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1.
BMC Cancer ; 24(1): 105, 2024 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-38342891

RESUMO

BACKGROUND: Histiocytoses are rare disorders manifested by increased proliferation of pathogenic myeloid cells sharing histological features with macrophages or dendritic cells and accumulating in various organs, i.a., bone and skin. Pre-clinical in vitro models that could be used to determine molecular pathways of the disease are limited, hence research on histiocytoses is challenging. The current study compares cytophysiological features of progenitor, stromal-like cells derived from histiocytic lesions (sl-pHCs) of three pediatric patients with different histiocytoses types and outcomes. The characterized cells may find potential applications in drug testing. METHODS: Molecular phenotype of the cells, i.e. expression of CD1a and CD207 (langerin), was determined using flow cytometry. Cytogenetic analysis included GTG-banded metaphases and microarray (aCGH) evaluation. Furthermore, the morphology and ultrastructure of cells were evaluated using a confocal and scanning electron microscope. The microphotographs from the confocal imaging were used to reconstruct the mitochondrial network and its morphology. Basic cytophysiological parameters, such as viability, mitochondrial activity, and proliferation, were analyzed using multiple cellular assays, including Annexin V/7-AAD staining, mitopotential analysis, BrdU test, clonogenicity analysis, and distribution of cells within the cell cycle. Biomarkers potentially associated with histiocytoses progression were determined using RT-qPCR at mRNA, miRNA and lncRNA levels. Intracellular accumulation of histiocytosis-specific proteins was detected with Western blot. Cytotoxicyty and IC50 of vemurafenib and trametinib were determined with MTS assay. RESULTS: Obtained cellular models, i.e. RAB-1, HAN-1, and CHR-1, are heterogenic in terms of molecular phenotype and morphology. The cells express CD1a/CD207 markers characteristic for dendritic cells, but also show intracellular accumulation of markers characteristic for cells of mesenchymal origin, i.e. vimentin (VIM) and osteopontin (OPN). In subsequent cultures, cells remain viable and metabolically active, and the mitochondrial network is well developed, with some distinctive morphotypes noted in each cell line. Cell-specific transcriptome profile was noted, providing information on potential new biomarkers (non-coding RNAs) with diagnostic and prognostic features. The cells showed different sensitivity to vemurafenib and trametinib. CONCLUSION: Obtained and characterized cellular models of stromal-like cells derived from histiocytic lesions can be used for studies on histiocytosis biology and drug testing.


Assuntos
Histiocitose de Células de Langerhans , Humanos , Criança , Histiocitose de Células de Langerhans/tratamento farmacológico , Histiocitose de Células de Langerhans/genética , Histiocitose de Células de Langerhans/diagnóstico , Vemurafenib , Macrófagos/metabolismo , Biomarcadores , Fenótipo , Antígenos CD , Lectinas Tipo C/metabolismo , Lectinas de Ligação a Manose/metabolismo
2.
Am J Obstet Gynecol ; 230(3): 368.e1-368.e12, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-37717890

RESUMO

BACKGROUND: The 22q11.2 deletion syndrome is the most common microdeletion syndrome and is frequently associated with congenital heart disease. Prenatal diagnosis of 22q11.2 deletion syndrome is increasingly offered. It is unknown whether there is a clinical benefit to prenatal detection as compared with postnatal diagnosis. OBJECTIVE: This study aimed to determine differences in perinatal and infant outcomes between patients with prenatal and postnatal diagnosis of 22q11.2 deletion syndrome. STUDY DESIGN: This was a retrospective cohort study across multiple international centers (30 sites, 4 continents) from 2006 to 2019. Participants were fetuses, neonates, or infants with a genetic diagnosis of 22q11.2 deletion syndrome by 1 year of age with or without congenital heart disease; those with prenatal diagnosis or suspicion (suggestive ultrasound findings and/or high-risk cell-free fetal DNA screen for 22q11.2 deletion syndrome with postnatal confirmation) were compared with those with postnatal diagnosis. Perinatal management, cardiac and noncardiac morbidity, and mortality by 1 year were assessed. Outcomes were adjusted for presence of critical congenital heart disease, gestational age at birth, and site. RESULTS: A total of 625 fetuses, neonates, or infants with 22q11.2 deletion syndrome (53.4% male) were included: 259 fetuses were prenatally diagnosed (156 [60.2%] were live-born) and 122 neonates were prenatally suspected with postnatal confirmation, whereas 244 infants were postnatally diagnosed. In the live-born cohort (n=522), 1-year mortality was 5.9%, which did not differ between groups but differed by the presence of critical congenital heart disease (hazard ratio, 4.18; 95% confidence interval, 1.56-11.18; P<.001) and gestational age at birth (hazard ratio, 0.78 per week; 95% confidence interval, 0.69-0.89; P<.001). Adjusting for critical congenital heart disease and gestational age at birth, the prenatal cohort was less likely to deliver at a local community hospital (5.1% vs 38.2%; odds ratio, 0.11; 95% confidence interval, 0.06-0.23; P<.001), experience neonatal cardiac decompensation (1.3% vs 5.0%; odds ratio, 0.11; 95% confidence interval, 0.03-0.49; P=.004), or have failure to thrive by 1 year (43.4% vs 50.3%; odds ratio, 0.58; 95% confidence interval, 0.36-0.91; P=.019). CONCLUSION: Prenatal detection of 22q11.2 deletion syndrome was associated with improved delivery management and less cardiac and noncardiac morbidity, but not mortality, compared with postnatal detection.


