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2.
Genet Med ; 2020 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-33299146

RESUMO

PURPOSE: This study aimsed to provide a comprehensive description of the phenotypic and genotypic spectrum of SNAP25 developmental and epileptic encephalopathy (SNAP25-DEE) by reviewing newly identified and previously reported individuals. METHODS: Individuals harboring heterozygous missense or loss-of-function variants in SNAP25 were assembled through collaboration with international colleagues, matchmaking platforms, and literature review. For each individual, detailed phenotyping, classification, and structural modeling of the identified variant were performed. RESULTS: The cohort comprises 23 individuals with pathogenic or likely pathogenic de novo variants in SNAP25. Intellectual disability and early-onset epilepsy were identified as the core symptoms of SNAP25-DEE, with recurrent findings of movement disorders, cerebral visual impairment, and brain atrophy. Structural modeling for all variants predicted possible functional defects concerning SNAP25 or impaired interaction with other components of the SNARE complex. CONCLUSION: We provide a comprehensive description of SNAP25-DEE with intellectual disability and early-onset epilepsy mostly occurring before the age of two years. These core symptoms and additional recurrent phenotypes show an overlap to genes encoding other components or associated proteins of the SNARE complex such as STX1B, STXBP1, or VAMP2. Thus, these findings advance the concept of a group of neurodevelopmental disorders that may be termed "SNAREopathies."

3.
Genet Med ; 2020 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-33173220

RESUMO

PURPOSE: We sought to delineate the genotypic and phenotypic spectrum of female and male individuals with X-linked, MSL3-related disorder (Basilicata-Akhtar syndrome). METHODS: Twenty-five individuals (15 males, 10 females) with causative variants in MSL3 were ascertained through exome or genome sequencing at ten different sequencing centers. RESULTS: We identified multiple variant types in MSL3 (ten nonsense, six frameshift, four splice site, three missense, one in-frame-deletion, one multi-exon deletion), most proven to be de novo, and clustering in the terminal eight exons suggesting that truncating variants in the first five exons might be compensated by an alternative MSL3 transcript. Three-dimensional modeling of missense and splice variants indicated that these have a deleterious effect. The main clinical findings comprised developmental delay and intellectual disability ranging from mild to severe. Autism spectrum disorder, muscle tone abnormalities, and macrocephaly were common as well as hearing impairment and gastrointestinal problems. Hypoplasia of the cerebellar vermis emerged as a consistent magnetic resonance image (MRI) finding. Females and males were equally affected. Using facial analysis technology, a recognizable facial gestalt was determined. CONCLUSION: Our aggregated data illustrate the genotypic and phenotypic spectrum of X-linked, MSL3-related disorder (Basilicata-Akhtar syndrome). Our cohort improves the understanding of disease related morbidity and allows us to propose detailed surveillance guidelines for affected individuals.

4.
Genet Med ; 2020 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-33106617

RESUMO

PURPOSE: Neurodevelopmental disorders (NDD) caused by protein phosphatase 2A (PP2A) dysfunction have mainly been associated with de novo variants in PPP2R5D and PPP2CA, and more rarely in PPP2R1A. Here, we aimed to better understand the latter by characterizing 30 individuals with de novo and often recurrent variants in this PP2A scaffolding Aα subunit. METHODS: Most cases were identified through routine clinical diagnostics. Variants were biochemically characterized for phosphatase activity and interaction with other PP2A subunits. RESULTS: We describe 30 individuals with 16 different variants in PPP2R1A, 21 of whom had variants not previously reported. The severity of developmental delay ranged from mild learning problems to severe intellectual disability (ID) with or without epilepsy. Common features were language delay, hypotonia, and hypermobile joints. Macrocephaly was only seen in individuals without B55α subunit-binding deficit, and these patients had less severe ID and no seizures. Biochemically more disruptive variants with impaired B55α but increased striatin binding were associated with profound ID, epilepsy, corpus callosum hypoplasia, and sometimes microcephaly. CONCLUSION: We significantly expand the phenotypic spectrum of PPP2R1A-related NDD, revealing a broader clinical presentation of the patients and that the functional consequences of the variants are more diverse than previously reported.

