Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 8 de 8
Filtrar
Mais filtros










Base de dados
Tipo de estudo
Intervalo de ano de publicação
1.
Am J Hum Genet ; 104(2): 319-330, 2019 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-30639322

RESUMO

ZMIZ1 is a coactivator of several transcription factors, including p53, the androgen receptor, and NOTCH1. Here, we report 19 subjects with intellectual disability and developmental delay carrying variants in ZMIZ1. The associated features include growth failure, feeding difficulties, microcephaly, facial dysmorphism, and various other congenital malformations. Of these 19, 14 unrelated subjects carried de novo heterozygous single-nucleotide variants (SNVs) or single-base insertions/deletions, 3 siblings harbored a heterozygous single-base insertion, and 2 subjects had a balanced translocation disrupting ZMIZ1 or involving a regulatory region of ZMIZ1. In total, we identified 13 point mutations that affect key protein regions, including a SUMO acceptor site, a central disordered alanine-rich motif, a proline-rich domain, and a transactivation domain. All identified variants were absent from all available exome and genome databases. In vitro, ZMIZ1 showed impaired coactivation of the androgen receptor. In vivo, overexpression of ZMIZ1 mutant alleles in developing mouse brains using in utero electroporation resulted in abnormal pyramidal neuron morphology, polarization, and positioning, underscoring the importance of ZMIZ1 in neural development and supporting mutations in ZMIZ1 as the cause of a rare neurodevelopmental syndrome.


Assuntos
Deficiências do Desenvolvimento/genética , Deficiência Intelectual/genética , Mutação Puntual , Fatores de Transcrição/genética , Alelos , Animais , Criança , Pré-Escolar , Deficiências do Desenvolvimento/patologia , Feminino , Humanos , Lactente , Deficiência Intelectual/patologia , Masculino , Camundongos , Síndrome , Fatores de Transcrição/química , Fatores de Transcrição/metabolismo
2.
Am J Med Genet A ; 2018 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-30346094

RESUMO

Interstitial deletions of chromosome 9q31 are very rare. The deletions in most reported patients have been detected by conventional cytogenetics, with reported breakpoints ranging between 9q21 and 9q34. Therefore, an accurate description of a "9q31 deletion syndrome" could not be established. However, based on microarray studies, a small region of overlap has recently been proposed. We report clinical features of two unrelated individuals with overlapping 9q deletions identified by SNP microarray analysis. Patient 1 has a 9 Mb deletion, while Patient 2's deletion was 21.6 Mb. The clinical features common to our patients and those in the literature include developmental delay and short stature. Patient 2 shows additional features not reported in other 9q31 deletions, such as hearing loss, ventriculomegaly, cleft lip and palate, and small kidneys, which could be due to the larger size of the deletion, hence the influence of the genes in the region beyond the smallest region of overlap. Based on the comparison of these patients with the previously reported patients, we redefine the smallest region of overlap and characterize the clinical features of the 9q31 deletion syndrome.

3.
Semin Pediatr Neurol ; 26: 135-139, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29961505

RESUMO

Intracranial calcifications in young infants, while suggesting intrauterine infections, can also be due to numerous other conditions, including rare genetic disorders. We describe 2 children in whom the presence and pattern of intracranial calcifications led to the diagnosis of uncommon genetic disorders, Adams-Oliver syndrome and Aicardi-Goutieres syndrome. Differentiating genetic conditions from intrauterine infections or other causes of intracranial calcifications enables practitioners to provide accurate counseling regarding prognosis and recurrence risk.


