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To determine the fetal ultrasound findings associated with Sotos syndrome caused by deletions at 5q35 including the NSD1 and a point mutation in this gene.This was a retrospective study of eight pregnancies with fetal Sotos syndrome identified by chromosomal microarray (CMA)/whole exome sequencing (WES). Clinical and laboratory data were collected and reviewed for these cases.Two cases had no significant fetal abnormalities, and were only diagnosed after birth. One case presented in the first trimester with increased nuchal translucency. The remaining five fetuses were identified at late gestation. One of the five fetuses presented in the second trimester with mild ventriculomegaly, and four in the third trimester with mild ventriculomegaly, macrocephaly and polyhydramnios. CMA was done on all cases and revealed 5q35 deletions in seven cases, and WES detected a maternally inherited NSD1 variant in one case.The fetal ultrasound findings in cases with Sotos syndrome, associated with deletions at 5q35 and a point mutation in the NSD1 are not specific with the most common finding being mild ventriculomegaly.

The aim of this study is to identify prenatally diagnosed cases of persistent left superior vena cava (PLSVC) in our clinic, to evaluate the associated structural and chromosomal results, and to review their outcome.During a four-year period, patients with fetal PLSVC were detected by echocardiography. We reviewed medical records of these affected pregnancies, including maternal demographics, sonographic findings, chromosomal microarray results and pregnancy outcomes.There were a total of 140 cases of fetal PLSVC. Eighty-nine fetuses (63.6%) had associated structural anomalies, while the remaining 51 fetuses (36.3%) had PLSVC as an isolated finding. In the non-isolated cases, cardiac anomalies were present in 72 fetuses (80.9%), and extracardiac abnormalities in 45 fetuses (50.6%). Among the 89 cases with non-isolated PLSVC, 12 cases had chromosomal abnormalities including 5 cases of aneuploidies. Among the 51 cases with isolated PLSVC, one pregnancy of chromosomal microduplication was detected.Isolated PLSVC is a benign vascular anomaly in low risk population. However, the information about background risk of identifying an abnormal clinically significant CMA result should be conveyed to all pregnant women when they consults this vascular variation.

The aim of this prospective study is to evaluate the performance of the intermediate 16-week ultrasound in fetuses with increased nuchal translucency (NT) and a normal chromosomal microarray analysis (CMA).During a one-year period, a detailed ultrasound was performed at 16 week' gestation for patients with an increased NT (≥3.5 mm) and normal CMA. Pregnancy work-up included a traditional 22-week ultrasound scan, an echocardiography, and the option of a 10-gene Rasopathy panel after a normal 16-week scan. Abnormal findings and pregnancy outcomes were collected and analyzed.In 52 fetuses with an isolated increased NT and normal CMA, 14 (26.5%) were noted to have structural defects on the 16-week ultrasound. Intrauterine fetal death occurred in one (1.9%) case identified by the 16-week scan. Of the remaining 37 cases, six opted for a RASopathy panel. In this group, one case of Noonan syndrome was detected. One case of unilateral duplex kidney had not been found until the 22-week scan. One case of fetal growth restriction was identified in the third trimester. The remaining 34 cases proceeded with normal ultrasound to term.The 16-week ultrasound scan performed on fetuses with increased NT and normal CMA could detect the majority of structural abnormalities that are expected to be identified traditionally at 20-24 weeks.

We aimed to investigate the value of exome sequencing (ES) in fetuses with callosal anomalies (CA) with or without other structural anomalies, but with normal findings by karyotyping and chromosome microarray analysis (CMA).Cases with CA with or without other structural anomalies were screened for eligibility. Fetuses with abnormal karyotyping or CMA results were excluded. We performed ES on DNA samples from eligible fetus-parental trios and identified diagnostic genetic variants based on the ultrasonographic features.A total of 50 eligible fetus-parental trios were successfully analyzed by ES. We found 17 likely pathogenic or pathogenic variants in 14 genes from 17 fetuses, with a total proportion of diagnostic genetic variants equal to 34.0% (17/50). Of the 17 cases with a diagnosis, 10 (29.4%, 10/35) were isolated and 7 (43.8%, 7/15) were non-isolated. Pregnancy outcome data showed that 70.0% (7/10) of the surviving isolated CA fetuses with negative ES results had a good prognosis in early childhood.Our study used ES prenatally for CA and showed that ES can be used diagnostically to define the molecular defects that underlie unexplained CA. Most subjects with isolated CA with negative results for genetic causes will have a favorable prognosis in early childhood.