5.
Mol Genet Genomic Med ; 8(10): e1397, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32730690

RESUMO

BACKGROUND: Resources within the Undiagnosed Diseases Network (UDN), such as genome sequencing (GS) and model organisms aid in diagnosis and identification of new disease genes, but are currently difficult to access by clinical providers. While these resources do contribute to diagnoses in many cases, they are not always necessary to reach diagnostic resolution. The UDN experience has been that participants can also receive diagnoses through the thoughtful and customized application of approaches and resources that are readily available in clinical settings. METHODS: The UDN Genetic Counseling and Testing Working Group collected case vignettes that illustrated how clinically available methods resulted in diagnoses. The case vignettes were classified into three themes; phenotypic considerations, selection of genetic testing, and evaluating exome/GS variants and data. RESULTS: We present 12 participants that illustrate how clinical practices such as phenotype-driven genomic investigations, consideration of variable expressivity, selecting the relevant tissue of interest for testing, utilizing updated testing platforms, and recognition of alternate transcript nomenclature resulted in diagnoses. CONCLUSION: These examples demonstrate that when a diagnosis is elusive, an iterative patient-specific approach utilizing assessment options available to clinical providers may solve a portion of cases. However, this does require increased provider time commitment, a particular challenge in the current practice of genomics.

6.
Am J Med Genet A ; 182(8): 1947-1951, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32445275

RESUMO

Schinzel-Giedion syndrome (SGS; OMIM 269150) is an ultra-rare genetic disorder associated with a distinctive facial gestalt, congenital malformations, severe intellectual disability, and a progressive neurological course. The prognosis for SGS is poor, with survival beyond the first decade rare. Germline, de novo heterozygous variants in the SETBP1 gene cause SGS with the pathogenic variants associated with the SGS phenotype missense and confined to exon 4 of the gene, clustered in a four amino acid (12 bp) hotspot in the SKI homologous region of the SETBP1 protein. We report a patient with a de novo I871S variant within the SKI homologous region, which has been associated with the severe phenotype previously; but our patient has fewer features of SGS and a milder course. This is the first report of a forme-fruste phenotype in a patient with a pathogenic variant within the SGS hotspot on the SETBP1 gene and it highlights the importance of considering atypical clinical presentations in the context of severe ultra-rare genetic disorders.

7.
Ann Neurol ; 86(2): 181-192, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31177578

RESUMO

OBJECTIVE: Recent reports have described single individuals with neurodevelopmental disability (NDD) harboring heterozygous KCNQ3 de novo variants (DNVs). We sought to assess whether pathogenic variants in KCNQ3 cause NDD and to elucidate the associated phenotype and molecular mechanisms. METHODS: Patients with NDD and KCNQ3 DNVs were identified through an international collaboration. Phenotypes were characterized by clinical assessment, review of charts, electroencephalographic (EEG) recordings, and parental interview. Functional consequences of variants were analyzed in vitro by patch-clamp recording. RESULTS: Eleven patients were assessed. They had recurrent heterozygous DNVs in KCNQ3 affecting residues R230 (R230C, R230H, R230S) and R227 (R227Q). All patients exhibited global developmental delay within the first 2 years of life. Most (8/11, 73%) were nonverbal or had a few words only. All patients had autistic features, and autism spectrum disorder (ASD) was diagnosed in 5 of 11 (45%). EEGs performed before 10 years of age revealed frequent sleep-activated multifocal epileptiform discharges in 8 of 11 (73%). For 6 of 9 (67%) recorded between 1.5 and 6 years of age, spikes became near-continuous during sleep. Interestingly, most patients (9/11, 82%) did not have seizures, and no patient had seizures in the neonatal period. Voltage-clamp recordings of the mutant KCNQ3 channels revealed gain-of-function (GoF) effects. INTERPRETATION: Specific GoF variants in KCNQ3 cause NDD, ASD, and abundant sleep-activated spikes. This new phenotype contrasts both with self-limited neonatal epilepsy due to KCNQ3 partial loss of function, and with the neonatal or infantile onset epileptic encephalopathies due to KCNQ2 GoF. ANN NEUROL 2019;86:181-192.


Assuntos
Transtorno Autístico/diagnóstico , Transtorno Autístico/genética , Deficiências do Desenvolvimento/diagnóstico , Deficiências do Desenvolvimento/genética , Mutação com Ganho de Função/genética , Canal de Potássio KCNQ3/genética , Sequência de Aminoácidos , Criança , Pré-Escolar , Variação Genética/genética , Humanos , Canal de Potássio KCNQ3/química , Masculino , Estrutura Secundária de Proteína , Adulto Jovem
8.
Am J Hum Genet ; 104(1): 164-178, 2019 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-30580808

