Head circumference is the most direct and easily recognized clinical indication of brain development.Autism spectrum disorder (ASD) is a group of complex neurodevelopmental disorders with significant clinical and genetic heterogeneity.Genetic factors play a major role in its pathogenesis.The study of ASD with macrocephaly facilitates the etiologic discovery and mechanistic elaboration of the disease with marked heterogeneity.In this paper, the genetics and mechanism of macrocephaly in ASD were reviewed in order to provide a theoretical basis for early identification and diagnosis of ASD.

Objective:To observe the effect of brain-computer interface exoskeleton(BCI-exoskeleton)on lower limb func-tional for stroke patients,and to explore the impact on the low-extremity function area of motor cortex in-duced by BCI-exoskeleton and its correlation with clinical efficacy.Method:Forty-two subjects with stroke were recruited and equally assigned to brain-computer interface exoskel-eton experiment group(BG,n=14),robotic exoskeleton experiment group(EG,n=14)and conventional con-trol group(CG,n=14)using random numbers generated by computer.Three groups were provided convention-al treatment,experiment groups received BCI-exoskeleton or lower-limb robotic exoskeleton training(LRET)for 4 weeks,respectively.FMA-LE,MBI,Berg and Holden scales were used to evaluate the lower limb func-tions pre-or post-treatment by a blinded assessor.The accuracy of BCI(BCIA),and the changes of α and β band event-related desynchronization(ERD)intensity at Cz channel of EEG were observed to explore its corre-lation with clinical efficacy.Result:All scales in the three groups were improved post-treatment,and the improvement of BG was better than that of EG and CG(FMA-LE:P＜0.001;MBI,Berg,Holden:P=0.001).The BCIA in BG were signif-icantly increased(P＜0.001).And ERD amplitude of Cz channel in BG were significantly decreased(P＜0.001).ERDα(P＜0.05)was significantly correlated with clinical scales and ERDβ had an extremely signifi-cant correlated with clinical scales(P＜0.01).Conclusion:The BCI-exoskeleton training is effective to improve the lower limb function and activities of dai-ly living for patients with stroke,and the effect is better than LRET and conventional rehabilitation.The effica-cy is related to the promotion of ERDα and ERDβ wave band activity in the lower limb functional area of mo-tor cortex,and the clinical efficacy is more closely correlated with ERD amplitude of Cz channel.

Objective:To explore the genetic etiology of Pontocerebellar Hypoplasia Type 2D (PCH2D) due to compound heterozygous variants of the SEPSECS gene and to conduct a literature review. Methods:A child with PCH2D diagnosed at the Children′s Hospital of Nanjing Medical University due to " motor and cognitive retardation" in June 2022 was selected as the study subject. Clinical and imaging data were collected. Genomic DNA was extracted from the peripheral blood samples of the child and her parents. Whole-exome sequencing (WES) was conducted using capture-based high-throughput sequencing technology. Candidate variants were confirmed by Sanger sequencing and bioinformatics analysis. The pathogenicity of variant was rated according to the Standards and Guidelines for the Interpretation of Sequence Variants released by American College of Medical Genetics and Genomics (ACMG). Additionally, relevant literature on PCH2D caused by SEPSECS gene variants was reviewed to assess the genotype-phenotype correlation. This study was approved by the Medical Ethics Committee of the Children′s Hospital of Nanjing Medical University (Ethical No.: 202402022-1). Results:The child, a 1-year-and-3-month-old girl, had presented with global developmental delay, progressive microcephaly, hypotonia, elevated blood lactic acid, feeding difficulties, and absent tendon reflexes. Cranial MRI indicated thinning of the splenium of the corpus callosum. Electromyography suggested peripheral neurogenic changes primarily affecting sensory nerves. WES revealed the she has harbored compound heterozygous variants of the SEPSECS gene, namely c. 194A>G (p.N65S) and c. 896_c.897insA (p.N299fs*2) (NM_016955), which were inherited from her father and mother, respectively. Neither of her parents had related clinical manifestations. According to the ACMG guidelines, the c. 194A>G (p.N65S) variant was classified as pathogenic (PM1+ PM2_Supporting+ PM3+ PP3), and the c. 896_c.897insA (p.N299fs*2) variant was as likely pathogenic (PVS1+ PM2_Supporting). A total of 18 relevant literature were retrieved, which have involved 32 patients (including this case). The p. N65S variant has been reported previously, while the p. N299fs*2 variant is novel. Conclusion:Compound heterozygous variants in the SEPSECS gene probably underlay the pathogenesis of PCH2D in this child. Above finding has expanded the mutational and phenotypic spectrum of the SEPSECS gene.

