Showing papers by "Wenhao Zhou published in 2020"

Clinical analysis of 10 neonates born to mothers with 2019-nCoV pneumonia

Abstract: Background The newly identified 2019-nCoV, which appears to have originated in Wuhan, the capital city of Hubei province in central China, is spreading rapidly nationwide. A number of cases of neonates born to mothers with 2019-nCoV pneumonia have been recorded. However, the clinical features of these cases have not been reported, and there is no sufficient evidence for the proper prevention and control of 2019-nCoV infections in neonates. Methods The clinical features and outcomes of 10 neonates (including 2 twins) born to 9 mothers with confirmed 2019-nCoV infection in 5 hospitals from January 20 to February 5, 2020 were retrospectively analyzed. Results Among these 9 pregnant women with confirmed 2019-nCoV infection, onset of clinical symptoms occurred before delivery in 4 cases, on the day of delivery in 2 cases, and after delivery in 3 cases. In most cases, fever and a cough were the first symptoms experienced, and 1 patient also had diarrhea. Of the newborns born to these mothers, 8 were male and 2 were female; 4 were full-term infants and 6 were born premature; 2 were small-for-gestational-age (SGA) infants and 1 was a large-for-gestational-age (LGA) infant; there were 8 singletons and 2 twins. Of the neonates, 6 had a Pediatric Critical Illness Score (PCIS) score of less than 90. Clinically, the first symptom in the neonates was shortness of breath (n=6), but other initial symptoms such as fever (n=2), thrombocytopenia accompanied by abnormal liver function (n=2), rapid heart rate (n=1), vomiting (n=1), and pneumothorax (n=1) were observed. Up to now, 5 neonates have been cured and discharged, 1 has died, and 4 neonates remain in hospital in a stable condition. Pharyngeal swab specimens were collected from 9 of the 10 neonates 1 to 9 days after birth for nucleic acid amplification tests for 2019-nCoV, all of which showed negative results. Conclusions Perinatal 2019-nCoV infection may have adverse effects on newborns, causing problems such as fetal distress, premature labor, respiratory distress, thrombocytopenia accompanied by abnormal liver function, and even death. However, vertical transmission of 2019-nCoV is yet to be confirmed.

Neonatal Early-Onset Infection With SARS-CoV-2 in 33 Neonates Born to Mothers With COVID-19 in Wuhan, China.

Abstract: This cohort study examines medical records of 33 neonates born to women with COVID-19 to provide information on maternal-child transmission and infant outcomes.

Chinese expert consensus on the perinatal and neonatal management for the prevention and control of the 2019 novel coronavirus infection (First edition)

Abstract: Since December 2019, there has been an outbreak of novel coronavirus (2019-nCoV) infection in China. Two cases of neonates with positive 2019-nCoV tests have been reported. Due to the immature immune system and the possibility of vertical transmission from mother to infant, neonates have become a high-risk group susceptible to 2019-nCoV, which emphasize a close cooperation from both perinatal and neonatal pediatrics. In neonatal intensive care unit (NICU), to prevent and control infection, there should be practical measures to ensure the optimal management of children potentially to be infected. According to the latest 2019-nCoV national management plan and the actual situation, the Chinese Neonatal 2019-nCoV expert working Group has put forward measures on the prevention and control of neonatal 2019-nCoV infection.

Altered gut microbiota and mucosal immunity in patients with schizophrenia.

Abstract: Evidence shows that gut microbiota may play important roles in schizophrenia pathogenesis via the "gut-brain" axis, but the mechanisms remain unclear. Here, eighty-four patients with schizophrenia and 84 sex- and age-matched healthy controls were enrolled. Shotgun metagenomic sequencing and 16S rRNA sequencing were performed, and the gut microbiota-associated epitopes (MEs) were predicted, which, together with IgA content, were used to determine the gut microbiota composition associated with gut immune status. Patients with schizophrenia had significantly reduced gut microbiota richnesses compared with those of the healthy controls, and the gut microbiota compositions clearly distinguished the patients with schizophrenia from the healthy controls. Based on two-stage metagenomic-wide association studies, nineteen gut microbiota taxonomies were associated with schizophrenia, and the microbial dysbiosis (MD) index was calculated based on the abundance of differential taxonomies. We found that MD index was positively correlated with MEs diversity and gut IgA levels, and negatively correlated with gut microbiota richness. Glutamate synthase (GOGAT) was more active in the guts of patients with schizophrenia than in those of healthy controls, and high GOGAT activity was associated with altered gut microbiota taxonomies associated with gut IgA levels. Our results may imply a role of the microbiome in the etiology of schizophrenia and contribute to the development of microbiome targeted interventions for schizophrenia.

