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SYNGAP1 encodes a brain-specific Ras GTPase activating protein (GAP) that regulates synaptic strength in glutamatergic neurons. Pathogenic variants in this gene are associated with a neurodevelopmental disorder characterized by intellectual and developmental disabilities, generalized epilepsy, hypotonia, and autism spectrum disorders. We describe a young male with suspected SYNGAP1-related disorder given clinical overlap and identification of an intronic variant of uncertain significance; clinical transcriptome analysis demonstrated activation of a cryptic acceptor splice site resulting in frameshift and introduction of a stop codon. This report highlights the utility of functional studies newly available to clinical practice in confirming a suspected genetic diagnosis, which can directly impact medical management and preclude the need for additional diagnostic testing.
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The HTML and PDF versions of this Article were updated after publication to remove images of one individual from Figure 1.
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The original version of this Article contained an error in the spelling of the author Laurence Faivre, which was incorrectly given as Laurence Faive. This has now been corrected in both the PDF and HTML versions of the Article.
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Chromatin remodeling is of crucial importance during brain development. Pathogenic alterations of several chromatin remodeling ATPases have been implicated in neurodevelopmental disorders. We describe an index case with a de novo missense mutation in CHD3, identified during whole genome sequencing of a cohort of children with rare speech disorders. To gain a comprehensive view of features associated with disruption of this gene, we use a genotype-driven approach, collecting and characterizing 35 individuals with de novo CHD3 mutations and overlapping phenotypes. Most mutations cluster within the ATPase/helicase domain of the encoded protein. Modeling their impact on the three-dimensional structure demonstrates disturbance of critical binding and interaction motifs. Experimental assays with six of the identified mutations show that a subset directly affects ATPase activity, and all but one yield alterations in chromatin remodeling. We implicate de novo CHD3 mutations in a syndrome characterized by intellectual disability, macrocephaly, and impaired speech and language.
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DNA Helicases/genética , Deficiências do Desenvolvimento/genética , Transtornos da Linguagem/genética , Megalencefalia/genética , Complexo Mi-2 de Remodelação de Nucleossomo e Desacetilase/genética , Mutação de Sentido Incorreto , Transtornos do Neurodesenvolvimento/genética , Domínios Proteicos/genética , Distúrbios da Fala/genética , Adenosina Trifosfatases , Pré-Escolar , Montagem e Desmontagem da Cromatina , Feminino , Expressão Gênica , Genótipo , Células HEK293 , Humanos , Deficiência Intelectual/genética , Masculino , Modelos Moleculares , Fenótipo , Sequenciamento Completo do GenomaRESUMO
BACKGROUND: Community-acquired (CA), methicillin-resistant Staphylococcus aureus (MRSA) infections among children are increasing in the United States. At Texas Children's Hospital (TCH), surveillance has been in place since August 2001. The objectives of this study were to describe the distribution of CA S. aureus among patients at TCH and to study genomic relationships of isolates collected between August 2001 and July 2003. METHODS: Genomic relationships were determined with repetitive element-polymerase chain reaction (PCR). Multilocus sequence typing was performed for selected strains representing major clones. Molecular characterization of CA-MRSA was performed with PCR, including staphylococcal cassette chromosome (SCCmec), pvl (lukS-PV plus lukF-PV), hla, hlb and selected microbial surface components recognizing adhesive matrix molecule genes, ie, cna, clfA, fnbA and fnbB. RESULTS: A 62% increase was observed in CA S. aureus infections from year 1 (2001-2002) to year 2 (2002-2003), whereas the annual number of hospital admissions was unchanged. CA methicillin-sensitive S. aureus isolates were more likely to be associated with invasive infections than were CA-MRSA isolates (P < 0.01). TCH clone A, sequence type (ST) 8, was responsible for approximately 94% of all CA-MRSA isolated from children in the greater Houston area. Clone A differed from clones B (ST30) and C (ST1) by lacking the cna gene while carrying the fnbB gene. CONCLUSIONS: One CA-MRSA clone, TCH clone A, has become the predominant cause of CA S. aureus infections among children in the Houston area. It causes a wide spectrum of diseases, including complicated pneumonia.
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Doenças Transmissíveis Emergentes/microbiologia , Infecções Comunitárias Adquiridas/epidemiologia , Resistência a Meticilina/genética , Reação em Cadeia da Polimerase/métodos , Infecções Estafilocócicas/epidemiologia , Staphylococcus aureus/genética , Bacteriemia/epidemiologia , Bacteriemia/microbiologia , Sequência de Bases , Criança , Pré-Escolar , Células Clonais , Doenças Transmissíveis Emergentes/epidemiologia , Infecções Comunitárias Adquiridas/microbiologia , DNA Bacteriano , Feminino , Hospitais Pediátricos , Humanos , Incidência , Masculino , Testes de Sensibilidade Microbiana , Dados de Sequência Molecular , Probabilidade , Prognóstico , Estudos Retrospectivos , Medição de Risco , Estudos de Amostragem , Índice de Gravidade de Doença , Infecções Estafilocócicas/diagnóstico , Infecções Estafilocócicas/genética , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/isolamento & purificação , Texas/epidemiologiaRESUMO
Pompe disease, especially in its infantile form, is a fatal disease. Most of the patients with this disease synthesize a nonfunctional form of the enzyme alpha glucosidase (GAA), the deficient enzyme in this disease. Patients producing some amount of this protein are labeled as cross-reactive immunologic material (CRIM)-positive. Few of them are unable to synthesize it and are labeled CRIM-negative. The clinical course of the disease has changed with the advent of enzyme replacement therapy (ERT) with recombinant alpha glucosidase enzyme (rhGAA). However, CRIM-negative patients have always been known to have poor outcome on ERT due to the development of anti-rhGAA antibodies in their bodies that neutralizes ERT efficacy. Here, we describe two CRIM-negative siblings on rhGAA ERT with unusually low anti-rhGAA antibody titer and good clinical outcome. Up to our current knowledge, this is the first report that describes such a good response to ERT in CRIM-negative patients.
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Graduate nurses experience stress transitioning from student to practicing professional nurse, moving from a familiar educational environment into the workforce, where expectations are to rapidly function as a competent nurse. This study identified the stresses and challenges experienced by cohorts of graduate nurses working in 6 acute care hospitals, during specific timed data periods, to better understand factors that may influence graduate nurse retention. Results report graduate nurses do not feel skilled, comfortable, and confident for as long as 1 year after being hired, highlighting the need for healthcare organizations to provide extended orientation and support programs to facilitate successful entry into practice.