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Abstract Background Syndromic ciliopathies are a group of congenital disorders characterized by broad clinical and genetic overlap, including obesity, visual problems, skeletal anomalies, mental retardation, and renal diseases. The hallmark of the pathophysiology among these disorders is defective ciliary functions or formation. Many different genes have been implicated in the pathogenesis of these diseases, but some patients still remain unclear about their genotypes. Methods The aim of this study was to identify the genetic causes in patients with syndromic ciliopathy. Patients suspected of or meeting clinical diagnostic criteria for any type of syndromic ciliopathy were recruited at a single diagnostic medical center in Southern Taiwan. Whole exome sequencing (WES) was employed to identify their genotypes and elucidate the mutation spectrum in Taiwanese patients with syndromic ciliopathy. Clinical information was collected at the time of patient enrollment. Results A total of 14 cases were molecularly diagnosed with syndromic ciliopathy. Among these cases, 10 had Bardet-Biedl syndrome (BBS), comprising eight BBS2 patients and two BBS7 patients. Additionally, two cases were diagnosed with Alström syndrome, one with Oral-facial-digital syndrome type 14, and another with Joubert syndrome type 10. A total of 4 novel variants were identified. A recurrent splice site mutation, BBS2: c.534 + 1G > T, was present in all eight BBS2 patients, suggesting a founder effect. One BBS2 patient with homozygous c.534 + 1G > T mutations carried a third ciliopathic allele, TTC21B: c.264_267dupTAGA, a nonsense mutation resulting in a premature stop codon and protein truncation. Conclusions Whole exome sequencing (WES) assists in identifying molecular pathogenic variants in ciliopathic patients, as well as the genetic hotspot mutations in specific populations. It should be considered as the first-line genetic testing for heterogeneous disorders characterized by the involvement of multiple genes and diverse clinical manifestations.

Purpose: To evaluate gestational age (GA) and small-for-gestational age (SGA) as continuums and gender on the incidences of autism spectrum disorder (ASD) and co-occurring intellectual disability (ID). Methods: This is a population-based cohort study using the 2004–2008 Taiwan Maternal and Child Health Database. The diagnosis of ASD was determined by International Classification of Diseases, 9th Revision (ICD-9). Generalized estimating equations models were fit to evaluate associations between perinatal variables and ASD. Results: This study included 916,315 individuals. A total of 9474 (1.0%) children were diagnosed with ASD, among whom 1594 (16.8%) had co-occurring ID. Lower GA carried higher odds of ASD with ID (GA < 28 weeks, aOR: 4.26, 95% CI: 2.13, 8.50; GA 28–30 weeks, aOR: 2.80, 95% CI: 1.57, 4.97; GA 31–33 weeks, aOR: 1.63, 95% CI: 1.05, 2.55; GA 34–36 weeks, aOR: 1.39, 95% CI: 1.16, 1.67) and ASD without ID (GA < 28 weeks, aOR:2.05, 95% CI: 1.25, 3.36; GA 28–30 weeks, aOR: 2.02, 95% CI: 1.46, 2.79; GA 31–33 weeks, aOR: 1.42, 95% CI: 1.13, 1.77; GA 34–36 weeks, aOR: 1.18, 95% CI: 1.08, 1.29). Male preterm infants had ASD risks negatively correlated to GA, while ASD risks were significantly increased only among female infants born late preterm. The degree of SGA showed a stepwise increased risk for ASD with and without ID in both male and female infants. Conclusion: Lower GA and the degree of SGA are both associated with ASD susceptibility, either with or without co-occurring ID, and remarkably increased the risk of ID.

Objective: Oxidative stress biomarkers (OSBs) may be strongly associated with disease progression and recurrent pregnancy loss (RPL). However, the research on associations of most OSBs (e.g., 8-nitroguanine [8-NO2Gua] and 4-hydroxy-2-nonenal-mercapturic acid [HNE-MA]) with RPL is limited. Therefore, we aimed to investigate the effect of OSBs exposure on RPL risk by performing a case-control study. Material and methods: We use our established dataset, Taiwan Recurrent Pregnancy Loss and Environmental Study (TREPLES), which included 514 Taiwanese reproductive age women (aged 20–50 years; 397 cases and 117 controls) from National Cheng Kung University Hospital. RPL is clinically defined by a history of two or more consecutive miscarriages, where a miscarriage is defined as the termination of pregnancy before 20 weeks of gestation. The urinary levels of several OSBs (e.g., 8-hydroxy-2′-deoxyguanosine [8-OHdG], 8-NO2Gua, 8-isoprostaglandin F2α [8-isoPGF2α], and HNE-MA) and malondialdehyde (MDA) were measured using isotope dilution liquid chromatography-tandem mass spectrometry and thiobarbituric acid reactive substances, respectively. Results: The median levels of 8-NO2Gua (6.15 vs. 3.76 ng/mL) and HNE-MA (30.12 and 21.54 ng/mL) were significantly higher in the RPL group than in the control group. By categorizing the OSBs data into tertiles, after we adjusted for age and urine creatinine levels discovered that the RPL risk associated with 8-NO2Gua and HNE-MA levels in the third tertile were approximately 2 times higher than those in the first tertile (8-NO2Gua, adjusted OR = 3.27, 95 % CI = 1.66–6.43; HNE-MA, adjusted OR = 1.96, 95 % CI = 1.05–3.64; p

Objective: Swyer syndrome, or 46, XY complete gonadal dysgenesis, is a disorder of human sexual development which present with female external genitalia, lack of female reproductive organs, and a 46, XY karyotype. Many genes that participate in human sexual development have been implicated in the pathogenesis of 46, XY gonadal dysgenesis. Case report: A 18-year-old phenotypically female was presented with primary amenorrhea. Surveillance revealed hypergonadotropic hypogonadism, a normal male 46, XY karyotype and absent of functional gonad, which was confirmed by pathological examination of the streak gonad. Whole exome sequencing showed germline mutations of a novel missense variant, c.570G > C, p.Lys190Asn, in exon 2 of MAP3K1 gene. Conclusion: Given evolutionary conservation of lysine residue at position 190, the amino acid substitution may interfere with interaction between MAP3K1 and RHOA, and contributes to complete gonadal dysgenesis in the context of 46,XY.

