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1.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(1): 41-43, 2020 Jan 10.
Artigo em Chinês | MEDLINE | ID: mdl-31922594

RESUMO

OBJECTIVE: To explore the genetic basis of a patient featuring global developmental delay, intellectual disability, cleft palate, seizures and hypotonia. METHODS: Clinical examination and laboratory tests were carried out. Peripheral blood samples were obtained from the patient and his parents. Whole genomic DNA was extracted and subjected to next generation sequencing. Candidate variation was analyzed by using bioinformatic software and validated by Sanger sequencing. RESULTS: The proband was found to carry a heterozygous c.2117T>C (p.Leu706Pro) variant of the NEDD4L gene, which was a de novo variant validated by Sanger sequencing and predicted to be likely pathogenic according to the American College of Medical Genetics Guidelines. CONCLUSION: The heterozygous variant of c.2117T>C (p.Leu706Pro) of the NEDD4L gene probably underlies the disorders in the patient.


Assuntos
Ubiquitina-Proteína Ligases Nedd4 , Heterotopia Nodular Periventricular , Testes Genéticos , Heterozigoto , Humanos , Deficiência Intelectual/etiologia , Deficiência Intelectual/genética , Masculino , Mutação , Ubiquitina-Proteína Ligases Nedd4/genética , Heterotopia Nodular Periventricular/complicações , Heterotopia Nodular Periventricular/genética
2.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(1): 57-59, 2020 Jan 10.
Artigo em Chinês | MEDLINE | ID: mdl-31922598

RESUMO

OBJECTIVE: To explore the genetic basis of a child with idiopathic mental retardation. METHODS: Clinical data and peripheral blood sample of the child were collected. Genomic DNA was extracted and subjected to copy number analysis using single nucleotide polymrophism array comparative genome hybridization (SNP-aCGH) and targeted capture and next generation sequencing (NGS). RESULTS: No microdeletion/microduplication were detected by SNP-aCGH. NGS has detected homozygous c.722delA (p.Asp241fs) variant of the LISN1 gene, which is known to underlie autosomal recessive mental retardation-27 (MRT 27). Both parents are carriers of the variant, conforming to the autosomal recessive inheritance. CONCLUSION: A novel pathogenic variant of the LINS1 gene has been identified, which probably underlies the MRT 27 in the patient.


Assuntos
Deficiência Intelectual , Proteínas , Criança , Hibridização Genômica Comparativa , Sequenciamento de Nucleotídeos em Larga Escala , Homozigoto , Humanos , Deficiência Intelectual/genética , Proteínas/genética
3.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(1): 64-66, 2020 Jan 10.
Artigo em Chinês | MEDLINE | ID: mdl-31922600

RESUMO

OBJECTIVE: To explore the genetic basis of a child with developmental delay and intellectual disability. METHODS: Peripheral blood samples of the child and his parents were collected for routine G-band karyotyping analysis and single nucleotide polymorphism array (SNP array) assay. Amniotic fluid sample was collected during the next pregnancy for prenatal diagnosis. RESULTS: No karyotypic abnormality was found in the child and his parents. SNP array showed that the child has carried a 855.3 kb microduplication in 15q11.2. His mother carried the same duplication but had no phenotypic anomaly. No microdeletion/microduplication was found in his father. Upon prenatal diagnosis, no abnormalities was found with the chromosomal karyotype and SNP array result of the fetus. CONCLUSION: 15q11.2 microduplication may result in developmental delay and intellectual disability, for which CYFIP1 may be a candidate gene. However, the duplication may increase the risk but with a low penetrance. This should attract attention during clinical consultation.


Assuntos
Duplicação Cromossômica , Cromossomos Humanos Par 15 , Deficiência Intelectual , Proteínas Adaptadoras de Transdução de Sinal , Criança , Bandeamento Cromossômico , Cromossomos Humanos Par 15/genética , Deficiências do Desenvolvimento/genética , Feminino , Humanos , Deficiência Intelectual/genética , Cariotipagem , Masculino , Gravidez , Diagnóstico Pré-Natal
4.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(11): 1111-1114, 2019 Nov 10.
Artigo em Chinês | MEDLINE | ID: mdl-31703138

RESUMO

OBJECTIVE: To explore the clinical features and molecular basis for a child featuring infantile epilepsy and developmental disorders. METHODS: Clinical data and peripheral blood samples of the child and his parents were collected. The coding regions of genes associated with nervous system development were subjected to target region capture sequencing. RESULTS: The child developed generalized spasm at 3 months and was diagnosed with epilepsy at 6 months of age. He was treated with Depakin but was diagnosed with mental retardation and developmental retardation at 3 years of age. A novel heterozygous c.3842T to G variant of the SYNE1 gene was detected. His father was found to carry the same variant and had a history of convulsions in infancy but with no mental or developmental anomalies. CONCLUSION: A novel variant of SYNE1 gene was identified in this child, and the prognosis may be poor.


