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1.
Genet Med ; 2019 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-31578471

RESUMO

PURPOSE: Lamb-Shaffer syndrome (LAMSHF) is a neurodevelopmental disorder described in just over two dozen patients with heterozygous genetic alterations involving SOX5, a gene encoding a transcription factor regulating cell fate and differentiation in neurogenesis and other discrete developmental processes. The genetic alterations described so far are mainly microdeletions. The present study was aimed at increasing our understanding of LAMSHF, its clinical and genetic spectrum, and the pathophysiological mechanisms involved. METHODS: Clinical and genetic data were collected through GeneMatcher and clinical or genetic networks for 41 novel patients harboring various types ofSOX5 alterations. Functional consequences of selected substitutions were investigated. RESULTS: Microdeletions and truncating variants occurred throughout SOX5. In contrast, most missense variants clustered in the pivotal SOX-specific high-mobility-group domain. The latter variants prevented SOX5 from binding DNA and promoting transactivation in vitro, whereas missense variants located outside the high-mobility-group domain did not. Clinical manifestations and severity varied among patients. No clear genotype-phenotype correlations were found, except that missense variants outside the high-mobility-group domain were generally better tolerated. CONCLUSIONS: This study extends the clinical and genetic spectrum associated with LAMSHF and consolidates evidence that SOX5 haploinsufficiency leads to variable degrees of intellectual disability, language delay, and other clinical features.

2.
Am J Hum Genet ; 104(4): 709-720, 2019 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-30905399

RESUMO

The Mediator is an evolutionarily conserved, multi-subunit complex that regulates multiple steps of transcription. Mediator activity is regulated by the reversible association of a four-subunit module comprising CDK8 or CDK19 kinases, together with cyclin C, MED12 or MED12L, and MED13 or MED13L. Mutations in MED12, MED13, and MED13L were previously identified in syndromic developmental disorders with overlapping phenotypes. Here, we report CDK8 mutations (located at 13q12.13) that cause a phenotypically related disorder. Using whole-exome or whole-genome sequencing, and by international collaboration, we identified eight different heterozygous missense CDK8 substitutions, including 10 shown to have arisen de novo, in 12 unrelated subjects; a recurrent mutation, c.185C>T (p.Ser62Leu), was present in five individuals. All predicted substitutions localize to the ATP-binding pocket of the kinase domain. Affected individuals have overlapping phenotypes characterized by hypotonia, mild to moderate intellectual disability, behavioral disorders, and variable facial dysmorphism. Congenital heart disease occurred in six subjects; additional features present in multiple individuals included agenesis of the corpus callosum, ano-rectal malformations, seizures, and hearing or visual impairments. To evaluate the functional impact of the mutations, we measured phosphorylation at STAT1-Ser727, a known CDK8 substrate, in a CDK8 and CDK19 CRISPR double-knockout cell line transfected with wild-type (WT) or mutant CDK8 constructs. These experiments demonstrated a reduction in STAT1 phosphorylation by all mutants, in most cases to a similar extent as in a kinase-dead control. We conclude that missense mutations in CDK8 cause a developmental disorder that has phenotypic similarity to syndromes associated with mutations in other subunits of the Mediator kinase module, indicating probable overlap in pathogenic mechanisms.

3.
Artigo em Inglês | MEDLINE | ID: mdl-29162653

RESUMO

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.


Assuntos
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
4.
Am J Hum Genet ; 95(5): 579-83, 2014 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-25439098

RESUMO

5q31.3 microdeletion syndrome is characterized by neonatal hypotonia, encephalopathy with or without epilepsy, and severe developmental delay, and the minimal critical deletion interval harbors three genes. We describe 11 individuals with clinical features of 5q31.3 microdeletion syndrome and de novo mutations in PURA, encoding transcriptional activator protein Pur-α, within the critical region. These data implicate causative PURA mutations responsible for the severe neurological phenotypes observed in this syndrome.


Assuntos
Anormalidades Múltiplas/genética , Deleção Cromossômica , Cromossomos Humanos Par 5/genética , Proteínas de Ligação a DNA/genética , Hipotonia Muscular/genética , Convulsões/genética , Fatores de Transcrição/genética , Sequência de Aminoácidos , Animais , Sequência de Bases , Caenorhabditis elegans/genética , Mapeamento Cromossômico , Humanos , Dados de Sequência Molecular , Mutação/genética , Análise de Sequência de DNA , Síndrome
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