RESUMO

SMARCC2 (BAF170) is one of the invariable core subunits of the ATP-dependent chromatin remodeling BAF (BRG1-associated factor) complex and plays a crucial role in embryogenesis and corticogenesis. Pathogenic variants in genes encoding other components of the BAF complex have been associated with intellectual disability syndromes. Despite its significant biological role, variants in SMARCC2 have not been directly associated with human disease previously. Using whole-exome sequencing and a web-based gene-matching program, we identified 15 individuals with variable degrees of neurodevelopmental delay and growth retardation harboring one of 13 heterozygous variants in SMARCC2, most of them novel and proven de novo. The clinical presentation overlaps with intellectual disability syndromes associated with other BAF subunits, such as Coffin-Siris and Nicolaides-Baraitser syndromes and includes prominent speech impairment, hypotonia, feeding difficulties, behavioral abnormalities, and dysmorphic features such as hypertrichosis, thick eyebrows, thin upper lip vermilion, and upturned nose. Nine out of the fifteen individuals harbor variants in the highly conserved SMARCC2 DNA-interacting domains (SANT and SWIRM) and present with a more severe phenotype. Two of these individuals present cardiac abnormalities. Transcriptomic analysis of fibroblasts from affected individuals highlights a group of differentially expressed genes with possible roles in regulation of neuronal development and function, namely H19, SCRG1, RELN, and CACNB4. Our findings suggest a novel SMARCC2-related syndrome that overlaps with neurodevelopmental disorders associated with variants in BAF-complex subunits.


Assuntos
Deficiências do Desenvolvimento/complicações , Deficiências do Desenvolvimento/genética , Deficiência Intelectual/complicações , Deficiência Intelectual/genética , Mutação , Fatores de Transcrição/genética , Anormalidades Múltiplas/genética , Adolescente , Criança , Pré-Escolar , Proteínas de Ligação a DNA , Face/anormalidades , Feminino , Deformidades Congênitas da Mão/genética , Humanos , Masculino , Micrognatismo/genética , Pescoço/anormalidades , Síndrome
9.
Gene Ther ; 25(3): 205-219, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29785047

RESUMO

The successful application of adeno-associated virus (AAV) gene delivery vectors as a therapeutic paradigm will require efficient gene delivery to the appropriate cells in affected organs. In this study, we utilized a rational design approach to introduce modifications to the AAV2 and AAVrh8R capsids and the resulting variants were evaluated for transduction activity in the retina and brain. The modifications disrupted either capsid/receptor binding or altered capsid surface charge. Specifically, we mutated AAV2 amino acids R585A and R588A, which are required for binding to its receptor, heparan sulfate proteoglycans, to generate a variant referred to as AAV2-HBKO. In contrast to parental AAV2, the AAV2-HBKO vector displayed low-transduction activity following intravitreal delivery to the mouse eye; however, following its subretinal delivery, AAV2-HBKO resulted in significantly greater photoreceptor transduction. Intrastriatal delivery of AAV2-HBKO to mice facilitated widespread striatal and cortical expression, in contrast to the restricted transduction pattern of the parental AAV2 vector. Furthermore, we found that altering the surface charge on the AAVrh8R capsid by modifying the number of arginine residues on the capsid surface had a profound impact on subretinal transduction. The data further validate the potential of capsid engineering to improve AAV gene therapy vectors for clinical applications.


Assuntos
Terapia Genética/métodos , Parvovirinae/crescimento & desenvolvimento , Parvovirinae/imunologia , Animais , Encéfalo/metabolismo , Capsídeo/metabolismo , Proteínas do Capsídeo/genética , Proteínas do Capsídeo/metabolismo , Dependovirus/imunologia , Técnicas de Transferência de Genes , Vetores Genéticos , Células HeLa , Heparitina Sulfato , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Células Fotorreceptoras/metabolismo , Retina/metabolismo , Transdução Genética/métodos
10.
Genet Med ; 20(4): 464-469, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-28914269

RESUMO

PurposeTo describe examples of missed pathogenic variants on whole-exome sequencing (WES) and the importance of deep phenotyping for further diagnostic testing.MethodsGuided by phenotypic information, three children with negative WES underwent targeted single-gene testing.ResultsIndividual 1 had a clinical diagnosis consistent with infantile systemic hyalinosis, although WES and a next-generation sequencing (NGS)-based ANTXR2 test were negative. Sanger sequencing of ANTXR2 revealed a homozygous single base pair insertion, previously missed by the WES variant caller software. Individual 2 had neurodevelopmental regression and cerebellar atrophy, with no diagnosis on WES. New clinical findings prompted Sanger sequencing and copy number testing of PLA2G6. A novel homozygous deletion of the noncoding exon 1 (not included in the WES capture kit) was detected, with extension into the promoter, confirming the clinical suspicion of infantile neuroaxonal dystrophy. Individual 3 had progressive ataxia, spasticity, and magnetic resonance image changes of vanishing white matter leukoencephalopathy. An NGS leukodystrophy gene panel and WES showed a heterozygous pathogenic variant in EIF2B5; no deletions/duplications were detected. Sanger sequencing of EIF2B5 showed a frameshift indel, probably missed owing to failure of alignment.ConclusionThese cases illustrate potential pitfalls of WES/NGS testing and the importance of phenotype-guided molecular testing in yielding diagnoses.