The third generation sequencing: the advanced approach to genetic diseases.

Abstract: Genomic sequencing technologies have revolutionized mutation detection of the genetic diseases in the past few years. In recent years, the third generation sequencing (TGS) has been gaining insight into more genetic diseases owing to the single molecular and real time sequencing technology. This paper reviews the genomic sequencing revolutionary history first and then focuses on the genetic diseases discovered through the TGS and the clinical effects of the TGS, which is followed by the discussion of the improvement in the bioinformatic analysis for the TGS and its limitations. In summary, the TGS has been enhancing the diagnostic accuracy of genetic diseases in molecular level as well as paving a new way for basic researches and therapies.

Clinical exome sequencing as the first-tier test for diagnosing developmental disorders covering both CNV and SNV: a Chinese cohort

Abstract: Background Developmental disorders (DDs) are early onset disorders affecting 5%–10% of children worldwide. Chromosomal microarray analysis detecting CNVs is currently recommended as the first-tier test for DD diagnosis. However, this analysis omits a high percentage of disease-causing single nucleotide variations (SNVs) that warrant further sequencing. Currently, next-generation sequencing can be used in clinical scenarios detecting CNVs, and the use of exome sequencing in the DD cohort ahead of the microarray test has not been evaluated. Methods Clinical exome sequencing (CES) was performed on 1090 unrelated Chinese DD patients who were classified into five phenotype subgroups. CNVs and SNVs were both detected and analysed based on sequencing data. Results An overall diagnostic rate of 41.38% was achieved with the combinational analysis of CNV and SNV. Over 12.02% of patients were diagnosed based on CNV, which was comparable with the published CMA diagnostic rate, while 0.74% were traditionally elusive cases who had dual diagnosis or apparently homozygous mutations that were clarified. The diagnostic rates among subgroups ranged from 21.82% to 50.32%. The top three recurrent cytobands with diagnostic CNVs were 15q11.2-q13.1, 22q11.21 and 7q11.23. The top three genes with diagnostic SNVs were: MECP2, SCN1A and SCN2A. Both the diagnostic rate and spectrums of CNVs and SNVs showed differences among the phenotype subgroups. Conclusion With a higher diagnostic rate, more comprehensive observation of variations and lower cost compared with conventional strategies, simultaneous analysis of CNVs and SNVs based on CES showed potential as a new first-tier choice to diagnose DD.

Optimized trio genome sequencing (OTGS) as a first-tier genetic test in critically ill infants: practice in China.

Abstract: Genome sequencing is used to make genetic diagnoses in critically ill infants with rapid turnaround time (TAT). Herein, to delineate the value of a genetic diagnosis, we provide the results from 130 pediatric patients in a large, comprehensive children’s hospital in China. This study was performed using an optimized trio genome sequencing (OTGS) test. The sequencing depth for patients was 40–50 × and for their parents, it was 8–10 × . Patients from the pediatric or neonatal intensive care unit (PICU/NICU) with complicated clinical features were enrolled between June 2018 and December 2018, each with a phenotype suggesting an underlying genetic disorder. OTGS testing identified pathogenic variants in 62 of 130 individuals, resulting in a diagnosis rate of 47.7%. The TAT varied from 72 to 120 h, with an average of 94 h and a median of 90 h. Of the 62 infants with diagnoses, 48 (77.4%) had pathogenic single-nucleotide variants (SNVs), 12 (19.4%) had pathogenic copy number variations (CNVs) or structure variants (SVs), and 2 (3.2%) had small deletions in one allele plus pathogenic variants in another allele of autosomal recessive genes. Therapeutic strategies for 48.4% (30/62) of the diagnosed patients were modified and included transplantation, dietary recommendations, or change of drugs, which avoided morbidity and improved prognosis. This study provided high-capacity OTGS testing in detecting SNVs and chromosomal abnormalities with fast response, higher diagnostic yield, and lower cost. OTGS demonstrates the potential to be the first-tier of genetic testing used in critically ill infants in developing countries.

Protective humoral immunity in SARS-CoV-2 infected pediatric patients.

Abstract: After the rapid spread of SARS-CoV-2 in Wuhan, China, at the beginning of 2020, about 1.5 million confirmed cases and over 80,000 deaths have been reported around 200 countries and territories all over the world and the number continues to increase. However, we still have limited knowledge of this new coronavirus, especially the interaction between SARS-CoV-2 and our immune system. In contrast with infected adults, the children have received more attention because of the lower infection rates and milder symptoms. Less than 1% of infected cases were aged 10 years or younger. Only 3.5% of SARS-COV-2 infected children had lymphocytopenia. It has been reported, coronaviruses, including SARS-CoV, MERS-CoV, and SARS-CoV-2, seem to cause fewer symptoms and less severe disease in children compared with adults. This phenomenon may be related to the differences in the immune responses against the infection of coronaviruses between children and adults. Here, we reported the characteristics of immune response after the SARS-CoV-2 attack in children and found that there is a protective humoral immunity in infected children, in which memory B cells and S-protein specific Abs against the SARS-CoV-2 have been detected. Our observation presents one possible explanation for the milder symptoms in children after exposure to SARS-CoV-2. We analyzed the T/B lymphocytes in PBMC and the production of antibodies in serum from confirmed cases in pediatrics. The respiratory samples obtained from six patients were all tested positive by RT-PCR for SARS-CoV-2. A cycle threshold value less than 35 was defined as a positive test. Mild cough and sore throat were common symptoms at disease onset among these six patients. None of the patients had diarrhea or dyspnea during illness. The body temperature of three patients was below 38 degrees at disease onset. Chest X-ray showed no pneumonia among three patients. The detailed clinical and epidemiological features of patient 1/2/3/4/5 have been reported previously. Patient 6 was admitted to Children’s Hospital of Fudan University on 6 Feb and started with mild symptoms as cough and sore throat without fever and other symptoms. Chest X-ray showed no pneumonia. She got infected by SARS-CoV-2 from the household but the interval between symptom onset and exposure to index case is unclear. All patients presented with mild respiratory infections and have been discharged. Informed consent was obtained from the parents or guardians of the patients infected and uninfected with SARS-CoV-2 for the publication of their clinical data. Ethical approval was provided by the Hospital Ethics Committee. Our results showed that pediatric patients had more active B-cell immune responses than uninfected children and obvious antigen-specific antibody production within 2–3 weeks after illness onset. The experiments demonstrated that the neutralizing antibody against the Spike protein of SARS-CoV-2 was detected. This result indicates that there is a protective humoral immunity in children after the SARS-CoV-2 attack. To have a signature picture of immune responses following the SARS-CoV-2 infection, the RNA prepared from peripheral blood mononuclear cells (PBMC) from a SARS-CoV-2 infected pediatric case and an uninfected control were subjected to RNA sequencing using for Illumina HiSeqTM 2000. An immune systemrelated GO category enrichment analysis was performed to gain insights into the biological roles of the differential expression genes. We found that B cell-related GO terms were significantly enriched and top of 14 main immune response-related GO categories (S-Fig. 1a). Groups of the differential expression genes were highly enriched in infected case, including mature Bcell differentiation involved in immune response (GO:0002322), positive regulation of humoral immune response (GO:0002922), B-cell activation involved in immune response (GO:0002312) and humoral immune response mediated by circulating immunoglobulin (GO:0002925) (Fig. 1a). The RNA-seq profiling indicates that there is an enhanced humoral immune response responding to SARS-CoV-2 infection in children. Flow cytometry analysis was performed to analyze T and B cells from four infected pediatric cases and five uninfected controls. The controls were patients hospitalized during the same period without SARS-CoV-2 infection. The T cell gating strategy was shown in S-Fig. 2a. The previous report showed that the white blood cell count (median: 7.35 × 10/L; normal range: 3.9–9.9 × 10/L) and lymphocyte count (median: 3.25 × 10/L; normal range: 1.2–4.0 × 10/L) were normal in these infected pediatric cases, which was different from the lymphocytopenia in infected adults. Similar to the unchanged lymphocyte count, the percentage of CD3+, CD4+, and CD8+ T cells between infected and uninfected cases were comparable (S-Fig. 2b). Expression of a chemokine receptor CCR7, in combination with the naive cell marker CD45RA, has been shown to discriminate naïve T cell (NT: CD45RA+CCR7+)

Clinical utility of 24-h rapid trio-exome sequencing for critically ill infants.

Abstract: Genetic diseases are a leading cause of death in infants in the intensive care setting; therefore, rapid and accurate genetic diagnosis is desired. To validate 24-h trio-exome sequencing (TES), samples from probands and their parents were processed by the AmpliSeq /Ion S5XL platform in a hospital clinical laboratory. Infants from the intensive care unit (ICU) suspected of having a genetic disease were enrolled. Regular and 24-h TES using the Agilent SureSelect capture kit/Illumina platform were performed on all samples in parallel. Of 33 enrolled infants, 23 received positive results with rapid TES, and an additional two diagnoses were achieved with regular TES. Among the 23 diagnosed patients, 10 experienced changes in medical management, such as hematopoietic stem cell transplant. Ten diagnosed cases were discharged prior to receiving the regular TES results; six received timely symptom control, and four withdrew medical support. Rapid TES enabled faster time to diagnosis, which resulted in an overall decrease in length of hospital stay. The 24-h TES can serve as a rapid response tool for patients with suspected monogenic disorders and can guide clinical decision-making in urgent cases.

Genetic aetiology of early infant deaths in a neonatal intensive care unit

Abstract: Background Congenital anomalies are the leading cause of early neonatal death in neonatal intensive care units (NICUs), but the genetic causes are unclear. This study aims to investigate the genetic causes of infant deaths in a NICU in China. Methods Newborns who died in the hospital or died within 1 week of discharge were enrolled from Children’s Hospital of Fudan University between January 1, 2015 and December 31, 2017. Whole exome sequencing was performed in all patients after death. Results There were 223 deceased newborns with a median age at death of 13 days. In total, 44 (19.7%) infants were identified with a genetic finding, including 40 with single nucleotide variants (SNVs), two with CNVs and two with both SNVs and CNVs. Thirteen (31%, 13/42) patients with SNVs had medically actionable disorders based on genetic diagnosis, which included 10 genes. Multiple congenital malformation was identified as the leading genetic cause of death in NICUs with 13 newborns identified with variants in genes related to multiple congenital malformations. For newborns who died on the first day, the most common genetic cause of death was major heart defects, while metabolic disorders and respiratory failure were more common for newborns who died in the first 2 weeks. Conclusion Our study shows genetic findings among early infant deaths in NICUs and provides critical genetic information for precise genetic counselling for the families. Effective therapies enable the improvement of more than a quarter of newborns with molecular diagnoses if diagnosed in time.

Erythropoietin prevents necrotizing enterocolitis in very preterm infants: a randomized controlled trial.

Abstract: Necrotizing enterocolitis (NEC) is one of the most severe complications in very preterm infants, but there are currently no accepted methods to prevent NEC. Studies have shown that erythropoietin (EPO) has the potential to prevent NEC or improve outcomes of preterm NEC. This study aimed to determine whether recombinant human EPO (rhEPO) could protect against NEC in very preterm infants. The study was a prospective randomized clinical trial performed among four NICU centers. A total of 1327 preterm infants with gestational age ≤ 32 weeks were admitted to the centers, and 42 infants were excluded leaving 1285 eligible infants to be randomized to the rhEPO or control group. Infants in the rhEPO group were given 500 IU/kg rhEPO intravenously every other day for 2 weeks, while the control group was given the same volume of saline. The primary outcome was the incidence of NEC in very preterm infants at 36 weeks of corrected gestational age. A total of 1285 infants were analyzed at 36 weeks of corrected age for the incidence of NEC. rhEPO treatment significantly decreased the incidence of NEC (stage I, II and III) (12.0% vs. 17.1%, p = 0.010), especially confirmed NEC (stage II and III) (3.0% vs. 5.4%, p = 0.027). Meanwhile, rhEPO treatment significantly reduced the number of red blood cells transfusion in the confirmed NEC cases (1.2 ± 0.4 vs. 2.7 ± 1.0, p = 0.004). Subgroup analyses showed that rhEPO treatment significantly decreased the incidence of confirmed NEC at gestational age 5 (p = 0.028). Repeated low-dose rhEPO treatment is beneficial against NEC in very preterm infants. Trial registration The protocol was registered retrospectively at ClinicalTrials.gov (NCT03919500) on April 18, 2019. https://clinicaltrials.gov/ct2/show/NCT03919500

Screening for primary immunodeficiency diseases by next-generation sequencing in early life.

