Objective:To explore the genotype and the clinical phenotype of SCN2A-related developmental delay in children. Methods:A case series study was adopted. Collect clinical data from 10 cases of children with SCN2A gene variants diagnosed with global developmental delay/intellectual disability who were admitted to the Children′s Hospital between July 2019 and March 2023. Summarize the clinical phenotype and genotype based on clinical data such as general information, clinical manifestations, imaging examinations, laboratory tests, genetic testing results, and comprehensive pediatric neuropsychological development assessment. Results:A total of 10 patients were recruited, including 7 males and 3 females, with an age range of 27 days to 5 years and 9 months. 9 patients underwent children′s neuropsychological and behavioral assessments, and the results were consistent with global developmental delay, including 2 mild cases, 4 moderate cases, and 3 severe cases. 3 cases had autism spectrum disorder, and 2 cases had epilepsy. 6 patients underwent complete head MRI examination, and 4 of them showed abnormalities, including delayed myelination, widening of the local extra brain space in the frontal lobe, and abnormal frontal lobe morphology. All 10 cases had point variants. Among them, 9 cases are de novo and 1 case is maternal inheritance. Out of 10 cases, there were 5 cases with copy number variations, but all of them were of unknown significance. Among the 10 variants, 8 have been reported and 2 have not been reported, namely c.4145A>T(p.N1382I) and c.4937T>A(p.I1646N). In this study, 4 out of 10 patients with SCN2A variants had variation sites located in the S4 segment of domain which constitute Nav1.2, the sodium ion channel encoded by SCN2A. The developmental quotient level was lower when the variation sites were located in the S4 segment of domain, and the difference was statistically significant ( t=-3.101, P=0.017), indicating that the severity of developmental delay may be related to the localization of amino acids corresponding to variant sites within the protein domain. Conclusion:SCN2A mutations are strongly associated with diverse neurodevelopmental disorders. In this study, the phenotypic spectrum of SCN2A variants encompassed epilepsy, global developmental delay, and autism spectrum disorder. Affected individuals exhibited early-onset developmental delays, predominantly moderate to severe in severity. Voltage-sensing domain dysfunction in sodium channels may constitute a critical pathomechanism underlying neurodevelopmental impairments. Further electrophysiological characterization and molecular mechanistic studies are warranted todelineate the genotype-phenotype correlations between specific variant loci and clinical severity.

Objective:To explore the association between adverse outcomes of preterm infants and obstetric factors such as infection,maternal disease and treatment measures in patients with preterm premature rupture of membranes(PPROM),so as to provide more accurate and effective prediction and intervention methods for im-proving maternal and infant prognosis.Methods:A retrospective analysis was conducted on the clinical data of 534 PPROM patients who gave births in the obstetrics department of The Second Hospital of Tianjin Medical Uni-versity from January 1,2018,to August 31,2023.Based on the presence of severe preterm birth complications in premature infants(including bronchopulmonary dysplasia,necrotizing enterocolitis,retinopathy of prematurity,neonatal infectious pneumonia,neonatal respiratory distress syndrome,neonatal hypoxic-ischemic encephalopa-thy,and neonatal sepsis)or death,the patients were divided into two groups:the adverse outcome group(n=121)and the non-adverse outcome group(n=413).The study compared differences between the two groups in general conditions,pregnancy complications and comorbidities,treatment and management,amniotic fluid and pla-cental infections.Logistics regression analysis was used to identify obstetric factors associated with adverse out-comes in preterm infants.Results:Univariate analysis revealed that patients in the adverse outcome group had smaller gestational weeks at delivery,longer intervals between membrane rupture and delivery,and a lower rate of vaginal delivery compared to those in the non-adverse outcome group.They also had a higher proportion of con-current cervical insufficiency,antepartum hemorrhage,hypertensive disorders of pregnancy,and anemia of preg-nancy.The use of prenatal magnesium sulfate and glucocorticoids for fetal lung maturity promotion before delivery was higher,and the effective coverage rates of prophylactic antibiotics was lower.The positive rates of amniotic fluid bacterial culture,the proportion of clinical chorioamnionitis,and histological chorioamnionitis were higher.All of the above differences were statistically significant(P＜0.05).Multivariate analysis revealed that positive amniotic fluid bacterial culture(OR 4.602,95％CI 2.303-9.196,P＜0.05),anemia of pregnancy(OR 4.192,95％CI 2.064-8.510,P＜0.05),and cervical insufficiency(OR 9.435,95％CI 1.138-78.261,P＜0.05)were independ-ent risk factors for adverse outcomes in preterm infants among PPROM patients,while gestational weeks at deliv-ery(OR0.466,95％CI 0.370-0.586,P＜0.05),effective coverage of prophylactic antibiotics before delivery(OR 0.286,95％CI 0.121-0.673,P＜0.05),and treatment for lung maturity promotion(OR 0.225,95％CI 0.107-0.474,P＜0.05)were protective factors for adverse outcomes in premature infants in PPROM patients.Conclu-sions:The adverse outcomes of preterm infants in PPROM patients are closely related to obstetric factors such as infection,maternal diseases,and treatment measures.Among these,positive amniotic fluid bacterial culture,a-nemia during pregnancy,and cervical insufficiency are independent risk factors for adverse outcomes in premature infants in PPROM patients.On the other hand,gestational age at deli very,effective coverage of prenatal antibiot-ics,and pulmonary maturity promotion therapy are protective factors.