Assuntos
Deficiências do Desenvolvimento/genética , Epilepsia/genética , Proteínas do Tecido Nervoso/genética , Proteínas Nucleares/genética , Pré-Escolar , Proteínas do Citoesqueleto , Deficiências do Desenvolvimento/complicações , Epilepsia/complicações , Humanos , Lactente , Deficiência Intelectual/complicações , Deficiência Intelectual/genética , Masculino , Mutação , Convulsões
5.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(11): 1115-1119, 2019 Nov 10.
Artigo em Chinês | MEDLINE | ID: mdl-31703139

RESUMO

OBJECTIVE: To explore the genetic basis for a boy with mental retardation. METHODS: Clinical data and peripheral blood samples of the family were collected. Potential variants were screened by using a panel for genes associated with intellectual impairment. Suspected variants were verified by PCR and Sanger sequencing. RESULTS: The child presented with mental retardation, language delay and poor self-care. Imaging analysis showed widening of brain fissures and subarachnoid space, and dysplasia of corpus callosum. Three novel heterozygous variants, namely c.1705T to C (p.S569P), c.1708dupC (p.R570Pfs*80) and c.2273delA (p.N758Tfs*22), were identified in the TRAPPC9 gene. The mother of the proband has carried the c.1708dupC (p.R570Pfs*80) and c.1705T to C (p.S569P) variants, while his father has carried the c.2273delA (p.N758Tfs*22) variant. CONCLUSION: The compound heterozygous variants of the TRAPPC9 gene probably underlie the disease in this family. Considering the clinical and genetic heterogeneity of mental retardation, genetic testing is essential for attaining diagnosis for patients with the relevant phenotype.


Assuntos
Proteínas de Transporte/genética , Deficiência Intelectual/genética , Criança , Testes Genéticos , Heterozigoto , Humanos , Peptídeos e Proteínas de Sinalização Intercelular , Masculino , Mutação , Fenótipo
6.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(10): 989-992, 2019 Oct 10.
Artigo em Chinês | MEDLINE | ID: mdl-31598942

RESUMO

OBJECTIVE: To explore the nature and origin of chromosomal copy number variants (CNVs) in a pedigree affected with mental retardation. METHODS: Genomic CNVs of the proband were analyzed by next generation sequencing (NGS). Chromosomal karyotypes of the proband and his relatives were analyzed with high-resolution karyotyping and fluorescence in situ hybridization (FISH). RESULTS: Clinical phenotypes of the proband and other patients from the pedigree included mental retardation and mild dysmorphism. The results of NGS revealed that the proband carried a 16.24 Mb microduplication at 4p16.3-15.32 and a 2.2 Mb microdeletion at 8p23.3-23.2. Other patients of the pedigree harbored the same variants, while those without the phenotypes did not harbor the variants. The results of high-resolution karyotyping and FISH revealed that the mother of the proband carried a reciprocal translocation between 4p and 8p, and her karyotype was 46,XX,t(4;8)(p16;p23). No karyotypic abnormality was detected in his father. CONCLUSION: The abnormal phenotypes of this pedigree may be attributed to 4p microduplication in conjunct with 8p microdeletion derived from a maternal balanced translocation between 4p and 8p.