Objective: To demonstrate the picture of a woman who had three times of pregnancies but fetuses were complicated with Fraser syndrome, a rare genetic disorder with multiple congenital anomalies. Case report: Here are three complicated pregnancies with predominant features of severe oligohydramnios and other variable intrafamilial presentations. We made a definite diagnosis, Fraser syndrome, with the assistance of whole exome sequencing (WES) via umbilical blood of the second and third fetus. The provision of a preimplantation diagnosis helped contribute a healthy newborn in this family. Conclusion: This paper provides insights into obscure antenatal presentations of Fraser syndrome with intrafamilial variance. Clinical uncertainty at the fetal stage suggests the role of WES to reach a final diagnosis, and a preimplantation diagnosis is applicable to avoid recurrence of genetic disorders in subsequent pregnancies.

Objective: Anophthalmia is an extreme form on the spectrum of anophthalmia-microphthalmia (A/M) syndrome. Most articles define fetal microphthalmia by an ocular diameter (OD) less than fifth percentile. Diagnosis of fetal microphthalmia using only orbital measurements such as interocular distance (IOD), and OD may neglect the presence or morphology of the fetal lens, hence failing to identify abnormalities of the fetal globe. Case report: We hereby present a case of isolated fetal anophthalmia in two consecutive pregnancies from the same mother. Both fetuses presented as full-sized globes with absence or small size of lens under fetal ultrasound examination. Magnetic resonance imaging and pathology of the second fetus further revealed a thorough view of the underdeveloped globes. Whole exon sequencing (WES) analysis for the parents-fetus trio revealed compound heterozygous mutations of the retinoids acid gene 6 (STRA6). Conclusion: Detailed examination for intraocular structures including fetal lens, in addition to orbital measurements by ultrasound is crucial for diagnosis of diseases in the A/M spectrum.

Objective: Cystic hygromas are frequently encountered in fetus with Turner syndrome (TS). Nevertheless, identification of genetic loci responsible for the cystic hygroma has been problematic. Here, we tried to elucidate the candidate gene for cystic hygroma through a rare case of complex Y chromosomal rearrangements involving duplication of partial Yq and monosomy of partial Yp. Case report: A 30-year-old woman, gravida 1 para 0, was diagnosed with fetal cystic hygroma at 12 weeks of gestation. The genetic analysis of the product of conception revealed complex rearrangement of Y chromosome: microdeletion in Yp11.2p11.31 and microduplicatin in Yq11.223q11.23. The deleted region spans about 6.25 Mb and includes 76 genes, including SRY. The duplicated region spans about 4.76 Mb and includes 145 genes. Conclusion: From this rare case with non-mosaic complex Y-chromosome rearrangements, we could narrow down Turner stigmata critical region to Yp11.2～p11.3. We also propose RPS4Y1 as lymphedema candidate gene.

Abstract The pathogenesis of nephrotic syndrome is unclear. We conducted a nationwide population-based cohort study to examine the associations between preterm births and subsequent development of NS. NS was defined as ≥ 3 records with ICD-9-CM codes for NS in hospital admission or outpatient clinic visits. To avoid secondary nephrotic syndrome or nephritis with nephrotic range proteinuria, especially IgA nephropathy, we excluded patients with associated codes. A total of 78,651 preterm infants (gestational age

ObjectiveChildren of women with systemic lupus erythematosus (SLE) are at risk for childhood-onset SLE (cSLE). This study evaluated the incidence of early-onset cSLE and associated risk factors, including concomitant maternal and paternal autoimmune diseases, for these children.MethodsA population-based cohort study was conducted using national databases including the linked information of children and parents. Children of women with SLE and those of women without SLE were identified between 2004 and 2015. The cumulative cSLE incidence was estimated using the Kaplan-Meier method. The marginal Cox model was used to calculate the hazard ratio (HR) for cSLE events.ResultsA total of 4,419 singletons of women with SLE and 1,996,759 singletons of women without SLE were identified. There were 9 (0.20%) and 503 (0.03%) incident cases of early-onset cSLE for offspring of women with and without SLE, respectively (incidence rate ratio, 8.34; 95% confidence interval [CI], 3.79–15.95]. The adjusted HR of incident cSLE in children of women with SLE was 4.65 (95% CI 2.11–10.24). Other risks for cSLE included pregnancy-induced hypertension/preeclampsia/eclampsia, paternal SLE, paternal Sjögren’s syndrome (SS), and maternal SS.ConclusionsThis national child-parent cohort study demonstrated that children of women with SLE are at significantly higher risk for cSLE during early childhood. Moreover, paternal SLE and parental SS increase the risk of cSLE for offspring.

