OBJECTIVE: To explore the clinical characteristics of a child with early-onset infantile epileptic encephalopathy type 8 associated with synonymous variant of ARHGEF9 gene. METHODS: Clinical data of the patient was summarized. The child and his parents were subjected to trio-whole exome sequencing. RESULTS: The child has presented with global developmental delay, epilepsy, impulsive behavior, hypersensitivity to sound, and mental retardation. He was found to harbor a de novo synonymous variant c.741C>T (p.Cys247Cys) of the ARHGEF9 gene. RNA splicing analysis confirmed that the variant has led to abnormal splicing of exon 5, resulting in a 55-bp deletion. CONCLUSION The clinical features of ARHGEF9 gene-related early-onset infantile epileptic encephalopathy type 8 includes mental and motor developmental delay, epilepsy, auditory allergy, and hyperactivity impulsivity. For synonymous variant, in vitro study and transcriptional experiment may be carried out to evaluate its functional and splicing effect. Above finding has enriched the phenotypic and genotypic spectrum of the ARHGEF9 gene.
Child ; Epilepsy/genetics* ; Exons ; Humans ; Infant ; Intellectual Disability/genetics* ; Male ; Rho Guanine Nucleotide Exchange Factors/genetics* ; Spasms, Infantile/genetics*

OBJECTIVE: To analyze the clinical phenotype and genetic variants of a child with X-linked mental retardation caused by IQSEC2 gene mutation, and provide reference for the diagnosis of the disease. METHODS: The child was subjected to next generation sequencing (NGS), and the diagnosis was made by taking consideration of her clinical characteristics. RESULTS: The child has presented with global developmental delay, particularly in fine motor skill and language development, in addition with intellectual disability. Genetic testing revealed that she has harbored a heterozygous c.1861dup variant of the IQSEC2 gene, which was not detected in either parent. CONCLUSION The de novo c.186ldup variant of the IQSEC2 gene probably underlay the X-linked mental retardation in this child. Above finding has, expanded the spectrum of IQSEC2 gene mutations and provide a basis for the diagnosis of similar cases.
Female ; Guanine Nucleotide Exchange Factors/genetics* ; Heterozygote ; Humans ; Intellectual Disability/genetics* ; Mental Retardation, X-Linked/genetics* ; Mutation ; Phenotype

Objective: To analyze the genotypes and clinical phenotypes of patients with epilepsy associated with IQSEC2 gene variants. Methods: The genotypes, seizure types, electroencephalogram, neuroimage of 6 patients with IQSEC2 gene variants in the Department of Pediatrics, Peking University First Hospital from July 2019 to October 2021 were analyzed. Results: There were 5 males and 1 female. Six variants were de novo, including 2 frameshift variants (c.3801_3808dup/p.Q1270Rfs*130, c.1459_1460delAT/p.M487Vfs*2), 2 nonsense variants (c.3163C>T/p.R1055*, c.1417G>T/p.E473*), 1 in-frame deletion (c.2295_2297del/p.N765del) and 1 missense variant (c.2293A>G/p.N765D). Age at seizure onset ranged from 3 months to 2 years and 5 months. Multiple seizure types were observed, including epileptic spasms in 5 patients, focal seizures in 5 patients, tonic seizures in 3 patients, myoclonic seizures in 3 patients, atypical absence seizures in 2 patients and atonic seizures in 2 patients. All 6 patients showed global developmental delay before seizure onset. There were other clinical manifestations, including autistic features in 3 patients, microcephaly in 3 patients, dystonia in 2 patients and binocular esotropia in 1 patient. The electroencephalogram showed slow background activity and hypsarrhythmia in all 6 patients. Brain magnetic resonance imaging showed abnormal in 5 patients and normal in 1 patient. Five patients were diagnosed with infantile spasms. Among them, 4 patients had late-onset infantile spasms. One patient was unclassified developmental epileptic encephalopathy. The age of last follow-up ranged from 3 years and 2 months to 7 years and 2 months. All 6 patients still had seizures after multiple anti-seizure medications. Conclusions: The seizure onset of patients with IQSEC2 gene variants usually begins after 1 year of age. The common seizure types include epileptic spasms and focal seizures. Patients usually have a global developmental delay before seizure onset. IQSEC2 variants could be related to developmental and epileptic encephalopathy, and most patients are diagnosed with late onset infantile spasms. Epilepsy associated with IQSEC2 gene variants is usually refractory.
Female ; Male ; Child ; Humans ; Spasms, Infantile/genetics* ; Genotype ; Phenotype ; Epilepsy/genetics* ; Seizures ; Spasm ; Guanine Nucleotide Exchange Factors

OBJECTIVETo study the single-nucleotide substitution (c.-16C to T) of the PURATROPHIN-1 gene in spinocerebellar ataxia (SCA) patients in China.

