Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 2 de 2
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Eur J Med Genet ; 65(9): 104551, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35803560

RESUMO

BACKGROUND: Next generation sequencing studies have revealed an ever-increasing number of causes for genetic disorders of central nervous system white matter. A substantial number of disorders are identifiable from their specific pattern of biochemical and/or imaging findings for which single gene testing may be indicated. Beyond this group, the causes of genetic white matter disorders are unclear and a broader approach to genomic testing is recommended. AIM: This study aimed to identify the genetic causes for a group of individuals with unclassified white matter disorders with suspected genetic aetiology and highlight the investigations required when the initial testing is non-diagnostic. METHODS: Twenty-six individuals from 22 families with unclassified white matter disorders underwent deep phenotyping and genome sequencing performed on trio, or larger, family groups. Functional studies and transcriptomics were used to resolve variants of uncertain significance with potential clinical relevance. RESULTS: Causative or candidate variants were identified in 15/22 (68.2%) families. Six of the 15 implicated genes had been previously associated with white matter disease (COL4A1, NDUFV1, SLC17A5, TUBB4A, BOLA3, DARS2). Patients with variants in the latter two presented with an atypical phenotype. The other nine genes had not been specifically associated with white matter disease at the time of diagnosis and included genes associated with monogenic syndromes, developmental disorders, and developmental and epileptic encephalopathies (STAG2, LSS, FIG4, GLS, PMPCA, SPTBN1, AGO2, SCN2A, SCN8A). Consequently, only 46% of the diagnoses would have been made via a current leukodystrophy gene panel test. DISCUSSION: These results confirm the importance of broad genomic testing for patients with white matter disorders. The high diagnostic yield reflects the integration of deep phenotyping, whole genome sequencing, trio analysis, functional studies, and transcriptomic analyses. CONCLUSIONS: Genetic white matter disorders are genetically and phenotypically heterogeneous. Deep phenotyping together with a range of genomic technologies underpin the identification of causes of unclassified white matter disease. A molecular diagnosis is essential for prognostication, appropriate management, and accurate reproductive counseling.


Assuntos
Leucoencefalopatias , Substância Branca , Flavoproteínas , Testes Genéticos/métodos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Leucoencefalopatias/diagnóstico por imagem , Leucoencefalopatias/genética , Proteínas Mitocondriais , Fenótipo , Monoéster Fosfórico Hidrolases , Tubulina (Proteína) , Substância Branca/diagnóstico por imagem
2.
Neurology ; 61(6): 765-9, 2003 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-14504318

RESUMO

BACKGROUND: Mutations in SCN1A, the gene encoding the alpha1 subunit of the sodium channel, have been found in severe myoclonic epilepsy of infancy (SMEI) and generalized epilepsy with febrile seizures plus (GEFS+). Mutations in SMEI include missense, nonsense, and frameshift mutations more commonly arising de novo in affected patients. This finding is difficult to reconcile with the family history of GEFS+ in a significant proportion of patients with SMEI. Infantile spasms (IS), or West syndrome, is a severe epileptic encephalopathy that is usually symptomatic. In some cases, no etiology is found and there is a family history of epilepsy. METHOD: The authors screened SCN1A in 24 patients with SMEI and 23 with IS. RESULTS: Mutations were found in 8 of 24 (33%) SMEI patients, a frequency much lower than initial reports from Europe and Japan. One mutation near the carboxy terminus was identified in an IS patient. A family history of seizures was found in 17 of 24 patients with SMEI. CONCLUSIONS: The rate of SCN1A mutations in this cohort of SMEI patients suggests that other factors may be important in SMEI. Less severe mutations associated with GEFS+ could interact with other loci to cause SMEI in cases with a family history of GEFS+. This study extends the phenotypic heterogeneity of mutations in SCN1A to include IS.


Assuntos
Epilepsia Mioclônica Juvenil/genética , Proteínas do Tecido Nervoso/genética , Canais de Sódio/genética , Espasmos Infantis/genética , Sequência de Aminoácidos , Substituição de Aminoácidos , Austrália , Criança , Pré-Escolar , Códon sem Sentido , Análise Mutacional de DNA , Éxons/genética , Feminino , Heterogeneidade Genética , Humanos , Lactente , Masculino , Modelos Moleculares , Dados de Sequência Molecular , Mutação de Sentido Incorreto , Canal de Sódio Disparado por Voltagem NAV1.1 , Proteínas do Tecido Nervoso/química , Polimorfismo Conformacional de Fita Simples , Estrutura Terciária de Proteína , Sítios de Splice de RNA/genética , Convulsões Febris/genética , Alinhamento de Sequência , Deleção de Sequência , Homologia de Sequência de Aminoácidos , Canais de Sódio/química , Relação Estrutura-Atividade
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...