Oxidative stress mediated decrement of spinal endomorphin-2 contributes to lumbar disc herniation sciatica in rats.

Increasing evidence supported that oxidative stress induced by herniated lumbar disc played important role in the formation of lumbar disc herniation sciatica (LDHS), however, the neural mechanisms underlying LDHS need further clarification. Endomorphin-2 (EM2) is the endogenous ligand for mu-opioid receptor (MOR), and there is increasing evidence implicating the involvement of spinal EM2 in neuropathic pain. In this study, using an nucleus pulposus implantation induced LDHS rat model that displayed obvious mechanical allodynia, it was found that the expression of EM2 in dorsal root ganglion (DRG) and spinal cord was significantly decreased. It was further found that oxidative stress in DRG and spinal cord was significantly increased in LDHS rats, and the reduction of EM2 in DRG and spinal cord was determined by oxidative stress dominated increment of dipeptidylpeptidase IV activity. A systemic treatment with antioxidant could prevent the forming of mechanical allodynia in LDHS rats. In addition, MOR expression in DRG and spinal cord remained unchanged in LDHS rats. Intrathecal injection of MOR antagonist promoted pain behavior in LDHS rats, and the analgesic effect of intrathecal injection of EM2 was stronger than that of endomorphin-1 and morphine. Taken together, our findings suggest that oxidative stress mediated decrement of EM2 in DRG and spinal cord causes the loss of endogenous analgesic effects and enhances the pain sensation of LDHS.

Ndufa4 Regulates the Proliferation and Apoptosis of Neurons via miR-145a-5p/Homer1/Ccnd2.

The Dandy-Walker malformation (DWM) is characterized by neuron dysregulation in embryonic development; however, the regulatory mechanisms associated with it are unclear. This study aimed to investigate the role of NADH dehydrogenase 1 alpha subcomplex 4 (NDUFA4) in regulating downstream signaling cascades and neuronal proliferation and apoptosis. Ndufa4 overexpression promoted the proliferation of neurons and inhibited their apoptosis in vitro, which underwent reverse regulation by the Ndufa4 short hairpin RNAs. Ndufa4-knockout (KO) mice showed abnormal histological alterations in the brain tissue, in addition to impaired spatial learning capacity and exploratory activity. Ndufa4 depletion altered the microRNA expressional profiles of the cerebellum: Ndufa4 inhibited miR-145a-5p expression both in the cerebellum and neurons. miR-145a-5p inhibited the proliferation of neurons and promoted their apoptosis. Ndufa4 promoted and miR-145a-5p inhibited the expression of human homer protein homolog 1 and cyclin D2 in neurons. Thus, Ndufa4 promotes the proliferation of neurons and inhibits their apoptosis by inhibiting miR-145a-5p, which directly targets and inhibits the untranslated regions of Homer1 and Ccnd2 expression.

The Value of a Comprehensive Genomic Evaluation in Prenatal Diagnosis of Genetic Diseases: A Retrospective Study.

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.

Prenatal isolated clubfoot increases the risk for clinically significant exome sequencing results.

OBJECTIVE: To examine the diagnostic yield of exome sequencing (ES) in singleton pregnancies with isolated fetal clubfoot. METHODS: 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. RESULTS: 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. CONCLUSION: Sonographic diagnosis of clubfoot, even isolated, increases the risk for monogenic syndromes. Exome sequencing should be an option for genetic investigation for such pregnancies.

Sotos syndrome: A study of antenatal presentation.

OBJECTIVE: 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. STUDY DESIGN: 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. RESULTS: 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. CONCLUSION: 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.

Prenatal Silver-Russell Syndrome in a Chinese Family Identified by Non-Invasive Prenatal Testing.

Russell-Silver syndrome (SRS) is a rare condition characterized by poor growth before and after birth along with multiple physical and psychosocial characteristics such as short stature, characteristic facial features, body asymmetry, feeding difficulties, and learning disabilities. In this study, we report a family with 2 recurrent SRS pregnancies due to a derivative chromosome 15 that is the result of a maternally derived t(11;15) translocation, detected by non-invasive prenatal testing (NIPT). The 2 SRS fetuses were diagnosed by chromosomal microarray analysis, but a balanced, reciprocal translocation of the mother was disclosed by the combination of routine karyotyping and FISH. This study demonstrates that NIPT has the ability to identify submicroscopic copy number variations (CNVs) in fetuses, which in some cases may result from a parent being a balanced rearrangement carrier. Because of the differences in resolution and the various benefits and limitations of each genetic technique, great care must be taken when deciding on which test(s) to employ in family studies.

Prenatal sonographic findings in a cohort of foetuses with a confirmed 22q11.2 microdeletion at a single Chinese Tertiary Centre.

The aim of this study was to present prenatal ultrasound findings, molecular testing results and pregnancy outcomes of cases with 22q11.2 deletion (del22q11.2) diagnosed prenatally. A total of 76 foetuses were included. All cases were diagnosed by using chromosomal microarray analysis. Data on prenatal diagnosis, ultrasound findings, pregnancy outcomes and inheritance of del22q11.2 were reviewed. Congenital heart defects (CHDs) were the most common indications (47/76, 61.8%) for prenatal testing and were isolated in 52.6% (40/76). The constitution of CHDs comprised predominantly of conotruncal defects (61.7%; 29/47). Other cardiac anomalies were encountered in 38.3% (18/47) of cases. Extracardiac findings, including unilateral multicystic dysplastic kidney, clubfoot, increased nuchal translucency, intrauterine growth retardation and polyhydramnios, were found in 31.6% (24/76) of cases, and were combined with CHDs in 7 cases. Twelve cases had normal sonographic scans at the time of prenatal diagnosis. Foetal CHDs, especially conotruncal defects, are the most predictive association with del22q11.2. The information about del22q11.2 should also be part of the contents in comprehensive pre-test counselling even for those who are referred for diagnostic testing with foetal extracardiac findings.Impact statementWhat is already known on this subject? 22q11.2 deletion (del22q11.2) is the most common microdeletion syndrome in humans. At present, the main indications for prenatal testing for del22q11.2 are pregnancies of abnormal sonographic findings, especially foetal congenital heart defects.What do the results of this study add? Many extracardiac malformations, including some lethal or mildly non-specific ones, could be associated with foetal del22q11.2. There were also del22q11.2 foetuses had normal sonographic scans at the time of prenatal diagnosis.What are the implications of these findings for clinical practice and/or further research? The information about del22q11.2 should also be part of the contents in comprehensive pre-test counselling even for those who are referred for diagnostic testing with indications other than foetal cardiac anomalies.

Prenatal diagnosis of Miller-Dieker syndrome/PAFAH1B1-related lissencephaly: Ultrasonography and genetically investigative results.

OBJECTIVE: To present the experience on prenatal diagnosis of Miller-Dieker syndrome (MDS)/PAFAH1B1-related lissencephaly to further determine fetal phenotypes of this syndrome. STUDY DESIGN: 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. RESULTS: 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. CONCLUSION: 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.

Fetal akinesia: The need for clinical vigilance in first trimester with decreased fetal movements.

OBJECTIVE: We present two cases of fetal akinesia detected by first trimester ultrasound with noticing reduced fetal movements. CASE REPORT: Both of the two cases presented with reduced fetal movements. Fetal microarray results were normal. Follow-up sonographic examinations showed that Case 1 had structural anomalies with reduced fetal movements, and Case 2 had findings of reduced fetal movements and olyhydramnios. Case 1 ended with termination of pregnancy, and was confirmed to suffer from distal arthrogryposis (DA) type 5D (DA5D) with two pathogenic ECEL1 variants, NM_004826: c.110_155del46 (p.F37Cfs∗151) and c.633G > C (p.W211C). Case 2 continued to term. However, the infant developed breathing problems and severe hypotonia after birth, and died at 3 months. Nemaline myopathy was diagnosed with two NEB variants, NM_001271208.1: c.3255+1G > T and c.7165delA (p.W211C) detected in the patient. CONCLUSION: The first trimester ultrasound can detect clues that lead to the diagnosis of fetal akinesias presenting with reduced or absent fetal movements. Our results would be useful in counselling parents of affected pregnancies and in alerting physicians to plan the appropriate follow-up investigations for such cases.

[Research on network pharmacology of Acori Tatarinowii Rhizoma combined with Curcumae Radix in treating epilepsy].

The chemical constituents and action targets of Acori Tatarinowii Rhizoma and Curcumae Radix were screened by network pharmacological method,and the mechanism of the combination of Acori Tatarinowii Rhizoma and Curcumae Radix in the treatment of epilepsy was analyzed. All chemical constituents of Acori Tatarinowii Rhizoma and Curcumae Radix were retrieved by TCMSP,and their action targets were screened. Component target PPI network was constructed. Epilepsy-related genes were retrieved from PharmGkb database,and PPI networks of disease targets were drawn by Cytoscape software. Cytoscape software was used to merge the network,screen the core network,and further analyze the gene GO function and KEGG pathway enrichment,which was verified by experimental research. One hundred and five chemical constituents of Acori Tatarinowii Rhizoma and 222 chemical constituents of Curcumae Radix were retrieved. Nineteen compounds were selected as candidate compounds according to OB and DL values. Among them,4 chemical constituents of Acori Tatarinowii Rhizoma and 15 chemical constituents of Curcumae Radix were found. A total of 88 target proteins were retrieved by retrieving TCMSP data,and PPI network was constructed. Through PharmGkb database,29 epilepsy-related genes were retrieved and disease target network was established. Cytoscape software and plug-ins were used for network merging and core network screening,and 69 genes were screened out. Through GO function analysis and KEGG pathway analysis,the mechanism of anti-epilepsy is related to prolactin signaling pathway,HTLV-Ⅰ infection signaling pathway,MAPK signaling pathway and herpes simplex infection signaling pathway. Further experimental verification showed that the serum prolactin level in epileptic rats was significantly increased. The neurons in hippocampal CA1 area degenerated,necrotized and lost 24 hours after epileptic seizure,and some neuron interstitial edema occurred. The possible mechanism of compatibility of Acori Tatarinowii Rhizoma and Curcumae Radix is related to serum prolactin level,MAPK signaling pathway,HTLV-Ⅰ infection and herpes simplex infection. The analysis may be related to viral encephalitis caused by HTLV-Ⅰ virus and herpes simplex infection,which damages nerve cells and causes seizures.

Chromosome microarray analysis in the investigation of children with congenital heart disease.

BACKGROUND: Our study was aimed to explore the clinical implication of chromosome microarray analysis (CMA) in genetically etiological diagnosis of children with congenital heart disease (CHD). METHODS: A total of 104 children with CHD with or without multiple congenital anomalies (MCA) or intellectual disabilities/developmental delay (ID/DD) but normal karyotype were investigated using Affymetrix CytoScan HD array. RESULT: Pathogenic copy number variations (PCNVs) were identified in 29 children (27.9%). The detection rates in children with simple CHD and complex CHD were 31.1% (19/61) and 23.2% (10/43), respectively. The detection rates of PCNVs were 17.9% (7/39), 20% (5/25), 63.2% (12/19) and 23.8% (5/21) in isolated CHD, CHD plus MCA, CHD plus ID/DD, CHD plus MCA and ID/DD, respectively. The PCNVs rate of CHD plus ID/DD was significantly higher than that of isolated CHD. Two genomic loci including 15q11.2 deletion and 1q43-q44 deletion were considered as CHD locus. The DVL1, SKI, STIM1, CTNNA3 and PLN were identified as candidate genes associated with CHD phenotypes. CONCLUSION: CMA can increase the diagnostic rate and improve the etiological diagnosis in children with CHD. We suggest CMA as a first-tier test in children with CHD, especially in children with CHD plus ID/DD.

Prenatal diagnosis of Smith-Magenis syndrome in two fetuses with increased nuchal translucency, mild lateral ventriculomegaly, and congenital heart defects.