Objective:To explore the genetic etiology of a child with Spastic paraplegia and psychomotor retardation with or without seizures (SPPRS).Methods:A child who was admitted to the Children′s Hospital Affiliated to Nanjing Medical University in April 2022 for motor developmental delay, intellectual disability, and hypertonia was selected as the study subject. Relevant clinical data were retrospectively analyzed. Whole exome sequencing (WES) was carried out for the child and his parents. Candidate variants were searched in the Single Nucleotide Polymorphism Database (dbSNP) and Online Mendelian Inheritance in Man (OMIM) database. Pathogenicity of the variants was assessed based on guidelines from the American College of Medical Genetics and Genomics (ACMG). Using key words such as " HACE1 gene" " Spastic paraplegia and psychomotor retardation with or without seizures" and " SPPRS", previous reports on SPPRS patients due to HACE1 gene variants were retrieved from the CNKI, Wanfang Data Knowledge Service Platform, CQVIP, and PubMed databases, with the time set from January 1, 2000 to April 7, 2024. A mutation map for the HACE1 protein in the patients was created. This study was approved by the Ethics Committee of the Children′s Hospital Affiliated to Nanjing Medical University (Ethics No. 202404008-1). Results:The clinical manifestations of the child had included motor developmental delay, intellectual disability and hypertonia. Magnetic resonance imaging revealed hypoplasia of posterior corpus callosum and splenium, with slight enlargement of lateral ventricles. WES revealed that the child has harbored compound heterozygous variants of the HACE1 gene, namely c. 535(exon7)_c.538(exon7)delACAG (p.T179fs*5) and c. 1678+ 2(IVS15)T>C, which were respectively inherited from his parents. Based on the guidelines from the ACMG, the variants were respectively rated as likely pathogenic (PVS1 + PM2_Supporting) and pathogenic (PVS1 + PM2_Supporting + PM3). Literature search has identified 8 papers, which reported 23 SPPRS cases due to HACE1 gene variants. All patients exhibited psychomotor developmental delay, among whom 18 HACE1 gene variants were identified. Conclusion:The c. 535(exon7)_c.538(exon7)delACAG (p.T179fs*5) and c. 1678+ 2(IVS15)T>C compound heterozygous variants of the HACE1 gene probably underlay the pathogenesis of SPPRS in this child. Above discovery has enriched the mutational and phenotypic spectrum of the HACE1 gene and provided a reference for clinical diagnosis and genetic counseling.

Objective:To explore the clinical phenotype and variants of KIF4A gene associated with X-linked intellectual disability type 100 (XLID100) in a child by whole-exome sequencing (WES). Methods:A child presented at the Children′s Hospital Affiliated to Nanjing Medical University in September 2023 was selected as the study subject. Clinical data of the child was retrospectively analyzed. Peripheral blood samples were collected from the child and his family members for WES analysis. Candidate variant was verified by Sanger sequencing. Pathogenicity of the candidate variant was rated based on the guidelines from the American College of Medical Genetics and Genomics (ACMG). The variant was also searched in dbSNP, OMIM, HGMD, ClinVar and gnomAD databases. Amino acid sequences of the KIF4A protein across various species were retrieved from the Ensembl Genome Browser Database and analyzed using Clustal Omega software. Relevant literature on KIF4A gene mutations associated with XLID100 was reviewed. This study has been approved by the Medical Ethics Committee of the Hospital (Ethics No. 202402022-1). Results:The child, a 3-year-6-month-old male, had manifested intellectual impairment, language delay, autism, and choroid cyst revealed by cranial magnetic resonance imaging. No facial dysmorphism, tooth anomaly, gross motor development delay or regression, and history of seizure and febrile convulsion was noted. WES revealed that he has harbored a c. 3385delinsTATC (p.Thr1129delinsTyrPro) variant of the KIF4A gene. Sanger sequencing confirmed that his mother and sister have harbored the same variant, whilst his father was of the wild type. Both of his parents had a normal phenotype. The variant was classified as of uncertain significance based on the guidelines from the ACMG. It was not recorded by the dbSNP, OMIM, HGMD, ClinVar and the gnomAD database. Conservative analysis suggested that the variant site, which normally encodes a cysteine, is highly conserved among various species. A review of the literature had retrieved 6 relevant articles documenting a total of 27 cases of KIF4A gene mutations, with only one case from China. Conclusion:The c. 3385delinsTATC (p.Thr1129delinsTyrPro) variant of the KIF4A gene probably underlay the XLID100 in this child. Above finding has provided a reference for the clinical diagnosis and genetic counseling and enriched the mutation spectrum of the KIF4A gene.

