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1.
Ugeskr Laeger ; 181(7A)2019 Apr 01.
Artigo em Dinamarquês | MEDLINE | ID: mdl-30950380

RESUMO

New technology for genetic testing results in more precise diagnostics and individualised treatment but also identification of variants in genes with unknown association to disease or variants with uncertain significance. Genetic knowledge may involve preconception genetic testing to reduce the risk of passing serious gene variants on to the foetus. Prenatal diagnostics and whole genome sequencing in childhood have also benefitted from the new technology, but ethical dilemmas such as diagnosing a child with a late-onset disorder and potentially harm the child's right to an open future arise.

2.
Am J Hum Genet ; 102(6): 1090-1103, 2018 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-29805044

RESUMO

The 6%-9% risk of an untoward outcome previously established by Warburton for prenatally detected de novo balanced chromosomal rearrangements (BCRs) does not account for long-term morbidity. We performed long-term follow-up (mean 17 years) of a registry-based nationwide cohort of 41 individuals carrying a prenatally detected de novo BCR with normal first trimester screening/ultrasound scan. We observed a significantly higher frequency of neurodevelopmental and/or neuropsychiatric disorders than in a matched control group (19.5% versus 8.3%, p = 0.04), which was increased to 26.8% upon clinical follow-up. Chromosomal microarray of 32 carriers revealed no pathogenic imbalances, illustrating a low prognostic value when fetal ultrasound scan is normal. In contrast, mate-pair sequencing revealed disrupted genes (ARID1B, NPAS3, CELF4), regulatory domains of known developmental genes (ZEB2, HOXC), and complex BCRs associated with adverse outcomes. Seven unmappable autosomal-autosomal BCRs with breakpoints involving pericentromeric/heterochromatic regions may represent a low-risk group. We performed independent phenotype-aware and blinded interpretation, which accurately predicted benign outcomes (specificity = 100%) but demonstrated relatively low sensitivity for prediction of the clinical outcome in affected carriers (sensitivity = 45%-55%). This sensitivity emphasizes the challenges associated with prenatal risk prediction for long-term morbidity in the absence of phenotypic data given the still immature annotation of the morbidity genome and poorly understood long-range regulatory mechanisms. In conclusion, we upwardly revise the previous estimates of Warburton to a morbidity risk of 27% and recommend sequencing of the chromosomal breakpoints as the first-tier diagnostic test in pregnancies with a de novo BCR.

3.
Am J Hum Genet ; 102(5): 744-759, 2018 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-29656859

RESUMO

RORα, the RAR-related orphan nuclear receptor alpha, is essential for cerebellar development. The spontaneous mutant mouse staggerer, with an ataxic gait caused by neurodegeneration of cerebellar Purkinje cells, was discovered two decades ago to result from homozygous intragenic Rora deletions. However, RORA mutations were hitherto undocumented in humans. Through a multi-centric collaboration, we identified three copy-number variant deletions (two de novo and one dominantly inherited in three generations), one de novo disrupting duplication, and nine de novo point mutations (three truncating, one canonical splice site, and five missense mutations) involving RORA in 16 individuals from 13 families with variable neurodevelopmental delay and intellectual disability (ID)-associated autistic features, cerebellar ataxia, and epilepsy. Consistent with the human and mouse data, disruption of the D. rerio ortholog, roraa, causes significant reduction in the size of the developing cerebellum. Systematic in vivo complementation studies showed that, whereas wild-type human RORA mRNA could complement the cerebellar pathology, missense variants had two distinct pathogenic mechanisms of either haploinsufficiency or a dominant toxic effect according to their localization in the ligand-binding or DNA-binding domains, respectively. This dichotomous direction of effect is likely relevant to the phenotype in humans: individuals with loss-of-function variants leading to haploinsufficiency show ID with autistic features, while individuals with de novo dominant toxic variants present with ID, ataxia, and cerebellar atrophy. Our combined genetic and functional data highlight the complex mutational landscape at the human RORA locus and suggest that dual mutational effects likely determine phenotypic outcome.