OBJECTIVE: Smith-Magenis syndrome (SMS) is a multiple congenital anomalies/mental retardation disorder characterized by an interstitial deletion involving chromosome 17p11.2 containing the retinoic acid-induced 1 (RAI1) gene or due to mutation of RAI1. Few cases have been reported in the medical literature regarding prenatal diagnosis of SMS. We report on the prenatal diagnosis of SMS in two fetuses with increased nuchal translucency (NT), mild lateral ventriculomegaly, and congenital heart defects by whole-genome and high-resolution chromosome microarray analysis (CMA). CASE REPORT: The CMA result of Fetus 1, which had increased NT, mild lateral ventriculomegaly, tricuspid regurgitation, and right aortic arch with left ductus arteriosus, revealed a de novo 4.79-Mb deletion at 17p12p11.2. Fetus 2 had increased NT, pulmonary stenosis, and a ventricular septal defect, and showed a de novo 3.68-Mb deletion at 17p11.2. CONCLUSION: The findings further confirm that increased NT is associated with genetic syndromes, and brain imaging is necessary for SMS fetuses. Both deletions encompass the SMS "critical region", which includes many genes including RAI1. However, the precise gene(s) responsible for the heart defects in SMS remain unclear; further efforts should be undertaken to understand the molecular basis of this syndrome.

[Effect of the Runoff-sediment Control of the Xiaolangdi Reservoir on DOC Transport].

The sampling was carried out in Sanmenxia hydrological station, Xiaolangdi hydrological station and Huayuankou hydrological station from November 2011 to October 2012. The impact of the runoff-sediment control of the Xiaolangdi reservoir on DOC transport,was analyzed. The results were as follows. DOC contents in Sanmenxia station, Xiaolangdi station and Huayuankou station were 1.97-2.71 mg-L(-1), 1.87-2.76 mg x L(-1) and 2.07-2.93 mg x L(-1), respectively, during the normal operation period of Xiaolangdi Reservoir and Sanmenxia reservoir, and the DOC content in the three reservoirs had obvious seasonal change. DOC contents in the three stations were 2.14-3.32 mg x L(-1), 2.21-2.84 mg x L(-1) and 2.11-2.84 mg x L(-1), respectively, during the runoff-sediment control, and the DOC content in the sediment-releasing period of reservoir was higher than that in the water-releasing period of reservoir. DOC content had no significant correlation with TSS and flow either during the normal operation or during the water-sediment regulation of the reservoir. But the DOC content had significant correlation with water temperature during the normal operation of the reservoir. DOC flux in Sanmenxia station was similar to that in Xiaolangdi station from November to March. DOC flux in Sanmenxia station was obviously less than that in Xiaolangdi station from April to July. And the DOC flux in Sanmenxia station was much higher than that in Xiaolangdi station from August to October. The result showed that DOC was retained from August to October by Xiaolangdi reservoir and discharged from Xiaolangdi reservoir from April to July. The yearly DOC fluxes were 8.6 x 10(10), 9.0 x 10(10) and 9.7 x 10(10) g respectively in Sanmenxia station, Xiaolangdi station and Huayuankou station. The DOC flux of Sanmenxia station was the highest in September, which accounted for 22.0% of the yearly DOC flux, and the DOC flux of Xiaolangdi station was the highest in June, which accounted for 17.6% of the yearly DOC flux. The DOC flux of Huayuankou station was the highest in July, which accounted for 16.7% of the yearly DOC flux. DOC fluxes during the runoff-sediment regulation accounted for 14.7% and 13.8% of the yearly DOC flux respectively in Xiaolangdi station and Huayuankou station, but the DOC fluxes during the runoff-sediment regulation accounted for only 3.6% of the yearly DOC flux in Sanmenxia station.

Thalassemia Intermedia Caused by 16p13.3 Sectional Duplication in a ß-Thalassemia Heterozygous Child.

Thalassemia intermedia is an inherited hemoglobin disorder characterized by a significant genetic and clinical heterogeneity. A wide spectrum of different genotypes-homozygous, heterozygous, and compound heterozygous-have been found to be responsible for it. The authors describe a Chinese child of ß-thalassemia heterozygote with the mutation IVS2-654 (C→T) (HBB:c.316-197C→T) presenting with severe thalassemia intermedia. Multiplex ligation-dependent probe amplification (MLPA) and array comparative genomic hybridization (CGH) analyses of the α gene cluster revealed an approximate 146-kb duplication at 16p13.3 including the complete α gene cluster. The duplicated allele and the normal allele in trans result in a total of 6 active α genes. The severe clinical phenotype seemed to be related to the considerable excess of the α-globin and the ß-globin deficit caused by the presence of the ß-thalassemia. The α gene duplication should be considered in patients heterozygous for ß-thalassemia who show a more severe phenotype than ß-thalassemia trait.