Abstract: Objective We aimed to use next-generation sequencing (NGS) for the early diagnosis of primary immunodeficiency diseases (PIDs) and define its effects on medical management for an infant cohort in early life. Methods A single-centre study was conducted from November 2015 to April 2018. Infants less than 3 months old with infections or abnormal white blood cell counts were enrolled in the study. Gene variants were analysed by NGS, and once a mutation was found in a PID-associated gene, the immune functions associated with this mutation were detected. The diagnosis rate of PIDs in the cohort was the main outcome. The patients received corresponding management and follow-up treatments. Results Among 2392 patients who were genetically tested with NGS, 51 infants were diagnosed with PIDs. Seven types of PIDs were detected, and the most common (25/51, 49%) were combined immunodeficiencies with associated or syndromic features. Thirty-five patients (68.6%) were cured or had improved outcomes after being diagnosed with PID. The NGS cost was US$280 per case. Conclusions This study not only highlighted the potential of NGS to rapidly deliver molecular diagnoses of PIDs but also indicated that the prevalence of PIDs is underestimated. With broader use, this approach has the potential to alter clinical strategies.

COQ8B nephropathy: Early detection and optimal treatment.

Abstract: Background Mutations in COQ8B (*615567) as a defect of coenzyme Q10 (CoQ10) cause steroid resistant nephrotic syndrome (SRNS). Methods To define the clinical course and prognosis of COQ8B nephropathy, we retrospectively assessed the genotype and phenotype in patients with COQ8B mutations from Chinese Children Genetic Kidney Disease Database. We performed the comparing study of renal outcome following CoQ10 treatment and renal transplantation between early genetic detection and delayed genetic detection group. Results We identified 20 (5.8%) patients with biallelic mutations of COQ8B screening for patients with SRNS, non-nephrotic proteinuria, or chronic kidney disease (CKD) of unknown origin. Patients with COQ8B mutations showed a largely renal-limited phenotype presenting with proteinuria and/or advanced CKD at the time of diagnosis. Renal biopsy uniformly showed focal segmental glomerulosclerosis. Proteinuria was decreased, whereas the renal function was preserved in five patients following CoQ10 administration combined with angiotensin-converting enzyme (ACE) inhibitor. The renal survival analysis disclosed a significantly better outcome in early genetic detection group than in delayed genetic detection group (Kaplan-Meier plot and log rank test, p = .037). Seven patients underwent deceased donor renal transplantation without recurrence of proteinuria or graft failure. Blood pressure showed decreased significantly during 6 to 12 months post transplantation. Conclusions COQ8B mutations are one of the most common causes of adolescent-onset proteinuria and/or CKD of unknown etiology in the Chinese children. Early detection of COQ8B nephropathy following CoQ10 supplementation combined with ACE inhibitor could slow the progression of renal dysfunction. Renal transplantation in patients with COQ8B nephropathy showed no recurrence of proteinuria.

Clinical features and underlying genetic causes in neonatal encephalopathy: A large cohort study.

Abstract: This study aimed to investigate the potential genetic causes of neonatal encephalopathy (NE) in a large cohort of Chinese patients. We included 366 neonates with encephalopathy. Whole exome sequencing was performed to assess the potential molecular defects. In this study, 43 patients (11.7%) were identified with pathogenic or likely pathogenic variants and 10 patients (2.7%) carried variants with unknown significance. Compared with patients without genetic findings (28.9%), patients with genetic findings (96.2%) displayed a significant higher incidence of seizure (P = .0009); however, a lower frequency of abnormal magnetic resonance imaging (MRI) results (P < .0001). Epileptic encephalopathy related genes account for nearly half (46.4%) of all genetic defects of NE with seizures. Follow-up results revealed genetic diagnosis, seizure and severe abnormal electroencephalograph results were significantly associated with high risk of developmental delay (P < .05). This study increases the understanding of genetic contribution to NE. Our findings suggest that the full-term NE patients with seizure, the greater the possibility of genetic diseases. However, for newborns especially the preterm babies with abnormal MRI findings, there is smaller possibility of genetic diseases. NE caused from genetic diseases have poor prognosis, and intensive intervention and follow-up is necessary for these newborns.