Objective:To explore the genotype and the clinical phenotype of SCN2A-related developmental delay in children. Methods:A case series study was adopted. Collect clinical data from 10 cases of children with SCN2A gene variants diagnosed with global developmental delay/intellectual disability who were admitted to the Children′s Hospital between July 2019 and March 2023. Summarize the clinical phenotype and genotype based on clinical data such as general information, clinical manifestations, imaging examinations, laboratory tests, genetic testing results, and comprehensive pediatric neuropsychological development assessment. Results:A total of 10 patients were recruited, including 7 males and 3 females, with an age range of 27 days to 5 years and 9 months. 9 patients underwent children′s neuropsychological and behavioral assessments, and the results were consistent with global developmental delay, including 2 mild cases, 4 moderate cases, and 3 severe cases. 3 cases had autism spectrum disorder, and 2 cases had epilepsy. 6 patients underwent complete head MRI examination, and 4 of them showed abnormalities, including delayed myelination, widening of the local extra brain space in the frontal lobe, and abnormal frontal lobe morphology. All 10 cases had point variants. Among them, 9 cases are de novo and 1 case is maternal inheritance. Out of 10 cases, there were 5 cases with copy number variations, but all of them were of unknown significance. Among the 10 variants, 8 have been reported and 2 have not been reported, namely c.4145A>T(p.N1382I) and c.4937T>A(p.I1646N). In this study, 4 out of 10 patients with SCN2A variants had variation sites located in the S4 segment of domain which constitute Nav1.2, the sodium ion channel encoded by SCN2A. The developmental quotient level was lower when the variation sites were located in the S4 segment of domain, and the difference was statistically significant ( t=-3.101, P=0.017), indicating that the severity of developmental delay may be related to the localization of amino acids corresponding to variant sites within the protein domain. Conclusion:SCN2A mutations are strongly associated with diverse neurodevelopmental disorders. In this study, the phenotypic spectrum of SCN2A variants encompassed epilepsy, global developmental delay, and autism spectrum disorder. Affected individuals exhibited early-onset developmental delays, predominantly moderate to severe in severity. Voltage-sensing domain dysfunction in sodium channels may constitute a critical pathomechanism underlying neurodevelopmental impairments. Further electrophysiological characterization and molecular mechanistic studies are warranted todelineate the genotype-phenotype correlations between specific variant loci and clinical severity.

