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J Med Genet ; 55(8): 561-566, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-28866611


BACKGROUND: The list of Mendelian disorders of the epigenetic machinery has expanded rapidly during the last 5 years. A few missense variants in the chromatin remodeler CHD1 have been found in several large-scale sequencing efforts focused on uncovering the genetic aetiology of autism. OBJECTIVES: To explore whether variants in CHD1 are associated with a human phenotype. METHODS: We used GeneMatcher to identify other physicians caring for patients with variants in CHD1. We also explored the epigenetic consequences of one of these variants in cultured fibroblasts. RESULTS: Here we describe six CHD1 heterozygous missense variants in a cohort of patients with autism, speech apraxia, developmental delay and facial dysmorphic features. Importantly, three of these variants occurred de novo. We also report on a subject with a de novo deletion covering a large fraction of the CHD1 gene without any obvious neurological phenotype. Finally, we demonstrate increased levels of the closed chromatin modification H3K27me3 in fibroblasts from a subject carrying a de novo variant in CHD1. CONCLUSIONS: Our results suggest that variants in CHD1 can lead to diverse phenotypic outcomes; however, the neurodevelopmental phenotype appears to be limited to patients with missense variants, which is compatible with a dominant negative mechanism of disease.

Montagem e Desmontagem da Cromatina/genética , DNA Helicases/genética , Proteínas de Ligação a DNA/genética , Deficiências do Desenvolvimento/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Mutação de Sentido Incorreto , Criança , Pré-Escolar , DNA Helicases/química , Proteínas de Ligação a DNA/química , Deficiências do Desenvolvimento/diagnóstico , Facies , Feminino , Fibroblastos/metabolismo , Estudos de Associação Genética/métodos , Histonas/metabolismo , Humanos , Lactente , Modelos Moleculares , Fenótipo , Conformação Proteica , Relação Estrutura-Atividade
Artigo em Inglês | MEDLINE | ID: mdl-29162653


Using whole-exome sequencing, we identified seven unrelated individuals with global developmental delay, hypotonia, dysmorphic facial features, and an increased frequency of short stature, ataxia, and autism with de novo heterozygous frameshift, nonsense, splice, and missense variants in the Early B-cell Transcription Factor Family Member 3 (EBF3) gene. EBF3 is a member of the collier/olfactory-1/early B-cell factor (COE) family of proteins, which are required for central nervous system (CNS) development. COE proteins are highly evolutionarily conserved and regulate neuronal specification, migration, axon guidance, and dendritogenesis during development and are essential for maintaining neuronal identity in adult neurons. Haploinsufficiency of EBF3 may affect brain development and function, resulting in developmental delay, intellectual disability, and behavioral differences observed in individuals with a deleterious variant in EBF3.

Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Adolescente , Sequência de Aminoácidos/genética , Ataxia/genética , Transtorno Autístico/genética , Criança , Pré-Escolar , Sequência Conservada/genética , Deficiências do Desenvolvimento/genética , Exoma , Feminino , Humanos , Lactente , Deficiência Intelectual , Masculino , Hipotonia Muscular/genética , Mutação , Transtornos do Neurodesenvolvimento/genética , Síndrome de Prader-Willi/genética , Sequenciamento Completo do Exoma/métodos , Adulto Jovem
Am J Hum Genet ; 100(1): 91-104, 2017 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-27939640


Identification of over 500 epigenetic regulators in humans raises an interesting question regarding how chromatin dysregulation contributes to different diseases. Bromodomain and PHD finger-containing protein 1 (BRPF1) is a multivalent chromatin regulator possessing three histone-binding domains, one non-specific DNA-binding module, and several motifs for interacting with and activating three lysine acetyltransferases. Genetic analyses of fish brpf1 and mouse Brpf1 have uncovered an important role in skeletal, hematopoietic, and brain development, but it remains unclear how BRPF1 is linked to human development and disease. Here, we describe an intellectual disability disorder in ten individuals with inherited or de novo monoallelic BRPF1 mutations. Symptoms include infantile hypotonia, global developmental delay, intellectual disability, expressive language impairment, and facial dysmorphisms. Central nervous system and spinal abnormalities are also seen in some individuals. These clinical features overlap with but are not identical to those reported for persons with KAT6A or KAT6B mutations, suggesting that BRPF1 targets these two acetyltransferases and additional partners in humans. Functional assays showed that the resulting BRPF1 variants are pathogenic and impair acetylation of histone H3 at lysine 23, an abundant but poorly characterized epigenetic mark. We also found a similar deficiency in different lines of Brpf1-knockout mice. These data indicate that aberrations in the chromatin regulator gene BRPF1 cause histone H3 acetylation deficiency and a previously unrecognized intellectual disability syndrome.

Proteínas Adaptadoras de Transdução de Sinal/genética , Cromatina/metabolismo , Histonas/metabolismo , Deficiência Intelectual/genética , Mutação , Proteínas Nucleares/genética , Acetilação , Adolescente , Alelos , Animais , Proteínas de Transporte/genética , Criança , Cromatina/química , Proteínas de Ligação a DNA , Deficiências do Desenvolvimento/genética , Face/anormalidades , Feminino , Histona Acetiltransferases/genética , Humanos , Lisina/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Hipotonia Muscular/genética , Síndrome