BACKGROUND: Recent studies have provided compelling evidence that exposure to brominated flame retardants (BFRs) can adversely affect human health. We aim to explore the potential impact of BFRs on adiposity and central obesity. METHODS: Data from the National Health and Nutrition Examination Surveys (NHANES) cycles conducted between 2009 and 2014 was used to study the connections between variables. After filtering, we analyzed a sample of 4,110 adults aged 20 years and above. Our goal was to examine the potential association between BFRs and consequences and investigate the part played by oxidative stress and inflammatory markers as intermediaries. To achieve this, we used advanced statistical methods such as weighted quantile sum (WQS) regression, quantile-based g-computation (QGC), and the Bayesian kernel machine regression (BKMR). RESULTS: The findings showed that among the examined chemicals, exposure to PBDE85 (weight: 41%), PBDE100 (24%), and PBB153 (23%) may be the dominant contributors to general obesity risk. Upon controlling for all variables that could impact the results, it was found that the QGC outcomes indicated a positive correlation between exposure to mixtures of brominated flame retardants and the occurrence of abdominal obesity (OR = 1.187, 95% CI: 1.056-1.334, p = 0.004). Significant contributions were made by PBDE85 (52%), PBB153 (27%), and PBDE100 (21%). Mediation analysis shows that lymphatic cells (LC) and albumin (ALB) partially mediate the link between brominated flame retardants and obesity. The results of BKMR are generally consistent with those of WQS and QGC. CONCLUSION At a population level, our research has revealed a noteworthy correlation between BFRs and obesity. However, further investigation is required through prospective cohort studies and in-depth mechanistic exploratory studies.
Humans ; Flame Retardants/adverse effects* ; Oxidative Stress/drug effects* ; Adult ; Male ; Female ; Middle Aged ; Inflammation/epidemiology* ; Obesity/chemically induced* ; Biomarkers/blood* ; Nutrition Surveys ; Mediation Analysis ; Young Adult ; United States/epidemiology* ; Environmental Exposure/adverse effects* ; Aged ; Environmental Pollutants/adverse effects* ; Halogenated Diphenyl Ethers/adverse effects*

Objective:To investigate the clinical features and elucidate the molecular pathogenesis of neurodevelopmental disorder with impaired speech and hyperkinetic movements (NEDISHM) associated with zinc finger protein 142 (ZNF142) gene variants.Methods:A retrospective case series analysis was performed. The clinical data were collected on 2 children diagnosed with NEDISHM at Children′s Hospital of Nanjing Medical University in February 2025. Whole-exome sequencing (WES) was conducted to identify pathogenic variants, subsequently validated by Sanger sequencing. Variant pathogenicity was assessed using computational predictors (SIFT, PolyPhen-2, MutationTaster) and structural modeling (PyMOL). Relative quantification of ZNF142 gene transcript levels was performed using real-time quantitative PCR, with expression values normalized against 2 rigorously age-and sex-matched healthy control subjects (normalized to 1.000).Results:Two monozygotic twin males aged 7 years and 3 months. Case 1 exhibited severe language impairment, moderate intellectual disability, attention deficits, hyperactivity, impulsivity, aggressive behavior, frontal bossing, and a flat nasal bridge. Case 2 presented with mild speech disorders, mild intellectual disability, while maintaining comparable craniofacial characteristics. WES revealed compound heterozygous ZNF142 gene variants in both affected individuals (NM_001105537.4): a paternally inherited nonsense variation (c.4030C>T, p.Arg1344Ter) and a de novo missense variation (c.1271C>T, p.Thr424Met). The latter, unreported previously, was predicted as pathogenic by in silico tools and structural analysis, demonstrating hydrogen bond disruption and altered thermodynamic stability. Quantitative PCR analysis showed relative expression level of ZNF142 gene mRNA in 2 cases were 0.230 and 0.173. Conclusions:Compound heterozygous variations of the ZNF142 gene can lead to the down-regulation of ZNF142 expression and thereby result in NEDISHM. Despite having exactly same genetic background, identical twin patients with NEDISHM still show significant clinical phenotypic heterogeneity.