While various septin GTPases have been reported for their physiological functions, their roles in orchestrating complex cognitive/emotional functions in adult mammals remained scarcely explored. A comprehensive behavioral test battery was administered to two sexes of 12-week-old Septin-14 (SEPT14) knockout (KO) and wild-type (WT) mice. The sexually dimorphic effects of brain SEPT14 KO on inhibitory avoidance (IA) and hippocampal mGluR5 expression were noticed with greater IA latency and elevated mGluR5 level exclusively in male KO mice. Moreover, SEPT14 KO appeared to be associated with stress-provoked anxiety increase in a stress-related navigation task regardless of animals’ sexes. While male and female WT mice demonstrated comparable cell proliferation in the dorsal and ventral hippocampal dentate gyrus (DG), both sexes of SEPT14 KO mice had increased cell proliferation in the ventral DG. Finally, male and female SEPT14 KO mice displayed dampened observational fear conditioning magnitude and learning-provoked corticosterone secretion as compared to their same-sex WT mice. These results, taken together, prompt us to conclude that male, but not female, mice lacking the Septin-14 gene may exhibit increased aversive emotion-related learning and dorsal/ventral hippocampal mGluR5 expressions. Moreover, deletion of SEPT14 may be associated with elevated ventral hippocampal DG cell proliferation and stress-provoked anxiety-like behavior, while dampening vicarious fear conditioning magnitudes.

Abstract Background Worldwide several studies have examined the associations of fetal sex, paternal age and maternal age with pregnancy outcomes, with the evidence regarding paternal age being less consistent. Although in Taiwan we keep good records on birth certificates, these issues have been seldom researched. Our objective was to assess the association of fetal sex and parental age with gestational hypertension/preeclampsia, eclampsia and preterm delivery in the Taiwanese population. Methods We conducted a nationwide study and included 1,347,672 live births born between 2004 and 2011 in Taiwan. Gestational hypertension/preeclampsia and eclampsia were ascertained based on the International Classification of Diseases codes; preterm delivery (

Phthalates, which are commonly used in flexible plastics and consumer products, have been reported to be toxic to reproductive and developmental function in mammals. Past studies have focused on the toxic effects on male reproduction, with only a few studies conducted on the risks that cumulative exposure to phthalates have on the female reproductive system. We recruited 260 patients with recurrent pregnancy loss (RPL) of unknown etiology and 203 controls from the clinics of Obstetrics and Gynecology at a medical center in southern Taiwan from 2013 to 2020. The daily intake of phthalates was estimated from urine samples using the back-calculation method, after which the cumulative risk was determined using multiple hazard indices, including a dose-addition model, a receptor effect model, and a hazard index approach. The patients with RPL had a significantly higher cumulative exposure to phthalates (p

Preeclampsia is a severe gestational hypertensive disorder that occurs after 20 weeks’ of gestation. It involves several maternal systems, such as cardiovascular, renal, coagulatory systems, and poses a major threat to the maternal and fetal health. Recent clinical evidence showed that aspirin is an effective preventative treatment for reducing the incidence of premature preeclampsia among high-risk pregnant women, however, the mechanism of drug action is not clear. miR-200 family has been shown to be associated with preeclampsia and upregulated in the plasma and placenta of preeclamptic patients. Here we revealed that miR-200 family inhibited trophoblast invasion and epithelial-mesenchymal transition (EMT) process by stimulating epithelial marker expression (E-cadherin and ZO-1) and repressing mesenchymal marker expression (ZEB1 and TGFβ1). Similarly, EMT markers in the placenta of preeclamptic patients showed higher E-cadherin and lower ZEB1 and TGF-β1 protein expression. Moreover, aspirin was shown to suppress miR-200 family and these miR-200 family-mediated cell functions, including cell invasion and EMT changes, were completely reversed. In conclusion, this study demonstrates the effect of miR-200 family on trophoblast invasion and EMT. For the first time, aspirin was shown to fully reverse miR-200-mediated trophoblast biology and act through the network signaling of TGF-β1/ZEB1/miR-200. These results provide a plausible mechanism explaining aspirin’s effect on preeclampsia prevention and a therapeutic target for disease intervention.

Objective: To examine changes in the number and causes of maternal deaths after the introduction of pregnancy checkbox on the death certificate in January 2014 in Taiwan. Materials and methods: We first used the cause-of-death (COD) mortality data for years 2010 through 2017 to examine the number of deaths by item of pregnancy checkbox. We then compared the distribution of the causes of maternal deaths before and after the introduction of pregnancy checkbox. Results: Between 2014 and 2017, 111 women died, for whom the certifiers indicated the following in the pregnancy checkbox items: 2 (pregnant at the time of death; n = 10), 3 (died within 42 days after the termination of pregnancy; n = 64), and 4 (died between 43 days and 1 year after the termination of pregnancy; n = 37). However, in only 61 of the 111 deaths, the certifiers reported pregnancy or delivery-related diagnosis in the COD section of the death certificate—5 each for items 2 and 4 and 51 for item 3. The number of maternal deaths was 55 in 2010–2013; this number increased to 82 in 2014–2017. A decline in the percentage of maternal deaths from obstetric hemorrhage was noted from 38% (21/55) in 2010–2013 to 21% (17/82) in 2014–2017. Conclusion: The number of maternal deaths increased, and the distribution of causes of maternal deaths changed after the introduction of pregnancy checkbox. Additional studies are required to examine the possible misclassification of pregnancy-associated deaths indicated in the pregnancy checkbox. Keywords: Cause-of-death, Death certificate, Pregnancy checkbox, Pregnancy-associated deaths, Maternal deaths