[Partial pressure of CO2 and CO2 degassing fluxes of Huayuankou and Xiaolangdi Station affected by Xiaolangdi Reservoir].

According to periodic sampling analysis per month in Xiaolangdi station and Huayuankou station from November 2011 to October 2012, combined with continuous sampling analysis of Xiaolangdi Reservoir during runoff and sediment control period in 2012, partial pressure of CO2 (pCO2) in surface water were calculated based on Henry's Law, pCO2 features and air-water CO2 degassing fluxes of Huayuankou station and Xiaolangdi station affected by Xiaolangdi Reservoir were studied. The results were listed as follows, when Xiaolangdi Reservoir operated normally, pCO2 in surface water of Xiaolangdi station and Huayuankou station varied from 82 to 195 Pa and from 99 to 228 Pa, moreover, pCO2 in surface water from July to September were distinctly higher than those in other months; meanwhile, pCO, in surface water from Huayuankou station were higher than that from Xiaolangdi station. During runoff and sediment control period of Xiaolangdi Reservoir, two hydrological stations commonly indicated that pCO2 in surface water during water draining were obviously lower than those during sediment releasing. Whether in the period of normal operation or runoff and sediment control, pCO2 in surface water had positive relations to DIC content in two hydrological stations. Since the EpCO,/AOU value was higher than the theoretical value of 0. 62, the biological aerobic respiration effect had distinct contribution to pCO2. Throughout the whole year, air-water CO2 degassing fluxes from Xiaolangdi station and Huayuankou station were 0.486 p.mol (m2 s) -l and 0.588 pmol (m2 x s)(-1) respectively; When Xiaolangdi Reservoir operated normally, air-water CO, degassing fluxes in Huayuankou station were higher than that in Xiaolangdi station; during runoff and sediment control from Xiaolangdi Reservoir, two hydrological stations had one observation result in common, namely, air-water CO2 degassing fluxes in the period of water draining were obviously lower than that in the period of sediment releasing.

Association of an α-globin gene cluster duplication and heterozygous ß-thalassemia in a patient with a severe thalassemia syndrome.

We describe a new case of a ß-thalassemia (ß-thal) heterozygote with the mutation IVS-II-654 (C>T) presenting with a transfusion-dependent phenotype. Multiplex ligation-dependent probe amplification (MLPA) and array comparative genomic hybridization (CGH) analyses of the α-globin gene cluster revealed a full duplication of the α-globin genes including the upstream regulatory element. The duplicated allele and the normal allele in trans resulted in a total of six active α-globin genes. The severe clinical phenotype seemed to be related to the considerable excess of the α- and ß-globin deficit caused by the presence of the ß-thal. α-Globin cluster duplication should be considered in patients heterozygous for ß-thal who show a more severe phenotype than ß-thal trait.

Prenatal diagnosis of 17q12 duplication and deletion syndrome in two fetuses with congenital anomalies.