Currently, there are still many challenges in prenatal diagnosis, such as limited or uncertain fetal phenotyping, variant interpretation, and rapid turnaround times. The aim of this study was to illustrate the value of a comprehensive genomic evaluation in prenatal diagnosis. We retrospectively reviewed 20 fetuses with clinically significant copy number variants (CNVs) detected by chromosomal microarray analysis (CMA) and no further exome sequencing testing in our tertiary center between 2019 and 2020. The residual DNA from the prenatal cases was used for the parallel implementation of CNV sequencing (CNV-seq) and trio-based clinical exome sequencing (trio-CES). CMA revealed 26 clinically significant CNVs (18 deletions and eight duplications) in 20 fetuses, in which five fetuses had two or more CNVs. There were eight fetuses with pathogenic CNVs (e.g., del 1p36), nine fetuses with likely pathogenic CNVs (e.g., dup 22q11.21), and three fetuses with variants of unknown significance (VOUS, e.g., dup 1q21.1q21.2). Trio-CES identified four fetuses with likely pathogenic mutations (SNV/InDels). Of note, a fetus was detected with a maternally inherited hemizygous variant in the SLX4 gene due to a 16p13.3 deletion on the paternal chromosome. The sizes of CNVs detected by CNV-seq were slightly larger than that of the SNP array, and four cases with mosaic CNVs were all identified by CNV-seq. In conclusion, microdeletion/duplication syndromes and monogenic disorders may co-exist in a subject, and CNV deletion may contribute to uncovering additional recessive disease alleles. The application of a comprehensive genomic evaluation (CNVs and SNV/InDels) has great value in the prenatal diagnosis arena. CNV-seq based on NGS technology is a reliable and a cost-effective technique for identifying CNVs.

To examine the diagnostic yield of exome sequencing (ES) in singleton pregnancies with isolated fetal clubfoot.Clinical data from singleton pregnancies with a sonographic diagnosis of isolated clubfoot and ES results between 2018 and 2021 were retrospectively obtained from a single referral medical center. The recorded data include maternal age, gestational age at sonographic diagnosis, the indication for genetic testing, ES results, and pregnancy outcomes.During the study period, 38 fetuses were prenatally diagnosed with isolated clubfoot by ultrasound and underwent ES after the copy number variant analysis was non-diagnostic. Through the trio-ES analysis, pathogenic or likely pathogenic variants were detected in 4 of 38 (10.5%) with the following genes: BRPF1, ANKRD17, FLNA, and KIF1A. All are de novo with three of autosomal dominant inheritance and one of X-linked recessive inheritance.Sonographic diagnosis of clubfoot, even isolated, increases the risk for monogenic syndromes. Exome sequencing should be an option for genetic investigation for such pregnancies.

Objective To determine monogenic syndromes in cases of fetal akinesia in order to understand the genetic aetiology. Study design Clinical trio exome sequencing (ES) was performed on DNA extracted from postnatal samples in 12 cases with fetal akinesia identified by prenatal ultrasound and a normal chromosomal micro-array analysis result. This test targets coding exons for 4200 clinically relevant disease-causing genes. The interpretation of variants was performed according to the guidelines of the American College of Medical Genetics. Results A definite molecular diagnosis was achieved in six (50 %) of the 12 cases using clinical trio ES. In five cases, the pathogenic variants were located in known fetal-akinesia-associated genes. In one case, the underlying pathogenic variants were in known disease genes that had not been linked to fetal akinesia previously. Six pregnancies were terminated by the parents, and six pregnancies were continued to term. Conclusion Genetic defects leading to fetal akinesia were found in half of the study cases using clinical trio ES. This information will be useful in genetic counselling with regard to prognosis and risk of recurrence.

Foetal macrosomia is associated with an increased risk of complications both for the mother and the newborn. Prenatal overgrowth can be easily demonstrated by measurements of foetal biometry on ult...

We describe a new α-globin chain variant in a Chinese subject. This novel variant, with a Val→Met substitution at codon 93 of the α-globin chain, has been named Hb Qingcheng (HBA1: c.280G>A) for where the proband was born. A woman with somatic mosaicism for Hb Qingcheng presented with the phenotype of mild α-thalassemia (α-thal).

