Here, we report a previously unrecognized syndromic neurodevelopmental disorder associated with biallelic loss-of-function variants in the RBM42 gene. The patient is a 2-year-old female with severe central nervous system (CNS) abnormalities, hypotonia, hearing loss, congenital heart defects, and dysmorphic facial features. Familial whole-exome sequencing (WES) reveals that the patient has two compound heterozygous variants, c.304C>T (p.R102*) and c.1312G>A (p.A438T), in the RBM42 gene which encodes an integral component of splicing complex in the RNA-binding motif protein family. The p.A438T variant is in the RRM domain which impairs RBM42 protein stability in vivo. Additionally, p.A438T disrupts the interaction of RBM42 with hnRNP K, which is the causative gene for Au-Kline syndrome with overlapping disease characteristics seen in the index patient. The human R102* or A438T mutant protein failed to fully rescue the growth defects of RBM42 ortholog knockout ΔFgRbp1 in Fusarium while it was rescued by the wild-type (WT) human RBM42. A mouse model carrying Rbm42 compound heterozygous variants, c.280C>T (p.Q94*) and c.1306_1308delinsACA (p.A436T), demonstrated gross fetal developmental defects and most of the double mutant animals died by E13.5. RNA-seq data confirmed that Rbm42 was involved in neurological and myocardial functions with an essential role in alternative splicing (AS). Overall, we present clinical, genetic, and functional data to demonstrate that defects in RBM42 constitute the underlying etiology of a new neurodevelopmental disease which links the dysregulation of global AS to abnormal embryonic development.
Female ; Animals ; Mice ; Humans ; Child, Preschool ; Intellectual Disability/genetics* ; Heart Defects, Congenital/genetics* ; Facies ; Cleft Palate ; Muscle Hypotonia

【Objective】 To understand the current situation of social emotional competence of infants and toddlers, and analyze its relationship with home rearing environment, in order to provide the basis for improving the level of infant social emotional development. 【Method】 A study was conducted on 390 individuals from a child health institution in Hubei and Henan provinces.The "Infant and Toddler Social-Emotional Assessment Scale" and "1 - 3 Years Child Home Rearing Environment Scale" were used to investigate the social emotions ability and home rearing environment of infants and toddlers. 【Results】 A total of 390 valid questionnaires were collected in this survey, of which 199 were boys (51.0%) and 191 girls (49.0%). The average age of infants was (27.13±6.86)months.The age distribution is mainly among infants and young children aged 24 to 36 months, with a total of 305 people (78.2%). The caregiver′s registered residence (Z=-3.570), father′s education level (H=17.106), mother′s education level (H=7.980), per capita monthly income of the family (H=13.986), and the home rearing environment (Z=-8.881) had statistical significance on the social emotional competence of infants(P<0.05 or <0.01).There was a significant positive correlation between family rearing environment and infants′ social emotion (r=0.582, P<0.01).Multiple regression analysis showed that the social adaptation/self-care(β=0.30, 95%CI: 0.18 - 0.52, P<0.01)and language cognition dimensions(β=0.22, 95%CI: 0.07 - 0.59, P<0.05) in the home rearing environment had a statistically significant impact on the social emotional ability of infants and toddlers. 【Conclusion】 The home rearing environment is closely related to the social emotional development of infants and young children.Improve the parenting knowledge and skills of the main caregivers of infants and young children, build a good family rearing environment for infants and young children, which is beneficial to promote the development of children′s social emotions.