4.
Acta Obstet Gynecol Scand ; 97(2): 195-203, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29194566

RESUMO

INTRODUCTION: Denmark was the first country in the world to implement a national, free-for-all offer of prenatal screening for Down syndrome to all pregnant women. It has a high uptake (>90%) compared to other countries. Thus, Denmark offers an interesting case for investigating the consequences of implementing comprehensive, national prenatal screening guidelines. The aim of this study was to describe the historical developments in invasive procedures, pre-/postnatal diagnoses of Down syndrome and Down syndrome live births in the period 1973-2016 in Denmark. MATERIAL AND METHODS: Data on invasive procedures, pre- and postnatal Down syndrome diagnoses were retrieved from the Danish Cytogenetic Central Registry. RESULTS: From 1973 to 1993, screening based on maternal age and high-risk indications resulted in a constant increase in invasive procedures. After the introduction of the triple test in 1994, invasive procedures decreased for the first time in 20 years. Following the introduction of an offer of combined screening to all pregnant women in 2004, the number of invasive procedures decreased markedly, while there was a concurrent increase in prenatal diagnoses of Down syndrome. Additionally, the number of Down syndrome live births decreased suddenly and significantly, but subsequently stabilized at 23-35 annual live births. Of these, the majority were diagnosed postnatally. CONCLUSION: Though prenatal screening technologies constantly improve, it was the introduction of and adherence to national guidelines that resulted in marked shifts in screening procedures and outcome in Denmark.


Assuntos
Síndrome de Down/diagnóstico , Programas de Rastreamento/métodos , Medição da Translucência Nucal/métodos , Diagnóstico Pré-Natal/métodos , Ultrassonografia Pré-Natal/métodos , Dinamarca/epidemiologia , Síndrome de Down/epidemiologia , Feminino , Humanos , Recém-Nascido , Masculino , Idade Materna
7.
Am J Hum Genet ; 100(6): 907-925, 2017 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-28575647

RESUMO

Yin and yang 1 (YY1) is a well-known zinc-finger transcription factor with crucial roles in normal development and malignancy. YY1 acts both as a repressor and as an activator of gene expression. We have identified 23 individuals with de novo mutations or deletions of YY1 and phenotypic features that define a syndrome of cognitive impairment, behavioral alterations, intrauterine growth restriction, feeding problems, and various congenital malformations. Our combined clinical and molecular data define "YY1 syndrome" as a haploinsufficiency syndrome. Through immunoprecipitation of YY1-bound chromatin from affected individuals' cells with antibodies recognizing both ends of the protein, we show that YY1 deletions and missense mutations lead to a global loss of YY1 binding with a preferential retention at high-occupancy sites. Finally, we uncover a widespread loss of H3K27 acetylation in particular on the YY1-bound enhancers, underscoring a crucial role for YY1 in enhancer regulation. Collectively, these results define a clinical syndrome caused by haploinsufficiency of YY1 through dysregulation of key transcriptional regulators.


Assuntos
Cromatina/metabolismo , Haploinsuficiência/genética , Deficiência Intelectual/genética , Transcrição Genética , Fator de Transcrição YY1/genética , Acetilação , Adolescente , Sequência de Bases , Pré-Escolar , Imunoprecipitação da Cromatina , Estudos de Coortes , Elementos Facilitadores Genéticos/genética , Feminino , Ontologia Genética , Haplótipos/genética , Hemizigoto , Histonas/metabolismo , Humanos , Linfócitos/metabolismo , Masculino , Metilação , Modelos Moleculares , Mutação de Sentido Incorreto/genética , Ligação Proteica/genética , Domínios Proteicos , Fator de Transcrição YY1/química
8.
Fetal Diagn Ther ; 41(3): 209-214, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-27455074