METHODSThe single-nucleotide substitution (c.-16C to T) of the PURATROPHIN-1 gene was detected by PCR, digested with EcoN I, separated on 8% polyacrylamide gel in 68 probands of autosomal dominant SCA families and 119 sporadic SCA patients, who had been excluded CAG/CAA repeat expansion at the SCA1, 2, 3, 6, 7, 17 and dentatorubral-pallidolluysian atrophy (DRPLA) loci. The results were confirmed in four patients by direct sequencing.

RESULTSThe single-nucleotide substitution (c.-16C to T) of the PURATROPHIN-1 gene was not identified in authors' cohort.

CONCLUSIONThe mutation of c.-16C to T of the PURATROPHIN-1 gene might be rare in SCA patients in China.

Asian Continental Ancestry Group ; genetics ; Cohort Studies ; Guanine Nucleotide Exchange Factors ; genetics ; Humans ; Mutation ; Polymerase Chain Reaction ; Polymorphism, Single Nucleotide ; Spectrin ; genetics ; Spinocerebellar Ataxias ; genetics

OBJECTIVE: To detect pathogenic mutation of DOCK6 gene in a patient with convulsive seizure and refractory epilepsy. METHODS: CytoScan HD-Array and next generation sequencing were used to detect the potential mutation in the patient. RESULTS: The proband has carried compound heterozygous mutations of c.188C>T (p.Arg63Gln) and c.5374C>T (p.Glu1792Lys) of the DOCK6 gene, which were respectively inherited from his mother and father. Neither mutation was reported previously. Bioinformatic analysis indicated that the two amino acids are highly conserved. Based on the ACMG guidelines, the c.188C>T mutation was predicted to be likely pathogenic, while the c.5374C>T mutation was of uncertain significance. CONCLUSION The compound heterozygous mutations of c.188C>T (p.Arg63Gln) and c.5374C>T (p.Glu1792Lys) of the DOCK6 gene probably underlie the disease in this patient.
Child ; Diabetes Mellitus, Type 2 ; Ectodermal Dysplasia ; genetics ; Guanine Nucleotide Exchange Factors ; genetics ; Humans ; Limb Deformities, Congenital ; genetics ; Mutation ; Pedigree ; Scalp Dermatoses ; congenital ; genetics

The radial migration of cortical pyramidal neurons (PNs) during corticogenesis is necessary for establishing a multilayered cerebral cortex. Neuronal migration defects are considered a critical etiology of neurodevelopmental disorders, including autism spectrum disorders (ASDs), schizophrenia, epilepsy, and intellectual disability (ID). TRIO is a high-risk candidate gene for ASDs and ID. However, its role in embryonic radial migration and the etiology of ASDs and ID are not fully understood. In this study, we found that the in vivo conditional knockout or in utero knockout of Trio in excitatory precursors in the neocortex caused aberrant polarity and halted the migration of late-born PNs. Further investigation of the underlying mechanism revealed that the interaction of the Trio N-terminal SH3 domain with Myosin X mediated the adherence of migrating neurons to radial glial fibers through regulating the membrane location of neuronal cadherin (N-cadherin). Also, independent or synergistic overexpression of RAC1 and RHOA showed different phenotypic recoveries of the abnormal neuronal migration by affecting the morphological transition and/or the glial fiber-dependent locomotion. Taken together, our findings clarify a novel mechanism of Trio in regulating N-cadherin cell surface expression via the interaction of Myosin X with its N-terminal SH3 domain. These results suggest the vital roles of the guanine nucleotide exchange factor 1 (GEF1) and GEF2 domains in regulating radial migration by activating their Rho GTPase effectors in both distinct and cooperative manners, which might be associated with the abnormal phenotypes in neurodevelopmental disorders.
Autism Spectrum Disorder/metabolism* ; Cell Movement/genetics* ; Humans ; Interneurons/metabolism* ; Neurodevelopmental Disorders/genetics* ; Neurons/metabolism* ; Rho Guanine Nucleotide Exchange Factors/genetics*

OBJECTIVE: To detect pathogenic variant of the FGD1 gene in a boy with Aarskog-Scott syndrome. METHODS: Genetic variant was detected by high-throughput sequencing. Suspected variant was verified by Sanger sequencing. The nature and impact of the candidate variant were predicted by bioinformatic analysis. RESULTS: The child was found to harbor a novel c.1906C>T hemizygous variant of the FGD1 gene, which has led to conversion of Arginine to Tryptophane at codon 636(p.Arg636Trp). The same variant was found in his mother but not father. Based on the American College of Medical Genetics and Genomics guidelines, the c.1906C>T variant of FGD1 gene was predicted to be likely pathogenic(PM1+PM2+PM5+PP2+PP3+PP4). CONCLUSION The novel c.1906C>T variant of the FGD1 gene may underlay the Aarskog-Scott syndrome in this child. Above finding has enabled diagnosis for the boy.
Child ; Dwarfism ; Face/abnormalities* ; Genetic Diseases, X-Linked ; Genitalia, Male/abnormalities* ; Guanine Nucleotide Exchange Factors/genetics* ; Hand Deformities, Congenital/genetics* ; Heart Defects, Congenital ; Humans ; Male ; Mutation

OBJECTIVETo investigate the association of single nucleotide polymorphisms (SNP) rs22833188 and rs2833195 in TIAM1 gene with the susceptibility to Kawasaki disease (KD) and its clinical characteristic in children.