Assuntos
Síndrome de DiGeorge , Cardiopatias Congênitas , Lactente , Recém-Nascido , Gravidez , Feminino , Humanos , Masculino , Síndrome de DiGeorge/diagnóstico , Síndrome de DiGeorge/genética , Estudos Retrospectivos , Diagnóstico Pré-Natal , Cardiopatias Congênitas/diagnóstico , Cardiopatias Congênitas/epidemiologia , Cardiopatias Congênitas/genética , Cuidado Pré-Natal
3.
Genet Med ; 25(3): 100344, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36729052

RESUMO

This review aimed to update the clinical practice guidelines for managing adults with 22q11.2 deletion syndrome (22q11.2DS). The 22q11.2 Society recruited expert clinicians worldwide to revise the original clinical practice guidelines for adults in a stepwise process according to best practices: (1) a systematic literature search (1992-2021), (2) study selection and synthesis by clinical experts from 8 countries, covering 24 subspecialties, and (3) formulation of consensus recommendations based on the literature and further shaped by patient advocate survey results. Of 2441 22q11.2DS-relevant publications initially identified, 2344 received full-text review, with 2318 meeting inclusion criteria (clinical care relevance to 22q11.2DS) including 894 with potential relevance to adults. The evidence base remains limited. Thus multidisciplinary recommendations represent statements of current best practice for this evolving field, informed by the available literature. These recommendations provide guidance for the recognition, evaluation, surveillance, and management of the many emerging and chronic 22q11.2DS-associated multisystem morbidities relevant to adults. The recommendations also address key genetic counseling and psychosocial considerations for the increasing numbers of adults with this complex condition.


Assuntos
Síndrome de DiGeorge , Adulto , Humanos , Relevância Clínica , Consenso , Síndrome de DiGeorge/genética , Síndrome de DiGeorge/terapia , Aconselhamento Genético , Inquéritos e Questionários
4.
Genet Med ; 25(3): 100338, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36729053

RESUMO

This review aimed to update the clinical practice guidelines for managing children and adolescents with 22q11.2 deletion syndrome (22q11.2DS). The 22q11.2 Society, the international scientific organization studying chromosome 22q11.2 differences and related conditions, recruited expert clinicians worldwide to revise the original 2011 pediatric clinical practice guidelines in a stepwise process: (1) a systematic literature search (1992-2021), (2) study selection and data extraction by clinical experts from 9 different countries, covering 24 subspecialties, and (3) creation of a draft consensus document based on the literature and expert opinion, which was further shaped by survey results from family support organizations regarding perceived needs. Of 2441 22q11.2DS-relevant publications initially identified, 2344 received full-text reviews, including 1545 meeting criteria for potential relevance to clinical care of children and adolescents. Informed by the available literature, recommendations were formulated. Given evidence base limitations, multidisciplinary recommendations represent consensus statements of good practice for this evolving field. These recommendations provide contemporary guidance for evaluation, surveillance, and management of the many 22q11.2DS-associated physical, cognitive, behavioral, and psychiatric morbidities while addressing important genetic counseling and psychosocial issues.