RESUMO

INTRODUCTION: The aim was to investigate the parental decisions about prenatal screening and diagnosis among infants with trisomy 21 (T21) in a national cohort with high uptake of combined first-trimester screening (cFTS). MATERIAL AND METHODS: This was a nationwide population-based study including infants born in 2009-2012. Information from the cFTS, fetal karyotype results and pregnancy outcome was obtained from the Danish Fetal Medicine Database on all women with a cFTS risk assessment. Cut-off for referral for invasive testing was ≥1:300. Karyotype results from pregnancies with no cFTS were obtained from the Danish Cytogenetic Central Registry. RESULTS: The uptake rate of cFTS was 91.6%, and 82.8% (8,032/9,704) of the screen-positive women opted for invasive testing. Overall, 82.2% (454/552) chose to terminate an affected pregnancy. In the 4-year period, 102 of 232,962 singletons were born alive with T21. The cFTS risk was true-positive, false-negative or not obtained in 21.6, 48.0 and 30.4%, respectively, of these pregnancies. DISCUSSION: In this large national cohort, 4.4 per 10,000 live-born infants had T21. Of 102 infants with T21 from 2009 to 2012, 52.0% were born after the women had not opted for cFTS or were true-positive but declined invasive testing or termination, and 48.0% were born after a false-negative risk assessment.


Assuntos
Tomada de Decisões , Síndrome de Down/diagnóstico , Síndrome de Down/genética , Pais , Primeiro Trimestre da Gravidez/genética , Diagnóstico Pré-Natal , Adulto , Estudos de Coortes , Dinamarca/epidemiologia , Síndrome de Down/epidemiologia , Feminino , Humanos , Pais/psicologia , Vigilância da População/métodos , Gravidez , Diagnóstico Pré-Natal/métodos , Diagnóstico Pré-Natal/psicologia , Sistema de Registros
9.
Prenat Diagn ; 36(6): 530-6, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27027563

RESUMO

OBJECTIVE: The objective of this study was to introduce non-invasive prenatal testing (NIPT) for fetal autosomal trisomies and gender in a Danish public health setting, using semi-conductor sequencing and published open source scripts for analysis. METHODS: Plasma-derived DNA from a total of 375 pregnant women (divided into three datasets) was whole-genome sequenced on the Ion Proton™ platform and analyzed using a pipeline based on WISECONDOR for fetal autosomal aneuploidy detection and SeqFF for fetal DNA fraction estimation. We furthermore validated a fetal sex determination analysis. RESULTS: The pipeline correctly detected 27/27 trisomy 21, 4/4 trisomy 18, and 3/3 trisomy 13 fetuses. Neither false negatives nor false positives (chromosomes 13, 18, and 21) were observed in our validation dataset. Fetal sex was identified correctly in all but one triploid fetus (172/173). SeqFF showed a strong correlation (R(2) = 0.72) to Y-chromosomal content of the male fetus samples. DISCUSSION: We have implemented NIPT into Danish health care using published open source scripts for autosomal aneuploidy detection and fetal DNA fraction estimation showing excellent false negative and false positive rates. SeqFF provides a good estimation of fetal DNA fraction. This coupled with an analysis of fetal sex that provides a complete NIPT workflow, which may easily be adapted for implementation in other public health laboratories. © 2016 John Wiley & Sons, Ltd.


Assuntos
Transtornos Cromossômicos/diagnóstico , DNA/sangue , Síndrome de Down/diagnóstico , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Testes para Triagem do Soro Materno/métodos , Análise de Sequência de DNA/métodos , Trissomia/diagnóstico , Adulto , Cromossomos Humanos Par 13 , Cromossomos Humanos Par 18 , DNA/genética , Dinamarca , Feminino , Sequenciamento de Nucleotídeos em Larga Escala/instrumentação , Humanos , Masculino , Gravidez , Diagnóstico Pré-Natal , Saúde Pública , Semicondutores , Análise de Sequência de DNA/instrumentação , Análise para Determinação do Sexo , Síndrome da Trissomia do Cromossomo 13 , Síndrome da Trissomía do Cromossomo 18
10.
Am J Med Genet A ; 167A(11): 2731-6, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26109418