METHODSA case-control study was performed in this study. One hundred and eighty-eight children with KD and 197 normal children served as controls were enrolled. The genotypes of two SNPs rs22833188 and rs2833195 in TIAM1 gene were detected using PCR-RFLP.

RESULTSThere were no significant differences in the genotype (AA, AG and GG) and allele frequencies of SNP rs2833188 between the KD and control groups. Significant differences in the genotype (CC, GC and GG) frequency of SNP rs2833195 were noted between the KD and control groups (P=0.017). The frequency of C allele in the KD group was higher than in the control group (P=0.015). The polymorphism of SNP rs2833188 was associated with the occurrence of rash (P=0.011), and the polymorphism of SNP rs2833195 was associated with the occurrence of conjunctival hyperemia (P=0.021).

CONCLUSIONSThe polymorphism of rs2833195 in TIAM1 gene is associated with the susceptibility to KD. The polymorphisms rs2833188 and rs2833195 in TIAM1 gene may be associated with some clinical characteristics in children with KD.

Child ; Child, Preschool ; Female ; Genetic Predisposition to Disease ; Genotype ; Guanine Nucleotide Exchange Factors ; genetics ; Humans ; Infant ; Male ; Mucocutaneous Lymph Node Syndrome ; genetics ; Polymorphism, Single Nucleotide ; T-Lymphoma Invasion and Metastasis-inducing Protein 1

Previously, we demonstrated that the p190 Rho guanine nucleotide exchange factor (p190RhoGEF) was induced following CD40 stimulation of B cells. In this study, we examined whether p190RhoGEF and a downstream effector molecule RhoA are required for B cell differentiation. Expression of p190RhoGEF positively correlated with the expression of surface markers and transcriptional regulators that are characteristic of mature B cells with plasma cell (PC) phenotypes. Moreover, either the overexpression of p190RhoGEF or the expression of a constitutively active RhoA drove cellular differentiation toward PC phenotypes. B cell maturation was abrogated in cells that overexpressed p190RhoGEF and a dominant-negative form of RhoA simultaneously. CD40-mediated maturation events were also abrogated in cells that overexpressed either dominant-negative p190RhoGEF or RhoA. Together, these data provide evidence that p190RhoGEF signaling through RhoA in CD40-activated B cells drives the induction of the PC differentiation.
Animals ; B-Lymphocytes/*cytology/*metabolism ; Cell Differentiation/genetics/*physiology ; Cell Line ; Cells, Cultured ; Female ; Guanine Nucleotide Exchange Factors/genetics/*metabolism ; Humans ; Lymphocyte Activation/genetics/*physiology ; Mice ; Mice, Inbred BALB C ; Plasma Cells/*cytology/*metabolism ; rhoA GTP-Binding Protein/genetics/metabolism

BACKGROUNDT-lymphoma and metastasis gene 1 (Tiam1) produces a guanine nucleotide exchange factor (GNEF) that regulates guanosine triphosphatase, which transforms guanosine diphosphate to guanosine triphosphate. Recently published data indicate that Tiam1 was associated with gastric cancer. The aim of this study was to investigate biological effects and potential mechanisms of Tiam1 in gastric carcinoma.

METHODSWe analyzed the expression of Tiam1 in 114 pair-matched gastric neoplastic and adjacent non-neoplastic tissues by quantitative real-time PCR. We investigated Tiam1 expression and its prognostic value for gastric cancer. Furthermore, the functions of Tiam1 over-expression were analyzed with stable-expression Tiam1 plasmid in human gastric cancer cell lines.

RESULTSTiam1 expression was significantly associated with cell differentiation and lymphatic metastasis; expression of Tiam1 mRNA was up-regulated in gastric cancer compared to pair-matched adjacent non-tumor tissues. Analyses of surgical tissue samples and 5-year survival of gastric cancer patients showed that those with strong Tiam1 expression had significantly shorter overall survival time than those with negative Tiam1 expression. Ectopic expression of Tiam1 promoted cell growth, migration and invasion of gastric cancer cells in vitro.

CONCLUSIONSIn gastric cancer cells, Tiam1 affects multiple properties associated with acquisition of the metastatic phenotype, and may be a marker of gastric cancer progression and metastasis in a subset of cancer.

Cell Line, Tumor ; Cell Movement ; genetics ; physiology ; Cell Proliferation ; Guanine Nucleotide Exchange Factors ; genetics ; metabolism ; Humans ; Neoplasm Metastasis ; genetics ; Stomach Neoplasms ; genetics ; metabolism ; pathology ; T-Lymphoma Invasion and Metastasis-inducing Protein 1