Aim To clarify the association of serum kisspeptin levels in women with polycystic ovary syndrome (PCOS) by meta-analysis. Methods Two English databases and two Chinese databases were searched for the relationship between kisspeptin and PCOS published from 2009. After the studies screening according to specific principles, we used STATA 12.0 for meta-analysis. Standardized mean difference (SMD) and its 95% confidence intervals (95% CIs) were used as the effect size and STATA 12.0 software was performed by this meta-analysis. Results Nine articles were included in the end, with a total of 1282 participants (699 patients and 583 controls). Heterogeneity between studies was statistically significant. Therefore, the random effects model was used to combine the effects. Meta-analysis showed statistically significant differences in serum kisspeptin levels between the PCOS patients and controls (SMD = 0.57, 95% CI [0.32, 0.82]), which indicated that there is a strong association between serum kisspeptin levels and PCOS. The source of high heterogeneity between the inclusion studies (I2 = 73.2%) might be due to the small sample size. The larger variation of kisspeptin concentration might be caused by different diagnosis criteria of PCOS and short half-time period of kisspeptin combined with nonstandard testing process. Conclusion Serum kisspeptin levels in PCOS patients were higher than non-PCOS patients. It is a hint to indicate us that kisspeptin might be an independent biomarker of PCOS patients.

To present both our center's and previously reported experience of prenatal diagnosis of Coffin-Siris syndrome (CSS) with regard to the laboratory testing and fetal features of this syndrome.This was a retrospective study of eight pregnancies with fetal CSS identified by prenatal or postnatal genetic testing. Clinical and laboratory data were collected and reviewed for these cases, including maternal demographics, prenatal sonographic findings, chromosomal microarray and exome sequencing (ES) results, and pregnancy outcomes.A total of eight cases of fetal CSS based on molecular testing were detected. Two cases presented with an increased nuchal translucency (NT) in the first trimester. The remaining six were identified at the second trimester scan. Agenesis of the corpus callosum (ACC) was the most common sonographic finding, accounting for 5/7 (71.4%) cases in which a second trimester sonogram was performed: four had ACC as an isolated finding, and one had additional features of cerebellar hypoplasia and left congenital diaphragmatic hernia.CSS should be included in the differential diagnosis when ACC is found by prenatal ultrasound. Both chromosomal microarray and ES should be options when counseling patients with a structurally anomalous fetus.

OBJECTIVE To assess the efficacy of positive feedback closed-loop management system (PFCMS) protocol in influencing parents' decision about pregnancy continuation in pregnancies diagnosed with omphalocele. METHODS This was a retrospective cohort study of patients who were diagnosed with fetal omphalocele prior to 20 weeks' gestation by ultrasound and were referred to Fetal Care Center at a mainland Chinese medical center during an 11-year period. Two management strategies were offered during the two stages of the study period: a single consultant with a routine protocol and a multidisciplinary support team with PFCMS, respectively. We analyzed the two protocols influencing parents' decision about pregnancy continuation. RESULTS Forty-nine patients diagnosed with fetal omphalocele were included in this study. In Group A including 16 patients with routine protocol during the first stage of the study period, the majority opted for termination, and only five continued the pregnancy. In Group B including 33 patients with PFCMS during the second stage of the study period, less than one third chose TOP, and 23 ended in live births. There was a significantly lower TOP rate in patients treated with the PFCMS protocol. CONCLUSION The PFCMS protocol may be an efficient approach in managing pregnancies complicated by omphalocele, which may help in preventing unnecessary pregnancy terminations.

Purpose: The aim of this study is to evaluate the impact of the utility of maternal cell-free DNA (cfDNA) on the number of chorionic villus sampling (CVS) at a mainland Chinese maternal hospital.Methods: This was a retrospective cohort study conducted in consecutive singleton pregnancies that underwent CVS between the 11th and 14th gestational weeks at a Chinese maternal hospital during a nine-year period. The indications, complications and prenatal diagnosis results were evaluated.Results: This study consisted of 5108 CVS procedures, including 2000 performed for fetal karyotyping, and 3108 performed for fetal single-gene genotyping. During the period with the introduction of cfDNA, the proportion of the number of CVS procedures for the indication of positive serum screening declined significantly, and abnormal ultrasound was the main indication for CVS performed for fetal karyotyping. Thalassemia was always the main indication for CVS, accounting for 50.5% of all CVS cases.Conclusions: cfDNA has changed the spectrum of CVS indications. CVS is now the invasive procedure performed for patients with a fetus having a very high risk of fetal genetic defects, including fetuses having major abnormal ultrasound or having a risk of single-gene disorder inherited from their parents.