RESUMO

Nervous system development is highly dependent on the function of microtubules, which are assembled from tubulin heterodimers containing several α- and ß-tubulin isotypes encoded by separate genes. A spectrum of neurological disorders with malformations of the central nervous system has recently been associated with missense mutations in this group of genes. Here, we report two patients, monozygotic twins, carrying a de novo 0.32 Mb deletion of chromosome 16q24.3 including the TUBB3 gene. The patients presented with global developmental delay, mild facial dysmorphism, secondary microcephaly, and mild spastic diplegia. Cerebral magnetic resonance imaging of the patients did not reveal cortical malformations, malformations of the corticospinal tracts, basal ganglia, corpus callosum, or optic nerves. This observation is in contrast to the group of neurological disorders that are associated with heterozygous missense mutations in genes encoding different neuronal α- and ß-tubulin isotypes, termed tubulinopathies. On the background of current knowledge regarding the function and genotype-phenotype correlations of mutations in the neuronal tubulin isotypes, the clinical and diagnostic findings in these patients are discussed. To our knowledge, this is the first report of patients with a de novo deletion of the TUBB3 gene. The lack of cortical or other cerebral malformations supports the current hypothesis that TUBB3-related tubulinopathies are caused by altered protein function.


Assuntos
Pareamento de Bases/genética , Encéfalo/anormalidades , Deficiências do Desenvolvimento/genética , Facies , Deleção de Sequência , Tubulina (Proteína)/genética , Gêmeos Monozigóticos/genética , Cromossomos Humanos Par 16/genética , Hibridização Genômica Comparativa , Humanos , Lactente , Recém-Nascido , Imagem por Ressonância Magnética
11.
Acta Obstet Gynecol Scand ; 94(6): 577-83, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25597330

RESUMO

OBJECTIVE: To describe the establishment and organization of the Danish Fetal Medicine Database and to report national results of first-trimester combined screening for trisomy 21 in the 5-year period 2008-2012. DESIGN: National register study using prospectively collected first-trimester screening data from the Danish Fetal Medicine Database. POPULATION: Pregnant women in Denmark undergoing first-trimester screening for trisomy 21. METHODS: Data on maternal characteristics, biochemical and ultrasonic markers are continuously sent electronically from local fetal medicine databases (Astraia Gmbh software) to a central national database. Data are linked to outcome data from the National Birth Register, the National Patient Register and the National Cytogenetic Register via the mother's unique personal registration number. First-trimester screening data from 2008 to 2012 were retrieved. MAIN OUTCOME MEASURES: Screening performance was assessed for the years 2008-2012 by calculating detection rates and screen-positive rates. RESULTS: A total of 268 342 first-trimester risk assessments for trisomy 21 were performed in singleton pregnancies. Participation rate in first-trimester screening was >90%. The national screen-positive rate increased from 3.6% in 2008 to 4.7% in 2012. The national detection rate of trisomy 21 was reported to be between 82 and 90% in the 5-year period. CONCLUSION: A national fetal medicine database has been successfully established in Denmark. Results from the database have shown that at a national level first-trimester screening performance for trisomy 21 is high with a low screen-positive rate and a high detection rate.


Assuntos
Pesquisa Biomédica , Bases de Dados Factuais , Síndrome de Down/diagnóstico , Programas de Rastreamento , Perinatologia , Dinamarca/epidemiologia , Síndrome de Down/epidemiologia , Feminino , Humanos , Gravidez , Primeiro Trimestre da Gravidez , Estudos Prospectivos , Sistema de Registros , Medição de Risco
12.
Ugeskr Laeger ; 176(30): 1379-82, 2014 Jul 21.
Artigo em Dinamarquês | MEDLINE | ID: mdl-25292226

RESUMO

Array-comparative genomic hybridization (array-CGH) is a very sensitive method for identifying chromosomal imbalances and is now used on a clinical basis for prenatal diagnosis. This article reviews the advantages and disadvantages of the method, the ethical considerations and the current recommendations for prenatal use in Denmark according to a new national guideline from The Danish Society of Foetal Medicine and the Danish Society of Medical Genetics.