Assuntos
Síndrome de DiGeorge , Adolescente , Humanos , Criança , Síndrome de DiGeorge/genética , Síndrome de DiGeorge/terapia , Aconselhamento Genético , Inquéritos e Questionários
5.
Arch Gynecol Obstet ; 307(1): 293-299, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-35554661

RESUMO

OBJECTIVES: To analyse additional structural and genetic anomalies in fetuses with acrania/exencephaly/anencephaly sequence (AEAS). METHODS: A retrospective analysis of 139 fetuses with AEAS diagnosed between 2006 and 2020 in a single tertiary referral ultrasound department. RESULTS: The median gestational age at diagnosis decreased from 15 weeks in 2006 to 13 weeks in 2020 (- 0.21 per each year; p = 0.009). In 103 fetuses, the defects were limited to the neural tube (NTD) (74.1%), in 36 fetuses (25.9%), there were additional structural non-NTD anomalies. The most common were ventral body wall defects present in 17.8% (23/139), followed by anomalies of the limbs (7.2%; 10/139), face (6.5%; 9/139) and heart (6.5%; 9/139). Genetic anomalies were diagnosed in 7 of the 74 conclusive results (9.5%; 7/74; trisomy 18, n = 5; triploidy, n = 1; duplication of Xq, n = 1). In univariate logistic regression models, male sex, limb anomalies and ventral body wall defects significantly increased the risk of genetic anomalies (OR 12.3; p = 0.024; OR 16.5; p = 0.002 and OR 10.4; p = 0.009, respectively). CONCLUSIONS: A significant number of fetuses with AEAS have additional structural non-NTD anomalies, which are mostly consistent with limb body wall complex. Genetic abnormalities are diagnosed in almost 10% of affected fetuses and trisomy 18 is the most common aberration. Factors that significantly increased the odds of genetic anomalies in fetuses with AEAS comprise male sex, limb anomalies and ventral body wall defects.


Assuntos
Anencefalia , Defeitos do Tubo Neural , Gravidez , Feminino , Masculino , Humanos , Lactente , Anencefalia/diagnóstico por imagem , Anencefalia/epidemiologia , Anencefalia/genética , Síndrome da Trissomía do Cromossomo 18 , Estudos Retrospectivos , Defeitos do Tubo Neural/diagnóstico por imagem , Defeitos do Tubo Neural/epidemiologia , Diagnóstico Pré-Natal
6.
J Assist Reprod Genet ; 39(2): 357-367, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-35079943

RESUMO

Spontaneous abortion occurs in 8-20% of recognized pregnancies and usually takes place in the first trimester (7-11 weeks). There are many causes of pregnancy loss, but the most important (about 75%) is the presence of chromosomal aberrations. We present the results of oligonucleotide array application in a cohort of 62 miscarriage cases. The inclusion criteria for the study were the loss after 8th week of pregnancy and the appearance of recurrent miscarriages. DNA was extracted from trophoblast or fetal skin fibroblasts. In the 62 tested materials from recurrent miscarriages, the detection rate was 56.5% (35/62). The most commonly found were aneuploidies (65%) (chromosomal trisomy 14, 16, 18, 21, and 22), Turner syndrome, and triploidy (17.1%). Other chromosomal abnormalities included pathogenic and likely pathogenic structural aberrations: 1) pathogenic: deletion 7p22.3p12.3 and duplication 9p24.3p13.2 inherited from the normal father, deletion 3q13.31q22.2 and deletion 3q22.3q23 of unknown inheritance and duplication of 17p12 inherited from father with foot malformation; 2) likely pathogenic variants: deletion 17p13.1 inherited from normal mother, deletion 5q14.3 of unknown inheritance and de novo deletion 1q21.1q21.2. Among these aberrations, six CNVs (copy number variants) were responsible for the miscarriage: deletion 7p22.3p12.3 and duplication 9p24.3p13.2, deletion 3q13.31q22.2 and deletion 3q22.3q23, and deletion 17p13.1 and deletion 1q21.1q21.2. Other two findings were classified as incidental findings (deletion 5q14.3 and 17p12 duplication). Our research shows that 17% of the aberrations (6/35 abnormal results) that cannot be identified by the routine kariotype analysis are structural aberrations containing genes important for fetal development, the mutations of which may cause spontaneous abortion.


Assuntos
Aborto Habitual , Aberrações Cromossômicas , Aborto Habitual/genética , Hibridização Genômica Comparativa , Variações do Número de Cópias de DNA/genética , Feminino , Humanos , Gravidez , Trissomia
7.
Int J Mol Sci ; 23(1)2021 Dec 21.
Artigo em Inglês | MEDLINE | ID: mdl-35008459

RESUMO

Fetal growth restriction (FGR) is one of the most formidable challenges in present-day antenatal care. Pathological fetal growth is a well-known factor of not only in utero demise in the third trimester, but also postnatal morbidity and unfavorable developmental outcomes, including long-term sequalae such as metabolic diseases, diabetic mellitus or hypertension. In this review, the authors present the current state of knowledge about the genetic disturbances responsible for FGR diagnosis, divided into fetal, placental and maternal causes (including preeclampsia), as well as their impact on prenatal diagnostics, with particular attention on chromosomal microarray (CMA) and noninvasive prenatal testing technique (NIPT).


Assuntos
Retardo do Crescimento Fetal/diagnóstico , Retardo do Crescimento Fetal/genética , Animais , Feminino , Patrimônio Genético , Humanos , Placenta/patologia , Gravidez , Diagnóstico Pré-Natal/métodos
8.
Genet Med ; 22(2): 326-335, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31474763

RESUMO

PURPOSE: The 22q11.2 deletion syndrome (22q11.2DS) is the most common microdeletion in humans, with highly variable phenotypic expression. Whereas congenital heart defects, palatal anomalies, immunodeficiency, hypoparathyroidism, and neuropsychiatric conditions are observed in over 50% of patients with 22q11DS, a subset of patients present with additional "atypical" findings such as craniosynostosis and anorectal malformations. Recently, pathogenic variants in the CDC45 (Cell Division Cycle protein 45) gene, located within the LCR22A-LCR22B region of chromosome 22q11.2, were noted to be involved in the pathogenesis of craniosynostosis. METHODS: We performed next-generation sequencing on DNA from 15 patients with 22q11.2DS and atypical phenotypic features such as craniosynostosis, short stature, skeletal differences, and anorectal malformations. RESULTS: We identified four novel rare nonsynonymous variants in CDC45 in 5/15 patients with 22q11.2DS and craniosynostosis and/or other atypical findings. CONCLUSION: This study supports CDC45 as a causative gene in craniosynostosis, as well as a number of other anomalies. We suggest that this association results in a condition independent of Meier-Gorlin syndrome, perhaps representing a novel condition and/or a cause of features associated with Baller-Gerold syndrome. In addition, this work confirms that the phenotypic variability observed in a subset of patients with 22q11.2DS is due to pathogenic variants on the nondeleted chromosome.


Assuntos
Proteínas de Ciclo Celular/genética , Síndrome de DiGeorge/genética , Alelos , Proteínas de Ciclo Celular/metabolismo , Criança , Pré-Escolar , Deleção Cromossômica , Cromossomos/genética , Cromossomos Humanos Par 22/genética , Craniossinostoses/genética , Síndrome de DiGeorge/metabolismo , Feminino , Cardiopatias Congênitas/genética , Humanos , Masculino , Fenótipo , Estudos Retrospectivos
9.
Clin Genet ; 97(4): 634-638, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31730230

RESUMO

We present a case of lethal fetal akinesia deformation sequence (FADS) caused by a frameshift variant in trans with a 148 kbp deletion encompassing 3-36 exons of AGRN. Pathogenic variants in AGRN have been described in families with a form of congenital myasthenic syndrome (CMS), manifesting in the early childhood with variable fatigable muscle weakness. To the best of our knowledge, this is the first case of FADS caused by defects in AGRN gene. FADS has been reported to be caused by pathogenic variants in genes previously associated with CMS including these involved in endplate development and maintenance: MuSK, DOK7, and RAPSN. FADS seems to be the most severe form of CMS. None of the reported in the literature CMS cases associated with AGRN had two null variants, like the case presented herein. This indicates a strong genotype-phenotype correlation.