Assuntos
Aberrações Cromossômicas , Duplicação Cromossômica , Testes Genéticos , Deficiência Intelectual/genética , Cromossomos Humanos Par 4 , Cromossomos Humanos Par 8 , Feminino , Humanos , Hibridização in Situ Fluorescente , Cariotipagem , Linhagem , Fenótipo
7.
Cytogenet Genome Res ; 159(1): 1-11, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31658463

RESUMO

The switch/sucrose non-fermenting (SWI/SNF) complex is an ATP-dependent chromatin remodeller that regulates the spacing of nucleosomes and thereby controls gene expression. Heterozygous mutations in genes encoding subunits of the SWI/SNF complex have been reported in individuals with Coffin-Siris syndrome (CSS), with the majority of the mutations in ARID1B. CSS is a rare congenital disorder characterized by facial dysmorphisms, digital anomalies, and variable intellectual disability. We hypothesized that mutations in genes encoding subunits of the ubiquitously expressed SWI/SNF complex may lead to alterations of the nucleosome profiles in different cell types. We performed the first study on CSS-patient samples and investigated the nucleosome landscapes of cell-free DNA (cfDNA) isolated from blood plasma by whole-genome sequencing. In addition, we studied the nucleosome landscapes of CD14+ monocytes from CSS-affected individuals by nucleosome occupancy and methylome-sequencing (NOMe-seq) as well as their expression profiles. In cfDNA of CSS-affected individuals with heterozygous ARID1B mutations, we did not observe major changes in the nucleosome profile around transcription start sites. In CD14+ monocytes, we found few genomic regions with different nucleosome occupancy when compared to controls. RNA-seq analysis of CD14+ monocytes of these individuals detected only few differentially expressed genes, which were not in proximity to any of the identified differential nucleosome-depleted regions. In conclusion, we show that heterozygous mutations in the human SWI/SNF subunit ARID1B do not have a major impact on the nucleosome landscape or gene expression in blood cells. This might be due to functional redundancy, cell-type specificity, or alternative functions of ARID1B.


Assuntos
Anormalidades Múltiplas/genética , Proteínas de Ligação a DNA/genética , Face/anormalidades , Deformidades Congênitas da Mão/genética , Deficiência Intelectual/genética , Micrognatismo/genética , Pescoço/anormalidades , Proteínas Nucleares/genética , Nucleossomos/genética , Fatores de Transcrição/genética , Adolescente , Ácidos Nucleicos Livres/sangue , Ácidos Nucleicos Livres/genética , Criança , Pré-Escolar , Feminino , Genoma Humano/genética , Estudo de Associação Genômica Ampla , Humanos , Masculino , Monócitos/citologia , Adulto Jovem
8.
Cytogenet Genome Res ; 159(1): 19-25, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31487712

RESUMO

The role of autosomal recessive (AR) variants in clinically heterogeneous conditions such as intellectual disability and developmental delay (ID/DD) has been difficult to uncover. Implication of causative pathogenic AR variants often requires investigation within large and consanguineous families, and/or identifying rare biallelic variants in affected individuals. Furthermore, detection of homozygous gene-level copy number variants during first-line genomic microarray testing in the pediatric population is a rare finding. We describe a 6.7-year-old male patient with ID/DD and a novel homozygous deletion involving the FRY gene identified by genomic SNP microarray. This deletion was observed within a large region of homozygosity on the long arm of chromosome 13 and in a background of increased low-level (2.6%) autosomal homozygosity, consistent with a reported common ancestry in the family. FRY encodes a protein that regulates cell cytoskeletal dynamics, functions in chromosomal alignment in mitosis in vitro, and has been shown to function in the nervous system in vivo. Homozygous mutation of FRY has been previously reported in 2 consanguineous families from studies of autosomal recessive ID in Middle Eastern and Northern African populations. This report provides additional supportive evidence that deleterious biallelic mutation of FRY is associated with ID/DD and illustrates the utility of genomic SNP microarray detection of low-level homozygosity.


Assuntos
Deficiências do Desenvolvimento/genética , Deficiência Intelectual/genética , Deleção de Sequência/genética , Sequência de Bases/genética , Criança , Consanguinidade , Citoesqueleto/genética , Citoesqueleto/metabolismo , Humanos , Masculino , Polimorfismo de Nucleotídeo Único/genética
9.
Hum Genet ; 138(10): 1183-1200, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31471722

RESUMO

The glutamate pyruvate transaminase 2 (GPT2) gene produces a nuclear-encoded mitochondrial enzyme that catalyzes the reversible transfer of an amino group from glutamate to pyruvate, generating alanine and alpha-ketoglutarate. Recessive mutations in GPT2 have been recently identified in a new syndrome involving intellectual and developmental disability (IDD), postnatal microcephaly, and spastic paraplegia. We have identified additional families with recessive GPT2 mutations and expanded the phenotype to include small stature. GPT2 loss-of-function mutations were identified in four families, nine patients total, including: a homozygous mutation in one child [c.775T>C (p.C259R)]; compound heterozygous mutations in two siblings [c.812A>C (p.N271T)/c.1432_1433delGT (p.V478Rfs*73)]; a novel homozygous, putative splicing mutation [c.1035C>T (p.G345=)]; and finally, a recurrent mutation, previously identified in a distinct family [c.1210C>T (p.R404*)]. All patients were diagnosed with IDD. A majority of patients had remarkably small stature throughout development, many < 1st percentile for height and weight. Given the potential biological function of GPT2 in cellular growth, this phenotype is strongly suggestive of a newly identified clinical susceptibility. Further, homozygous GPT2 mutations manifested in at least 2 of 176 families with IDD (approximately 1.1%) in a Pakistani cohort, thereby representing a relatively common cause of recessive IDD in this population, with recurrence of the p.R404* mutation in this population. Based on variants in the ExAC database, we estimated that approximately 1 in 248 individuals are carriers of moderately or severely deleterious variants in GPT2.


Assuntos
Deficiências do Desenvolvimento/diagnóstico , Deficiências do Desenvolvimento/genética , Genes Recessivos , Predisposição Genética para Doença , Mutação , Fenótipo , Transaminases/genética , Adolescente , Alelos , Substituição de Aminoácidos , Deficiências do Desenvolvimento/metabolismo , Ativação Enzimática , Éxons , Feminino , Frequência do Gene , Estudos de Associação Genética , Genética Populacional , Genótipo , Humanos , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Imagem por Ressonância Magnética , Masculino , Mitocôndrias/genética , Mitocôndrias/metabolismo , Modelos Moleculares , Linhagem , Conformação Proteica , Sítios de Splice de RNA , Análise de Sequência de DNA , Relação Estrutura-Atividade , Transaminases/química , Transaminases/metabolismo
10.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(8): 829-833, 2019 Aug 10.
Artigo em Chinês | MEDLINE | ID: mdl-31400139

RESUMO

OBJECTIVE: To explore the genetic basis for a family affected with mental retardation combined with autism. METHODS: For the family featuring X-linked recessive inheritance of mental retardation combined with autism, clinical data and peripheral blood samples were collected. Potential mutations of genes associated with intellectual impairment were sequenced with an Ion PGM platform. Suspected mutations were verified with a PCR-Sanger sequencing method. RESULTS: The patient with mental retardation had mild abnormal electroencephalograph(EEG), while brain MRI and CT scans showed no obvious abnormality. Two ABC (autism behavior checklist) testing scores were 73 and 66 when he was 7- and 13-year-old, respectively. A novel hemizygous mutation, c.64C>T (p.L22F), was detected in the GRIA3 gene in the patient, for which his mother was a heterozygous carrier. The mutation site was predicted to be possibly damaging and disease causing by PolyPhen_2 and MutationTaster. CONCLUSION: The novel hemizygous c.64C>T (p.L22F) mutation of the GRIA3 gene probably underlies the phenotypes of mental retardation combined with autism in this family. Considering the variable clinical manifestation of mental retardation and genetic heterogeneity of autism, genetic testing is essential for making the correct diagnosis.


Assuntos
Transtorno Autístico/genética , Deficiência Intelectual/genética , Retardo Mental Ligado ao Cromossomo X/genética , Receptores de AMPA/genética , Adolescente , Criança , Humanos , Masculino , Mutação
11.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(8): 837-840, 2019 Aug 10.
Artigo em Chinês | MEDLINE | ID: mdl-31400141

RESUMO

OBJECTIVE: To analyze the clinical and molecular genetic characteristics of patient with Kleefstra syndrome 1. METHODS: Clinical data, chromosomal karyotype and whole genome copy number variations (CNVs) of the patient were analyzed. RESULTS: The patient was found to have a karyotype of 45,XX,-9[4]/46,XX,r(9)(p24q34)[56]. Whole-genome CNVs detection revealed that she has carried a heterozygous deletion of approximately 670 kb at 9q34.3, which encompassed the entire EHMT1 gene. The region is strongly associated with Kleefstra syndrome (1/9q telomere deletion). In addition, the patient also had heterozygous deletion of 9pter, which may predispose to formation of ring chromosome 9. CONCLUSION: The child was diagnosed with Kleefstra syndrome type 1 in conjunct with ring chromosome 9.


Assuntos
Cromossomos Humanos Par 9/genética , Anormalidades Craniofaciais/genética , Cardiopatias Congênitas/genética , Deficiência Intelectual/genética , Cromossomos em Anel , Criança , Deleção Cromossômica , Variações do Número de Cópias de DNA , Feminino , Humanos
12.
BMC Med Genet ; 20(1): 134, 2019 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-31382906

RESUMO

BACKGROUND: Wolf-Hirschhorn syndrome (WHS) is a contiguous gene syndrome caused by partial 4p deletion highly variable in size in individual patients. The core WHS phenotype is defined by the association of growth delay, typical facial characteristics, intellectual disability and seizures. The WHS critical region (WHSCR) has been narrowed down and NSD2 falls within this 200 kb region. Only four patients with NSD2 variants have been documented with phenotypic features in detail. CASE PRESENTATION: Herein, we report the case of a 12-year-old boy with developmental delay. He had dysmorphic facial features including wide-spaced eyes, prominent nasal bridge continuing to forehead, abnormal teething and micrognathia. He also had mild clinodactyly of both hands. Using whole-exome sequencing, we identified a pathogenic mutation in NSD2 [c.4029_4030insAA, p.Glu1344Lysfs*49] isolated from peripheral blood DNA. Sanger confirmation of this variant revealed it as a de novo truncating variant in the family. CONCLUSION: Here, we reported a boy with de novo truncating variant in NSD2 with atypical clinical features comparing with 4p16.3 deletion related WHS. Our finding further supported the pathogenesis of truncating variants in NSD2 and delineated the possible symptom spectrum caused by these variants.


Assuntos
Predisposição Genética para Doença/genética , Histona-Lisina N-Metiltransferase/genética , Fenótipo , Proteínas Repressoras/genética , Síndrome de Wolf-Hirschhorn/genética , Sequência de Bases , Criança , Cromossomos Humanos Par 4 , DNA/sangue , Deficiências do Desenvolvimento/genética , Humanos , Deficiência Intelectual/genética , Masculino , Convulsões/genética , Sequenciamento Completo do Exoma , Síndrome de Wolf-Hirschhorn/fisiopatologia
13.
Cytogenet Genome Res ; 158(4): 192-198, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31394532

RESUMO

Prader-Willi syndrome (PWS) and recurrent 15q13.3 microdeletion syndrome can be caused by genomic rearrangements in the complex 15q11q13 chromosomal region. Here, we describe the first female child with PWS and 15q13.3 microdeletion syndrome resulting from an unusual 10.7-Mb deletion from 15pter to 15q13.3 due to an unbalanced de novo 15;19 translocation. The patient presents with hypotonia, microcephaly, developmental delay with lack of speech, intellectual disability, happy demeanor, clinodactyly of the 4th and 5th fingers, and dysmorphic facial features discordant for PWS and consistent with an atypical phenotype.


Assuntos
Transtornos Cromossômicos/complicações , Transtornos Cromossômicos/genética , Deficiência Intelectual/complicações , Deficiência Intelectual/genética , Síndrome de Prader-Willi/complicações , Síndrome de Prader-Willi/genética , Convulsões/complicações , Convulsões/genética , Translocação Genética/genética , Pré-Escolar , Deleção Cromossômica , Cromossomos Humanos Par 15/genética , Feminino , Humanos , Recém-Nascido
14.
Klin Padiatr ; 231(5): 233-239, 2019 Sep.
Artigo em Alemão | MEDLINE | ID: mdl-31340405

RESUMO

BACKGROUND: Shared decision-making is indispensable when it comes to molecular genetic investigations, but data on the expectations of the parents is scarce. METHODS: Using a step-by-step approach we initially performed free in-depth-interviews with five parents on which base we developed a half standardized questionnaire. This questionnaire was then applied in interviews with 30 parents of children with intellectual disability, autism or epilepsy subject to genetic examination. RESULTS: Pre-diagnostic discussions are challenging for the parents in an intellectual as well as emotional way. The most important general aspects are diagnosis and therapy. Self-assessment of prior knowledge is very variable and many parents expressed problems in understanding. During the conversation parents rate the following specific aspects as "very important" or "important": findings of unclear relevance, incidental findings, psychic consequences, prognostic aspects, possible therapeutic interventions. 10 Parents did not have any school-degree and 20 parents were not native speakers. DISCUSSION: All parents express a high need for information covering almost all aspects of the investigation. Communicational hurdles pose additional challenges leaving a large room for improvement. Trustworthy internet-based information systems in different languages including plain language could be a first step.


Assuntos
Deficiências do Desenvolvimento/genética , Epilepsia/genética , Deficiência Intelectual/genética , Pais/psicologia , Criança , Humanos , Inquéritos e Questionários
15.
Nat Commun ; 10(1): 3043, 2019 07 10.
Artigo em Inglês | MEDLINE | ID: mdl-31292440

RESUMO

There are established associations between advanced paternal age and offspring risk for psychiatric and developmental disorders. These are commonly attributed to genetic mutations, especially de novo single nucleotide variants (dnSNVs), that accumulate with increasing paternal age. However, the actual magnitude of risk from such mutations in the male germline is unknown. Quantifying this risk would clarify the clinical significance of delayed paternity. Using parent-child trio whole-exome-sequencing data, we estimate the relationship between paternal-age-related dnSNVs and risk for five disorders: autism spectrum disorder (ASD), congenital heart disease, neurodevelopmental disorders with epilepsy, intellectual disability and schizophrenia (SCZ). Using Danish registry data, we investigate whether epidemiologic associations between each disorder and older fatherhood are consistent with the estimated role of dnSNVs. We find that paternal-age-related dnSNVs confer a small amount of risk for these disorders. For ASD and SCZ, epidemiologic associations with delayed paternity reflect factors that may not increase with age.


Assuntos
Testes Genéticos , Modelos Genéticos , Idade Paterna , Adulto , Fatores Etários , Transtorno do Espectro Autista/epidemiologia , Transtorno do Espectro Autista/genética , Criança , Dinamarca/epidemiologia , Epilepsia/epidemiologia , Epilepsia/genética , Feminino , Cardiopatias Congênitas/epidemiologia , Cardiopatias Congênitas/genética , Humanos , Incidência , Deficiência Intelectual/epidemiologia , Deficiência Intelectual/genética , Masculino , Pessoa de Meia-Idade , Mutação , Polimorfismo de Nucleotídeo Único , Prevalência , Sistema de Registros/estatística & dados numéricos , Medição de Risco/métodos , Esquizofrenia/epidemiologia , Esquizofrenia/genética , Sequenciamento Completo do Exoma
16.
Nat Commun ; 10(1): 2966, 2019 07 04.
Artigo em Inglês | MEDLINE | ID: mdl-31273213

RESUMO

Mutations in genes encoding components of BAF (BRG1/BRM-associated factor) chromatin remodeling complexes cause neurodevelopmental disorders and tumors. The mechanisms leading to the development of these two disease entities alone or in combination remain unclear. We generated mice with a heterozygous nervous system-specific partial loss-of-function mutation in a BAF core component gene, Smarcb1. These Smarcb1 mutant mice show various brain midline abnormalities that are also found in individuals with Coffin-Siris syndrome (CSS) caused by SMARCB1, SMARCE1, and ARID1B mutations and in SMARCB1-related intellectual disability (ID) with choroid plexus hyperplasia (CPH). Analyses of the Smarcb1 mutant animals indicate that one prominent midline abnormality, corpus callosum agenesis, is due to midline glia aberrations. Our results establish a novel role of Smarcb1 in the development of the brain midline and have important clinical implications for BAF complex-related ID/neurodevelopmental disorders.