Oxidative and nitrosative stress have been linked to thyroid function in both animal and human studies. In the present study, the associations between oxidative and nitrosative stress and thyroid hormones were investigated. Measurements were obtained from 97 Taiwanese pregnant women at the first, second, and third trimesters. Levels of five oxidative and nitrosative stress biomarkers (8-hydroxy-2′-deoxyguanosine [8-OHdG], 8-nitroguanine [8-NO2Gua], 4-hydroxy-2-nonenal-mercapturic acid [HNE-MA], 8-isoprostaglandin F2α [8-isoPGF2α], and malondialdehyde [MDA]) were measured using urine samples, and levels of five thyroid hormones (triiodothyronine [T3], thyroxine [T4], free T4, thyroid-stimulating hormone [TSH], and T4-binding globulin [TBG]) were measured in blood samples. Multiple linear regressions and linear mixed-model regressions were conducted to determine the associations between oxidative or nitrosative stress biomarkers and thyroid hormones in pregnant women. We found that TSH was negatively and significantly associated with 8-NO2Gua (−14%, 95% CI [−26.9% to −1.1%]) and HNE-MA (−23%, 95% CI [−35.9% to −10.0%]) levels. However, T4 (3%, 95% CI [0.2%–5.8%]) and free T4 (4.3%, 95% CI [0.8%–7.8%]) levels were positively and significantly associated with 8-NO2Gua. The T4 to TBG and free T4 to TBG ratios were positively and significantly associated with 8-NO2Gua level (T4/TBG: 3.6%, 95% CI [0.5%–6.7%]; free T4/TBG: 5.6%, 95% CI [0.2%–11.1%]). However, the TSH to T4 ratio was negatively and significantly associated with 8-NO2Gua level (−17.3%, 95% CI [−30.4% to −4.3%]). The T3 to TSH ratio was positively and significantly associated with HNE-MA level (25.2%, 95% CI [11.2%–39.2%]). However, the TSH to T4 and TSH to free T4 ratios were negatively and significantly associated with HNE-MA level (TSH/T4: −21.2%, 95% CI [−34.5% to −7.8%] and TSH/free T4: −24.0%, 95% CI [−38.3% to −9.6%]). Our findings suggest that an imbalance of oxidative and nitrosative stress may alter thyroid hormone homeostasis during pregnancy. Disruption of the maternal thyroid homeostasis during pregnancy would affect embryonic and fetal development.

Abstract Background Nucleotide-binding oligomerization domain (NACHT), leucine rich repeat (LRR) and pyrin domain (PYD) 7 containing protein, NLRP7, is a member of the NLR family which serves as innate immune sensors. Mutations and genetic variants of NLRP7 have been found in women with infertility associated conditions, such as recurrent hydatidiform mole, recurrent miscarriage, and preeclampsia. Decidualization of endometrial stromal cells is a hallmark of tissue remodeling to support embryo implantation and proper placental development. Given defective decidualization has been implicated in miscarriage as well as preeclampsia, we aimed to explore the link between the NLRP7 gene and decidualization. Methods Endometrial samples obtained from pregnant women in the first trimester and non-pregnant women were used to study NLRP7 expression pattern. The human telomerase reverse transcriptase (hTERT)-immortalized human endometrial stromal cells (T-HESCs) were used to study the effect of NLRP7 on decidualization. Decidualization of T-HESCs was induced with 1 μM medroxyprogesterone acetate (MPA) and 0.5 mM 8-bromoadenosine 3':5'-cyclic monophosphate (8-Br-cAMP). siRNA was used to knock down NLRP7 while lentiviral vectors were used to overexpress NLRP7 in cells. NLRP7 expression was detected by immunofluorescence, qRT-PCR, and Western blotting. Decidualization markers, Insulin-like growth factor-binding protein 1 (IGFBP-1) and prolactin (PRL), were detected by qRT-PCR and ELISA. Nuclear translocation of NLRP7 was detected by the subcellular fractionation and confocal microscopy. The effect of NLRP7 on progesterone receptor (PR) activity was evaluated by a reporter system. Results NLRP7 was up-regulated in the decidual stromal cells of human first-trimester endometrium. After in vitro decidualization, T-HESCs presented with the swollen phenotype and increased expressions of IGFBP-1 and PRL. Knockdown or over-expression of NLRP7 reduced or enhanced the decidualization, respectively, according to the expression level of IGFBP-1. NLRP7 was found to translocate in the nucleus of decidualized T-HESCs and able to promote PR activity. Conclusions NLRP7 was upregulated and translocated to the nucleus of the endometrial stromal cells in an in vitro decidualization model. Overexpressed NLRP7 promoted the IGFBP-1 expression and PR reporter activation. IGFBP-1 expression decreased with the knockdown of NLRP7. Therefore, we suggest that NLRP7 contributes to in vitro decidualization of endometrial stromal cells.

Placental mesenchymal dysplasia (PMD) and partial hydatidiform mole (PHM) placentas share similar characteristics, such as placental overgrowth and grape-like placental tissues. Distinguishing PMD from PHM is critical because the former can result in normal birth, while the latter diagnosis will lead to artificial abortion. Aneuploidy and altered dosage of imprinted gene expression are implicated in the pathogenesis of PHM and also some of the PMD cases. Diandric triploidy is the main cause of PHM, whereas mosaic diploid androgenetic cells in the placental tissue have been associated with the formation of PMD. Here, we report a very special PMD case also presenting with trophoblast hyperplasia phenotype, which is a hallmark of PHM. This PMD placenta has a normal biparental diploid karyotype and is functionally sufficient to support normal fetal growth. We took advantage of this unique case to further dissected the potential common etiology between these two diseases. We show that the differentially methylated region (DMR) at NESP55, a secondary DMR residing in the GNAS locus, is significantly hypermethylated in the PMD placenta. Furthermore, we found heterozygous mutations in NLRP2 and homozygous variants in NLRP7 in the mother’s genome. NLRP2 and NLRP7 are known maternal effect genes, and their mutation in pregnant females affects fetal development. The variants/mutations in both genes have been associated with imprinting defects in mole formation and potentially contributed to the mild abnormal imprinting observed in this case. Finally, we identified heterozygous mutations in the X-linked ATRX gene, a known maternal–zygotic imprinting regulator in the patient. Overall, our study demonstrates that PMD and PHM may share overlapping etiologies with the defective/relaxed dosage control of imprinted genes, representing two extreme ends of a spectrum.

