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Epilepsia ; 59(9): 1635-1642, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30098010


Genomic findings are emerging rapidly in 2 large, closely related epilepsy research consortia: the Epilepsy Phenome/Genome Project and Epi4K. Disclosure of individual results to participants in genomic research is increasingly viewed as an ethical obligation, but strategies for return of results were not included in the design of these consortia, raising complexities in establishing criteria for which results to offer, determining participant preferences, managing the large number of sites involved, and covering associated costs. Here, we describe the challenges faced, alternative approaches considered, and progress to date. Experience from these 2 consortia illustrates the importance, for genomic research in epilepsy and other disorders, of including a specific plan for return of results in the study design, with financial support for obtaining clinical confirmation and providing ongoing support for participants. Participant preferences for return of results should be established at the time of enrollment, and methods for allowing future contacts with participants should be included. In addition, methods should be developed for summarizing meaningful, comprehensible information about findings in the aggregate that participants can access in an ongoing way.

Hum Genet ; 136(7): 821-834, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28393272


Pathogenic variants in genes encoding subunits of the spliceosome are the cause of several human diseases, such as neurodegenerative diseases. The RNA splicing process is facilitated by the spliceosome, a large RNA-protein complex consisting of small nuclear ribonucleoproteins (snRNPs), and many other proteins, such as heterogeneous nuclear ribonucleoproteins (hnRNPs). The HNRNPU gene (OMIM *602869) encodes the heterogeneous nuclear ribonucleoprotein U, which plays a crucial role in mammalian development. HNRNPU is expressed in the fetal brain and adult heart, kidney, liver, brain, and cerebellum. Microdeletions in the 1q44 region encompassing HNRNPU have been described in patients with intellectual disability (ID) and other clinical features, such as seizures, corpus callosum abnormalities (CCA), and microcephaly. Recently, pathogenic HNRNPU variants were identified in large ID and epileptic encephalopathy cohorts. In this study, we provide detailed clinical information of five novels and review two of the previously published individuals with (likely) pathogenic de novo variants in the HNRNPU gene including three non-sense and two missense variants, one small intragenic deletion, and one duplication. The phenotype in individuals with variants in HNRNPU is characterized by early onset seizures (6/7), severe ID (6/6), severe speech impairment (6/6), hypotonia (6/7), and central nervous system (CNS) (5/6), cardiac (4/6), and renal abnormalities (3/4). In this study, we broaden the clinical and mutational HNRNPU-associated spectrum, and demonstrate that heterozygous HNRNPU variants cause epilepsy, severe ID with striking speech impairment and variable CNS, cardiac, and renal anomalies.

Epilepsia/genética , Ribonucleoproteínas Nucleares Heterogêneas Grupo U/genética , Heterozigoto , Deficiência Intelectual/genética , Idade de Início , Agenesia do Corpo Caloso/genética , Sistema Nervoso Central/anormalidades , Sistema Nervoso Central/patologia , Deleção Cromossômica , Cromossomos Humanos Par 1 , Epilepsia/diagnóstico , Feminino , Variação Genética , Humanos , Lactente , Deficiência Intelectual/diagnóstico , Rim/anormalidades , Masculino , Microcefalia/diagnóstico , Microcefalia/genética , Hipotonia Muscular/diagnóstico , Hipotonia Muscular/genética , Fenótipo , Processamento de RNA , Ribonucleoproteínas Nucleares Pequenas/genética , Convulsões/diagnóstico , Convulsões/genética