Assuntos
Anormalidades Múltiplas/genética , Agenesia do Corpo Caloso/genética , Corpo Caloso/crescimento & desenvolvimento , Face/anormalidades , Deformidades Congênitas da Mão/genética , Deficiência Intelectual/genética , Micrognatismo/genética , Pescoço/anormalidades , Proteína SMARCB1/genética , Anormalidades Múltiplas/diagnóstico por imagem , Agenesia do Corpo Caloso/diagnóstico por imagem , Agenesia do Corpo Caloso/patologia , Alelos , Animais , Criança , Pré-Escolar , Corpo Caloso/citologia , Corpo Caloso/diagnóstico por imagem , Modelos Animais de Doenças , Embrião de Mamíferos , Face/diagnóstico por imagem , Feminino , Deformidades Congênitas da Mão/diagnóstico por imagem , Humanos , Lactente , Deficiência Intelectual/diagnóstico por imagem , Mutação com Perda de Função , Imagem por Ressonância Magnética , Masculino , Camundongos , Camundongos Transgênicos , Micrognatismo/diagnóstico por imagem , Pescoço/diagnóstico por imagem , Neuroglia/patologia , Cultura Primária de Células
17.
Nucleic Acids Res ; 47(16): 8720-8733, 2019 09 19.
Artigo em Inglês | MEDLINE | ID: mdl-31276587

RESUMO

Expression of human mitochondrial DNA is indispensable for proper function of the oxidative phosphorylation machinery. The mitochondrial genome encodes 22 tRNAs, 2 rRNAs and 11 mRNAs and their post-transcriptional modification constitutes one of the key regulatory steps during mitochondrial gene expression. Cytosine-5 methylation (m5C) has been detected in mitochondrial transcriptome, however its biogenesis has not been investigated in details. Mammalian NOP2/Sun RNA Methyltransferase Family Member 2 (NSUN2) has been characterized as an RNA methyltransferase introducing m5C in nuclear-encoded tRNAs, mRNAs and microRNAs and associated with cell proliferation and differentiation, with pathogenic variants in NSUN2 being linked to neurodevelopmental disorders. Here we employ spatially restricted proximity labelling and immunodetection to demonstrate that NSUN2 is imported into the matrix of mammalian mitochondria. Using three genetic models for NSUN2 inactivation-knockout mice, patient-derived fibroblasts and CRISPR/Cas9 knockout in human cells-we show that NSUN2 is necessary for the generation of m5C at positions 48, 49 and 50 of several mammalian mitochondrial tRNAs. Finally, we show that inactivation of NSUN2 does not have a profound effect on mitochondrial tRNA stability and oxidative phosphorylation in differentiated cells. We discuss the importance of the newly discovered function of NSUN2 in the context of human disease.


Assuntos
5-Metilcitosina/metabolismo , Eczema/genética , Transtornos do Crescimento/genética , Deficiência Intelectual/genética , Metiltransferases/genética , Microcefalia/genética , Processamento Pós-Transcricional do RNA , RNA Mitocondrial/genética , RNA de Transferência/genética , Animais , Sistemas CRISPR-Cas , Eczema/metabolismo , Eczema/patologia , Facies , Fibroblastos/metabolismo , Fibroblastos/patologia , Edição de Genes , Técnicas de Inativação de Genes , Transtornos do Crescimento/metabolismo , Transtornos do Crescimento/patologia , Células HEK293 , Humanos , Deficiência Intelectual/metabolismo , Deficiência Intelectual/patologia , Metilação , Metiltransferases/deficiência , Camundongos , Camundongos Knockout , Microcefalia/metabolismo , Microcefalia/patologia , Mitocôndrias/genética , Mitocôndrias/metabolismo , Conformação de Ácido Nucleico , Fosforilação Oxidativa , Cultura Primária de Células , Transporte Proteico , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Mitocondrial/metabolismo , RNA de Transferência/metabolismo
18.
Artigo em Russo | MEDLINE | ID: mdl-31317896