Assuntos
Agrina/genética , Artrogripose/genética , Genes Letais/genética , Síndromes Miastênicas Congênitas/genética , Adulto , Artrogripose/diagnóstico por imagem , Artrogripose/patologia , Criança , Feminino , Feto/diagnóstico por imagem , Feto/patologia , Humanos , Masculino , Mutação/genética , Síndromes Miastênicas Congênitas/patologia , Linhagem , Gravidez
11.
Prenat Diagn ; 40(5): 612-617, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32003477

RESUMO

OBJECTIVES: To determine the frequency of genetic and additional structural abnormalities as well as pregnancy outcomes in fetuses with prenatally diagnosed cephalocele. METHODS: A retrospective analysis of data retrieved from ultrasound examinations and genetic testing in fetuses with cephalocele diagnosed between 2006 and 2018 in a tertiary referral hospital along with a systematic literature search in the PubMed database on fetuses with prenatally diagnosed cephalocele. RESULTS: Twenty-one out of 36 fetuses were found to have additional structural anomalies (58.3%). In four fetuses, anomalies were consistent with limb-body wall complex, in five with Meckel-Gruber syndrome, and in one with amniotic band syndrome. Genetic abnormalities were present in 11.1% of fetuses (trisomy 6; microdeletion 22q11.21; microduplication 16p13.11; pathogenic variant in gene CC2D2A). Twenty-eight pregnancies were terminated (77.8%; 28/36); two were miscarried (5.6%; 2/36). All six children from pregnancies that continued were liveborn but only two survived the surgery and developed neurological sequence. Overall survival rate was 25% (2/8) with 0% intact survival. CONCLUSIONS: Additional structural anomalies are common in fetuses with cephalocele. A significant number of fetuses have genetic abnormalities, and a detailed genetic testing should be performed in all cases. The prognosis is poor with high mortality rate and 0% intact survival.


Assuntos
Anormalidades Múltiplas/diagnóstico , Síndrome de Bandas Amnióticas/diagnóstico , Transtornos da Motilidade Ciliar/diagnóstico , Encefalocele/diagnóstico por imagem , Doenças Renais Policísticas/diagnóstico , Retinose Pigmentar/diagnóstico , Trissomia/diagnóstico , Anormalidades Múltiplas/genética , Aborto Induzido , Aborto Espontâneo , Síndrome de Bandas Amnióticas/genética , Deleção Cromossômica , Duplicação Cromossômica , Cromossomos Humanos Par 16 , Cromossomos Humanos Par 22 , Cromossomos Humanos Par 6 , Transtornos da Motilidade Ciliar/genética , Estudos de Coortes , Proteínas do Citoesqueleto/genética , Encefalocele/diagnóstico , Encefalocele/genética , Feminino , Humanos , Recém-Nascido , Masculino , Morte Perinatal , Doenças Renais Policísticas/genética , Gravidez , Retinose Pigmentar/genética , Estudos Retrospectivos , Trissomia/genética , Ultrassonografia Pré-Natal
12.
Acta Derm Venereol ; 97(5): 564-570, 2017 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-27958613

RESUMO

Psoriasis is an inflammatory immunogenetic skin disease, often accompanied by itch. Opioid receptors are known regulators of itch sensation in the central nervous system. In the brain, µ-opioid receptors may potentiate itch, while activation of κ-opioid receptors may reduce or even alleviate itch; however, the role of opioid receptors in itch perception in the skin is poorly understood. To further elucidate the role of opioid receptors in the neurobiology of psoriatic itch, punch biopsies of non-lesional and lesional skin of patients with psoriasis and healthy controls were studied. Real-time polymerase chain reaction and immunofluorescence microscopy were used to detect opioid receptor genes and protein expression, respectively. The OPRK1/κ-opioid receptor pathway was found to be downregulated in lesional skin of psoriasis, correlating positively with itch sensation. In contrast, the OPRM1/µ-opioid receptor system was uniformly expressed by epidermal keratinocytes in all analysed groups. These findings suggest that imbalance of epidermal opioid receptors may result in disordered neuroepidermal homeostasis in psoriasis, which could potentiate transmission of itch.


Assuntos
Epiderme/química , Prurido/metabolismo , Psoríase/metabolismo , Receptores Opioides kappa/análise , Receptores Opioides mu/análise , Adulto , Idoso , Biópsia , Estudos de Casos e Controles , Epiderme/patologia , Feminino , Imunofluorescência , Humanos , Queratinócitos/química , Masculino , Microscopia de Fluorescência , Pessoa de Meia-Idade , Prurido/genética , Prurido/patologia , Psoríase/genética , Psoríase/patologia , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Receptores Opioides kappa/genética , Receptores Opioides mu/genética , Limiar Sensorial , Transdução de Sinais , Adulto Jovem
13.
Prenat Diagn ; 37(5): 446-452, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28233318

RESUMO

OBJECTIVE: To present five new cases of prenatally diagnosed Pallister-Killian syndrome (PKS) and to propose an approach for a targeted diagnosis. METHOD: We retrospectively analyzed ultrasound findings and cytogenetic results in PKS. We also searched through dysmorphology databases for features occurring in PKS that could potentially be seen in prenatal ultrasound examination. RESULTS: On the basis of collected data, frequent and distinctive features in fetuses with PKS were established. The most appropriate material and method of testing were proposed. Rhizomelic limb shortening, diaphragmatic hernia, thickened nuchal fold, increased prenasal thickness, polydactyly and polyhydramnios were frequent and distinctive findings in fetuses with PKS. Amniocentesis was the most frequent prenatal procedure for material collection. Percentage of aneuploid cells was higher in amniotic fluid than in cord blood. Cytomolecular tests were useful as confirmation as well as preliminary tests. Cytogenetic identification of the isochromosome was done in all cases except one. CONCLUSIONS: In case of ultrasound evaluation of features frequent and distinctive for PKS in second and third trimesters of pregnancy, targeted diagnosis should be considered. Amniotic fluid instead of cord blood collection is preferable. Communication with the laboratory is important because modification of routine procedures enhances a chance for correct diagnosis. © 2017 John Wiley & Sons, Ltd.


Assuntos
Transtornos Cromossômicos/diagnóstico , Diagnóstico Pré-Natal/métodos , Aborto Eugênico , Adulto , Cromossomos Humanos Par 12 , Análise Citogenética , Feminino , Idade Gestacional , Humanos , Idade Materna , Gravidez , Resultado da Gravidez , Estudos Retrospectivos , Ultrassonografia Pré-Natal , Adulto Jovem
14.
Dev Period Med ; 21(2): 91-94, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28796977

RESUMO

Copy-number variants (CNVs) are an important cause of human neurodevelopmental disorders. We present the first case of a 424 kb de novo 20q13.11q13.12 microdeletion in a patient with attention deficit disorder, tics and autistic behaviors, such as emotional and behavioral problems, and movement stereotypes. This region includes three genes expressed in the brain: SFRS6, PTPRT and L3MBTL. Our results suggest that loss of the chromosomal region 20q13.11q13.12 is causative for the clinical findings observed in the patient.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 20 , Transtornos do Neurodesenvolvimento/genética , Proteínas Tirosina Fosfatases Classe 2 Semelhantes a Receptores/genética , Adolescente , Proteínas Cromossômicas não Histona , Haploinsuficiência , Humanos , Masculino , Transtornos do Neurodesenvolvimento/diagnóstico , Transtornos do Neurodesenvolvimento/patologia , Fosfoproteínas , Proteínas Repressoras , Fatores de Processamento de Serina-Arginina , Proteínas Supressoras de Tumor
15.
Genome Res ; 23(3): 411-8, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23212949

RESUMO

Large-scale analysis of balanced chromosomal translocation breakpoints has shown nonhomologous end joining and microhomology-mediated repair to be the main drivers of interchromosomal structural aberrations. Breakpoint sequences of de novo unbalanced translocations have not yet been investigated systematically. We analyzed 12 de novo unbalanced translocations and mapped the breakpoints in nine. Surprisingly, in contrast to balanced translocations, we identify nonallelic homologous recombination (NAHR) between (retro)transposable elements and especially long interspersed elements (LINEs) as the main mutational mechanism. This finding shows yet another involvement of (retro)transposons in genomic rearrangements and exposes a profoundly different mutational mechanism compared with balanced chromosomal translocations. Furthermore, we show the existence of compound maternal/paternal derivative chromosomes, reinforcing the hypothesis that human cleavage stage embryogenesis is a cradle of chromosomal rearrangements.


Assuntos
Alelos , Recombinação Homóloga , Retroelementos , Translocação Genética , Mapeamento Cromossômico , Genômica , Humanos , Hibridização in Situ Fluorescente , Cariótipo , Análise em Microsséries , Reação em Cadeia da Polimerase , Polimorfismo de Nucleotídeo Único , Análise de Sequência de DNA
16.
Am J Med Genet A ; 170A(5): 1325-9, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26834018

RESUMO

Neurodevelopmental disorders have long been associated with chromosomal abnormalities, including microdeletions and microduplications. Submicroscopic 14q11.2 deletions involving the CHD8 and SUPT16H genes have been reported in patients with developmental delay (DD)/intellectual disability (ID) or autism spectrum disorders (ASDs) and/or macrocephaly. Recently, disruptive CHD8 mutations were described in patients with similar phenotypes further showing pivotal role of CHD8 gene in the pathogenesis of DD/ID or ASDs. We report here the first case of ~445 kb de novo microduplication, encompassing the minimal critical 14q11.2 deletion region, in 8-year-old boy showing DD, cognitive impairment and facial dysmorphism. Our results suggest that gain of the chromosomal region 14q11.2 is causative for clinical findings present in the patient.


Assuntos
Transtorno do Espectro Autista/genética , Proteínas de Ciclo Celular/genética , Proteínas de Ligação a DNA/genética , Deficiências do Desenvolvimento/genética , Fatores de Transcrição/genética , Transtorno do Espectro Autista/fisiopatologia , Criança , Aberrações Cromossômicas , Deleção Cromossômica , Cromossomos Humanos Par 14/genética , Hibridização Genômica Comparativa , Deficiências do Desenvolvimento/fisiopatologia , Deleção de Genes , Humanos , Deficiência Intelectual/genética , Deficiência Intelectual/fisiopatologia , Masculino
17.
Adv Exp Med Biol ; 912: 1-9, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26987320

RESUMO

Major congenital anomalies are detectable in 2-3 % of the newborn population. Some of their genetic causes are attributable to copy number variations identified by array comparative genomic hybridization (aCGH). The value of aCGH screening as a first-tier test in children with multiple congenital anomalies has been studied and consensus adopted. However, array resolution has not been agreed upon, specifically in the newborn or infant population. Moreover, most array studies have been focused on mixed populations of intellectual disability/developmental delay with or without multiple congenital anomalies, making it difficult to assess the value of microarrays in newborns. The aim of the study was to determine the optimal quality and clinical sensitivity of high-resolution array comparative genomic hybridization in neonates with multiple congenital anomalies. We investigated a group of 54 newborns with multiple congenital anomalies defined as two or more birth defects from more than one organ system. Cytogenetic studies were performed using OGT CytoSure 8 × 60 K microarray. We found ten rearrangements in ten newborns. Of these, one recurrent syndromic microduplication was observed, whereas all other changes were unique. Six rearrangements were definitely pathogenic, including one submicroscopic and five that could be seen on routine karyotype analysis. Four other copy number variants were likely pathogenic. The candidate genes that may explain the phenotype were discussed. In conclusion, high-resolution array comparative hybridization can be applied successfully in newborns with multiple congenital anomalies as the method detects a significant number of pathogenic changes, resulting in early diagnoses. We hypothesize that small changes previously considered benign or even inherited rearrangements should be classified as potentially pathogenic at least until a subsequent clinical assessment would exclude a developmental delay or dysmorphism.


Assuntos
Anormalidades Múltiplas/genética , Hibridização Genômica Comparativa/métodos , Variações do Número de Cópias de DNA , Feminino , Humanos , Recém-Nascido , Masculino
18.
Pol Merkur Lekarski ; 40(238): 255-9, 2016 Apr.
Artigo em Polonês | MEDLINE | ID: mdl-27137828

RESUMO

17p13.3 duplication is a rare and heterogeneous genetic syndrome. Microdeletions of this region are responsible for the symptoms of Miller-Dieker syndrome. We present a case of 17p13.3 duplication consisting of about 730kb in a patient with psychomotor developmental delay, concerning eye-hand coordination, posture, locomotion and speech. Among other symptoms, we found excessive physical development in relation to age, hypotonia, dysmorphic facial features (high and prominent forehead, low-set ears, hypertelorism, short nose, small upturned nose, narrow lips and pointed chin) and discrete changes in the CNS - enhanced frontal horns of the lateral ventricles and quite narrow corpus callosum. These symptoms overlap with phenotype of previously described patients with 17p13.3 duplication. The aberration has been identified by array comparative genomic hybridization (aCGH) and confirmed by fluorescence in situ hybridization (FISH). This publication presents a detailed, comparative characteristic of clinical fetures expression in discussed patient with 17p13.3 duplication and patients previously described in medical literature. Further cases with different variants of 17p13.3 duplication may contribute to characterise the specific genotypephenotype correlation.


Assuntos
Hipotonia Muscular/genética , Malformações do Sistema Nervoso/genética , Transtornos Psicomotores/genética , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Transtornos Cromossômicos/diagnóstico , Transtornos Cromossômicos/genética , Duplicação Cromossômica/genética , Hibridização Genômica Comparativa , Deficiências do Desenvolvimento/diagnóstico , Deficiências do Desenvolvimento/genética , Face/anormalidades , Feminino , Humanos , Hibridização in Situ Fluorescente , Lactente , Malformações do Sistema Nervoso/diagnóstico , Transtornos Psicomotores/diagnóstico , Síndrome
19.
Am J Med Genet A ; 167A(2): 445-9, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25756154

RESUMO

The identification of chromosomal breakpoints in association with human abnormal phenotypes can enable elucidation of gene function. We report on epiphyseal aseptic necrosis of the lesser head of the second metatarsal bone, known as Freiberg's infraction (FI), in two female carriers of the apparently balanced t(5;7)(p13.3;p22.2) ascertained by a 16-year-old girl with cri-du-chat syndrome and unusual skeletal features in association with an unbalanced translocation der(5) t(5;7)(p13.3;p22.2). Mapping of the chromosome breakpoints using fluorescent in situ hybridization (FISH) narrowed them to the coding sequence of ADAMTS12 on chromosome 5p13.3 and SDK1 on 7p22.2. In addition, several skeletal abnormalities classified as brachydactyly type A1B (BDA1B) were present in the proband and in both carriers of t(5;7)(p13.3;p22.2), suggesting a potential role of ADAMTS12 in the development of the BDA1B observed in this family.


Assuntos
Braquidactilia/genética , Cromossomos Humanos Par 5 , Cromossomos Humanos Par 7 , Síndrome de Cri-du-Chat/genética , Metatarso/anormalidades , Osteocondrite/congênito , Translocação Genética , Adolescente , Braquidactilia/diagnóstico , Criança , Síndrome de Cri-du-Chat/diagnóstico , Fácies , Evolução Fatal , Feminino , Humanos , Osteocondrite/diagnóstico , Osteocondrite/genética , Fenótipo , Radiografia , Coluna Vertebral/anormalidades , Coluna Vertebral/diagnóstico por imagem
20.
Am J Hum Genet ; 89(2): 295-301, 2011 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-21802062

RESUMO

We report eight unrelated individuals with intellectual disability and overlapping submicroscopic deletions of 8q21.11 (0.66-13.55 Mb in size). The deletion was familial in one and simplex in seven individuals. The phenotype was remarkably similar and consisted of a round face with full cheeks, a high forehead, ptosis, cornea opacities, an underdeveloped alae, a short philtrum, a cupid's bow of the upper lip, down-turned corners of the mouth, micrognathia, low-set and prominent ears, and mild finger and toe anomalies (camptodactyly, syndactyly, and broadening of the first rays). Intellectual disability, hypotonia, decreased balance, sensorineural hearing loss, and unusual behavior were frequently observed. A high-resolution oligonucleotide array showed different proximal and distal breakpoints in all of the individuals. Sequencing studies in three of the individuals revealed that proximal and distal breakpoints were located in unique sequences with no apparent homology. The smallest region of overlap was a 539.7 kb interval encompassing three genes: a Zinc Finger Homeobox 4 (ZFHX4), one microRNA of unknown function, and one nonfunctional pseudogen. ZFHX4 encodes a transcription factor expressed in the adult human brain, skeletal muscle, and liver. It has been suggested as a candidate gene for congenital bilateral isolated ptosis. Our results suggest that the 8q21.11 submicroscopic deletion represents a clinically recognizable entity and that a haploinsufficient gene or genes within the minimal deletion region could underlie this syndrome.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 8/genética , Deficiência Intelectual/genética , Adolescente , Criança , Pré-Escolar , Hibridização Genômica Comparativa , Fácies , Feminino , Humanos , Hibridização in Situ Fluorescente , Masculino , Fenótipo , Reprodutibilidade dos Testes , Síndrome
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