Septins are GTP-binding proteins that form heteromeric filaments for proper cell growth and migration. Among the septins, septin7 (SEPT7) is an important component of all septin filaments. Here we show that protein kinase A (PKA) phosphorylates SEPT7 at Thr197, thus disrupting septin filament dynamics and ciliogenesis. The Thr197 residue of SEPT7, a PKA phosphorylating site, was conserved among different species. Treatment with cAMP or overexpression of PKA catalytic subunit (PKACA2) induced SEPT7 phosphorylation, followed by disruption of septin filament formation. Constitutive phosphorylation of SEPT7 at Thr197 reduced SEPT7‒SEPT7 interaction, but did not affect SEPT7‒SEPT6‒SEPT2 or SEPT4 interaction. Moreover, we noted that SEPT7 interacted with PKACA2 via its GTP-binding domain. Furthermore, PKA-mediated SEPT7 phosphorylation disrupted primary cilia formation. Thus, our data uncover the novel biological function of SEPT7 phosphorylation in septin filament polymerization and primary cilia formation.

Objective: Euchromatic variants (EVs) of 8q21.2 are extremely rare chromosomal abnormalities. So, far there have only been two reports on EVs of 8q21.2. Here, we report an 8q21.2 EV detected in cultured amniotic-fluid cells of twins. It was later found to be inherited from the mother, who did not present with abnormal phenotypes. Case Report: A pregnant woman underwent amniocentesis at 16 weeks of gestation because of advanced maternal age. This pregnancy was monozygotic twins conceived naturally. A cytogenetic analysis of cultured amniocytes revealed 46,XY,?dup(8)(q21.2). Chromosomal microarray revealed no abnormalities. C-banding and fluorescent in situ hybridization using chromosome 8 painting probe suggested euchromatic nature of the extra chromosomal band. Karyotyping of the parents showed that the EV was inherited from the mother. Conclusion: Many, but not all, EVs are clinically innocuous. This is the first case of 8q21.2 EV reported in the ethnic Han. More cases are needed to clarify whether 8q21.2 duplication as a bona fide EV.

Objective: Prenatal detection of trisomy 8 mosaicism can be misleading and remains challenging in genetic counseling. Identifying cases of partial or complete trisomy 8 mosaicism will highlight the pitfalls of conventional karyotyping in prenatal amniocentesis for partial or complete trisomy 8 mosaicism. Case report: The patient was born uneventfully at term to a healthy 34-year-old mother. Analysis of the amniotic fluid (AF) cells showed a normal male karyotype. At birth, the newborn presented dysmorphic features, including asymmetric mandibles and ears, anteverted nostrils with a relatively long philtrum, retrognathia, and a clenched hand on the left side. Imaging studies revealed agenesis of the corpus callosum with bilateral colpocephaly, a common arterial trunk bifurcating into the left subclavian and carotid arteries, and bilateral pelviectasis. Cytogenetic analysis of the blood revealed mosaicism of partial trisomy 8: 47,XY,+del(8) (q21.3) [8]/46,XY [12]. Array comparative genomic hybridization (array-CGH) revealed 82.9 Mb duplications at chromosome 8p23.3-8q21.3 with dosage variations. Interphase fluorescence in situ hybridization analysis of urine sediments and buccal smears were compatible with mosaic compositions. A small colony of AF cells was found to have partial trisomy 8 in repeated analysis. Conclusion: Conventional karyotyping through amniocentesis has limitations particularly in detecting rare trisomy mosaicism if trisomic cells show growth disadvantage. Array-CGH using uncultured cells may be of help in providing more information on genetic dosage variations in such cases.

Septins are critical for numerous cellular processes through the formation of heteromeric filaments and rings indicating the importance of structural regulators in septin assembly. Several posttranslational modifications (PTMs) mediate the dynamics of septin filaments in yeast. However, little is known about the role of PTMs in regulating mammalian septin assembly, and the in vivo significance of PTMs on mammalian septin assembly and function remains unknown. Here, we showed that SEPT12 was phosphorylated on Ser198 using mass spectrometry, and we generated SEPT12 phosphomimetic knock-in (KI) mice to study its biological significance. The homozygous KI mice displayed poor male fertility due to deformed sperm with defective motility and loss of annulus, a septin-based ring structure. Immunohistochemistry of KI testicular sections suggested that SEPT12 phosphorylation inhibits septin ring assembly during annulus biogenesis. We also observed that SEPT12 was phosphorylated via PKA, and its phosphorylation interfered with SEPT12 polymerization into complexes and filaments. Collectively, our data indicate that SEPT12 phosphorylation inhibits SEPT12 filament formation, leading to loss of the sperm annulus/septin ring and poor male fertility. Thus, we provide the first in vivo genetic evidence characterizing importance of septin phosphorylation in the assembly, cellular function and physiological significance of septins.

Objective: To establish a multilocus model for studying the effect of steroid-related genes on advanced stage endometriosis. Materials and methods: A total of 121 patients with advanced stage endometriosis and 171 control women were included. Eighteen single-nucleotide polymorphisms (SNPs) from nine genes (HSD17B1, HSD17B2, HSD17B5, HSD17B6, CYP17, CYP19, ERα, ERβ, and PGR) were genotyped using the TaqMan assays. Logistic regression models were used to evaluate the genetic effects, with adjustment for other covariates. Results: Only the presence of the mutant CYP19 (aromatase gene) was associated with a significantly increased risk of endometriosis after adjusting for age, BMI, and parity (p = 0.002, OR = 2.69; 95% CI = 1.44–5.02). No association was ascertained between the other investigated SNPs and endometriosis. Conclusion: Polymorphisms of the aromatase gene confer susceptibility to advanced stage endometriosis in the Taiwanese Han population.