OBJECTIVE: The objective of this study was to characterize the genetic abnormalities in two fetuses with congenital anomalies in prenatal screening. MATERIALS AND METHODS: The mother of Fetus 1 was 26 years old and had a second trimester serum screening that indicated the fetus was at low risk. The prenatal ultrasound and magnetic resonance imaging (MRI) at 28 weeks of gestation showed mild ventriculomegaly, microcephaly, and agenesis of the corpus callosum. The mother of Fetus 2 was 25 years old and also had a second trimester serum screening that indicated the fetus was at low risk. The prenatal ultrasound at 32 weeks of gestation showed the presence of hyperechogenic and enlarged kidneys with multicystic renal dysplasia bilaterally and a persistent left superior vena cava (PLSVC). Both pregnant women underwent cord blood samplings because of the abnormal imaging results. Karyotype analysis revealed normal results in the two fetuses. Chromosome microarray analysis (CMA) was then performed to provide genetic analysis of the cord blood and parental blood samples. Ultimately, the pregnancies were both terminated. RESULTS: CMA detected a 1.56-Mb duplication at 17q12 in Fetus 1 and a 1.93-Mb deletion of 17q12 in Fetus 2. Both the duplicated and deleted regions included the HNF1B and LHX1 genes. Neither the duplication nor deletion was inherited from the parents. CONCLUSION: This study is the first to report the prenatal diagnosis of a 17q12 duplication syndrome. Our results further confirmed that genes in this region, including HNF1B and LHX1, are essential for normal brain and kidney development, and also indicated some genes that may be associated with the cardiovascular abnormality. Combined with imaging examination, the use of CMA will improve the diagnosis of submicroscopic chromosomal aberrations in fetuses with congenital anomalies.

Prenatal diagnosis of foetuses with congenital abnormalities and duplication of the MECP2 region.

MECP2 duplication results in a well-recognised syndrome in 100% of affected male children; this syndrome is characterised by severe neurodevelopmental disabilities and recurrent infections. However, no sonographic findings have been reported for affected foetuses, and prenatal molecular diagnosis has not been possible for this disease due to lack of prenatal clinical presentation. In this study, we identified a small duplication comprising the MECP2 and L1CAM genes in the Xq28 region in a patient from a family with severe X-linked mental retardation and in a prenatal foetus with brain structural abnormalities. Using high-resolution chromosome microarray analysis (CMA) to screen 108 foetuses with congenital structural abnormalities, we identified additional three foetuses with the MECP2 duplication. Our study indicates that ventriculomegaly, hydrocephalus, agenesis of the corpus callosum, choroid plexus cysts, foetal growth restriction and hydronephrosis might be common ultrasound findings in prenatal foetuses with the MECP2 duplication and provides the first set of prenatal cases with MECP2 duplication, the ultrasonographic phenotype described in these patients will help to recognise the foetuses with possible MECP2 duplication and prompt the appropriate molecular testing.

Noninvasive prenatal diagnosis of common aneuploidies by semiconductor sequencing.

Massively parallel sequencing (MPS) of cell-free fetal DNA from maternal plasma has revolutionized our ability to perform noninvasive prenatal diagnosis. This approach avoids the risk of fetal loss associated with more invasive diagnostic procedures. The present study developed an effective method for noninvasive prenatal diagnosis of common chromosomal aneuploidies using a benchtop semiconductor sequencing platform (SSP), which relies on the MPS platform but offers advantages over existing noninvasive screening techniques. A total of 2,275 pregnant subjects was included in the study; of these, 515 subjects who had full karyotyping results were used in a retrospective analysis, and 1,760 subjects without karyotyping were analyzed in a prospective study. In the retrospective study, all 55 fetal trisomy 21 cases were identified using the SSP with a sensitivity and specificity of 99.94% and 99.46%, respectively. The SSP also detected 16 trisomy 18 cases with 100% sensitivity and 99.24% specificity and 3 trisomy 13 cases with 100% sensitivity and 100% specificity. Furthermore, 15 fetuses with sex chromosome aneuploidies (10 45,X, 2 47,XYY, 2 47,XXX, and 1 47,XXY) were detected. In the prospective study, nine fetuses with trisomy 21, three with trisomy 18, three with trisomy 13, and one with 45,X were detected. To our knowledge, this is the first large-scale clinical study to systematically identify chromosomal aneuploidies based on cell-free fetal DNA using the SSP and provides an effective strategy for large-scale noninvasive screening for chromosomal aneuploidies in a clinical setting.

A new hemoglobin variant: Hb Henan [ß90(F6)Glu → Gln; HBB: c.271G < C].

We have identified a new ß chain hemoglobin (Hb) variant in a Chinese individual. Sequencing of the ß-globin gene revealed a mutation in exon 2 at nucleotide 271, which results in the replacement of a glutamic acid by glutamine at codon 90 [ß90(F6)Glu → Gln; GAG > CAG; HBB: c.271G > C] that we have named Hb Henan.