RESUMO

AIM: Long continuous stretches of homozygosity (LCSH) are regularly detected in studies using molecular karyotyping (SNP array). Despite this type of variation being able to provide meaningful data on the parents' kinship, uniparental disomy and chromosome rearrangements, LCSH are rarely considered as a possible epigenetic cause of neurodevelopmental disorders. Despite their direct relationship to imprinting, LCSH in imprinted loci have not been considered in terms of pathogenicity. The present work is aimed at studying LCSH in chromosomal regions containing imprinted genes previously associated with disease in children with idiopathic intellectual disability, autism, congenital malformations and/or epilepsy. MATERIAL AND METHODS: Five hundred and four patients with autism spectrum disorders and intellectual disability were examined. RESULTS: LCSH affecting imprinted loci associated with various diseases were identified in 40 (7.9%) individuals. Chromosomal region 7q21.3 was affected in twenty three cases, 15q11.2 in twelve, 11p15.5 in five, 7q32.2 in four. Four patients had 2 LCSH affecting imprinted loci. Besides one LCSH in 7q31.33q32.3 (~4 Mbp) region, all LCSH were 1-1.6 Mbp. Clinically, these cases resembled the corresponding imprinting diseases (e.g. Silver-Russell, Beckwith-Wiedemann, Prader-Willi, Angelman syndromes). Parental kinship was identified in 8 cases (1.59%), which were not affected by LCSH at imprinted loci. CONCLUSION: The present study shows that LCSH affecting chromosomal regions 7q21.3, 7q32.2, 11p15.5 and 15p11.2 occur in about 7.9% of children with intellectual disability, autism, congenital malformations and/or epilepsy. Consequently, this type of epigenetic mutations is obviously common in a group of children with neurodevelopmental disorders. LCSH less than 2.5-10 Mbp are usually ignored in molecular karyotyping (SNP array) studies and, therefore, an important epigenetic cause of intellectual disability, autism or epilepsy with high probability remains without attention.


Assuntos
Síndrome de Angelman , Transtorno do Espectro Autista , Epigenômica , Deficiência Intelectual , Síndrome de Angelman/genética , Transtorno do Espectro Autista/genética , Criança , Humanos , Deficiência Intelectual/genética , Perda de Heterozigosidade
19.
Nat Commun ; 10(1): 3094, 2019 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-31300657

RESUMO

AMPA receptors (AMPARs) are tetrameric ligand-gated channels made up of combinations of GluA1-4 subunits encoded by GRIA1-4 genes. GluA2 has an especially important role because, following post-transcriptional editing at the Q607 site, it renders heteromultimeric AMPARs Ca2+-impermeable, with a linear relationship between current and trans-membrane voltage. Here, we report heterozygous de novo GRIA2 mutations in 28 unrelated patients with intellectual disability (ID) and neurodevelopmental abnormalities including autism spectrum disorder (ASD), Rett syndrome-like features, and seizures or developmental epileptic encephalopathy (DEE). In functional expression studies, mutations lead to a decrease in agonist-evoked current mediated by mutant subunits compared to wild-type channels. When GluA2 subunits are co-expressed with GluA1, most GRIA2 mutations cause a decreased current amplitude and some also affect voltage rectification. Our results show that de-novo variants in GRIA2 can cause neurodevelopmental disorders, complementing evidence that other genetic causes of ID, ASD and DEE also disrupt glutamatergic synaptic transmission.


Assuntos
Deficiência Intelectual/genética , Transtornos do Neurodesenvolvimento/genética , Receptores de AMPA/genética , Adolescente , Adulto , Encéfalo/diagnóstico por imagem , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Heterozigoto , Humanos , Lactente , Mutação com Perda de Função , Imagem por Ressonância Magnética , Masculino , Transtornos do Neurodesenvolvimento/diagnóstico por imagem , Adulto Jovem
20.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(7): 672-675, 2019 Jul 10.
Artigo em Chinês | MEDLINE | ID: mdl-31302908

RESUMO

OBJECTIVE: To explore the genetic basis for three patients with development delay and to correlate their clinical phenotypes with genetic findings. METHODS: The karyotypes of the probands and their parents were analyzed by conventional G-banding. Chromosomal microarray analysis (CMA) was used to detect microdeletion and microduplication. RESULTS: No kartotypic abnormality was detected in the patients and their parents. CMA analysis identified a de novo 3.10 Mb deletion on chromosome 15q24.1q24.2 in case 1, a de novo 3.14 Mb deletion at 15q24.1q24.2 in case 2, and a 3.13 Mb deletion at 15q24.1q24.2 in case 3. All deletions have encompassed the CPLX3,SEMA7A and SIN3A genes. CONCLUSION: The three patients were diagnosed with 15q24 microdeletion syndrome. CPLX3,SEMA7A and SIN3A may be the key genes responsible for this syndrome.


Assuntos
Transtornos Cromossômicos/genética , Deficiência Intelectual/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Antígenos CD/genética , Criança , Deleção Cromossômica , Cromossomos Humanos Par 15/genética , Proteínas Ligadas por GPI/genética , Humanos , Proteínas Repressoras/genética , Semaforinas/genética
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