OBJECTIVE: To explore the clinical characteristics and genetic basis of a child with Mental retardation autosomal dominant 51 (MRD51). METHODS: A child with MRD51 who was hospitalized at Guangzhou Women and Children's Medical Center on March 4, 2022 was selected as the study subject. Clinical data of the child was collected. Peripheral blood samples of the child and her parents were collected and subjected to whole exome sequencing (WES). Candidate variants were verified by Sanger sequencing and bioinformatic analysis. RESULTS: The child, a 5-year-and-3-month-old girl, had manifested autism spectrum disorder (ASD), mental retardation (MR), recurrent febrile convulsions and facial dysmorphism. WES revealed that she has harbored a novel heterozygous variant of c.142G>T (p.Glu48Ter) in the KMT5B gene. Sanger sequencing confirmed that neither of her parents has carried the same variant. The variant has not been recorded in the ClinVar, OMIM and HGMD, ESP, ExAC and 1000 Genomes databases. Analysis with online software including Mutation Taster, GERP++ and CADD indicated it to be pathogenic. Prediction with SWISS-MODEL online software suggested that the variant may have a significant impact on the structure of KMT5B protein. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the variant was predicted to be pathogenic. CONCLUSION The c.142G>T (p.Glu48Ter) variant of the KMT5B gene probably underlay the MRD51 in this child. Above finding has expanded the spectrum of KMT5B gene mutations and provided a reference for clinical diagnosis and genetic counseling for this family.
Humans ; Female ; Child, Preschool ; Intellectual Disability/genetics* ; Autism Spectrum Disorder/genetics* ; Mutation

OBJECTIVE: To explore the clinical characteristics and genetic basis of a child with autism spectrum disorder (ASD) in conjunct with congenital heart disease (CHD). METHODS: A child who was hospitalized at the Third People's Hospital of Chengdu on April 13, 2021 was selected as the study subject. Clinical data of the child were collected. Peripheral blood samples of the child and his parents were collected and subjected to whole exome sequencing (WES). A GTX genetic analysis system was used to analyze the WES data and screen candidate variants for ASD. Candidate variant was verified by Sanger sequencing and bioinformatics analysis. Real-time fluorescent quantitative PCR (qPCR) was carried out to compare the expression of mRNA of the NSD1 gene between this child and 3 healthy controls and 5 other children with ASD. RESULTS: The patient, an 8-year-old male, has manifested with ASD, mental retardation and CHD. WES analysis revealed that he has harbored a heterozygous c.3385+2T>C variant in the NSD1 gene, which may affect the function of its protein product. Sanger sequencing showed that neither of his parent has carried the same variant. By bioinformatic analysis, the variant has not been recorded in the ESP, 1000 Genomes and ExAC databases. Analysis with Mutation Taster online software indicated it to be disease causing. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the variant was predicted to be pathogenic. By qPCR analysis, the expression level of mRNA of the NSD1 gene in this child and 5 other children with ASD was significantly lower than that of the healthy controls (P < 0.001). CONCLUSION The c.3385+2T>C variant of the NSD1 gene can significantly reduce its expression, which may predispose to ASD. Above finding has enriched the mutational spectrum the NSD1 gene.
Male ; Child ; Humans ; Autism Spectrum Disorder/genetics* ; Heart Defects, Congenital/genetics* ; Computational Biology ; Genomics ; Mutation ; RNA, Messenger/genetics* ; Histone-Lysine N-Methyltransferase/genetics*

OBJECTIVE: To assess the value of copy number variation sequencing (CNV-seq) for the diagnosis of children with intellectual disability (ID), developmental delay (DD), and autistic spectrum disorder (ASD). METHODS: Forty patients with ID/DD/ASD referred to Nanshan Maternity and Child Health Care Hospital from September 2018 to January 2022 were enrolled. G-banded karyotyping analysis was carried out for the patients. Genomic DNA was extracted from peripheral blood samples and subjected to CNV-Seq analysis to detect chromosome copy number variations (CNVs) in such patients. ClinVar, DECIPHER, OMIM and other database were searched for data annotation. RESULTS: Among the 40 patients (including 30 males and 10 females), 16, 15 and 6 were diagnosed with ID, DD and ASD, respectively. One patient had combined symptoms of ID and DD, whilst the remaining two had combined ID and ASD. Four patients were found with abnormal karyotypes, including 47,XY,+mar, 46,XY,inv(8)(p11.2q21.2), 46,XX,del(5)(p14) and 46,XX[76]/46,X,dup(X)(p21.1q12). Chromosome polymorphism was also found in two other patients. CNV-seq analysis has detected 32 CNVs in 20 patients (50.0%, 20/40). Pathogenic CNVs were found in 10 patients (25.0%), 15 CNVs of uncertain clinical significance were found in 12 patients (30.0%), and 7 likely benign CNVs were found in 4 patients (10.0%). CONCLUSION Chromosome CNVs play an important role in the pathogenesis of ID/DD/ASD. CNV-seq can detect chromosomal abnormalities including microdeletions and microduplications, which could provide a powerful tool for revealing the genetic etiology of ID/DD/ASD patients.
Pregnancy ; Child ; Male ; Humans ; Female ; DNA Copy Number Variations ; Intellectual Disability/genetics* ; Autism Spectrum Disorder/genetics* ; Developmental Disabilities/genetics* ; Abnormal Karyotype