Objectives: An increase in the proportion of male-to-female live births has raised concerns in Taiwan. Disclosure of fetal sex during prenatal screening is not allowed by the Taiwan government. Fetal sex annotation in clinical genetic reports is also prohibited. This study tested the hypothesis that the male-to-female sex ratio at amniocentesis should be lower than the sex ratio at birth, if a certain percentage of female fetuses are being selectively aborted after amniocentesis. Therefore, we examined the differences between fetal sex ratio at amniocentesis at a tertiary medical center in southern Taiwan and the nationwide sex ratio at birth in Taiwan from 1992 to 2011. Materials and Methods: Data of normal male and female karyotypes during the study period were collected from the cytogenetic laboratory of the National Cheng Kung University Hospital (NCKUH) in southern Taiwan. Data of sex ratio at birth nationwide in Taiwan were obtained from the Department of Statistics, Ministry of the Interior, Taiwan. We calculated 95% binominal confidence intervals for the sex ratios and differences between fetal sex ratio at amniocentesis, and nationwide sex ratio at birth were tested by the χ2 test and Bonferroni correction. Results: The nationwide sex ratio at birth ranged from 1.07 to 1.11 during the period from 1992 to 2011 in Taiwan, with the highest in 2004 and the lowest in 1993. The fetal sex ratio at amniocentesis at NCKUH ranged more widely (0.82–1.28), with the lowest in 1993 and the highest in 2007. After regression analysis, both trends of sex ratio at amniocentesis during midtrimester and at birth were not significantly increased by years. Furthermore, the sex distribution at amniocentesis during midtrimester did not differ significantly from the nationwide sex ratio at birth (1.113 vs. 1.092, p = 0.151). Conclusions: The results showed that sex ratio was already skewed toward male at midtrimester. Our data imply that artificial sex selection, if it were present, might have already emerged prior to the timing of amniocentesis. However, more large nationwide studies on sex ratios in Taiwan are warranted.

Previous studies revealed that phthalate exposure could alter thyroid hormones during the last trimester of pregnancy. However, thyroid hormones are crucial for fetal development during the first trimester. We aimed to clarify the effect of phthalate exposure on thyroid hormones during early pregnancy.We recruited 97 pregnant women who were offered an amniocentesis during the early trimester from an obstetrics clinic in southern Taiwan from 2013 to 2014. After signing an informed consent form, we collected amniotic fluid and urine samples from pregnant women to analyze 11 metabolites, including mono-ethyl phthalate (MEP), mono-(2-ethyl-5-carboxypentyl) phthalate (MECPP), mono-(2-ethylhexyl) phthalate (MEHP), mono-butyl phthalate (MnBP), of 9 phthalates using liquid chromatography/ tandem mass spectrometry. We collected blood samples from each subject to analyze serum thyroid hormones including thyroxine (T4), free T4, and thyroid-binding globulin (TBG).Three phthalate metabolites were discovered to be >80% in the urine samples of the pregnant women: MEP (88%), MnBP (81%) and MECPP (86%). Median MnBP and MECPP levels in pregnant Taiwanese women were 21.5 and 17.6 μg/g-creatinine, respectively, that decreased after the 2011 Taiwan DEHP scandal. Results of principal component analysis suggested two major sources (DEHP and other phthalates) of phthalates exposure in pregnant women. After adjusting for age, gestational age, TBG, urinary creatinine, and other phthalate metabolites, we found a significantly negative association between urinary MnBP levels and serum T4 (β = -5.41; p-value = 0.012; n = 97) in pregnant women using Bonferroni correction.We observed a potential change in the thyroid hormones of pregnant women during early pregnancy after DnBP exposure. Additional study is necessitated to clarify these associations.

X-chromosome inactivation (XCI) is a phenomenon that occurs in female mammals. Typically, maternally- and paternally-derived X chromosomes are inactivated at approximately the same frequency. If preferential inactivation occurs, the person is considered to have skewed XCI. Skewed XCI has been reported to occur more frequently in women who experience recurrent pregnancy loss (RPL). In this study, we sought to investigate if there is an association between skewed XCI and unexplained RPL in Taiwanese women. A total of 194 women who had experienced unexplained RPL were recruited into the study. Human androgen receptor or DXS6673E and DX15-134 loci were used in the XCI assay. The results of our study suggested that a cut-off point < 90% may not be justified for skewed XCI. Only extremely skewed (> 95%) XCI is associated with RPL. Extremely skewed XCI occurs in a subset of Taiwanese women with RPL.

Male infertility affects approximately 50% of all infertile couples. The male-related causes of intracytoplasmic sperm injection failure include the absence of sperm, immotile or immature sperm, and sperm with structural defects such as those caused by premature chromosomal condensation and DNA damage. Our previous studies based on a knockout mice model indicated that SEPT12 proteins are critical for the terminal morphological formation of sperm. SEPT12 mutations in men result in teratozospermia and oligozospermia. In addition, the spermatozoa exhibit morphological defects of the head and tail, premature chromosomal condensation, and nuclear damage. However, the molecular functions of SEPT12 during spermatogenesis remain unclear. To determine the molecular functions of SEPT12, we applied a yeast 2-hybrid system to identify SEPT12 interactors. Seven proteins that interact with SEPT12 were identified: SEPT family proteins (SEPT4 and SEPT6), nuclear or nuclear membrane proteins (protamine 2, sperm-associated antigen 4, and NDC1 transmembrane nucleoproine), and sperm-related structural proteins (pericentriolar material 1 and obscurin-like 1). Sperm-associated antigen 4 (SPAG4; also known as SUN4) belongs to the SUN family of proteins and acts as a linker protein between nucleoskeleton and cytoskeleton proteins and localizes in the nuclear membrane. We determined that SEPT12 interacts with SPAG4 in a male germ cell line through coimmunoprecipitation. During human spermiogenesis, SEPT12 is colocalized with SPAG4 near the nuclear periphery in round spermatids and in the centrosome region in elongating spermatids. Furthermore, we observed that SEPT12/SPAG4/LAMINB1 formed complexes and were coexpressed in the nuclear periphery of round spermatids. In addition, mutated SEPT12, which was screened from an infertile man, affected the integration of these nuclear envelope complexes through coimmunoprecipitation. This was the first study that suggested that SEPT proteins link to the SUN/LAMIN complexes during the formation of nuclear envelopes and are involved in the development of postmeiotic germ cells.