Assuntos
Transtornos Cromossômicos/diagnóstico , Hibridização Genômica Comparativa/métodos , Diagnóstico Pré-Natal/métodos , Transtornos Cromossômicos/genética , Hibridização Genômica Comparativa/ética , Feminino , Humanos , Análise em Microsséries/ética , Análise em Microsséries/métodos , Gravidez , Diagnóstico Pré-Natal/ética
13.
Am J Med Genet A ; 164A(12): 3027-34, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25258245

RESUMO

Distal limb contractures (DLC) represent a heterogeneous clinical and genetic condition. Overall, 20-25% of the DLC are caused by mutations in genes encoding the muscle contractile apparatus. Large interstitial deletions of the 3p have already been diagnosed by standard chromosomal analysis, but not associated with a specific phenotype. We report on four patients with syndromic DLC presenting with a de novo 3p14.1p13 microdeletion. The clinical features associated multiple contractures, feeding problems, developmental delay, and intellectual disability. Facial dysmorphism was constant with low-set posteriorly rotated ears and blepharophimosis. Review of previously reported cases with a precise mapping of the deletions, documented a 250 kb smallest region of overlap (SRO) necessary for DLC. This region contained one gene, EIF4E3, the first three exons of the FOXP1 gene, and an intronic enhancer of FOXP1 named hs1149. Sanger sequencing and locus quantification of hs1149, EIF4E3, and FOXP1 in a cohort of 11 French patients affected by DLC appeared normal. In conclusion, we delineate a new microdeletion syndrome involving the 3p14.1p13 locus and associated with DLC and severe developmental delay.


Assuntos
Artrogripose/epidemiologia , Aberrações Cromossômicas , Cromossomos Humanos Par 3/genética , Contratura/epidemiologia , Contratura/genética , Extremidades/patologia , Animais , Proteínas de Transporte/genética , Hibridização Genômica Comparativa , Contratura/patologia , Feminino , Fatores de Transcrição Forkhead/genética , França/epidemiologia , Humanos , Masculino , Camundongos , Camundongos Knockout , Proteínas Repressoras/genética , Síndrome
15.
Am J Med Genet A ; 164A(5): 1277-83, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24664804

RESUMO

Proximal deletions of the long arm of chromosome 13 have been reported only rarely. Here we present three unrelated patients with heterozygous, apparently de novo deletions encompassing 13q12.3. The patients present with moderate demonstrated or apparent intellectual disability, postnatal microcephaly, and eczema/atopic dermatitis as the predominant symptoms. In addition, they had pronounced feeding difficulties in early infancy. They displayed similar facial features such as malar flattening, a prominent nose with underdeveloped alae nasi, a smooth philtrum, and a thin vermillion of the upper lip. The proximal and distal breakpoints were clustered and the deletions spanned from 1.4 to 1.7 Mb, comprising at least 11 RefSeq genes. However, heterozygous deletions partially overlapping those observed in the present patients have been described in healthy parents of patients with Peters-Plus syndrome, an autosomal recessive disorder caused by inactivation of the B3GALTL gene. We therefore propose that the critical region of the 13q12.3 microdeletion syndrome contains only three genes, namely, KATNAL1, HMGB1, and LINC00426, a non-protein coding RNA. The KATNAL1 protein belongs to a family of microtubule severing enzymes that have been implicated in CNS plasticity in experimental models, but little is known about its function in humans. The HMGB1 protein is an evolutionarily conserved chromatin-associated protein involved in many biologically important processes. In summary, we propose that microdeletion 13q12.3 represents a novel clinically recognizable condition and that the microtubule severing gene KATNAL1 and the chromatin-associated gene HMGB1 are candidate genes for intellectual disability inherited in an autosomal dominant pattern.


Assuntos
Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Adenosina Trifosfatases/genética , Deleção Cromossômica , Cromossomos Humanos Par 13 , Proteína HMGB1/genética , Fenótipo , Adolescente , Criança , Pré-Escolar , Hibridização Genômica Comparativa , Dermatite Atópica , Eczema , Facies , Feminino , Humanos , Deficiência Intelectual , Cariotipagem , Katanina , Masculino , Microcefalia
16.
Am J Hum Genet ; 93(5): 798-811, 2013 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-24140112

RESUMO

Copy-number variants (CNVs) represent a significant interpretative challenge, given that each CNV typically affects the dosage of multiple genes. Here we report on five individuals with coloboma, microcephaly, developmental delay, short stature, and craniofacial, cardiac, and renal defects who harbor overlapping microdeletions on 8q24.3. Fine mapping localized a commonly deleted 78 kb region that contains three genes: SCRIB, NRBP2, and PUF60. In vivo dissection of the CNV showed discrete contributions of the planar cell polarity effector SCRIB and the splicing factor PUF60 to the syndromic phenotype, and the combinatorial suppression of both genes exacerbated some, but not all, phenotypic components. Consistent with these findings, we identified an individual with microcephaly, short stature, intellectual disability, and heart defects with a de novo c.505C>T variant leading to a p.His169Tyr change in PUF60. Functional testing of this allele in vivo and in vitro showed that the mutation perturbs the relative dosage of two PUF60 isoforms and, subsequently, the splicing efficiency of downstream PUF60 targets. These data inform the functions of two genes not associated previously with human genetic disease and demonstrate how CNVs can exhibit complex genetic architecture, with the phenotype being the amalgam of both discrete dosage dysfunction of single transcripts and also of binary genetic interactions.


Assuntos
Variações do Número de Cópias de DNA , Proteínas de Membrana/genética , Proteínas de Ligação a RNA/genética , Proteínas Repressoras/genética , Proteínas Supressoras de Tumor/genética , Adolescente , Alelos , Animais , Criança , Pré-Escolar , Mapeamento Cromossômico , Cromossomos Humanos Par 8/genética , Deficiências do Desenvolvimento/genética , Feminino , Deleção de Genes , Técnicas de Silenciamento de Genes , Células HeLa , Humanos , Deficiência Intelectual/genética , Masculino , Microcefalia/genética , Fenótipo , Fatores de Processamento de RNA , Peixe-Zebra/genética
17.
Eur J Pediatr ; 172(12): 1657-63, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23900523

RESUMO

UNLABELLED: The 'vanishing bone' syndrome multicentric osteolysis with nodulosis and arthropathy (MONA) is a rare chronic skeleton disorder caused by matrix metalloproteinase 2 (MMP2) deficiency, mimicking erosive polyarticular juvenile idiopathic arthritis. MONA is characterised by facial dysmorphism, subcutaneous fibrocollagenous nodules, carpal and tarsal osteolysis and interphalangeal joint erosions. We present the case of a 5-year-old boy with double outlet right ventricle, ventricular septal defect, coarctation of the aorta and MONA. Previously, a total of 24 cases of MONA have been reported of which six also had congenital cardiac malformations. Despite treatment attempts of our patient with methotrexate, eternacept and prednisolone, serial X-ray studies documented continuous severe bone degeneration. CONCLUSION: The case documents the natural history of MONA and establishes a link between MMP2 deficiency and heart development, and given the recurring cardiac association, we suggest that all MONA patients be examined for possible cardiac defects.