Brain size abnormality is correlated with an increased frequency of autism spectrum disorder (ASD) in offspring. Genetic analysis indicates that heterozygous mutations of the WD repeat domain 62 (WDR62) are associated with ASD. However, biological evidence is still lacking. Our study showed that Wdr62 knockout (KO) led to reduced brain size with impaired learning and memory, as well as ASD-like behaviors in mice. Interestingly, Wdr62 Nex-cKO mice (depletion of WDR62 in differentiated neurons) had a largely normal brain size but with aberrant social interactions and repetitive behaviors. WDR62 regulated dendritic spinogenesis and excitatory synaptic transmission in cortical pyramidal neurons. Finally, we revealed that retinoic acid gavages significantly alleviated ASD-like behaviors in mice with WDR62 haploinsufficiency, probably by complementing the expression of ASD and synapse-related genes. Our findings provide a new perspective on the relationship between the microcephaly gene WDR62 and ASD etiology that will benefit clinical diagnosis and intervention of ASD.
Mice ; Animals ; Microcephaly/genetics* ; Autistic Disorder/metabolism* ; Autism Spectrum Disorder/metabolism* ; Nerve Tissue Proteins/metabolism* ; Brain/metabolism* ; Mice, Knockout ; Cell Cycle Proteins/metabolism*

Autism spectrum disorder (ASD) is a highly heritable neurodevelopmental disorder characterized by deficits in social interactions and repetitive behaviors. Although hundreds of ASD risk genes, implicated in synaptic formation and transcriptional regulation, have been identified through human genetic studies, the East Asian ASD cohorts are still under-represented in genome-wide genetic studies. Here, we applied whole-exome sequencing to 369 ASD trios including probands and unaffected parents of Chinese origin. Using a joint-calling analytical pipeline based on GATK toolkits, we identified numerous de novo mutations including 55 high-impact variants and 165 moderate-impact variants, as well as de novo copy number variations containing known ASD-related genes. Importantly, combined with single-cell sequencing data from the developing human brain, we found that the expression of genes with de novo mutations was specifically enriched in the pre-, post-central gyrus (PRC, PC) and banks of the superior temporal (BST) regions in the human brain. By further analyzing the brain imaging data with ASD and healthy controls, we found that the gray volume of the right BST in ASD patients was significantly decreased compared to healthy controls, suggesting the potential structural deficits associated with ASD. Finally, we found a decrease in the seed-based functional connectivity between BST/PC/PRC and sensory areas, the insula, as well as the frontal lobes in ASD patients. This work indicated that combinatorial analysis with genome-wide screening, single-cell sequencing, and brain imaging data reveal the brain regions contributing to the etiology of ASD.
Humans ; Autism Spectrum Disorder/metabolism* ; Autistic Disorder ; Exome Sequencing ; DNA Copy Number Variations ; East Asian People ; Brain/metabolism* ; Mutation/genetics* ; Genetic Predisposition to Disease/genetics*