Positive impact of COVID-19 on career choice in pediatric medical students: a longitudinal study

Abstract: BACKGROUND: On March 11(th), 2020, the WHO made the assessment that coronavirus disease 2019 (COVID-19) could be characterized as a pandemic Medical students experienced a greater degree of anxiety and psychological stress than during previous pandemics Negative emotions were related to decreased medical career interest, increased career choice regret and dropout rates in medical students, which affected academic and professional development The goal of this study was to investigate the impact of the current COVID-19 outbreak on the career preferences of pediatric medical students and to explore the underlying factors contributing to it METHODS: A prospective, longitudinal study was conducted among all 120 pediatric medical students from Shanghai Medical College of Fudan University on November 23(rd), 2019, and February 21(st), 2020 using a 7-item online questionnaire about career choice RESULTS: A total of 106 (41 male and 65 female) students with a mean age of 21 years consented to participate in this study The response rate was 100% in November 2019 and 98 1% in February 2020 Since the outbreak, career choices to practice medicine or pediatrics did not drop significantly, decreasing by only 4 3% and 2 2%, respectively There was a positive impact of the COVID-19 outbreak on strengthening 66 7% of students' beliefs and choices to become good pediatricians (P<0 001) Only 14 students (13 5%) thought that COVID-19 had a negative impact on their career choices, but the majority of them were in the 3(rd) (28 6%) and 4(th) (64 3%) years of medical education and had insufficient knowledge about the hospital environment and clinics CONCLUSIONS: The outbreak of COVID-19 might have an overall positive impact on career choice by strengthening students' belief and choice to become good doctors and may decrease the choice regret and drop rates of the next generation of doctors Special attention should be paid to students with insufficient clinical experience Good protection for students, sharing outstanding stories regarding fighting the pandemic, and innovations of needs-based curriculum could be helpful during this pandemic Future studies are warranted to confirm these findings

Novel PAK3 gene missense variant associated with two Chinese siblings with intellectual disability: a case report

Abstract: Intellectual disability (ID) constitutes the most common group of neurodevelopmental disorders. Exome sequencing has enabled the discovery of genetic mutations responsible for a wide range of ID disorders. In this study, we reported on two male siblings, aged 4 and 2 years, with motor and mental developmental delays and mild dysmorphic facial features. To identify the genetic causes of these symptoms, we employed trio-whole exome sequencing for the proband. We found a novel hemizygous missense variant in the PAK3 gene (c.1112G > A, p.Cys371Tyr), which encodes the p21-activated kinase 3, in the proband, which inherited from mother. The younger brother also has the hemizygous variant, which was confirmed by Sanger sequencing. The variant is located in the kinase domain and was regarded as a likely pathogenic variant in this family. We diagnosed two male siblings with developmental delays as having a PAK3 likely pathogenic variant. This finding expands the list of PAK3 gene mutations associated with neurodevelopmental disorders and provides further details on its clinical features.

Genotype and phenotype correlation in a cohort of Chinese congenital hypothyroidism patients with DUOX2 mutations.

Abstract: Background This study aimed to explore the relationship between the phenotype and genotype of congenital hypothyroidism (CH) caused by dual oxidase 2 (DUOX2) mutation in Chinese children, and to investigate the genetic causes of permanent and transient hypothyroidism through next-generation genetic testing technology and long-term clinical follow-up data. Methods We recruited 61 patients with thyroid stimulating hormone (TSH) levels of >10 mIU/mL during newborn screening, clinical diagnosis of CH, and L-thyroxine (L-T4) oral treatment within 1 month of birth; they were followed up until the present. All CH infants and their parents were genotyped using whole-exome sequencing (WES); DUOX2 variants were detected in 20 infants, and the longitudinal prognosis, genotype, and phenotype correlations were analyzed. Results Biallelic DUOX2 mutations were detected in 20 participants. All of them were born full term. All patients were treated with L-T4 when diagnosed with CH; 9 of them stopped L-T4 eventually before 3 years old; and 2 were treated with a reduced dose of L-T4 (12.5 µg per day). The others were still treated with L-T4 at a dose of 37.5-87.5 µg per day. Of these 20 participants, 5 carried an R1110Q variant and 5 carried K530X variants. A total of 7 novel variants were discovered in our cohort. The variants carried in transient CH patients were located extracellularly and not near the functional domain. Conclusions Most CH patients with DUOX2 mutations were those with transient or subclinical CH. The R1110Q, R885L, and K530X were the most common variants in our Chinese cohort. The R1110Q and K530X variants may play a founder effect in the transient CH. The R885L variant may play a benign role in transient CH. Intracellular variants or those near the functional domain may cause permanent CH.

What can we learn from neonates with COVID-19?

Abstract: The coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a global pandemic. Studies on epidemiological and clinical characteristics of patients with COVID-19 have indicated that children are susceptible to SARS-CoV-2 [1–3]. To date, the largest study in China reported that over 90% of 2143 children with COVID-19 were asymptomatic, or had mild or moderate illness, and that 5.8% presented critical illness [3]. Although the data of neonates are limited and only six neonates with COVID-19 have been reported thus far, several important points should be addressed from these neonatal cases.