OBJECTIVE The aim of this study is to explore the utility of rapid medical trio exome sequencing (ES) for prenatal diagnosis using the skeletal dysplasia as an exemplar. METHOD Pregnant women who were referred for genetic testing because of ultrasound detection of fetal abnormalities suggestive of a skeletal dysplasia were identified prospectively. Fetal samples (amniocytes or cord blood), along with parental blood, were send for rapid copy number variations testing and medical trio ES in parallel. RESULTS Definitive molecular diagnosis was made in 24/27 (88.9%) cases. Chromosomal abnormality (partial trisomy 18) was detected in one case. Sequencing results had explained the prenatal phenotype enabling definitive diagnoses to be made in 23 cases. There were 16 de novo dominant pathogenic variants, four dominant pathogenic variants inherited maternally or paternally, two recessive conditions with pathogenic variants inherited from unaffected parents, and one X-linked condition. The turnaround time from receipt of samples in the laboratory to reporting sequencing results was within 2 weeks. CONCLUSION Medical trio ES can yield very timely and high diagnostic rates in fetuses presenting with suspected skeletal dysplasia. These definite diagnoses aided parental counseling and decision making in most of cases.

Background Individuals with δβ-thalassemia/HPFH and β-thalassemia usually present with intermedia or thalassemia major. No large-scale survey on HPFH/δβ-thalassemia in southern China has been reported to date. The purpose of this study was to examine the molecular epidemiology and hematologic characteristics of these disorders in Guangzhou, the largest city in Southern China, to offer advice for thalassemia screening programs and genetic counseling. Methods A total of 125,661 couples participated in pregestational thalassemia screening. 654 subjects with fetal hemoglobin (HbF) level ≥ 5% were selected for further investigation. Gap-PCR combined with Multiplex ligation dependent probe amplification (MLPA) was used to screen for β-globin gene cluster deletions. Gene sequencing for the promoter region of HBG1 /HBG2 gene was performed for all those subjects. Results A total of 654 individuals had hemoglobin (HbF) levels≥5, and 0.12% of the couples were found to be heterozygous for HPFH/δβ-thalassemia, including Chinese Gγ (Aγδβ)0-thal, Southeast Asia HPFH (SEA-HPFH), Taiwanese deletion and Hb Lepore–Boston–Washington. The highest prevalence was observed in the Huadu district and the lowest in the Nansha district. Three cases were identified as carrying β-globin gene cluster deletions, which had not been previously reported. Two at-risk couples (0.0015%) were required to receive prenatal diagnosis. We also found 55cases of nondeletional-HPFH (nd-HPFH), including 54 with Italian nd-HPFH and one with the Aγ-197C-T heterozygous state. It is difficult to discriminate between Chinese Gγ (Aγδβ)0-thal and Italian nd-HPFH carriers using hemoglobin (Hb) analysis. Conclusions This study is the first to describe the familial prevalence of HPFH/δβ-thalassemia and the high-risk rate in Greater Guangzhou Area, and the findings will support the implementation of thalassemia screening for three common deletions by gap-PCR. We also presented a systematic description of genotype-phenotype relationships which will be useful for genetic counseling and prenatal diagnostic services for β-thalassemia intermedia.

To present the experience on prenatal diagnosis of Miller-Dieker syndrome (MDS)/PAFAH1B1-related lissencephaly to further determine fetal phenotypes of this syndrome.This was a retrospective study of ten pregnancies with fetal MDS/PAFAH1B1-related lissencephaly identified by chromosomal microarray (CMA)/exome sequencing (ES). Clinical and laboratory data were collected and reviewed for these cases, including maternal demographics, prenatal sonographic findings, CMA or ES results and pregnancy outcomes.Two cases were diagnosed in the first trimester because of an increased nuchal translucency. The remaining eight cases were identified at late gestation, including four in the second trimester because of fetal cardiac anomalies or ventriculomegaly, and four in the third trimester because of ventriculomegaly. CMA revealed 17p13.3 deletions in nine cases, and ES detected a de novo PAFAH1B1 missense mutation in one case.The prenatal presentation of MDS/PAFAH1B1-related lissencephaly depended on the gestational age when the diagnosis was made. Mild ventriculomegaly was the most common prenatal sonographic sign identified in cases of MDS/PAFAH1B1-related lissencephaly. It is important that fetal MRI and invasive testing with CMA should be considered in fetuses with apparently 'isolated' mild ventriculomegaly.