Objective: Holoprosencephaly is a kind of brain anomaly characterized by inadequate cleavage of the prosencephalon during early embryogenesis. In addition, holoprosencephaly associated with cystic hygroma and hydrops fetalis has never been reported. In this article, we report a rare case of holoprosencephaly associated with cystic hygroma and hydrops fetalis diagnosed prenatally. Case Report: A 28-year-old woman, gravida 2, para 0, artificial abortion 1, was referred to our antenatal clinic at 16 weeks of gestation due to fetal cystic hygroma detected by prenatal routine ultrasonography at a local hospital. In our clinic, single ventricle with fused thalami and cystic mass at the fetal neck as well as hydrops fetalis were noted by level II ultrasound. Under the impression of holoprosencephaly with cystic hygroma and hydrops fetalis, termination of pregnancy with misoprostol was undertaken. The histopathology of fetal autopsy confirmed our diagnosis and disclosed additional intracranial abnormalities. Conclusion: Fetus with holoprosencephaly might have other associated structural abnormalities. Cystic hygroma and hydrops fetalis are rare associations. Meticulous sonographic examination to depict the associated defects are necessary in any fetus with holoprosencephaly.

Objective: Epidermoid cyst of the presacral space is a rare congenital lesion of ectodermal origin. Presacral epidermoid cyst with hydronephrosis is even rarer and has never been reported in Taiwan. Herein, we present a patient with presacral epidermoid cyst with right hydronephrosis. Case Report: A 62-year-old woman had low abdominal pain for 2 weeks and was referred to our hospital for further management. In our hospital, computed tomography revealed a multilobulated cystic tumor (20 ×15 ×12 cm) in the lower abdomen, complicated with right severe hydronephrosis. Laparotomy was undertaken and a presacral tumor was removed. The pathologic diagnosis was an epidermoid cyst. Conclusion: A presacral epidermoid tumor is a rare tumor and a large presacral cystic tumor may mimic an ovarian tumor in imaging. All presacral tumors with or without symptoms should be evaluated thoroughly before operation. Complete surgical excision, preserving adjacent organs' function, should be kept in mind.

Objective: To report a rare case of bilateral torsion of ovarian dermoid cysts as well as one parasitic teratoma at the omentum. Case Report: A 40-year-old female presented with lower abdominal pain. Physical examination detected one huge abdominal mass from the pelvic area up to the level of the umbilicus. An ultrasound examination revealed two abdominal masses; the central mass was an irregular hyperechogenic cystic tumor (25 cm), and the other (4 cm), which had the same echo appearance, was located in the right adnexa. Kidney-ureter-bladder radiography illustrated a calcified ring over the right lower abdomen. Nevertheless, the concentrations of five tumor markers were all within normal ranges. After laparotomy, we found that the two masses were of ovarian origin, both with torsion to the contralateral side, and the smaller mass had a blood supply from the omentum, i.e. a parasitic teratoma at the omentum. Conclusions: Autoamputation and reimplantation of an ovarian dermoid cyst is the most common etiology of a parasitic omental teratoma. For omental mature cystic teratoma, simple resection is the best choice of treatment.

Serine/threonine kinase 31 (STK31) is one of the novel cancer/testis antigens for which its biological functions remain largely unclear. Here, we demonstrate that STK31 is overexpressed in many human colorectal cancer cell lines and tissues. STK31 co-localizes with pericentrin in the centrosomal region throughout all phases of the cell cycle. Interestingly, when cells undergo mitosis, STK31 also localizes to the centromeres, central spindle, and midbody. This localization behavior is similar to that of chromosomal passenger proteins, which are known to be the important players of the spindle assembly checkpoint. The expression of STK31 is cell cycle-dependent through the regulation of a putative D-box near its C-terminal region. Ectopically-expressed STK31-GFP increases cell migration and invasive ability without altering the proliferation rate of cancer cells, whereas the knockdown expression of endogenous STK31 by lentivirus-derived shRNA results in microtubule assembly defects that prolong the duration of mitosis and lead to apoptosis. Taken together, our results suggest that the aberrant expression of STK31 contributes to tumorigenicity in somatic cancer cells. STK31 might therefore act as a potential therapeutic target in human somatic cancers.