OBJECTIVE: To explore the genetic etiology of a child with Spastic paraplegia and psychomotor retardation with or without seizures (SPPRS). METHODS: A child who was admitted to the Children's Hospital Affiliated to Nanjing Medical University in April 2022 for motor developmental delay, intellectual disability, and hypertonia was selected as the study subject. Relevant clinical data were retrospectively analyzed. Whole exome sequencing (WES) was carried out for the child and his parents. Candidate variants were searched in the Single Nucleotide Polymorphism Database (dbSNP) and Online Mendelian Inheritance in Man (OMIM) database. Pathogenicity of the variants was assessed based on guidelines from the American College of Medical Genetics and Genomics (ACMG). Using key words such as "HACE1 gene" "Spastic paraplegia and psychomotor retardation with or without seizures" and "SPPRS", previous reports on SPPRS patients due to HACE1 gene variants were retrieved from the CNKI, Wanfang Data Knowledge Service Platform, CQVIP, and PubMed databases, with the time set from January 1, 2000 to April 7, 2024. A mutation map for the HACE1 protein in the patients was created. This study was approved by the Ethics Committee of the Children's Hospital Affiliated to Nanjing Medical University (Ethics No. 202404008-1). RESULTS: The clinical manifestations of the child had included motor developmental delay, intellectual disability and hypertonia. Magnetic resonance imaging revealed hypoplasia of posterior corpus callosum and splenium, with slight enlargement of lateral ventricles. WES revealed that the child has harbored compound heterozygous variants of the HACE1 gene, namely c.535(exon7)_c.538(exon7)delACAG (p.T179fs*5) and c.1678+2(IVS15)T>C, which were respectively inherited from his parents. Based on the guidelines from the ACMG, the variants were respectively rated as likely pathogenic (PVS1 + PM2_Supporting) and pathogenic (PVS1 + PM2_Supporting + PM3). Literature search has identified 8 papers, which reported 23 SPPRS cases due to HACE1 gene variants. All patients exhibited psychomotor developmental delay, among whom 18 HACE1 gene variants were identified. CONCLUSION The c.535(exon7)_c.538(exon7)delACAG (p.T179fs*5) and c.1678+2(IVS15)T>C compound heterozygous variants of the HACE1 gene probably underlay the pathogenesis of SPPRS in this child. Above discovery has enriched the mutational and phenotypic spectrum of the HACE1 gene and provided a reference for clinical diagnosis and genetic counseling.
Humans ; Male ; Seizures/genetics* ; Ubiquitin-Protein Ligases/genetics* ; Heterozygote ; Mutation ; Child ; Child, Preschool ; Paraplegia/genetics* ; Intellectual Disability/genetics* ; Polymorphism, Single Nucleotide ; Exome Sequencing ; Psychomotor Disorders/genetics*