Endometrial epithelial cells (EECs) and stromal cells (ESCs) have a close functional association. During the peri-implantation period, EECs with enhanced functional activities secrete a variety of paracrine factors to promote the decidualization of ESCs. However, little is known about the specific process by which EECs secrete paracrine factors to induce the decidualization of ESCs. Some evidence suggests that the activation of sodium-glucose cotransporter 3a (SGLT3a) induces the depolarization of ESCs to affect their function. Therefore, SGLT3a acts as a sensor molecule in certain cell types. In this study, the expression of SGLT3a was investigated in EECs to determine whether its levels increased during the peri-implantation period in female mice. The activation of SGLT3a in mouse EECs induced Na+ -dependent depolarization of the cell membrane and an influx of extracellular Ca2+ , which further promoted the expression and release of the paracrine factors prostaglandin E2 (PGE2) and F2-alpha (PGF2α) by upregulating the expression of cyclooxygenase-2. In turn, PGE2 and PGF2α induced the decidualization of ESCs. Importantly, we identified SGLT3a as a key molecule involved in the cross-talk between EECs and ESCs during the process of uterine decidualization.

Uterine receptivity to the embryo is crucial for successful implantation. The establishment of uterine receptivity requires a large amount of energy, and abnormal energy regulation causes implantation failure. Glucose metabolism in the endometrium is tissue specific. Glucose is largely stored in the form of glycogen, which is the main energy source for the endometrium. AMP-activated protein kinase (AMPK), an important energy-sensing molecule, is a key player in the regulation of glucose metabolism and its regulation is also tissue specific. However, the mechanism of energy regulation in the endometrium for the establishment of uterine receptivity remains to be elucidated. In this study, we aimed to investigate the energy regulation mechanism of mouse uterine receptivity and its significance in embryo implantation. The results showed that the AMPK, p-AMPK, glycogen synthase 1, and glycogen phosphorylase M levels and the glycogen content in mouse endometrial epithelium varied in a periodic manner under regulation by the ovarian hormone. Specifically, progesterone significantly activated AMPK, promoted glycogenolysis, and upregulated glycogen phosphorylase M expression. AMPK regulated glycogen phosphorylase M expression and promoted glycogenolysis. AMPK was also found to be activated by changes in the energy or glycogen of the endometrial epithelial cells. The inhibition of AMPK activity or glycogenolysis altered the uterine receptivity markers during the window of implantation and ultimately interfered with implantation. In summary, consistency and synchronization of AMPK and glycogen metabolism constitute the core regulatory mechanism in mouse endometrial epithelial cells involved in the establishment of uterine receptivity.

We describe a new δ/β fusion gene causing β-thalassemia (β-thal) trait and its formation mechanism. The proband was a 39-year-old woman who presented with persistent microcytic microcytosis without iron deficiency. Molecular diagnoses revealed a δβ configuration within a 54 bp region between the Cap site (+22) and codon 8, causing a deletion (NG_000007.3: g.63154_70565del). This results in a variant that has been named Hb Lepore-Hong Kong and shows a decreased β-globin mRNA in carriers compared to that of normal subjects. It is assumed that combination of this variant with β-thal may cause severe β-thal syndrome.

Objective To report the experience on the clinical use of noninvasive cell-free (cf) DNA testing at late pregnancy. Study design A cohort of 1539 women with singleton gestations of ≥23 weeks receiving cfDNA testing in a 3-year period were included for this study. Maternal characteristics and data on cfDNA testing, confirming diagnostic testing and pregnancy outcome were reviewed. Results During the study period, 1539 patients had cfDNA testing although they had a normal first-trimester screening. Of these, 7 cases had a positive result, including 5 for chromosome 21, one for chromosome 18, and one for chromosome 13. The most common indication was soft markers on ultrasound, followed by polyhydramnios. Cytogenetic testing was done for the 5 trisomy 21 positive cases, and confirmed the cfDNA results. Confirmative testing was declined in the two cases with positive cfDNA for trisomy 18/13, and postnatal placental investigation showed confined placental mosaicism with normal karyotype in the cord blood of newborns. There were no confirmed false negatives reported. The cfDNA screening achieved a positive predictive value of 71.4 % and a negative predictive value of 100 % in late pregnancy for common trisomies. Conclusions There is no gestational age upper limit for cfDNA use in the clinical practice. Most of the time, cfDNA was used in late gestation for reassurance in patients who is at low risk for aneuploidies but had second-trimester soft markers on ultrasound.

The aim of this study was to analyse the factors associated with fetal pleural effusion over the past five years in a single institute in the South of China. Between January 2011 and May 2016, 129 foetuses with pleural effusion were referred to the Fetal Medicine Unit in Guangzhou's Women and Children's Medical Center. Seventy-nine women accepted an invasive procedure to rule out chromosomal abnormalities, fetal anaemia, intrauterine infections or some of the submicroscopic chromosomal abnormalities. Our results showed that chromosomal anomalies occurred in 15.2% (12/79) of cases including 8 Turner syndrome (45, X) (10.1%), 3 trisomy 21 (3.8%) and 1 trisomy 13 (1.3%). Pathological microdeletion or microduplication syndrome occurred in 3 out of 36 (8.3%) prenatal samples with normal karyotype and structural defects. Eight foetuses (10.1%) affected with haemoglobin Bart's disease showed pleural effusion at second or third trimester. Two cases (2.5%) were found to have an intrauterine infection. In conclusion, fetal pleural effusion has a close correlation with chromosomal abnormality. CMA may increase the detection rate of chromosomal aberrations, especially for micro-deletion or micro-duplication syndromes. In the South of China, Thalassemia must be considered when a fetal pleural effusion is detected.Impact statementWhat is already known on this subject? The aetiology of fetal pleural effusion includes a chromosomal abnormality, a congenital heart disease, congenital infections and a number of genetic syndromes.What do the results of this study add? This is the first retrospective study to analyse the aetiology of fetal pleural effusion in one institute in the South of China.What are the implications of these findings for clinical practice and/or further research? Besides the chromosomal abnormality, micro-deletion and micro-duplication syndromes were also detected in our study. We feel that thalassemia must be considered when fetal pleural effusion is detected in South China.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a critical role in the cholesterol metabolism by negatively regulating the low-density lipoprotein receptor (LDLR). Lipid metabolic and ovarian disorders are the common clinical manifestation of polycystic ovary syndrome (PCOS). Here, we intended to elucidate the role of PCSK9 in the pathogenesis of PCOS conducted on a human population in case-control design and animal part in an interventional study.We firstly investigated the serum levels of PCSK9 in 46 PCOS patients compared with 49 healthy women as controls, and then developed a PCOS mouse model induced by dehydroepiandrosterone (DHEA) and a high-fat diet (HFD) to determine the role of PCSK9 in abnormal lipid metabolism and ovarian dysfunction of PCOS in four groups (n = 40 per group): control, PCOS mice, PCOS plus alirocumab group, and PCOS plus vehicle group. The expression of PCSK9 in their serum, hepatic and ovarian tissues, serum lipid profiles and hormones were measured. Additionally, mRNA and protein expression levels of LDLR in hepatic and ovarian tissues, ovarian morphology and function were determined. Finally, we used freshly isolated theca-interstitial cells (TICs) and granulosa cells (GCs) from prepubertal normal mice to explore the effect of PCSK9 on LDL uptake of the cells.Serum PCSK9 concentrations were higher in PCOS patients than normal controls (P 0.05). The PCOS model mice exhibited significantly increased serum levels of total cholesterol (TC), LDL-C and high-density lipoprotein-cholesterol (HDL-C; P 0.001, P 0.001, P = 0.0004, respectively). Moreover, the serum PCSK9 protein level was significantly increased in PCOS mice (P = 0.0002), which positively correlated with serum LDL-C (r = 0.5279, P = 0.0004) and TC (r = 0.4151, P = 0.035). In both liver and ovary of PCOS mice, PCSK9 mRNA and protein levels were significantly increased (P 0.05), but LDLR levels were significantly decreased (P 0.05). Furthermore, alirocumab inhibiting PCSK9 partly increased in LDLR expression in both liver and ovary in PCOS mice, also ameliorated the lipid metabolic disorders and pathological changes of ovarian morphology and function and serum reproductive hormones but not in the PCOS plus vehicle group. In vitro experiment, recombinant PCSK9 decreased LDL uptake in TICs and GCs (P 0.001, P = 0.0011, respectively), which were partly reversed by alirocumab (P 0.001, P = 0.012, respectively).Abnormal high expression of PCSK9 in the blood, liver and ovary may be involved in the pathogenesis of PCOS by affecting lipid metabolism and ovarian function, and the inhibition of PCSK9 may partly reverse the pathological changes of PCOS. Our research suggests a possibility of PCSK9 as a new attractive target for diagnosis and treatment of PCOS.

Objectives: To present the prenatal findings and the molecular cytogenetic analyses of a de novo interstitial deletion of 1q23.3 encompassing PBX1 gene. Case report: A 32-year-old woman (gravida 1, para 0) underwent amniocentesis at 26 weeks' gestation because of constant small fetal kidneys on prenatal ultrasound. Chromosome microarray analysis (CMA) detected a de novo deletion of 1.871 Mb at 1q23.3. The deletion encompassed 2 genes of PBX1 and LMX1A. PBX1 haploinsufficiency had been reported to lead syndromic congenital anomalies of kidney and urinary tract (CAKUT) in humans. Furthermore, at 31 weeks’ gestation, borderline oligohydramnios and restricted fetal dimensions were revealed. Ultimately, the pregnancy was terminated at 32 weeks with a 1500-g female fetus presenting polydactyl of left hand. Conclusions: The shared phenotypes between this case and the previously published prenatal cases demonstrate that loss of function mutation in PBX1 should be suspicious in fetus with bilateral renal hypoplasia, oligohydramnios and intrauterine growth retardation (IUGR). Keywords: PBX1, Renal hypoplasia, Prenatal diagnosis, Chromosome microarray analysis

Background and methods: Chromosome microarray analysis (CMA) is currently the first-tier diagnostic assay for the evaluation of developmental delay (DD) and intellectual disability (ID) with unknown etiology. Here, we present our clinical experience in implementing whole-genome high-resolution single nucleotide polymorphism (SNP) arrays to investigate 489 patients with unexplained DD/ID in whom standard karyotyping analyses showed normal karyotypes. This study aimed to assess the usefulness of CMA for clinical diagnostic testing in the Chinese population. Results: A total of 489 children were classified into three groups: isolated DD/ID (n = 358), DD/ID with epilepsy (n = 49), and DD/ID with other structural anomalies (n = 82). We identified 126 cases (25.8%, 126/489) of pathogenic copy number variants (CNVs) by CMA, including 89 (24.9%, 89/358) with isolated DD/ID, 13 (26.5%, 13/49) with DD/ID with epilepsy, and 24 (29.3%, 24/82) with DD/ID with other structural anomalies. Among the 126 cases of pathogenic CNVs, 79 cases were identified as microdeletion/microduplication syndromes, among which 76 cases were classified as common syndromes, and 3 cases were classified as rare syndromes, including 15q24 microdeletion syndrome, Xq28 microduplication syndrome and Lowe syndrome. Additionally, there were forty-seven cases of non-syndromic pathogenic CNVs. The ABAT, FTSJ1, DYNC1H1, and SETBP1 genes were identified as DD/ID candidate genes. Conclusion: Our findings suggest the necessity of CMA as a routine diagnostic test for unexplained DD/ID in South China. Key Words: developmental delay, intellectual disability, chromosome microarray analysis, CNVs, microdeletion/microduplication

Objective: The aim of this study was to evaluate the utility of chromosomal microarray (CMA) in patients who were solely referred for molecular diagnosis.Methods: During a 2-year period, CMA was th...

The 17q12 deletion syndrome is a chromosomal anomaly resulting from the interstitial microdeletion of the long arm of chromosome 17. The aim of this study was to present the experience on prenatal diagnosis of 17q12 deletion to further define the prenatal phenotypes of this syndrome. Eleven pregnancies with foetal 17q12 deletion detected by chromosomal microarray (CMA) were retrospectively included at a single Chinese tertiary medical centre. Clinical data were reviewed for these cases, including the maternal demographics, foetal ultrasound findings, CMA results and pregnancy outcomes. The deletion sizes of 17q12 ranged from 1.42 to 1.94 Mb. The deletion had arisen de novo in 10 cases and inherited from one of the parents in one case. Variable kidney abnormalities were found by ultrasound in all of the cases, with bilateral or unilateral hyperechogenic kidneys being the most common findings. This study indicates that a strikingly high correlation between prenatal hyperechogenic kidneys and 17q12 deletion, and prenatal testing with CMA should be offered to the foetal cases of hyperechogenic kidneys. Impact statement What is already known on this subject? 17q12 deletion syndrome is a cause of renal abnormalities, maturity-onset diabetes of the young and neurodevelopmental disorders. Prenatal diagnosis has been reported in several isolated cases with the use of microarray-based technologic means. What do the results of this study add? The results provide further evidence that a strikingly high correlation between prenatal hyperechogenic kidneys and 17q12 deletion, and genetic testing should be offered to foetal cases with hyperechogenic kidneys. A rare prenatal case of 17q12 deletion with multiple structural malformations and anhydramnios is presented. What are the implications of these findings for clinical practice and/or further research? There should be a high index of suspicion of carriers in parents when 17q12 deletion is confirmed prenatally. An extremely wide phenotype spectrum of this deletion should be emphasised in the prenatal counselling.