Assuntos
Antirreumáticos/uso terapêutico , Artrite Juvenil/diagnóstico , Síndrome de Hajdu-Cheney/diagnóstico , Cardiopatias Congênitas/diagnóstico , Metaloproteinase 2 da Matriz/deficiência , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Pré-Escolar , Diagnóstico Diferencial , Progressão da Doença , Síndrome de Hajdu-Cheney/tratamento farmacológico , Cardiopatias Congênitas/genética , Humanos , Masculino , Metaloproteinase 2 da Matriz/análise , Metaloproteinase 2 da Matriz/genética , Mutação de Sentido Incorreto , Análise de Sequência de DNA
18.
Am J Hum Genet ; 93(1): 124-31, 2013 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-23746550

RESUMO

An increasing number of genes involved in chromatin structure and epigenetic regulation has been implicated in a variety of developmental disorders, often including intellectual disability. By trio exome sequencing and subsequent mutational screening we now identified two de novo frameshift mutations and one de novo missense mutation in CTCF in individuals with intellectual disability, microcephaly, and growth retardation. Furthermore, an individual with a larger deletion including CTCF was identified. CTCF (CCCTC-binding factor) is one of the most important chromatin organizers in vertebrates and is involved in various chromatin regulation processes such as higher order of chromatin organization, enhancer function, and maintenance of three-dimensional chromatin structure. Transcriptome analyses in all three individuals with point mutations revealed deregulation of genes involved in signal transduction and emphasized the role of CTCF in enhancer-driven expression of genes. Our findings indicate that haploinsufficiency of CTCF affects genomic interaction of enhancers and their regulated gene promoters that drive developmental processes and cognition.


Assuntos
Mutação da Fase de Leitura , Deficiência Intelectual/genética , Mutação de Sentido Incorreto , Proteínas Repressoras/genética , Adolescente , Fator de Ligação a CCCTC , Criança , Pré-Escolar , Cromatina/genética , Cromatina/metabolismo , Análise Mutacional de DNA , Elementos Facilitadores Genéticos , Exoma , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Genoma Humano , Haploinsuficiência , Humanos , Masculino , Microcefalia/genética , Mutação Puntual , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas , Transdução de Sinais
19.
Am J Med Genet A ; 161A(7): 1594-8, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23704076

RESUMO

We report on three males with de novo overlapping 7.5, 9.8, and 10 Mb duplication of chromosome 20q11.2. Together with another patient previously published in the literature with overlapping 20q11 microduplication, we show that such patients display common clinical features including metopic ridging/trigonocephaly, developmental delay, epicanthal folds, and short hands. The duplication comprised the ASXL1 gene, in which de novo heterozygous nonsense or truncating mutations have recently been reported in patients with Borhing-Opitz syndrome. Because of craniofacial features in common with Borhing-Opitz syndrome, in particular metopic ridging/trigonocephaly, we suggest that duplication of ASXL1 contributes to the phenotype. These observations suggest a novel microduplication syndrome, and reporting of additional patients with molecular characterization will allow more detailed genotype-phenotype correlations.


Assuntos
Craniossinostoses/genética , Proteínas Repressoras/genética , Trissomia/genética , Criança , Pré-Escolar , Cromossomos Humanos Par 20/genética , Deficiências do Desenvolvimento/genética , Feminino , Deformidades Congênitas da Mão/genética , Heterozigoto , Humanos , Lactente , Deficiência Intelectual/genética , Masculino , Mosaicismo , Mutação , Gravidez , Síndrome
20.
Prenat Diagn ; 32(12): 1212-7, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23065819

RESUMO

Submicroscopic terminal 6q deletions are rare. We report on two familial submicroscopic terminal 6q deletions ascertained because of prenatally detected isolated ventriculomegaly and further delineate the variable prenatal and postnatal phenotype. We review published cases of <5 Mb terminal 6q deletions.


Assuntos
Hidrocefalia/genética , Anormalidades Múltiplas/genética , Adulto , Deleção Cromossômica , Cromossomos Humanos Par 6/fisiologia , Feminino , Humanos , Hidrocefalia/diagnóstico , Hidrocefalia/diagnóstico por imagem , Lactente , Recém-Nascido , Cariotipagem , Masculino , Fenótipo , Gravidez , Ultrassonografia
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