Assuntos
Exoma , Estudos de Associação Genética , Predisposição Genética para Doença , Técnicas de Diagnóstico Molecular , Alelos , Biópsia , Criança , Pré-Escolar , Feminino , Estudos de Associação Genética/métodos , Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/genética , Genótipo , Humanos , Lactente , Técnicas de Diagnóstico Molecular/métodos , Técnicas de Diagnóstico Molecular/normas , Fenótipo , Polimorfismo de Nucleotídeo Único , Doenças Raras/diagnóstico , Doenças Raras/genética , Sequenciamento Completo do Exoma , Sequenciamento Completo do Genoma
11.
Hum Gene Ther ; 25(7): 619-30, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24617515

RESUMO

Spinal muscular atrophy (SMA) is a neuromuscular disease caused by mutations in survival motor neuron 1 (SMN1). Previously, we showed that central nervous system (CNS) delivery of an adeno-associated viral (AAV) vector encoding SMN1 produced significant improvements in survival in a mouse model of SMA. Here, we performed a dose-response study in SMA mice to determine the levels of SMN in the spinal cord necessary for efficacy, and measured the efficiency of motor neuron transduction in the spinal cord after intrathecal delivery in pigs and nonhuman primates (NHPs). CNS injections of 5e10, 1e10, and 1e9 genome copies (gc) of self-complementary AAV9 (scAAV9)-hSMN1 into SMA mice extended their survival from 17 to 153, 70, and 18 days, respectively. Spinal cords treated with 5e10, 1e10, and 1e9 gc showed that 70-170%, 30-100%, and 10-20% of wild-type levels of SMN were attained, respectively. Furthermore, detectable SMN expression in a minimum of 30% motor neurons correlated with efficacy. A comprehensive analysis showed that intrathecal delivery of 2.5e13 gc of scAAV9-GFP transduced 25-75% of the spinal cord motor neurons in NHPs. Thus, the extent of gene expression in motor neurons necessary to confer efficacy in SMA mice could be obtained in large-animal models, justifying the continual development of gene therapy for SMA.


Assuntos
Dependovirus , Vetores Genéticos/farmacologia , Injeções Espinhais , Atrofia Muscular Espinal/terapia , Biossíntese de Proteínas , Proteína 1 de Sobrevivência do Neurônio Motor , Animais , Vetores Genéticos/genética , Vetores Genéticos/metabolismo , Camundongos , Camundongos Knockout , Neurônios Motores/metabolismo , Neurônios Motores/patologia , Atrofia Muscular Espinal/genética , Atrofia Muscular Espinal/metabolismo , Atrofia Muscular Espinal/patologia , Medula Espinal/metabolismo , Medula Espinal/patologia , Proteína 1 de Sobrevivência do Neurônio Motor/biossíntese , Proteína 1 de Sobrevivência do Neurônio Motor/genética , Suínos
12.
J Hepatol ; 47(5): 658-63, 2007 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-17637480

RESUMO

BACKGROUND/AIMS: Because dietary modifications have prolonged the life expectancy of patients with glycogen storage disease type Ia (GSD Ia), the incidence of hepatocellular adenoma (HCA) to carcinoma (HCC) transformation is increasing. The objective of this retrospective study is to assess the safety and effectiveness of HCA resection in GSD Ia patients. METHODS: Clinicopathologic, peri-operative, and long-term data were reviewed from patients who underwent HCA resection. Comparisons were made with Fisher's exact, Mann-Whitney U, and log-rank tests; survival was estimated with Kaplan-Meier analysis. RESULTS: From 1998 to 2006, 38 patients underwent HCA resection. Seven (22%) had GSD Ia. Post-operative mortality occurred in one GSD Ia patient. GSD Ia patients had greater morbidity (86% vs. 20%) and shorter time to adenoma progression (median 23 months vs. not yet reached) after partial hepatectomy compared to the general population (p<0.05). Six GSD Ia patients had no evidence of HCC and recovered after resection without long-term morbidity. Three GSD Ia patients underwent liver transplantation 77, 32, and 23 months after adenoma resection. CONCLUSIONS: Despite substantial morbidity, partial hepatectomy is feasible in GSD Ia patients and is an effective intermediate step in the prevention of HCC until definitive treatment with liver transplantation.


