RESUMO
Pre-mRNA splicing is a highly coordinated process. While its dysregulation has been linked to neurological deficits, our understanding of the underlying molecular and cellular mechanisms remains limited. We implicated pathogenic variants in U2AF2 and PRPF19, encoding spliceosome subunits in neurodevelopmental disorders (NDDs), by identifying 46 unrelated individuals with 23 de novo U2AF2 missense variants (including 7 recurrent variants in 30 individuals) and 6 individuals with de novo PRPF19 variants. Eight U2AF2 variants dysregulated splicing of a model substrate. Neuritogenesis was reduced in human neurons differentiated from human pluripotent stem cells carrying two U2AF2 hyper-recurrent variants. Neural loss of function (LoF) of the Drosophila orthologs U2af50 and Prp19 led to lethality, abnormal mushroom body (MB) patterning, and social deficits, which were differentially rescued by wild-type and mutant U2AF2 or PRPF19. Transcriptome profiling revealed splicing substrates or effectors (including Rbfox1, a third splicing factor), which rescued MB defects in U2af50-deficient flies. Upon reanalysis of negative clinical exomes followed by data sharing, we further identified 6 patients with NDD who carried RBFOX1 missense variants which, by in vitro testing, showed LoF. Our study implicates 3 splicing factors as NDD-causative genes and establishes a genetic network with hierarchy underlying human brain development and function.
Assuntos
Transtornos do Neurodesenvolvimento , Spliceossomos , Humanos , Spliceossomos/genética , Redes Reguladoras de Genes , Transtornos do Neurodesenvolvimento/genética , Mutação de Sentido Incorreto , Splicing de RNA , Fatores de Processamento de RNA/genética , Proteínas Nucleares/genética , Enzimas Reparadoras do DNA/genéticaRESUMO
Copy number variants (CNVs) and intragenic rearrangements of the NRXN1 (neurexin 1) gene are associated with a wide spectrum of developmental and neuropsychiatric disorders, including intellectual disability, speech delay, autism spectrum disorders (ASDs), hypotonia and schizophrenia. We performed a detailed clinical and molecular characterization of 24 patients who underwent clinical microarray analysis and had intragenic deletions of NRXN1. Seventeen of these deletions involved exons of NRXN1, whereas seven deleted intronic sequences only. The patients with exonic deletions manifested developmental delay/intellectual disability (93%), infantile hypotonia (59%) and ASDs (56%). Congenital malformations and dysmorphic features appeared infrequently and inconsistently among this population of patients with NRXN1 deletions. The more C-terminal deletions, including those affecting the ß isoform of neurexin 1, manifested increased head size and a high frequency of seizure disorder (88%) when compared with N-terminal deletions of NRXN1.
Assuntos
Moléculas de Adesão Celular Neuronais/genética , Éxons/genética , Deleção de Genes , Genótipo , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Proteínas do Tecido Nervoso/genética , Fenótipo , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Adolescente , Adulto , Proteínas de Ligação ao Cálcio , Criança , Transtornos Globais do Desenvolvimento Infantil/diagnóstico , Transtornos Globais do Desenvolvimento Infantil/genética , Variações do Número de Cópias de DNA , Feminino , Humanos , Lactente , Íntrons , Masculino , Análise em Microsséries , Hipotonia Muscular/congênito , Hipotonia Muscular/diagnóstico , Hipotonia Muscular/genética , Moléculas de Adesão de Célula Nervosa , Isoformas de Proteínas/genéticaRESUMO
Great strides in the identification, etiologic understanding, and treatment of metabolic and genetic disorders associated with infantile seizures have occurred in recent years. We explain the cause, pathogenesis, diagnosis, presentation, and treatment of certain metabolic disorders that now have defined interventions that improve and optimize neurologic outcome. A systematic approach to infantile seizures will allow the primary practitioner to more effectively create a differential diagnosis with close attention to the disorders that have specific treatment applications.
Assuntos
Anticonvulsivantes/uso terapêutico , Eletroencefalografia/métodos , Espasmos Infantis/diagnóstico , Diagnóstico Diferencial , Seguimentos , Humanos , Lactente , Masculino , Espasmos Infantis/tratamento farmacológicoRESUMO
Chiari malformations are multifactorial and heterogeneous entities, characterized by abnormalities in the posterior fossa. They have been identified in association with various genetic syndromes in recent years. Two previous studies have noted an association of Chiari malformations with Rubinstein-Taybi syndrome (RTS). In this clinical report, we highlight identical twins with RTS caused by a mutation in CREBBP that presented with slightly different Chiari malformations in association with an extensive multiloculated syrinx and scoliosis. RTS has been found to be associated with craniocervical abnormalities in literature review, and this clinical report demonstrates the prudent consideration of the physician who cares for patients impacted by RTS to effectively screen via symptomatology and physical examination for Chiari pathology or other craniocervical abnormalities.