Objective To evaluate the utility of clinical exome sequencing (ES)-based carrier screening in Chinese consanguineous couples. Methods Consanguineous couples were screened for autosomal recessive (AR) disorders using the clinical ES of 5000 genes associated with human diseases. Results We recruited 14 couples who elected to have sequencing. One couple was related as first cousins and 13 as second cousins. Both partners carrying the same pathogenic variant were detected in four couples. One couple was found in which one partner carried a splice variant, and the other had a missence variant of the same gene. These five couples were identified as being at risk of having a child affected by an AR disorder. Conclusion Our study demonstrates that ES-based preconception screening yields a clinical value for Chinese consanguineous couples. It enables to detect at-risk couples for rare AR diseases.

Objectives To investigate the ratio of Crown to Chin length (CCL) to Crown-rump length (CRL) between triploid and normal fetuses at first trimester and establish a reference range of fetal CCL/CRL ratio. Methods Three hundred and twenty-five normal and 12 triploid fetuses were reviewed in this study. The image of fetal Crown-rump length (CRL) was acquired retrospectively. CCL and CRL were measured offline by two experienced sonographers, we obtained each averaged value of CCL and CRL as the final data for analysis. A normal range of CCL was established and CCL/CRL ratio was analyzed in normal and triploid fetuses. Results In 325 normal fetuses, CCL increased with gestational age following a linear trend from 20 mm at a CRL of 45-36 mm at a CRL of 84 mm (CCL (mm) = 3.65 + 0.38 CRL, R2 = 0.821, P = .000). The CCL/CRL ratio decreased with gestational age from a mean of 0.46 at a CRL of 45 mm to 0.41 at a CRL of 84 mm (PML/CRL = 0.502-0.001 CRL, R2 = 0.093, P = .000). All 12 triploid fetuses had a CCL/CRL ratio above the 95th percentile. When the 95th percentile are used as cutoff values, the detection rate, false-positive rate, and the positive likelihood ratio are 100%, 5%, and 20, respectively. Conclusions The present study demonstrates that fetal CCL/CRL ratio can be used and effective ultrasound marker in screening for triploidy during the first trimester.

The incidence of polycystic ovary syndrome (PCOS) due to high-fat diet (HFD) consumption has been increasing significantly. However, the mechanism by which a HFD contributes to the pathogenesis of PCOS has not been elucidated. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a key protein that regulates cholesterol metabolism. Our previous study revealed abnormally high PCSK9 levels in serum from patients with PCOS and in serum and hepatic and ovarian tissues from PCOS model mice, suggesting that PCSK9 is involved in the pathogenesis of PCOS. However, the factor that induces high PCSK9 expression in PCOS remains unclear. In this study, Pcsk9 knockout mice were used to further explore the role of PCSK9 in PCOS. We also studied the effects of a HFD on the expression of PCSK9 and sterol regulatory element-binding protein 2 (SREBP2), a regulator of cholesterol homeostasis and a key transcription factor that regulates the expression of PCSK9, and the roles of these proteins in PCOS pathology. Our results indicated HFD may play an important role by inducing abnormally high PCSK9 expression via SREBP2 upregulation. We further investigated the effects of an effective SREBP inhibitor, fatostain, and found that it could reduce HFD-induced PCSK9 expression, ameliorate hyperlipidemia and improve follicular development in PCOS model mice. Our study thus further elucidates the important role of an HFD in the pathogenesis of PCOS and provides a new clue in the prevention and treatment of this disorder.

Objective To evaluate the prognosis of fetuses with a prenatal diagnosis of micrognathia in the first trimester. Study design Over a 3-year period, patients with fetal micrognathia were detected at the time of nuchal translucency screening. The medical records of these pregnancies were reviewed, including maternal demographics, sonographic findings, genetic testing results and pregnancy outcomes. Results Forty-three cases of first-trimester micrognathia were included in this study. Chromosomal abnormalities were detected in seven cases. Of the fetuses with a normal array, further investigation of monogenic disorders with whole-exome sequencing was undertaken in 13 cases. Monogenic syndromes were identified in eight cases, including six with de-novo dominant alleles and two with recessive conditions. Whole-exome sequencing was refused in 23 cases; among these, other additional anomalies were found on anatomic ultrasound in 10 cases. Conclusion This study demonstrated that caution should be adopted when finding an apparently isolated micrognathia in early gestation, even with a normal array. A diagnosis of genetic syndrome or multiple anomalies on subsequent scans is most likely, and will affect the final prognosis.