy in preventing or reducing the severity of alloimmune injury to the fetal liver.Ethics and disseminationThe clinical trial is being performed in accordance with the Declaration of Helsinki. The trial protocol was approved by the Clinical Research Review Board at four hospitals. Before enrolment, written informed consent would be obtained from eligible pregnant women. The results are expected to be published in a scientific journal.Protocol version28 October 2024, V.8.0.Trial registration numberjRCT1091220353.

In-person models of genetic counseling (GC) have been the common method in Japan for pregnant women to receive GC. However, recent increases in the number of pregnant women considering undergoing prenatal testing have made it challenging to retain individualized in-person care. To explore pregnant women’s opinions toward pretest GC models and the ideal time duration, a self-administered questionnaire survey was conducted for women at their first prenatal visit. A total of 114 valid respondents (93.4%) were included in the analyses. Of these, 80.7% of women preferred in-person GC, followed by classroom (9.6%), group (3.5%), and telegenetic-based GC (2.6%). Women with experience in undergoing prenatal testing significantly did not prefer in-person GC ( p  = 0.05). Sixty-two women (54.4%) preferred a duration of 15–29 min for pretest GC sessions, followed by 30–59 min (28.9%) and <15 min (14.9%). Women’s preference of ≥30 min in length was significantly associated with anhedonia, singleton pregnancies, acquaintance with people with trisomy 21, and awareness of prenatal testing. Women who were unaware of the need for agreement with the partner for prenatal testing and who did not know the average life expectancy of a trisomy 21 patient significantly preferred <15 min in length over other durations. While the majority of women preferred in-person GC for <30 min, their preferences varied by their background characteristics, experiences, attitudes, and knowledge. These findings will help establish a prenatal GC system offering a choice of GC models in Japan; however, further large-scale studies are needed to confirm these findings.

To avoid hemolytic disease of the fetus and newborn resulting from maternal alloantibodies against fetal Rh antigens, anti-D immunoglobulin is routinely administered to RhD-negative pregnant women in Japan. Fetal genotyping using cell-free DNA may prevent unnecessary antibody administration; however, current PCR-based methods, which detect deletion, do not address the higher rates of -positive D antigen-negative alleles in nonwhite populations without additional inspections. We developed an amplicon-sequencing method that could estimate the type of paternally inherited fetal allele from 4 major alleles in the Japanese population: the D antigen-positive allele ( * , 92.9%) and 3 D antigen-negative alleles ( * , 6.6%; * , 0.3%; * , 0.1%) using cell-free DNA obtained from the blood plasma of pregnant women. The method correctly determined the fetal RhD type even when RhD-negative pregnant women possessed an -positive D antigen-negative allele: * or * . This method is a reliable noninvasive fetal genotyping method for Japanese and other East Asian populations. The genotyping principle of amplifying 2 different regions using the same primer pair and distinguishing them by their sequence difference during the subsequent mapping procedure is also theoretically applicable to -positive D antigen-negative alleles prevalent in Africans. Therefore, this method offers an opportunity to consider targeted administration of anti-D immunoglobulin to RhD-negative pregnant women in East Asian and African countries and to increase the specificity of the fetal genotyping implemented nationwide in several European countries.

The management of secondary findings (SFs), which are beyond the intended purpose of the analysis, from clinical comprehensive genomic analysis using next generation sequencing (NGS) presents challenges. Policy statements regarding their clinical management have been announced in Japan and other countries. In Japan, however, the current status of and attitudes of clinical genetics professionals toward reporting them are unclear. We conducted a questionnaire survey of clinical genetics professionals at two time points (2013 and 2019) to determine the enforcement of the SF management policy in cases of comprehensive genetic analysis of intractable diseases and clinical cancer genome profiling testing. According to the survey findings, 40% and 70% of the respondents stated in the 2013 and 2019 surveys, respectively, that they had an SF policy in the field of intractable diseases, indicating that SF policy awareness in Japan has changed significantly in recent years. Furthermore, a total of 80% of respondents stated that their facility had established a policy for clinical cancer genome profiling testing in the 2019 survey. In both surveys, the policies included the selection criteria for genes to be disclosed and the procedure to return SFs, followed by recommendations and proposals regarding SFs in Japan and other countries. To create a better list of the genes to be disclosed, further examination is needed considering the characteristics of each analysis.