The new-generation non-invasive prenatal screening technology (NIPT2.0) is a new method successfully realized in recent years based on high-throughput sequencing to synchronously and accurately detect fetal chromosomal aneuploidies, microdeletion/microduplication syndromes and dominantly inherited monogenic disorders. NIPT2.0 can circumvent the shortcomings of previous non-invasive prenatal screening techniques (NIPT and NIPT Plus) including incapability to detect fetal monogenic disorders, insufficient accuracy of detection and low positive predictive values for certain chromosomal abnormalities (in particular trisomy 13, sex chromosomal abnormalities, and small-segment microdeletions and microduplication syndromes). How to apply NIPT2.0 reasonably and normatively to maximize its clinical value has become an issue which requires clarification. The Reproductive Health Branch of the Chinese Maternal and Child Health Care Association has organized experts to fully discuss and jointly drafted this consensus, which has put forwards suggestions over the clinical application strategy for NIPT2.0, including the scope of application, target disease, pre-test consultation, clinical application pathway, post-test genetic counseling and intervention, quality control and limitations, for the reference by peers, with a view to standardize its application and provide better clinical service.

OBJECTIVE: To carry out prenatal diagnosis for families with high risk for spinal muscular atrophy (SMA) by using multiplex ligation-dependent probe amplification (MLPA). METHODS: Twenty-one families were enrolled. MLPA was used to detect copy numbers of SMN1 and SMN2 genes. Maternal contamination was excluded by using a short tandem repeat method. RESULTS: For 23 fetuses from the 21 families, 14 were identified as carriers, 1 as SMA patient, and 8 as normal. By linkage analysis of parental samples, three individuals were determined as silent (2+0) carriers. CONCLUSION MLPA can determine the carrier status of SMA. The identification of three silent (2+0) carriers among the 44 parental samples indicated a risk for such families, for which genetic counseling and reproduction guidance should be provided.
Female ; Genetic Counseling ; Heterozygote ; Humans ; Multiplex Polymerase Chain Reaction ; Muscular Atrophy, Spinal/genetics* ; Pregnancy ; Prenatal Diagnosis ; Survival of Motor Neuron 1 Protein/genetics*

Birth defects and rare diseases are serious challenges in China and even in the world, and most of them lack effective treatment. Preimplantation genetic testing (PGT) prevents the occurrence of this kind of disease at the source by carrying out genetic testing in the preimplantation stage and selecting normal embryos for transplantation. In this paper, the methods of PGT for birth defects and rare diseases and their latest progress are described.

Birth defects and rare diseases are serious challenges in China and even in the world, and most of them lack effective treatment. Preimplantation genetic testing (PGT) prevents the occurrence of this kind of disease at the source by carrying out genetic testing in the preimplantation stage and selecting normal embryos for transplantation. In this paper, the methods of PGT for birth defects and rare diseases and their latest progress are described.

Blocking the programmed death-ligand 1 (PD-L1) on tumor cells with monoclonal antibody therapy has emerged as powerful weapon in cancer immunotherapy. However, only a minority of patients presented immune responses in clinical trials. To develop an alternative treatment method based on immune checkpoint blockade, we designed a novel and efficient CRISPR-Cas9 genome editing system delivered by cationic copolymer aPBAE to downregulate PD-L1 expression on tumor cells specifically knocking out Cyclin-dependent kinase 5 () gene . The expression of PD-L1 on tumor cells was significantly attenuated by knocking out , leading to effective tumor growth inhibition in murine melanoma and lung metastasis suppression in triple-negative breast cancer. Importantly, we demonstrated that aPBAE/Cas9-Cdk5 treatment elicited strong T cell-mediated immune responses in tumor microenvironment that the population of CD8 T cells was significantly increased while regulatory T cells (Tregs) was decreased. It may be the first case to exhibit direct PD-L1 downregulation CRISPR-Cas9 genome editing technology for cancer therapy. It will provide promising strategy for preclinical antitumor treatment through the combination of nanotechnology and genome engineering.

Objective To investigate whether routine laboratory findings should be awaited before intravenous thrombolytic therapy for ischemic stroke.Methods Emergency patients (including ischemic and non-ischemic stroke cases) treated at the Department of Neurology,Beijing Tsinghua Changgung Hospital between January 1st 2016 and October 1st 2017 were analyzed retrospectively.The platelet count,prothrombin time (PT),activated partial thromboplastin time (APTT),and international normalized ratio (INR) in the first test were used as the main indicators.The proportion of patients with abnormalities between the overall population and the ischemic stroke subgroup was analyzed,and the above indicators between all patients with ischemic stroke and those receiving intravenous thrombolytic therapy were compared.The specific causes of failure to receive intravenous thrombolytic therapy in patients with ischemic stroke were analyzed descriptively.Results A total of 3 348 patients were enrolled.The emergency blood routine data were available in all patients.The emergency blood biochemical data were available in 3 278 patients (97.9％),and the emergency coagulation function data were available 1 742 patients (52.0％).There were no significant differences in the proportion of platelet count ＜ 100 × 109/L (1.3％ vs.1.5％;x2=0.29,P=0.586),APTT＞36.5s (3.8％ vs.3.6％;x2=0.06,P=0.809),PT ＞15s (2.6％ vs.2.8％;x2 =0.03,P=0.866),and INR ＞ 1.5 (2.0％ vs.2.0％;x2 =0.01,P=0.970) between the general population and the ischemic stroke subgroup.In a total of 687 patients with ischemic stroke,57 (8.3％) received intravenous thrombolysis.There were no significant difference in mean platelet count,APTT,PT,and INR between the thrombolytic group and the entire ischemic stroke group.Forty-nine patients (5.1％) with ischemic stroke had abnormal main indicators,of which 57.1％ (28/49) had a history of related diseases at the same time,while only 6.1％ (3/49) had abnormal laboratory indicators as the main factor of contraindication for intravenous thrombolysis.Conclusions Patients with acute ischemic stroke (especially in the absence of a history of related disease) have a low proportion of abnormal blood test findings and are less likely to be the main contributor of contraindication for intravenous thrombolysis.Therefore,when there is no reason to suspect that the test findings are abnormal,intravenous thrombolytic therapy should not be delayed because of waiting for the test findings.

In the past 20 years,molecular genetic technology has developed rapidly.The leap forward development of single-cell genetic diagnosis technologies represented by whole genome amplification combined with microarray technology or next-generation sequencing not only increased the accuracy of preimplantation genetic diagnosis (PGD) but also greatly expanded the variety and scope of detectable diseases.This paper systematically reviews the clinical application of PGD as well as recent progress of related technologies.

Objective: To evaluate the prevalence and risk factors of aortic valve calcification among the elderly (≥65 years old) resident of Wuxi city, Jiangsu province. Methods: The household registration population aged ≥65 years old in Wuxi city was selected as the research subject by stratified sampling method from August 2017 to December 2018. Echocardiography was performed to assess the aortic valve calcification, and the participants were divided into calcification group and non-calcification group. Multivariate logistic regression analysis was used to explore the related risk factors of aortic valve calcification. Results: The age of the respondents was (73.6±7.1) years old, of which 48.8% (461 cases) were males.The prevalence rate of aortic valve calcification was 22.0% (208/944) in the elderly (≥ 65 years old) residents in Wuxi city. The prevalence rate in 65-69 years old, 70-74 years old, 75-79 years old, 80-84 years old and ≥85 years old was 16.7% (58/347),16.7% (41/245),16.2% (26/161),23.3% (24/103), and 67.0% (59/88),respectively. There were significant differences in age, weight, abdominal circumference, hip circumference, high-salt diets, exercise, hypertension, hyperlipidemia, diabetes, coronary heart disease, cerebrovascular disease, and carotid atherosclerosis between the non-calcified group (736 cases) and the calcified group (208 cases) (P<0.01 or 0.05).Multivariate logistic regression analysis showed that age (OR=1.077, 95%CI 1.053-1.101, P<0.001), diabetes mellitus (OR=1.697, 95%CI 1.174-2.453, P=0.005), and coronary heart disease (OR=1.964, 95%CI 1.378-2.799, P<0.001) were the risk factors of aortic valve calcification. Conclusions The prevalence of aortic valve calcification in the elderly (≥65 years old) residents in Wuxi city of Jiangsu province increases with aging. Age, diabetes mellitus and coronary heart disease are the risk factors of aortic valve calcification in this population cohort.