Identification of eight novel mutations in 11 Chinese patients with maple syrup urine disease

Abstract: Maple syrup urine disease (MSUD) is an autosomal recessive inherited disorder that affects the degradation of branched-chain amino acids and is associated with acute and chronic brain dysfunction. This study presents 11 new patients with MSUD and describes the clinical characteristics and gene mutations reported in Chinese individuals. During 2011–2018, 11 pedaitric patients with MSUD from 11 Chinese families were analyzed based on clinical characteristics and mass spectrometry, with confirmation via gene sequencing. Novel mutations affecting protein function were predicted with Mutation-Taster, PolyPhen-2, CADD and SIFT software. 3D models of the mutated proteins were generated by using the SWISS-MODEL online server, and the models were visualized in PyMOL. The characteristics and gene mutations in patients with MSUD were analyzed retrospectively. Seventeen mutations in the BCKDHA, BCKDHB and DBT genes were found, 8 of which are novel: c.55C>/T, c.349C>T, c.565C>T, c.808G>A, c.859C>G, and c.1270dupC in BCKDHA; c.275-2A>G in BCKDHB; and c.1291C>T in DBT. Eight patients died. Two patients had severe mental retardation and were physically handicapped. One patient with the intermediate type had relatively good prognosis, with mild psychomotor retardation and adiposity. Four mothers underwent amniocentesis for prenatal diagnosis during their second pregnancy; two fetuses were wild type, and two were carriers of one heterozygous mutation. Eight novel mutations were associated with MSUD in Chinese patients. Prenatal diagnosis was successfully performed by genetic analysis. Mutations in the BCKDHB gene were found in the majority of Chinese patients with MSUD.

A multicentre observational study on neonates exposed to SARS-CoV-2 in China: the Neo-SARS-CoV-2 Study protocol.

Abstract: Introduction An outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) occurred in Wuhan, China starting in December 2019. Yet the clinical features and long-term outcomes of neonates with SARS-CoV-2 exposure are lacking. The purpose of this study is to describe the clinical course and prognosis of the neonates exposed to SARS-CoV-2. Methods and analysis This is a multicentre observational study conducted at the designated children and maternal and child hospitals in the mainland of China. Neonates exposed to SARS-CoV-2 infection will be recruited. The data to be collected via case report forms include demographic details, clinical features, laboratory and imaging results, as well as outcomes. Primary outcomes are the mortality of neonates with COVID-19 and SARS-CoV-2 infection of neonates born to mothers with COVID-19. Secondary outcomes are the birth weight, premature delivery and neurological development of neonates exposed to SARS-CoV-2. The neurological development is assessed by the Chinese standardised Denver Developmental Screening Test at the corrected age of 6 months. Ethics and dissemination This study has been approved by the Children9s Hospital of Fudan University ethics committee (No. (2020)31). The study findings will be disseminated in peer-reviewed journals and presented at national and international conferences in order to improve the understanding of the clinical course among neonates exposed to SARS-CoV-2 and to provide evidence-based treatment and prevention strategies for this group. Trial registration number NCT04279899.

An interpretation on perinatal and neonatal management plan for prevention and control of SARS-CoV-2 infection (2nd Edition)

Abstract: The epidemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection continues so far. The cases of SARS-CoV-2 infection have been reported in pregnant women and neonates as special groups. Perinatal and neonatal management plan for prevention and control of SARS-CoV-2 infection (2nd Edition) has been worked out by the Editorial Committee of Chinese Journal of Contemporary Pediatrics. This paper presents an interpretation on the 2nd Edition of the management plan, so as to facilitate readers to better understand it.

Frequent mutation of hypoxia-related genes in persistent pulmonary hypertension of the newborn.