OBJECTIVE: To analyze the clinical characteristics and genetic etiology of a child with Helsmoortel-Van der Aa syndrome (HVDAS). METHODS: Genetic testing was carried out for the child and his parents, and the clinical phenotypes and genetic variants of reported cases were summarized through literature review. RESULTS: The child has featured peculiar facies, accompanied by autism spectrum disorder, intellectual disability and motor retardation, and curving of the second toes, which was unreported previously. Genetic testing revealed that the child has harbored a heterozygous c.2157C>G (p.Tyr719*) variant of the ADNP gene, which was not found in either parent. Based on the guidelines of the American College of Medical Genetics and Genomics, this variant was rated as pathogenic. Among 80 HVDAS cases described in the literature, most had various degrees of behavioral abnormalities, intellectual disability, language retardation and motor retardation, with common features involving the nervous system, gastrointestinal system and eye. Variants of the ADNP gene mainly included frameshift variants and nonsense variants, with the hotspot variants including p.Tyr719*, p.Asn832lysfs*81 and p.Arg730*. CONCLUSION The clinical phenotype of the child is closely correlated with the heterozygous variant of the ADNP gene, which expanded the phenotypic spectrum of HVDAS. As HVDAS may involve multiple systems and have high phenotypic heterogeneity, genetic testing technology can facilitate accurately diagnose.
Abnormalities, Multiple/genetics* ; Autism Spectrum Disorder/genetics* ; Autistic Disorder/genetics* ; Homeodomain Proteins/genetics* ; Humans ; Intellectual Disability/genetics* ; Mutation ; Nerve Tissue Proteins/genetics* ; Rare Diseases/complications*

Fragile X syndrome (FXS) is the most common monogenic form of inherited intellectual disability and autism spectrum disorder (ASD). More than 99% of individuals with FXS are caused by the unstable expansion of CGG repeats located within the 5'-untranslated region of the FMR1 gene. The clinical features of FXS include various degrees of cognitive deficit, physical, behavioral and psychiatric problems. Early treatment and prevention from having further affected children can be guided by molecular genetic testing of the FMR1 gene. The following guideline has combined the relevant research, guidelines and consensus worldwide, and summarized the genetic knowledge and clinical treatment for FXS in order to achieve a standardized diagnosis, treatment and prevention for patients and families affected by this disease.
Child ; Humans ; Autism Spectrum Disorder/therapy* ; Fragile X Mental Retardation Protein/genetics* ; Fragile X Syndrome/therapy* ; Intellectual Disability/genetics*

Humans ; Autistic Disorder ; China/epidemiology* ; Cohort Studies ; Autism Spectrum Disorder/genetics* ; Asian People

Objective: To investigate the clinical manifestations and genetic features of 2 children with Smith-Kingsmore syndrome caused by MTOR gene variation and review the literature. Methods: The clinical data of 2 children carrying MTOR gene variant, diagnosed at Xi'an Children's Hospital from April 2018 to April 2021, were retrospectively summarized."MTOR"and"Smith-Kingsmore syndrome"were used as key words to search at China National Knowledge Infrastructure, Wanfang Data Knowledge Service Platform, PubMed and OMIM up to August 2021. The characteristics of MTOR gene variation and the clinical phenotype of children with Smith-Kingsmore syndrome were summarized. Results: Two children were both females, aged 1.5 years and 2 years respectively, the onset age were both in infancy. They both had developmental delay, megalencephaly and abnormal face. Both whole exome sequencing revealed a de novo heterozygous missense variant in MTOR gene. One case carried c.5395G>A (p.Glu1799Lys) and the other case carried c.7234G>C (p.Asp2412His). There was no literature of MTOR gene variation in Chinese. So far, a total of 45 cases were reported worldwide with detailed clinical information. Eleven variations in MTOR gene were involved, which were all heterozygous missense mutations. Among them, p.Glu1799Lys was the most common sites (28 cases,62%). Another case carried c.7234G>C (p.Asp2412His) was not reported before. Summarizing the 47 cases (including these 2 cases), 46 cases had developmental delay or intellectual disability, 9 cases had developmental regression,42 cases had megalencephaly, 30 cases had facial malformation,16 cases had hypotonia, 17 cases had autism spectrum disorders, 3 cases had hyperactivity, 3 cases had obsessive compulsive disorder, 13 cases had eye diseases, 11 cases had cutaneous vascular malformation, and 9 cases had hypoglycemia. Conclusions: The main clinical features of Smith-Kingsmore syndrome include megalencephaly, developmental delay or intellectual disability, and facial malformation, which can be combined with epilepsy, autism spectrum disorder, hypotonia, hypoglycemia and so on. The variation of MTOR gene is the cause of Smith-Kingsmore syndrome.
Autism Spectrum Disorder ; Female ; Humans ; Hypoglycemia ; Intellectual Disability/genetics* ; Megalencephaly/genetics* ; Muscle Hypotonia ; Mutation ; Retrospective Studies ; TOR Serine-Threonine Kinases/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*