Objective: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hematologic disorder characterized by complement-mediated intravascular hemolysis. As maternal complication of PNH is already severe, it becomes much more complex when preeclampsia is superimposed. We present a case of PNH superimposed with severe preeclampsia in the third trimester. Case Report: A 30-year-old, gravida 1, para 0, woman had PNH, diagnosed at the age of 17. Her PNH was stable under medication. In 2004, she conceived and had prenatal care at our hospital. At 35 weeks of gestation, preeclampsia with elevated blood pressure and proteinuria were superimposed and managed with close surveillance. A live male baby was delivered vaginally at 38 weeks of gestation. During parturition, her blood pressure increased to 180/100 mmHg. Thrombocytopenia, hyponatremia, hyperkalemia, hypoalbuminemia, elevated liver enzymes and lactate dehydrogenase were also noted. Preeclampsia continued to postpartum and eventually disappeared. Conclusion: The most frequent causes of PNH-related fetomaternal morbidity and mortality are hemolysis and thrombosis. The situation becomes even more complicated when PNH is superimposed with preeclampsia. Appropriate clinical surveillance, awareness of the potential risks of hemolysis and thrombosis, as well as evaluation of fetal wellbeing are essential.

Objective: Acute viral hepatitis C-induced jaundice in pregnancy is very rare and may be fatal. Here, we report a complicated case with acute hepatitis C-induced jaundice in pregnancy with successful management Case Report: A 27-year-old pregnant woman, gravida 2, para 1, with gestational age of 36 weeks and 5 days, was referred to our hospital due to jaundice and elevated liver enzymes of undetermined cause. She had been suffering from general weakness, diarrhea and vomiting for 1 week, and jaundice with tea-colored urine for 3 days. At our medical center, acute viral hepatitis C-induced jaundice was suspected. Since her general condition deteriorated at 36 weeks and 6 days of gestation, we decided to induce labor. A male baby was born smoothly via the vaginal route, with birth weight 2,857 g, birth length 48.6 cm, and 1- and 5-minute Apgar scores of 7 and 9, respectively. Maternal condition improved dramatically after delivery and her serum liver enzymes and bilirubin levels gradually approached normal ranges. Conclusion: Mothers and fetuses with acute viral hepatitis C-induced jaundice during pregnancy are at great risk of mortality and morbidity. Timely termination may be one of the choices of treatment when fetal maturity has been reached and the maternal condition has deteriorated.

Objective: Assisted reproductive technology has contributed to the rising rate of multiple and ectopic pregnancies. We report a case of heterotopic cornual pregnancy with delayed uterine rupture despite successful fetal reduction. To our knowledge, this has not been previously reported. Case Report: A 32-year-old woman, gravida 2, para 0, had secondary infertility. She had undergone laparoscopic tuboplasty for bilateral tubal obstruction and laparoscopic bilateral salpingectomy for hydrosalpinx. Successful pregnancy was achieved after transfer of five frozen embryos for this pregnancy. At 7 weeks of gestation, routine pelvic sonography identified three gestational sacs, two in the intrauterine cavity and one in the right cornua. Fetal reduction with potassium chloride injection into the cornual pregnancy was performed at 8 weeks of gestation in a private clinic. At 13 weeks of gestation, she had sudden-onset low abdominal pain and hypovolemic shock. Emergency laparotomy revealed right cornual rupture, with a 3.4-cm translucent sac extruding into the peritoneal cavity. The uterus was repaired by simple closure of the right cornua. The twins survived the operation and were born smoothly at 34 weeks of gestation by cesarean section due to preterm labor and malpresentation. Conclusion: Uterine rupture can occur in women who have undergone successful fetal reduction for cornual heterotopic pregnancy.

Objective: Ring chromosome 7 is a very rare chromosomal anomaly that may have a grave prognosis. Nevertheless, the clinical features associated with ring chromosome 7 are highly variable. Here, we report a case with ring chromosome 7 and the perinatal findings. Case Report: A 32-year-old, gravida 1, para 0, woman was referred to our hospital because of intrauterine growth restriction (IUGR) and oligohydramnios at 35 weeks of gestation. Prenatal ultrasound revealed a severe IUGR fetus presenting with multicystic kidney, hydronephrosis and oligohydramnios. At parturition, the birth weight of this male infant was 1,720 g, and a battery of anomalies were also noted, including imperforate anus, hypospadia, micropenis, right cryptorchidism, severe IUGR, multiple nevi on the forehead, shoulder and left thigh, brain atrophy, right multicystic kidney, and left mild hydronephrosis. Cytogenetic study from cord blood revealed a ring chromosome 7. Conclusion: Ring chromosome 7 is extremely rare and our case might be the 15th and youngest case in the medical literature. Our case had multicystic kidney and imperforate anus, which have not been reported previously. Prenatal diagnosis of ring chromosome 7 is very difficult. When fetuses present with severe IUGR, oligohydramnios and multicystic kidney, chromosomal aberrations should be kept in mind, and perinatal cytogenetic workup is warranted.

It is estimated that 10-15% of couples are infertile and male factors account for about half of these cases. With the advent of intracytoplasmic sperm injection (ICSI), many infertile men have been able to father offspring. However, teratozoospermia still remains a big challenge to tackle. Septins belong to a family of cytoskeletal proteins with GTPase activity and are involved in various biological processes e.g. morphogenesis, compartmentalization, apoptosis and cytokinesis. SEPTIN12, identified by c-DNA microarray analysis of infertile men, is exclusively expressed in the post meiotic male germ cells. Septin12(+/+)/Septin12(+/-) chimeric mice have multiple reproductive defects including the presence of immature sperm in the semen, and sperm with bent neck (defect of the annulus) and nuclear DNA damage. These facts make SEPTIN12 a potential sterile gene in humans. In this study, we sequenced the entire coding region of SEPTIN12 in infertile men (n = 160) and fertile controls (n = 200) and identified ten variants. Among them is the c.474 G>A variant within exon 5 that encodes part of the GTP binding domain. The variant creates a novel splice donor site that causes skipping of a portion of exon 5, resulting in a truncated protein lacking the C-terminal half of SEPTIN12. Most individuals homozygous for the c.474 A allele had teratozoospermia (abnormal sperm