OBJECTIVE: To explore the clinical phenotype and variants of KIF4A gene associated with X-linked intellectual disability type 100 (XLID100) in a child by whole-exome sequencing (WES). METHODS: A child presented at the Children's Hospital Affiliated to Nanjing Medical University in September 2023 was selected as the study subject. Clinical data of the child was retrospectively analyzed. Peripheral blood samples were collected from the child and his family members for WES analysis. Candidate variant was verified by Sanger sequencing. Pathogenicity of the candidate variant was rated based on the guidelines from the American College of Medical Genetics and Genomics (ACMG). The variant was also searched in dbSNP, OMIM, HGMD, ClinVar and gnomAD databases. Amino acid sequences of the KIF4A protein across various species were retrieved from the Ensembl Genome Browser Database and analyzed using Clustal Omega software. Relevant literature on KIF4A gene mutations associated with XLID100 was reviewed. This study has been approved by the Medical Ethics Committee of the Hospital (Ethics No. 202402022-1). RESULTS: The child, a 3-year-6-month-old male, had manifested intellectual impairment, language delay, autism, and choroid cyst revealed by cranial magnetic resonance imaging. No facial dysmorphism, tooth anomaly, gross motor development delay or regression, and history of seizure and febrile convulsion was noted. WES revealed that he has harbored a c.3385delinsTATC (p.Thr1129delinsTyrPro) variant of the KIF4A gene. Sanger sequencing confirmed that his mother and sister have harbored the same variant, whilst his father was of the wild type. Both of his parents had a normal phenotype. The variant was classified as of uncertain significance based on the guidelines from the ACMG. It was not recorded by the dbSNP, OMIM, HGMD, ClinVar and the gnomAD database. Conservative analysis suggested that the variant site, which normally encodes a cysteine, is highly conserved among various species. A review of the literature had retrieved 6 relevant articles documenting a total of 27 cases of KIF4A gene mutations, with only one case from China. CONCLUSION The c.3385delinsTATC (p.Thr1129delinsTyrPro) variant of the KIF4A gene probably underlay the XLID100 in this child. Above finding has provided a reference for the clinical diagnosis and genetic counseling and enriched the mutation spectrum of the KIF4A gene.
Humans ; Kinesins/genetics* ; Male ; Child, Preschool ; Intellectual Disability/genetics* ; Mutation ; Exome Sequencing ; X-Linked Intellectual Disability/genetics* ; Phenotype

OBJECTIVE: To explore the genetic etiology of Pontocerebellar Hypoplasia Type 2D (PCH2D) due to compound heterozygous variants of the SEPSECS gene and to conduct a literature review. METHODS: A child with PCH2D diagnosed at the Children's Hospital of Nanjing Medical University due to "motor and cognitive retardation" in June 2022 was selected as the study subject. Clinical and imaging data were collected. Genomic DNA was extracted from the peripheral blood samples of the child and her parents. Whole-exome sequencing (WES) was conducted using capture-based high-throughput sequencing technology. Candidate variants were confirmed by Sanger sequencing and bioinformatics analysis. The pathogenicity of variant was rated according to the Standards and Guidelines for the Interpretation of Sequence Variants released by American College of Medical Genetics and Genomics (ACMG). Additionally, relevant literature on PCH2D caused by SEPSECS gene variants was reviewed to assess the genotype-phenotype correlation. This study was approved by the Medical Ethics Committee of the hospital (Ethical No.: 202402022-1). RESULTS: The child, a 1-year-and-3-month-old girl, had presented with global developmental delay, progressive microcephaly, hypotonia, elevated blood lactic acid, feeding difficulties, and absent tendon reflexes. Cranial MRI indicated thinning of the splenium of the corpus callosum. Electromyography suggested peripheral neurogenic changes primarily affecting sensory nerves. WES revealed the she has harbored compound heterozygous variants of the SEPSECS gene, namely c.194A>G (p.N65S) and c.896_c.897insA (p.N299fs*2) (NM_016955), which were inherited from her father and mother, respectively. Neither of her parents had related clinical manifestations. According to the ACMG guidelines, the c.194A>G (p.N65S) variant was classified as pathogenic (PM1+PM2_Supporting+PM3+PP3), and the c.896_c.897insA (p.N299fs*2) variant was as likely pathogenic (PVS1+PM2_Supporting). A total of 18 relevant literature were retrieved, which have involved 32 patients (including this case). The p.N65S variant has been reported previously, while the p.N299fs*2 variant is novel. CONCLUSION Compound heterozygous variants in the SEPSECS gene probably underlay the pathogenesis of PCH2D in this child. Above finding has expanded the mutational and phenotypic spectrum of the SEPSECS gene.
Humans ; Female ; Infant ; Heterozygote ; Cerebellar Diseases/genetics* ; Membrane Proteins/genetics* ; Exome Sequencing ; Mutation