Here we report a patient with holoprosencephaly (HPE) associated with 45, XY,der(18)t(18;21)(p11.2;q21.3),-21 derived from a paternal balanced reciprocal translocation. Array comparative genomic hybridization analysis revealed 18p11.32-p11.21 and 21q11.2-q21.3 deletions. So far, nine cases of monosomy 18p with an unbalanced translocation (18;21) have been reported, four of which presented with HPE. Our case provides a detailed long-term clinical course and helps us to better understand these rare genetic events.

Objective We aimed to simplify our fetal RHD genotyping protocol by changing the method to attach Illumina’s sequencing adaptors to PCR products from the ligation-based method to a PCR-based method, and to improve its reliability and robustness by introducing unique molecular indexes, which allow us to count the numbers of DNA fragments used as PCR templates and to minimize the effects of PCR and sequencing errors. Results Both of the newly established protocols reduced time and cost compared with our conventional protocol. Removal of PCR duplicates using UMIs reduced the frequencies of erroneously mapped sequences reads likely generated by PCR and sequencing errors. The modified protocols will help us facilitate implementing fetal RHD genotyping for East Asian populations into clinical practice.

Knowledge of the basic reproductive physiology of snow leopards is required urgently in order to develop a suitable management conditions under captivity. In this study, the long-term monitoring of concentrations of three steroid hormones in fecal matter of three female snow leopards was performed using enzyme immunoassays: (1) estradiol-17β, (2) progesterone and (3) cortisol metabolite. Two of the female animals were housed with a male during the winter breeding season, and copulated around the day the estradiol-17β metabolite peaked subsequently becoming pregnant. The other female was treated in two different ways: (1) first housed with a male in all year round and then (2) in the winter season only. She did not mate with him on the first occasion, but did so latter around when estradiol-17β metabolite peaked, and became pseudopregnant. During pregnancy, progesterone metabolite concentrations increased for 92 or 94 days, with this period being approximately twice as long as in the pseudopregnant case (31, 42, 49 and 53 days). The levels of cortisol metabolite in the pseudopregnant female (1.35 µg/g) were significantly higher than in the pregnant females (0.33 and 0.24 µg/g) (P<0.05). Similarly, during the breeding season, the levels of estradiol-17β metabolite in the pseudopregnant female (2.18 µg/g) were significantly higher than those in the pregnant females (0.81 and 0.85 µg/g) (P<0.05). Unlike cortisol the average levels of estradiol-17β during the breeding season were independent of reproductive success.The hormone levels may also be related to housing conditions and the resulting reproductive success in female leopards. The female housed with a male during the non-breeding season had high levels of cortisol metabolites and low levels of estradiol-17β in the breeding season, and failed to become pregnant. This indicates that housing conditions in snow leopards may be an important factor for normal endocrine secretion and resulting breeding success.

Background Monozygotic twins with 45,X/46,XY mosaicism, discordant for phenotypic sex, are extremely rare. Methods This report describes the clinical findings of a rare case of 45,X/46,XY mosaicism in monozygotic twins with different external genitalia. Single nucleotide polymorphism (SNP) array analysis, performed by collecting DNA from each umbilical cord, showed identical SNPs in the autosomal chromosomes of both fetuses. Results Chorionic villus sampling of a 37‐year‐old primigravida carrying monozygotic twins revealed a 45,X/46,XY karyotype. Autopsy of the aborted fetuses revealed a penis and testes on one fetus and a vagina, uterus, and ovaries in the other fetus––which also had severe cystic hygroma. Cell counting using fluorescence in situ hybridization with XY probes (XY‐FISH) showed 20% and 80% abundance of 45,X cells in the internal genitalia, liver, heart, lung, adrenal gland, bone marrow, and spine of the male and female fetuses, respectively. Conclusion These results indicated that the fetuses were genetically monozygotic twins and their different degrees of mosaicism may have resulted in different genital phenotypes. This report was case of 45,X/46,XY mosaicism in monozygotic twins with different external genitalia. Cell counting using fluorescence in situ hybridization with XY probes (XY‐FISH) showed 20% and 80% abundance of 45,X cells in the internal genitalia, liver, heart, lung, adrenal gland, bone marrow, and spine of the male and female fetuses, respectively.