Assuntos
Adenoma de Células Hepáticas/cirurgia , Procedimentos Cirúrgicos do Sistema Biliar/estatística & dados numéricos , Doença de Depósito de Glicogênio Tipo I/complicações , Neoplasias Hepáticas/cirurgia , Fígado/cirurgia , Adenoma de Células Hepáticas/complicações , Adenoma de Células Hepáticas/fisiopatologia , Adolescente , Adulto , Comorbidade , Progressão da Doença , Feminino , Humanos , Fígado/metabolismo , Fígado/patologia , Neoplasias Hepáticas/complicações , Neoplasias Hepáticas/fisiopatologia , Transplante de Fígado/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Taxa de Sobrevida , Resultado do Tratamento
15.
Mol Genet Metab ; 88(1): 90-2, 2006 May.
Artigo em Inglês | MEDLINE | ID: mdl-16466958

RESUMO

Glutaric acidemia type I (GA-I) is an autosomal recessive disorder of the catabolism of lysine, hydroxylysine, and tryptophan caused by deficiency of glutaryl-CoA dehydrogenase (GCD). Among our patients with GA-I, we noted a prevalence of Lumbee individuals. The Lumbee are a close-knit Native American tribe of eastern North Carolina. Five Lumbee individuals with GA-I had homozygous 1240G>A mutations in GCD. This is a rare, known mutation that was likely introduced by a Lumbee founder.


Assuntos
Glutaratos/sangue , Glutaril-CoA Desidrogenase/genética , Adulto , Erros Inatos do Metabolismo dos Aminoácidos/epidemiologia , Erros Inatos do Metabolismo dos Aminoácidos/genética , Substituição de Aminoácidos , Criança , Pré-Escolar , Grupos Étnicos , Feminino , Humanos , Índios Norte-Americanos/genética , Lactente , Recém-Nascido , Masculino , Triagem Neonatal , North Carolina/epidemiologia
16.
J Child Adolesc Psychopharmacol ; 16(6): 755-65, 2006 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17201619

RESUMO

Individuals with Down syndrome (DS) exhibit a cholinergic deficiency similar to that found in Alzheimer's disease. Cholinesterase inhibitors, used to treat Alzheimer's disease, may improve cognitive function in individuals with DS. This is the first investigation of the safety and efficacy of rivastigmine (an acetyl and butyryl cholinesterase inhibitor) on specific cognitive domains in pediatric DS. Eleven subjects with DS (ages 10-17 years) were treated with a liquid formulation of rivastigmine. Four subjects experienced no adverse events (AEs). Seven subjects reported AEs that were mild, transient and consistent with adverse events typically noted with cholinesterase inhibitors. Significant improvements were found in overall adaptive function (Vineland Adaptive Behavior Scales and Clinician's Interview-Based Impression of Change), attention (Leiter Attention Sustained tests A and B), memory (NEPSY: Narrative and Immediate Memory for Names subtests) and language (Test of Verbal Expression and Reasoning and Clinical Evaluation of Language Fundamentals-Preschool) domains. Improved language performance was found across all functional levels. These results underscore the need for larger, controlled studies employing a carefully constructed test battery capable of measuring the full scope of performance across multiple domains and a wide range of functional levels.


Assuntos
Inibidores da Colinesterase/uso terapêutico , Síndrome de Down/tratamento farmacológico , Fenilcarbamatos/uso terapêutico , Adaptação Psicológica/efeitos dos fármacos , Adolescente , Atenção/efeitos dos fármacos , Criança , Inibidores da Colinesterase/administração & dosagem , Inibidores da Colinesterase/efeitos adversos , Síndrome de Down/psicologia , Feminino , Humanos , Idioma , Masculino , Memória/efeitos dos fármacos , Cooperação do Paciente , Fenilcarbamatos/administração & dosagem , Fenilcarbamatos/efeitos adversos , Rivastigmina , Comportamento Verbal/efeitos dos fármacos
19.
J Genet Couns ; 12(3): 265-9, 2003 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26141069
20.
J Genet Couns ; 12(1): 1-3, 2003 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26142380
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