Abstract: Persistent pulmonary hypertension of the newborn (PPHN) is characterized by sustained high levels of pulmonary vascular resistance after birth with etiology unclear; Arterial blood oxygen saturation of Tibetan newborns at high latitudes is higher than that of Han newborns at low latitudes, suggesting that genetic adaptation may allow sufficient oxygen to confer Tibetan populations with resistance to pulmonary hypertension; We have previously identified genetic factors related to PPHN through candidate gene sequencing; In this study, we first performed whole exome sequencing in PPHN patients to screen for genetic-related factors. In this two-phase genetic study, we first sequenced the whole exome of 20 Tibetan PPHN patients and compared it with the published genome sequences of 50 healthy high-altitude Tibetanshypoxia-related genes, a total of 166 PPHN-related variants were found, of which 49% were from 43 hypoxia-related genes; considering many studies have shown that the differences in the genetic background between Tibet and Han are characterized by hypoxia-related genetic polymorphisms, so it is necessary to further verify whether the association between hypoxia-related variants and PPHN is independent of high-altitude life. During the validation phase, 237 hypoxia-related genes were sequenced in another 80 Han PPHN patients living in low altitude areas, including genes at the discovery stage and known hypoxia tolerance, of which 413 variants from 127 of these genes were shown to be significantly associated with PPHN.hypoxia-related genes. Our results indicates that the association of hypoxia-related genes with PPHN does not depend on high-altitude life, at the same time, 21 rare mutations associated with PPHN were also found, including three rare variants of the tubulin tyrosine ligase-like family member 3 gene (TTLL3:p.E317K, TTLL3:p.P777S) and the integrin subunit alpha M gene (ITGAM:p.E1071D). These novel findings provide important information on the genetic basis of PPHN.

Mutations of CNTNAP1 led to defects in neuronal development.

Abstract: Mutations of CNTNAP1 were associated with myelination disorders, suggesting the role of CNTNAP1 in myelination processes. Whether CNTNAP1 may have a role in early cortical neuronal development is largely unknown. In this study, we identified 4 compound heterozygous mutations of CNTNAP1 in 2 Chinese families. Using mouse models, we found that CNTNAP1 is highly expressed in neurons and is located predominantly in MAP2+ neurons during the early developmental stage. Importantly, Cntnap1 deficiency results in aberrant dendritic growth and spine development in vitro and in vivo, and it delayed migration of cortical neurons during early development. Finally, we found that the number of parvalbumin+ neurons in the cortex and hippocampus of Cntnap1-/- mice is strikingly increased by P15, suggesting that excitation/inhibition balance is impaired. Together, this evidence elucidates a critical function of CNTNAP1 in cortical development, providing insights underlying molecular and circuit mechanisms of CNTNAP1-related disease.

First maternal uniparental disomy for chromosome 2 with PREPL novel frameshift mutation of congenital myasthenic syndrome 22 in an infant

Abstract: Background Congenital myasthenic syndrome 22 (CMS22) is a rare autosomal recessive disorder due to isolated PREPL deficiency and characterized by neonatal hypotonia, muscular weakness, and feeding difficulties. Eight such cases have already been reported, while maternal uniparental disomy with a PREPL pathogenic mutation has never been involved. Methods Trio whole-exome sequencing (WES), comparative genomic hybridization microarray (arry-CGH), and Sanger sequencing were performed on a 6-month-old girl with severe neonatal hypotonia and feeding difficulties. Also, the phenotype and genotype of reported CMS22 patients were reviewed. Results In this female infant, we identified a novel homozygous frameshift mutation in PREPL (c.1282_1285delTTTG, p.Phe428Argfs*18) by trio-WES. Sanger sequencing confirmed that her mother was heterozygous and her father was normal. Trio-WES data showed that 96.70% (1668/1725) variants on chromosome 2 were homozygous and maternally inherited, suggesting maternal uniparental disomy of chromosome 2 [UPD(2)mat]. Array-CGH did not show copy number variants (CNVs) but revealed complete UPD(2). Conclusion To date, nine patients with CMS22 have been reported including our patient, and we report the youngest and the first UPD(2)mat with PREPL novel homozygous pathogenic mutation case, which expand the mutation spectrum of PREPL gene.

Method for detecting and identifying pathogens of children infectious diseases based on metagenomic sequencing

Abstract: The invention relates to a method for detecting and identifying pathogens of children infectious diseases based on metagenomic sequencing. The method comprises the following specific steps: extractingtrace sample DNA after infection of a child, and carrying out concentration determination and quality control on the DNA; establishing a sequencing library of the sample DNA, and then carrying out high-throughput sequencing and screening; and comparing the treated sample sequence with a reference database to obtain a sequence with a comparison ratio of 70% or above and no multiple comparison, andthen carrying out screening of pathogenic microorganisms to complete the detection and identification method. According to the method disclosed by the invention, a DNA extraction method and a database establishment method are optimized aiming at trace samples of children, so that the success rate of database establishment of the trace samples and the effective data volume of sequencing are improved. A pathogenic microorganism screening and identifying strategy is established, laboratory and reagent pollution is effectively eliminated, and identification of pathogenic microorganisms can be effectively completed.