Assuntos
Doenças Autoimunes do Sistema Nervoso/diagnóstico , Encefalopatias/diagnóstico , Calcinose/diagnóstico , Displasia Ectodérmica/diagnóstico , Deformidades Congênitas dos Membros/diagnóstico , Malformações do Sistema Nervoso/diagnóstico , Dermatoses do Couro Cabeludo/congênito , Doenças Autoimunes do Sistema Nervoso/genética , Encéfalo/diagnóstico por imagem , Encefalopatias/genética , Calcinose/genética , Criança , Diagnóstico Diferencial , Displasia Ectodérmica/genética , Feminino , Humanos , Deformidades Congênitas dos Membros/genética , Malformações do Sistema Nervoso/genética , Dermatoses do Couro Cabeludo/diagnóstico , Dermatoses do Couro Cabeludo/genética
4.
Eur J Med Genet ; 2018 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-29753921

RESUMO

De novo variants of ASH1L, which encodes a histone methyltransferase, have been reported in a few patients with intellectual disability and autistic features. Here, we identified a novel de novo frame-shift variant, c.2422_2423delAAinsT which predicts p.(Lys808TyrfsTer40), in ASH1L in a patient with multiple congenital anomalies (MCA), fine motor developmental delay, learning difficulties, attention deficit hyperactivity disorder, sleep apnea, and scoliosis. This frame-shift variant is expected to result in loss-of-function. Our report provides further evidence to support loss-of-function alterations of ASH1L as causative for an emergent neurodevelopmental syndrome characterized by MCA, intellectual disability, and behavioral problems, and further delineates this genetic disorder.

5.
Am J Med Genet A ; 173(8): 2158-2165, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28577347

RESUMO

22q11.2 deletion syndrome (22q11.2DS) is a common genetic disorder with enormous phenotypic heterogeneity. Despite the established prevalence of developmental and neuropsychiatric issues in this syndrome, its neuroanatomical correlates are not as well understood. A retrospective chart review was performed on 111 patients diagnosed with 22q11.2DS. Of the 111 patients, 24 with genetically confirmed 22q11.2 deletion and brain MRI or MRA were included in this study. The most common indications for imaging were unexplained developmental delay (6/24), seizures of unknown etiology (5/24), and unilateral weakness (3/24). More than half (13/24) of the patients had significant radiographic findings, including persistent cavum septi pellucidi and/or cavum vergae (8/24), aberrant cortical veins (6/24), polymicrogyria or cortical dysplasia (4/24), inner ear deformities (3/24), hypoplastic internal carotid artery (2/24), and hypoplastic cerebellum (1/24). These findings reveal the types and frequencies of brain malformations in this case series, and suggest that the prevalence of neuroanatomical abnormalities in 22q11.2DS may be underestimated. Understanding indications for imaging and frequently encountered brain malformations will result in early diagnosis and intervention in an effort to optimize patient outcomes.


Assuntos
Anormalidades Múltiplas/fisiopatologia , Cerebelo/anormalidades , Síndrome de DiGeorge/fisiopatologia , Malformações do Desenvolvimento Cortical/fisiopatologia , Malformações do Sistema Nervoso/fisiopatologia , Anormalidades Múltiplas/diagnóstico por imagem , Anormalidades Múltiplas/genética , Encéfalo/diagnóstico por imagem , Encéfalo/fisiopatologia , Cerebelo/diagnóstico por imagem , Cerebelo/fisiopatologia , Criança , Pré-Escolar , Deleção Cromossômica , Cromossomos Humanos Par 22/genética , Deficiências do Desenvolvimento/diagnóstico por imagem , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/fisiopatologia , Síndrome de DiGeorge/diagnóstico por imagem , Síndrome de DiGeorge/genética , Feminino , Humanos , Lactente , Recém-Nascido , Imagem por Ressonância Magnética , Masculino , Malformações do Desenvolvimento Cortical/diagnóstico por imagem , Malformações do Sistema Nervoso/diagnóstico por imagem , Malformações do Sistema Nervoso/genética
6.
Ann Neurol ; 80(4)2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27543892

RESUMO

The hereditary spastic paraplegias (HSPs) are heterogeneous neurodegenerative disorders with over 50 known causative genes. We identified a recurrent mutation in KCNA2 (c.881G>A, p.R294H), encoding the voltage-gated K(+) -channel, KV 1.2, in two unrelated families with HSP, intellectual disability (ID), and ataxia. Follow-up analysis of > 2,000 patients with various neurological phenotypes identified a de novo p.R294H mutation in a proband with ataxia and ID. Two-electrode voltage-clamp recordings of Xenopus laevis oocytes expressing mutant KV 1.2 channels showed loss of function with a dominant-negative effect. Our findings highlight the phenotypic spectrum of a recurrent KCNA2 mutation, implicating ion channel dysfunction as a novel HSP disease mechanism. Ann Neurol 2016.