Objective:To explore the association between adverse outcomes of preterm infants and obstetric factors such as infection,maternal disease and treatment measures in patients with preterm premature rupture of membranes(PPROM),so as to provide more accurate and effective prediction and intervention methods for im-proving maternal and infant prognosis.Methods:A retrospective analysis was conducted on the clinical data of 534 PPROM patients who gave births in the obstetrics department of The Second Hospital of Tianjin Medical Uni-versity from January 1,2018,to August 31,2023.Based on the presence of severe preterm birth complications in premature infants(including bronchopulmonary dysplasia,necrotizing enterocolitis,retinopathy of prematurity,neonatal infectious pneumonia,neonatal respiratory distress syndrome,neonatal hypoxic-ischemic encephalopa-thy,and neonatal sepsis)or death,the patients were divided into two groups:the adverse outcome group(n=121)and the non-adverse outcome group(n=413).The study compared differences between the two groups in general conditions,pregnancy complications and comorbidities,treatment and management,amniotic fluid and pla-cental infections.Logistics regression analysis was used to identify obstetric factors associated with adverse out-comes in preterm infants.Results:Univariate analysis revealed that patients in the adverse outcome group had smaller gestational weeks at delivery,longer intervals between membrane rupture and delivery,and a lower rate of vaginal delivery compared to those in the non-adverse outcome group.They also had a higher proportion of con-current cervical insufficiency,antepartum hemorrhage,hypertensive disorders of pregnancy,and anemia of preg-nancy.The use of prenatal magnesium sulfate and glucocorticoids for fetal lung maturity promotion before delivery was higher,and the effective coverage rates of prophylactic antibiotics was lower.The positive rates of amniotic fluid bacterial culture,the proportion of clinical chorioamnionitis,and histological chorioamnionitis were higher.All of the above differences were statistically significant(P＜0.05).Multivariate analysis revealed that positive amniotic fluid bacterial culture(OR 4.602,95％CI 2.303-9.196,P＜0.05),anemia of pregnancy(OR 4.192,95％CI 2.064-8.510,P＜0.05),and cervical insufficiency(OR 9.435,95％CI 1.138-78.261,P＜0.05)were independ-ent risk factors for adverse outcomes in preterm infants among PPROM patients,while gestational weeks at deliv-ery(OR0.466,95％CI 0.370-0.586,P＜0.05),effective coverage of prophylactic antibiotics before delivery(OR 0.286,95％CI 0.121-0.673,P＜0.05),and treatment for lung maturity promotion(OR 0.225,95％CI 0.107-0.474,P＜0.05)were protective factors for adverse outcomes in premature infants in PPROM patients.Conclu-sions:The adverse outcomes of preterm infants in PPROM patients are closely related to obstetric factors such as infection,maternal diseases,and treatment measures.Among these,positive amniotic fluid bacterial culture,a-nemia during pregnancy,and cervical insufficiency are independent risk factors for adverse outcomes in premature infants in PPROM patients.On the other hand,gestational age at deli very,effective coverage of prenatal antibiot-ics,and pulmonary maturity promotion therapy are protective factors.

Objective To explore the myopia control effect of orthokeratology(OK)lenses and build a prediction model of myopia control effect based on random forest and Logistic regression,so as to provide a basis for further impro-ving adolescent vision.Methods A total of 289 patients who wore OK lenses after seeing an ophthalmologist in Shiji-azhuang People's Hospital from January to June 2019 were selected as the OK lens group,and a total of 289 patients who wore framed glasses during the same period were selected as the framed glass group.After 2 and 4 years of wearing,the in-crease in axial length(AL)of the patients was observed.The patients were divided into a well-controlled myopia group and a poorly-controlled myopia group according to the changes in AL of the eyes after wearing OK lenses for 4 years.The fac-tors influencing the myopia control effect were analyzed based on random forest and Logistic regression,and a nomogram prediction model was constructed.The performance of the model was evaluated using the receiver operating characteristic(ROC)curve,calibration curve,and decision curve analysis(DCA).Results After 2 and 4 years,the diopter increase and AL increase of patients wearing OK lenses were lower than those of patients wearing framed glasses(all P＜0.001).There were no significant changes in corneal endothelial cell parameters and central corneal thickness at the thinnest point before,2 years and 4 years after wearing between the two groups(all P＞0.05).The random forest model showed that basic AL,daily wear time,correct eye health behavior,pupil diameter,daily outdoor activity time,homework time after school,and daily sleep time were the top 7 variables in importance ranking.Logistic regression analysis showed that home-work time after school was a risk factor for poor myopia control in OK lens wearers,while basic AL,pupil diameter,daily wear time,correct eye health behavior,daily outdoor activity time,and daily sleep time were protective factors for myopia control.The ROC curve,calibration curve,and DCA suggested that the nomogram prediction model constructed based on random forest and Logistic regression analysis had good accuracy,consistency and clinical effectiveness.Conclusion OK lens shows good myopia control effect,has little effect on corneal endothelial cells and corneal thickness,and demon-strates high safety.Homework time after school,basic AL,pupil diameter,daily wear time,correct eye health behavior,daily outdoor activity time,and daily sleep time are influencing factors of myopia control.Strengthening the construction of a prediction model is helpful in identifying high-risk groups with poor myopia control and guiding clinical interventions in time.

Objective To investigate the correlation between the level of circulating placental growth factor(PLGF)and the severity of preeclampsia(PE),maternal and infant outcomes and placental pathology.Methods A total of 159 PE patients were selected as the study subjects and divided into the PE1 group(62 PE patients with termination of pregnancy<34 weeks)and the PE2 group(97 PE patients with termination of pregnancy≥34 weeks)according to the gestational age of pregnancy termination.A total of 107 non-PE patients who gave birth during the same period were selected as the control group.Patients were divided into two groups according to the gestational age of termination:the non-PE1 group(41 non-PE patients with termination of pregnancy at<34 weeks)and the non-PE2 group(66 non-PE patients with termination of pregnancy at≥34 weeks).General data were collected in each group of pregnant women,including age,body mass index(BMI),admission systolic blood pressure,diastolic blood pressure,24 h urinary protein quantity,gestational times,presence of FGR and fetal embarrassment.General information of newborns during the operation were collected,for example,whether there was fecal contamination of amniotic fluid,neonatal asphyxia,and days of newborn stayed in NICU.PLGF in venous blood of pregnant women was detected on the day of delivery.The placenta was pathologically detected and scored.After delivery,blood gas of umbilical artery was analyzed,and PH(pH),base surplus(BE),lactic acid(LAC)were recorded.Results There were no significant differences in age,gestational times and delivery times between the PE1 group and the PE2 group and the corresponding the non-PE1 group and the non-PE2 group.BMI was higher in the PE1 group and the PE2 group than that in the non-PE1 group and the non-PE2 group.PLGF was lower in the PE1 group and the PE2 group than that in the non-PE1 group and the non-PE2 group,respectively,and PLGF was lower in the PE1 group than that in the PE2 group(P＜0.05).The 24 h urinary protein quantity,systolic blood pressure,diastolic blood pressure and pathological changes of placenta were higher in the PE1 group than those in the PE2 group(P＜0.05).There were no significant differences in fecal staining of amniotic fluid,fetal embarrassed condition and pH value of umbilical artery blood gas during delivery between the PE1 group and the PE2 group.Compared with the PE2 group,the proportion of neonatal asphyxia and FGR,the umbilical artery blood gas LAC were increased,the BE value was decreased,and the time of staying in NICU was prolonged in the PE1 group(P＜0.05).Conclusion The level of circulating PLGF is decreased in patients with preeclampsia.PLGF has certain value in evaluating PE and predicting adverse pregnancy outcome.

OBJECTIVE: To analyze the clinical characteristics and spectrum of SPTB gene variants among 16 Chinese children with Hereditary spherocytosis (HS) and explore their genotype-phenotype correlation. METHODS: Sixteen children who were diagnosed with HS at the Affiliated Hospital of Capital Institute of Pediatrics from November 2018 to July 2022 were selected as the research subjects. Genetic testing was carried out by whole exome sequencing. Candidate variants were verified by Sanger sequencing and subjected to bioinformatic analysis and prediction of 3D structure of the protein. Correlation between the SPTB genotypes and clinical phenotypes was analyzed using Chi-squared test. RESULTS: The male-to-female ratio of the HS patients was 6 : 10, with the median age being 7-year-and-10-month. Clinical features of the patients have included anemia, reticulocytosis and gradual onset of splenomegaly. Mild, moderate and severe anemia have respectively occurred in 56.25% (9/16), 31.25% (5/16) and 12.50% (2/16) of the patients. SPTB gene variants were detected in all patients, among which 10 were unreported previously and 7 were de novo in origin. Loss of function (LOF) variants accounted for 93.75% (15/16). Only one missense variant was detected. Eleven, 4 and 1 of the variants had occurred in the repeat domain, CH1 domain, and dimerization domain, respectively. There was no significant correlation between the type or domain of the SPTB gene variants with the clinical features such as severity of anemia (x² = 3.345, P > 0.05). All of the variants were predicted to be pathogenic or likely pathogenic based on the guidelines from the American College of Medical Genetics and Genomics. CONCLUSION Mild to moderate anemia are predominant clinical features of the HS children harboring a SPTB gene variant, for which LOF variants are the main mutational type. The clinical feature of HS is unaffected by the type of the variants.
Child ; Female ; Humans ; Male ; Computational Biology ; Genetic Testing ; Genomics ; Genotype ; Spherocytosis, Hereditary/genetics* ; East Asian People/genetics* ; Spectrin/genetics*

Copy number variants (CNVs) are common causes of human genetic diseases. CNVs detection has become a routine component of genetic testing, especially for pediatric neurodevelopmental disorders, multiple congenital abnormalities, prenatal evaluation of fetuses with structural anomalies detected by ultrasound. Although the technologies for CNVs detection are continuously improving, the interpretation is still challenging, with significant discordance across different laboratories. In 2020, the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen) developed a guideline for the interpreting and reporting of constitutional copy number variants, which introduced a quantitative, evidence-based scoring framework. Here, we detailed the key points of interpreting the copy number gain based on the guideline, used six examples of different categories to illuminate the scoring process and principles. We encourage a professional understanding and application of this guideline for the detected copy number gains in China in order to further improve the clinical evaluation accuracy and consistency across different laboratories.
Child ; DNA Copy Number Variations ; Female ; Genetic Testing ; Genetics, Medical ; Genome, Human/genetics* ; Genomics ; Humans ; Pregnancy ; United States

Objective:To evaluate the utility of whole-exome sequencing (WES) in early diagnosis for children with language delay/disorder.Methods:Children with language delay/disorder who were admitted to the Department of Health Care, Children′s Hospital Affiliated to the Capital Pediatric Institute from January 2019 to December 2020 were analyzed retrospectively. Based on informed consent, the peripheral blood of the children and their parents was collected for WES. Combining the clinical phenotypes of the children, the candidate variants, including single nucleotide variants (SNVs) and copy number variations (CNVs), were selected for validation and family segregation analysis using Sanger sequencing, real-time PCR or CNV-Seq. The pathogenicity of variants was evaluated based on ACMG guideline following with finial genetic diagnosis. Based on whether genetic diagnosis was achieved or not, 125 children with comprehensive examination of the Children Neuropsychological and Behavioral Scale(CNBS-R2016) were sub-grouped (positive/negative group), and the total scores and the detailed scores of five developmental sections (gross motor, fine motor, adaptive ability, language and social behavior ability) between two subgroups were compared.Results:A total of 165 children with language delay/disorder were recruited, including 109 males and 56 females. The ratio of boys to girls was 1.95∶1.The age of the children was (3.2±1.2) years old, the median age was 3.0 years. 45 children carry disease-related pathogenic/likely pathogenic variants, including 36 SNVs and 9 CNVs. The genetic diagnostic yield of this cohort was 27.3% (45/165). The inheritance analysis for core family members showed de novo variant accounted for 86% of genetic diagnosis (31/36). The positive diagnosis rate in girls was 45% (25/56), which was significantly higher than that in boys (18.3%, 20/109, χ2=12.171, P<0.05). There was no significant difference in the rate of positive diagnosis among all age groups (χ2=4.349, P>0.05). Interestingly, the scores of gross motors of positive group were significantly lower than that of negative group (61.5 vs. 69.4, t=-2.610, P<0.05). Otherwise, no significant difference was seen between two groups( t=-0.933, -1.298, -0.114, -0.214, all P>0.05). Conclusions:Language delay/disorder has complex genetic heterogeneity. WES has important application value in early etiological diagnosis for children with language delay/disorder.

Objective:To evaluate the utility of whole-exome sequencing (WES) in early diagnosis for children with language delay/disorder.Methods:Children with language delay/disorder who were admitted to the Department of Health Care, Children′s Hospital Affiliated to the Capital Pediatric Institute from January 2019 to December 2020 were analyzed retrospectively. Based on informed consent, the peripheral blood of the children and their parents was collected for WES. Combining the clinical phenotypes of the children, the candidate variants, including single nucleotide variants (SNVs) and copy number variations (CNVs), were selected for validation and family segregation analysis using Sanger sequencing, real-time PCR or CNV-Seq. The pathogenicity of variants was evaluated based on ACMG guideline following with finial genetic diagnosis. Based on whether genetic diagnosis was achieved or not, 125 children with comprehensive examination of the Children Neuropsychological and Behavioral Scale(CNBS-R2016) were sub-grouped (positive/negative group), and the total scores and the detailed scores of five developmental sections (gross motor, fine motor, adaptive ability, language and social behavior ability) between two subgroups were compared.Results:A total of 165 children with language delay/disorder were recruited, including 109 males and 56 females. The ratio of boys to girls was 1.95∶1.The age of the children was (3.2±1.2) years old, the median age was 3.0 years. 45 children carry disease-related pathogenic/likely pathogenic variants, including 36 SNVs and 9 CNVs. The genetic diagnostic yield of this cohort was 27.3% (45/165). The inheritance analysis for core family members showed de novo variant accounted for 86% of genetic diagnosis (31/36). The positive diagnosis rate in girls was 45% (25/56), which was significantly higher than that in boys (18.3%, 20/109, χ2=12.171, P<0.05). There was no significant difference in the rate of positive diagnosis among all age groups (χ2=4.349, P>0.05). Interestingly, the scores of gross motors of positive group were significantly lower than that of negative group (61.5 vs. 69.4, t=-2.610, P<0.05). Otherwise, no significant difference was seen between two groups( t=-0.933, -1.298, -0.114, -0.214, all P>0.05). Conclusions:Language delay/disorder has complex genetic heterogeneity. WES has important application value in early etiological diagnosis for children with language delay/disorder.