PurposeTo clarify the associations of the maternal age, history of miscarriage, and embryonic/fetal size at miscarriage with the frequencies and profiles of cytogenetic abnormalities detected in spontaneous early miscarriages.MethodsMiscarriages before 12 weeks of gestation, whose karyotypes were evaluated by G-banding between May 1, 2005, and May 31, 2017, were included in this study. The relationships between their karyotypes and clinical findings were assessed using trend or chi-square/Fisher’s exact tests and multivariate logistic analyses.ResultsThree hundred of 364 miscarriage specimens (82.4%) had abnormal karyotypes. An older maternal age was significantly associated with the frequency of abnormal karyotype (ptrend < 0.001), particularly autosomal non-viable and viable trisomies (ptrend 0.001 and 0.025, respectively). Women with ≥ 2 previous miscarriages had a significantly lower possibility of miscarriages with abnormal karyotype than women with < 2 previous miscarriages (adjusted odds ratio [aOR], 0.48; 95% confidence interval [95% CI], 0.27–0.85). Although viable trisomy was observed more frequently in proportion to the increase in embryonic/fetal size at miscarriage (ptrend < 0.001), non-viable trisomy was observed more frequently in miscarriages with an embryonic/fetal size < 10 mm (aOR, 2.41; 95% CI, 1.27–4.58), but less frequently in miscarriages with an embryonic/fetal size ≥ 20 mm (aOR, 0.01; 95% CI, 0.00–0.07) than in anembryonic miscarriages.ConclusionsThe maternal age, history of miscarriage, and embryonic/fetal size at miscarriage may be independently associated with the frequencies or profiles of cytogenetic abnormalities in early miscarriages.

PurposeTo investigate perinatal outcomes in late primiparous women aged 35–39 and ≥40 years. Our main research question: “Was the rate of cesarean section similar between these 2 groups of advanced maternal age?”MethodsPrimiparous women aged ≥35 years, who delivered in our center between April 2004 and March 2007, were enrolled in this study. They were divided into two groups: women aged 35–39 years and those aged ≥40 years. Antenatal complications, deliveries, and neonatal outcomes were analyzed. Fetal abnormalities, abortions, and multiple gestations were excluded.ResultsWe assessed 752 cases (35–39 years, 610 cases; ≥40 years, 142 cases). Incidence of cesarean section (CS) was significantly higher in pregnant women aged ≥40 years (P < 0.01). The CS rate amounted to 50.0% of all deliveries in this age group. Among patients with labor deliveries, the CS rate was also significantly higher in the older age group (P < 0.05). With regard to indication for CS with labor deliveries, the rate of non-progressive labor/dystocia was 19.4% in primiparous women aged ≥40 years and 11.0% in those aged 35–39 years, respectively (P < 0.05). In contrast, the rates of antenatal complications were not different between the two groups, except for gestational diabetes or leiomyoma. No significant differences between the two groups could be found for neonatal outcomes such as birth weight, Apgar score, and admission to neonatal intensive care unit.ConclusionsCS rate was 50.0% in primiparous women aged ≥40 years. In addition, CS caused by dystocia was almost twice as frequent in primiparous women aged ≥40 years as in women aged 35–39 years. Among late pregnancies, primiparous women aged 40 years and older had higher risk of CS.