Assuntos
Ataxia/genética , Deficiência Intelectual/genética , Canal de Potássio Kv1.2/genética , Paraplegia Espástica Hereditária/genética , Adulto , Animais , Ataxia/fisiopatologia , Criança , Exoma , Feminino , Humanos , Deficiência Intelectual/fisiopatologia , Masculino , Pessoa de Meia-Idade , Mutação , Oócitos/metabolismo , Linhagem , Paraplegia Espástica Hereditária/fisiopatologia , Xenopus laevis , Adulto Jovem
7.
Am J Med Genet A ; 167A(12): 2916-35, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26333794

RESUMO

In order to describe the physical characteristics, medical complications, and natural history of classic 7q11.23 duplication syndrome [hereafter Dup7 (MIM 609757)], reciprocal duplication of the region deleted in Williams syndrome [hereafter WS (MIM 194050)], we systematically evaluated 53 individuals aged 1.25-21.25 years and 11 affected adult relatives identified in cascade testing. In this series, 27% of probands with Dup7 had an affected parent. Seven of the 26 de novo duplications that were examined for inversions were inverted; in all seven cases one of the parents had the common inversion polymorphism of the WS region. We documented the craniofacial features of Dup7: brachycephaly, broad forehead, straight eyebrows, broad nasal tip, low insertion of the columella, short philtrum, thin upper lip, minor ear anomalies, and facial asymmetry. Approximately 30% of newborns and 50% of older children and adults had macrocephaly. Abnormalities were noted on neurological examination in 88.7% of children, while 81.6% of MRI studies showed structural abnormalities such as decreased cerebral white matter volume, cerebellar vermis hypoplasia, and ventriculomegaly. Signs of cerebellar dysfunction were found in 62.3%, hypotonia in 58.5%, Developmental Coordination Disorder in 74.2%, and Speech Sound Disorder in 82.6%. Behavior problems included anxiety disorders, ADHD, and oppositional disorders. Medical problems included seizures, 19%; growth hormone deficiency, 9.4%; patent ductus arteriosus, 15%; aortic dilation, 46.2%; chronic constipation, 66%; and structural renal anomalies, 18%. We compare these results to the WS phenotype and offer initial recommendations for medical evaluation and surveillance of individuals who have Dup7.


Assuntos
Síndrome de Williams/etiologia , Adolescente , Criança , Pré-Escolar , Cromossomos Humanos Par 7 , Deficiências do Desenvolvimento/etiologia , Deficiências do Desenvolvimento/genética , Face/anormalidades , Feminino , Humanos , Lactente , Masculino , Megalencefalia , Gravidez , Complicações na Gravidez/genética , Síndrome de Williams/genética , Adulto Jovem
8.
Am J Med Genet A ; 167(6): 1396-9, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25899461

RESUMO

Latent TGFB-binding protein 3 (LTBP3) is known to increase bio-availability of TGFB. A homozygous mutation in this gene has previously been associated with oligodontia and short stature in a single family. We report on two sisters with homozygous truncating mutations in LTBP3. In addition to oligodontia and short stature, both sisters have mitral valve prolapse, suggesting a link between truncating LTBP3 mutations and mitral valve disease mediated through the TGFB pathway.


Assuntos
Anodontia/genética , Nanismo/genética , Exoma , Proteínas de Ligação a TGF-beta Latente/genética , Prolapso da Valva Mitral/genética , Mutação , Adolescente , Anodontia/diagnóstico , Anodontia/patologia , Sequência de Bases , Nanismo/diagnóstico , Nanismo/patologia , Feminino , Expressão Gênica , Genes Recessivos , Sequenciamento de Nucleotídeos em Larga Escala , Homozigoto , Humanos , Prolapso da Valva Mitral/diagnóstico , Prolapso da Valva Mitral/patologia , Dados de Sequência Molecular , Linhagem , Fenótipo , Irmãos , Fator de Crescimento Transformador beta/genética , Adulto Jovem
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA