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1.
Lancet Child Adolesc Health ; 5(3): 201-209, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33453761

RESUMO

BACKGROUND: Nocturnal enuresis (bedwetting) is a common disorder affecting 10-16% of 7-year-old children globally. Nocturnal enuresis is highly heritable, but its genetic determinants remain unknown. We aimed to identify genetic variants associated with nocturnal enuresis and explore its genetic architecture and underlying biology. METHODS: We did a genome-wide association study (GWAS) of nocturnal enuresis. Nocturnal enuresis cases were identified in iPSYCH2012, a large Danish population-based case cohort established to investigate mental disorders, on the basis of 10th revision of the International Statistical Classification of Diseases (ICD-10) diagnoses and redeemed desmopressin prescriptions in Danish registers. The GWAS was done in a genetically homogeneous sample of unrelated individuals using logistic regression with relevant covariates. All genome-wide significant variants were analysed for their association with nocturnal enuresis in an independent Icelandic sample from deCODE genetics. Standardised polygenic risk scores for attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorder were constructed from summary statistics of large GWASs and analysed for association with nocturnal enuresis. FINDINGS: The GWAS included 3882 nocturnal enuresis cases and 31 073 controls. We found two loci at chromosome 6 and chromosome 13 significantly associated with nocturnal enuresis. Six genetic variants at the two loci (five variants at chromosome 6q16.2 and one variant at chromosome 13q22.3) surpassed the threshold for genome-wide significance (p<5 × 10-8). There were two lead variants: rs9376454 (chromosome 6q16.2), with an odds ratio (OR) of 1·199 (95% CI 1·135-1·267; p=9·91 × 10-11), and rs60721117 (chromosome 13q22.3), with an OR of 1·149 (1·095-1·205; p=1·21 × 10-8). All associated variants in the chromosome 6 locus were replicated (p<8 × 10-3) in the independent Icelandic cohort of 5475 nocturnal enuresis cases and 303 996 controls, whereas the associated variant in the chromosome 13 locus showed nominal significant association (p=0·031). The percentage of nocturnal enuresis phenotypic variance explained by the common genetic variants was 23·9-30·4%. Polygenic risk for ADHD was associated with nocturnal enuresis (OR 1·06, 95% CI, 1·01-1·10; p=0·011). Among the potential nocturnal enuresis risk genes mapped, PRDM13 and EDNRB have biological functions associated with known pathophysiological mechanisms in nocturnal enuresis, and SIM1 regulates the formation of the hypothalamic neuroendocrine lineage that produces arginine vasopressin, a well known nocturnal enuresis drug target. INTERPRETATION: This study shows that common genetic variants contribute considerably to nocturnal enuresis, and it identifies potential nocturnal enuresis risk genes with roles in sleep, urine production, and bladder function. Given that available treatments target these mechanisms, any of the identified genes and their functional gene networks are potential drug targets. FUNDING: The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Stanley Foundation.


Assuntos
Loci Gênicos/genética , Estudo de Associação Genômica Ampla , Enurese Noturna/genética , Transtorno do Deficit de Atenção com Hiperatividade/genética , Transtorno do Espectro Autista/genética , Criança , Cromossomos Humanos Par 13/genética , Cromossomos Humanos Par 6/genética , Desamino Arginina Vasopressina/uso terapêutico , Feminino , Variação Genética/genética , Humanos , Masculino , Enurese Noturna/tratamento farmacológico , Fenótipo
3.
Gene ; 753: 144816, 2020 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-32473250

RESUMO

Hemizygosity of the MIR17HG gene encoding the miR-17 ~ 92 cluster is associated with Feingold syndrome 2 characterized by intellectual disability, skeletal abnormalities, short stature, and microcephaly. Here, we report on a female with a de novo 13q31.3 microduplication encompassing MIR17HG but excluding GPC5. She presented developmental delay, skeletal and digital abnormalities, and features such as tall stature and macrocephaly mirroring those of Feingold syndrome 2 patients. The limited extent of the proband's rearrangement to the miR cluster and the corresponding normal expression level of the neighboring GPC5 in her cells, together with previously described data on affected individuals of two families carrying overlapping duplications of the miR-17 ~ 92 cluster that comprise part of GPC5, who likewise presented macrocephaly, developmental delay, as well as skeletal, digital and stature abnormalities, allow to define a new syndrome due to independent microduplication of the miR-17 ~ 92 cluster.


Assuntos
Transtornos Cromossômicos/genética , Pálpebras/anormalidades , Deficiência Intelectual/genética , Deformidades Congênitas dos Membros/genética , MicroRNAs/genética , Microcefalia/genética , Fístula Traqueoesofágica/genética , Adolescente , Deleção Cromossômica , Cromossomos Humanos Par 13/genética , Hibridização Genômica Comparativa/métodos , Deficiências do Desenvolvimento/genética , Nanismo/genética , Feminino , Duplicação Gênica/genética , Glipicanas/genética , Glipicanas/metabolismo , Humanos , Fenótipo
4.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(5): 547-550, 2020 May 10.
Artigo em Chinês | MEDLINE | ID: mdl-32335883

RESUMO

OBJECTIVE: To analyze the clinical features and pathogenesis of a fetus with holoprosencephaly. METHODS: The findings of prenatal ultrasonography was reviewed. Following elective abortion, whole exome sequencing (WES) was carried out to identify potential pathogenic variant. Copy number variants (CNVs) of the abortus and its parents were detected by low-depth high-throughput sequencing. The parents were also analyzed by chromosomal karyotyping. RESULTS: Prenatal ultrasound suggested that the fetus had holoprosencephaly. WES revealed that it had approximately 33 Mb deletion at chromosome 13 involving ZIC2, a haploid dose sensitive gene. The results of low-depth high-throughput sequencing confirmed that the fetus carried a de novo 32.32 Mb deletion at 13q31.1-34. Karyotyping analysis has excluded gross chromosomal aberration in both parents. CONCLUSION: The fetus was diagnosed with holoprosencephaly, which may be attributable to the 13q31.1-34 deletion involving the ZIC2 gene.


Assuntos
Holoprosencefalia , Deleção de Sequência , Adulto , Cromossomos Humanos Par 13/genética , Feminino , Feto , Testes Genéticos , Holoprosencefalia/diagnóstico por imagem , Holoprosencefalia/genética , Holoprosencefalia/patologia , Humanos , Cariotipagem , Masculino , Proteínas Nucleares/genética , Gravidez , Diagnóstico Pré-Natal , Fatores de Transcrição/genética , Ultrassonografia Pré-Natal , Sequenciamento Completo do Exoma
5.
Cytogenet Genome Res ; 160(2): 72-79, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32187601

RESUMO

In this report, we present a new case of mosaic trisomy 13 with prolonged survival, firstly detected by array-CGH analysis which was carried out because of moderate intellectual disability with postaxial hexadactyly, dermatologic features, ventricular septal defect, bicuspid aortic valve, and aortic dystrophy in a 19-year-old male patient. In a subset of 15% of the cells, the patient carried a derivative chromosome 10 generated by a nonreciprocal (10;13) translocation inherited from his healthy mother who carried the translocation in a balanced and homogeneous state. FISH analyses showed interstitial telomeric sequences at the breakpoints. To our knowledge, this is the second report of a patient with trisomy 13 mosaicism displaying a severe aortic root dilatation. We also discuss the mechanisms which could explain the mosaic state, the most likely one being related to the instability of the interstitial telomere.


Assuntos
Aorta/anormalidades , Síndrome de Marfan/etiologia , Mosaicismo , Síndrome da Trissomia do Cromossomo 13/diagnóstico , Cromossomos Humanos Par 10/genética , Cromossomos Humanos Par 13/genética , Hibridização Genômica Comparativa , Humanos , Hibridização in Situ Fluorescente , Masculino , Translocação Genética , Síndrome da Trissomia do Cromossomo 13/genética , Adulto Jovem
6.
Leukemia ; 34(2): 358-368, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31462731

RESUMO

Sole trisomies of chromosomes 4, 8, 11, 13 and 21 account for 89-95% of all sole trisomies in adult AML patients. We analyzed clinical and molecular characteristics of 138 de novo AML patients with sole +4, +8, +11, +13 or +21, and compared them with AML patients with those trisomies occurring in addition to other chromosome abnormalities (non-sole trisomy) and with cytogenetically normal AML (CN-AML) patients. Mutations in methylation-related genes were most commonly observed within each sole trisomy group (+4, 55%; +8, 58%; +11, 71%; +13, 71%; +21, 75% of patients). Patients with sole trisomies, excluding +4, also had frequent mutations in spliceosome genes (+8, 43%; +11, 65%; +13, 65%; +21, 45% of patients). In contrast, +4 patients frequently had mutations in transcription factor genes (44%) and NPM1 (36%). While 48% of patients with sole trisomies harbored mutations in a spliceosome gene, spliceosome mutations were observed in only 24% of non-sole trisomy (n = 131, P < 0.001) and 19% of CN-AML patients (n = 716, P < 0.001). Our data suggest that mutations affecting methylation-related genes are a molecular hallmark of sole trisomies. Mutations in spliceosome genes were also commonly observed in many sole trisomy patients and represent a novel finding in this cytogenetic subgroup.


Assuntos
Leucemia Mieloide Aguda/genética , Trissomia/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Cromossomos Humanos Par 11/genética , Cromossomos Humanos Par 13/genética , Cromossomos Humanos Par 21/genética , Cromossomos Humanos Par 4/genética , Cromossomos Humanos Par 8/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
7.
BMC Med Genomics ; 12(1): 182, 2019 12 05.
Artigo em Inglês | MEDLINE | ID: mdl-31806026

RESUMO

BACKGROUND: Female carriers of a balanced X; autosome translocation generally undergo selective inactivation of the normal X chromosome. This is because inactivation of critical genes within the autosomal region of the derivative translocation chromosome would compromise cellular function. We here report a female patient with bilateral retinoblastoma and a severe intellectual disability who carries a reciprocal X-autosomal translocation. CASE PRESENTATION: Cytogenetic and molecular analyses, a HUMARA (Human androgen receptor) assay, and methylation specific PCR (MSP) and bisulfite sequencing were performed using peripheral blood samples from the patient. The patient's karyotype was 46,X,t(X;13)(q28;q14.1) by G-banding analysis. Further cytogenetic analysis located the entire RB1 gene and its regulatory region on der(X) with no translocation disruption. The X-inactivation pattern in the peripheral blood was highly skewed but not completely selected. MSP and deep sequencing of bisulfite-treated DNA revealed that an extensive 13q region, including the RB1 promoter, was unusually methylated in a subset of cells. CONCLUSIONS: The der(X) region harboring the RB1 gene was inactivated in a subset of somatic cells, including the retinal cells, in the patient subject which acted as the first hit in the development of her retinoblastoma. In addition, the patient's intellectual disability may be attributable to the inactivation of the der(X), leading to a 13q deletion syndrome-like phenotype, or to an active X-linked gene on der (13) leading to Xq28 functional disomy.


Assuntos
Cromossomos Humanos Par 13/genética , Cromossomos Humanos X/genética , Deficiência Intelectual/complicações , Deficiência Intelectual/genética , Proteínas de Ligação a Retinoblastoma/genética , Retinoblastoma/complicações , Translocação Genética , Ubiquitina-Proteína Ligases/genética , Feminino , Humanos , Lactente , Neoplasias da Retina/complicações
8.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(12): 1213-1218, 2019 Dec 10.
Artigo em Chinês | MEDLINE | ID: mdl-31813151

RESUMO

OBJECTIVE: To explore the genetic etiology of a child with moderate mental retardation and multiple malformations. METHODS: The child and his parents underwent conventional G banding karyotype analysis and single nucleotide polymorphism-based mircoarray (SNP-array) scan. A systematic review for chromosome 13q deletions was also conducted to explore the correlation between genotype and clinical phenotypes. RESULTS: G banding karyotype of the child showed a partial deletion in the long arm of chromosome 13 described as 46,XY,del(13)(q32). SNP-array detected a deletion fragment of 11.367 Mb in 13q32.1-q33.3 region, which encompassed 30 OMIM (Online Mendelian Inheritance in Man) genes including FARP1, STK24 and ZIC2. The parents were found with no obvious abnormality in their karyotypes and SNP-array results, suggesting a de novo origin for the deletion. Combined with previous reported cases, chromosomal 13q deletions seem to have various pathogenic effects on the patients. CONCLUSION: Chromosomal 13q32.1-q33.3 deletion probably underlies the disease phenotype in the child, and EFNB2 may be a candidate gene for congenital heart defect, genital malformation, hypospadias and anorectal malformations.


Assuntos
Anormalidades Múltiplas/genética , Deleção Cromossômica , Transtornos Cromossômicos , Criança , Bandeamento Cromossômico , Cromossomos Humanos Par 13/genética , Humanos , Cariotipagem , Masculino
9.
Clin Lab ; 65(11)2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31710435

RESUMO

BACKGROUND: Complex chromosome rearrangement (CCR) often results in patients with mental retardation, stunted growth, and multiple abnormalities. CCR carriers are at high risk of adverse pregnancy, and prenatal diagnosis should be made even in normal pregnancy. The incidence of spermatogenesis disorder is high in male CCR carriers, and the chromosome involved with CCR has an impact on the fertility of male carriers. METHODS: We report a case of complex chromosome translocation: 46, XY, t(4; 10; 13) (q31; q23; q12). The lymphocytes in peripheral blood were cultured to examine the patient's karyotype. RESULTS: The patient's karyotype was detected and identified as 46, XY, t(4;10;13) (4pter→4q31::13q12→13qter; 10pter→10q23::4q31→4qter; 13pter→13q12::10q23→10qter). Complex chromosome translocations occurred on chromosomes 4, 10, and 13. When combined with normal gamete, one or two derived chromosomes may be obtained in the offspring, resulting in the increase or decrease of the translocation segments of a chromosome (part of trisomy or part of monomers), thus resulting in fetal abortion, stillbirth or deformed children, etc. Conclusions: Fertility and pregnancy outcome cannot be completely determined according to the complexity of karyotype. For patients with such chromosomal abnormalities, prenatal diagnosis should be strictly carried out to prevent the birth of children with chromosomal diseases if they want to have healthy children.


Assuntos
Aborto Espontâneo/genética , Cromossomos Humanos Par 10 , Cromossomos Humanos Par 13 , Cromossomos Humanos Par 4 , Transtorno 46,XY do Desenvolvimento Sexual/genética , Fertilidade/genética , Infertilidade Masculina/genética , Translocação Genética , Aborto Espontâneo/fisiopatologia , Adulto , Transtorno 46,XY do Desenvolvimento Sexual/diagnóstico , Transtorno 46,XY do Desenvolvimento Sexual/fisiopatologia , Feminino , Predisposição Genética para Doença , Humanos , Infertilidade Masculina/diagnóstico , Infertilidade Masculina/fisiopatologia , Cariótipo , Masculino , Fenótipo , Gravidez
11.
Arch Iran Med ; 22(10): 627-628, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31679365

RESUMO

Monosomy 18p syndrome is one of the prototypical examples of autosomal terminal deletions. This deletion can be the consequence of de novo deletions, malsegregation of a balanced parental translocation, cryptic subtelomeric deletions or ring chromosome 18. The present case is a rare cytogenetic variant of monosomy 18 as a consequence of whole-arm translocation between chromosomes 13 and 18 which has been reported only three times previously.


Assuntos
Transtornos Cromossômicos/genética , Cromossomos Humanos Par 13 , Translocação Genética , Deleção Cromossômica , Transtornos Cromossômicos/diagnóstico , Cromossomos Humanos Par 18/genética , Análise Citogenética , Humanos , Lactente , Masculino , Cromossomos em Anel
12.
Taiwan J Obstet Gynecol ; 58(6): 798-800, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31759530

RESUMO

OBJECTIVE: The aim of this study was to evaluate the usefulness of ultrasound in pregnancies with a positive non-invasive prenatal testing (NIPT) result for trisomy 18/13. MATERIALS AND METHODS: During a four-year period, the pregnant women who were referred for invasive genetic testing because of positive NIPT results for trisomy 18/13 were included in this study. An in-depth ultrasound was done for these patients before invasive procedures. The data of fetal ultrasound and cytogenetic results were collected. RESULTS: There were 81 patients with a positive NIPT result for trisomy 18/13, including 39 (30 positive for trisomy 18; 9 positive for trisomy 13) within 12-14 weeks of gestation, and 42 (31 positive for trisomy 18; 11 positive for trisomy 13) within 15-22 weeks. The PPV of NIPT was 60.7% for trisomy 18, and 30% for trisomy 13, respectively. When adding ultrasound to NIPT, the new PPV for trisomy 18 was 100%, and the negative predictive value (NPV) was 92.3%, with a NPV of 85.7% in the first trimester and a NPV of 100% in the second trimester, respectively. The new PPV and NPV for trisomy 13 were 100% and 100%, respectively. CONCLUSION: By adding ultrasound to the NIPT, we achieved much higher PPVs and NPVs for trisomy 18/13. A normal scan can help to alleviate stress in parents caused by false positive NIPT results.


Assuntos
Síndrome da Trissomia do Cromossomo 13/diagnóstico , Síndrome da Trissomía do Cromossomo 18/diagnóstico , Ultrassonografia Pré-Natal/métodos , Adulto , Cromossomos Humanos Par 13/genética , Cromossomos Humanos Par 18/genética , DNA/análise , Feminino , Seguimentos , Testes Genéticos/métodos , Idade Gestacional , Humanos , Recém-Nascido , Cariotipagem , Gravidez , Resultado da Gravidez , Reprodutibilidade dos Testes , Estudos Retrospectivos , Fatores de Tempo
13.
Nat Commun ; 10(1): 4495, 2019 10 03.
Artigo em Inglês | MEDLINE | ID: mdl-31582743

RESUMO

Aneuploidy is a major source of gene dosage imbalance due to copy number alterations (CNA), and viable human trisomies are model disorders of altered gene expression. We study gene and allele-specific expression (ASE) of 9668 single-cell fibroblasts from trisomy 21 (T21) discordant twins and from mosaic T21, T18, T13 and T8. We examine 928 single cells with deep scRNAseq. Expected and observed overexpression of trisomic genes in trisomic vs. diploid bulk RNAseq is not detectable in trisomic vs. diploid single cells. Instead, for trisomic genes with low-to-average expression, their altered gene dosage is mainly due to the higher fraction of trisomic cells simultaneously expressing these genes, in agreement with a stochastic 2-state burst-like model of transcription. These results, confirmed in a further analysis of 8740 single fibroblasts with shallow scRNAseq, suggest that the specific transcriptional profile of each gene contributes to the phenotypic variability of trisomies. We propose an improved model to understand the effects of CNA and, generally, of gene regulation on gene dosage imbalance.


Assuntos
Variações do Número de Cópias de DNA , Dosagem de Genes , Modelos Genéticos , Transcriptoma/genética , Trissomia/genética , Alelos , Cromossomos Humanos Par 13/genética , Cromossomos Humanos Par 18/genética , Cromossomos Humanos Par 8/genética , Síndrome de Down/genética , Feminino , Fibroblastos , Perfilação da Expressão Gênica , Humanos , Masculino , Mosaicismo , Fenótipo , RNA-Seq , Análise de Célula Única
14.
Hum Mol Genet ; 28(21): 3600-3609, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31509193

RESUMO

Multiple sclerosis (MS) is known as an autoimmune demyelinating disease of the central nervous system. However, its cause remains elusive. Given previous studies suggesting that dysfunctional oligodendrocytes (OLs) may trigger MS, we tested whether single nucleotide polymorphisms (SNPs) associated with MS affect OL enhancers, potentially increasing MS risk by dysregulating gene expression of OL lineage cells. We found that two closely spaced OL enhancers, which are 3 Kb apart on chromosome 13, overlap two MS SNPs in linkage disequilibrium-rs17594362 and rs12429256. Our data revealed that the two MS SNPs significantly up-regulate the associated OL enhancers, which we have named as Rgcc-E1 and Rgcc-E2. Analysis of Hi-C data and epigenome editing experiments shows that Rgcc is the primary target of Rgcc-E1 and Rgcc-E2. Collectively, these data indicate that the molecular mechanism of rs17594362 and rs12429256 is to induce Rgcc overexpression by potentiating the enhancer activity of Rgcc-E1 and Rgcc-E2. Importantly, the dosage of the rs17594362/rs12429256 risk allele is positively correlated with the expression level of Rgcc in the human population, confirming our molecular mechanism. Our study also suggests that Rgcc overexpression in OL lineage cells may be a key cellular mechanism of rs17594362 and rs12429256 for MS.


Assuntos
Esclerose Múltipla/genética , Polimorfismo de Nucleotídeo Único , Alelos , Cromossomos Humanos Par 13/genética , Elementos Facilitadores Genéticos , Predisposição Genética para Doença , Humanos , Desequilíbrio de Ligação
15.
J Eur Acad Dermatol Venereol ; 33 Suppl 6: 32-33, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31535764

RESUMO

Hidradenitis suppurativa (HS) is a chronic relapsing disorder of the apocrine gland affecting mainly areas subjected to friction (e.g. the axillae, groin, perineum and medial aspects of the thighs). This condition can be linked to different comorbidities: autoimmune and inflammatory disease, hormone-related disorders, obesity and the metabolic syndrome, as well as rare syndromes such as Bazex-Dupré-Christol, Down's, KID, PAPASH, PASS, PASH, and SAPHO syndromes, or Dowling-Degos disease. We report a case of severe HS in a patient with Trisomy 1q;13, a very rare cytogenetic anomaly characterized by severe anomalies including dysmorphisms, multiple congenital malformations, heart defects and intellectual disability.


Assuntos
Cromossomos Humanos Par 1 , Hidradenite Supurativa/genética , Trissomia , Anormalidades Múltiplas/genética , Adulto , Cromossomos Humanos Par 13 , Feminino , Humanos
16.
Int J Mol Sci ; 20(19)2019 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-31546608

RESUMO

We present the analysis of defective pathways in multiple myeloma (MM) using two recently developed sampling algorithms of the biological pathways: The Fisher's ratio sampler, and the holdout sampler. We performed the retrospective analyses of different gene expression datasets concerning different aspects of the disease, such as the existing difference between bone marrow stromal cells in MM and healthy controls (HC), the gene expression profiling of CD34+ cells in MM and HC, the difference between hyperdiploid and non-hyperdiploid myelomas, and the prediction of the chromosome 13 deletion, to provide a deeper insight into the molecular mechanisms involved in the disease. Our analysis has shown the importance of different altered pathways related to glycosylation, infectious disease, immune system response, different aspects of metabolism, DNA repair, protein recycling and regulation of the transcription of genes involved in the differentiation of myeloid cells. The main difference in genetic pathways between hyperdiploid and non-hyperdiploid myelomas are related to infectious disease, immune system response and protein recycling. Our work provides new insights on the genetic pathways involved in this complex disease and proposes novel targets for future therapies.


Assuntos
Células da Medula Óssea/metabolismo , Cromossomos Humanos Par 13/genética , Células-Tronco Hematopoéticas/metabolismo , Mieloma Múltiplo/metabolismo , Algoritmos , Aneuploidia , Antígenos CD34/imunologia , Cromossomos Humanos Par 13/metabolismo , Perfilação da Expressão Gênica , Células-Tronco Hematopoéticas/imunologia , Humanos , Mieloma Múltiplo/genética , Mieloma Múltiplo/imunologia , Estudos Retrospectivos , Transdução de Sinais , Células Estromais/metabolismo
17.
Prenat Diagn ; 39(11): 1011-1015, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31429096

RESUMO

OBJECTIVE: To evaluate clinical performance of a new automated cell-free (cf)DNA assay in maternal plasma screening for trisomies 21, 18, and 13, and to determine fetal sex. METHOD: Maternal plasma samples from 1200 singleton pregnancies were analyzed with a new non-sequencing cfDNA method, which is based on imaging and counting specific chromosome targets. Reference outcomes were determined by either cytogenetic testing, of amniotic fluid or chorionic villi, or clinical examination of neonates. RESULTS: The samples examined included 158 fetal aneuploidies. Sensitivity was 100% (112/112) for trisomy 21, 89% (32/36) for trisomy 18, and 100% (10/10) for trisomy 13. The respective specificities were 100%, 99.5%, and 99.9%. There were five first pass failures (0.4%), all in unaffected pregnancies. Sex classification was performed on 979 of the samples and 99.6% (975/979) provided a concordant result. CONCLUSION: The new automated cfDNA assay has high sensitivity and specificity for trisomies 21, 18, and 13 and accurate classification of fetal sex, while maintaining a low failure rate. The study demonstrated that cfDNA testing can be simplified and automated to reduce cost and thereby enabling wider population-based screening.


Assuntos
Teste Pré-Natal não Invasivo/métodos , Trissomia/diagnóstico , Cromossomos Humanos Par 13 , Cromossomos Humanos Par 18 , Cromossomos Humanos Par 21 , Feminino , Humanos , Gravidez
18.
Hum Genet ; 138(10): 1145-1153, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31321490

RESUMO

The objective of this study is to shed light on the phenotype and inheritance pattern of rare 13q33-q34 microdeletions. Appropriate cases were retrieved using local databases of two largest Israeli centers performing CMA analysis. In addition, literature search in PubMed, DECIPHER and ClinVar databases was performed. Local database search yielded eight new patients with 13q33.1-q34 microdeletions (three of which had additional copy number variants). Combined with 15 cases detected by literature search, an additional 23 cases were reported in DECIPHER database, and 17 cases from ClinVar, so overall 60 patients with isolated 13q33.1-q34 microdeletions were described. Developmental delay and/or intellectual disability were noted in the vast majority of affected individuals (81.7% = 49/60). Of the 23 deletions involving the 13q34 cytoband only, in 3 cases, developmental delay and/or intellectual disability was not reported. Interestingly, in two of these cases (66.7%), the deletions did not involve the terminal CHAMP1 gene, as opposed to 3/20 (15%) of patients with 13q34 deletions and neurocognitive disability. Facial dysmorphism and microcephaly were reported in about half of the overall cases, convulsions were noted in one-fifth of the patients, while heart anomalies, short stature and hypotonia each involved about 10-30% of the cases. None of the 13q33-q34 deletions were inherited from a reported healthy parent. 13q33-q34 microdeletions are rare chromosomal aberrations, associated with high risk for neurodevelopmental disability. The rarity of this chromosomal aberration necessitates continuous reporting and collection of available evidence, to improve the ability to provide accurate genetic counseling, especially in the context of prenatal setting.


Assuntos
Deleção Cromossômica , Transtornos Cromossômicos/diagnóstico , Transtornos Cromossômicos/genética , Cromossomos Humanos Par 13 , Fenótipo , Adolescente , Adulto , Criança , Pré-Escolar , Bandeamento Cromossômico , Deficiências do Desenvolvimento/diagnóstico , Deficiências do Desenvolvimento/genética , Feminino , Humanos , Lactente , Recém-Nascido , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Masculino , Adulto Jovem
19.
Cytogenet Genome Res ; 158(4): 199-204, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31315112

RESUMO

Here, we report a molecular characterization of a small supernumerary marker chromosome (sSMC) derived from the most proximal region of 13q present in a fetus with coarctation of the aorta at ultrasound examination during prenatal diagnosis. Cultured umbilical cord blood cells showed a de novo extra ring-shaped sSMC in 76% of the cells using a standard banding technique. SNP array revealed a tetrasomy of about 28.4 Mb in the long arm of chromosome 13 from band 13q11 to 13q14.11 in the fetus's cells. Metaphase/interphase FISH using specific probes located at 13q11, 13q12.11, and 13q14.11, respectively, demonstrated that the supernumerary ring chromosome was derived from an inverted duplication of the region 13q11q14.11 with a conventional centromere. To the best of our knowledge, this is the first time that an inverted duplication of the most proximal region 13q11q14.11 in a ring chromosome is characterized. The findings we presented here deepen our understanding of the clinical consequences of tetrasomy in this region and may be of help for further studies of critical regions in chromosome 13.


Assuntos
Coartação Aórtica/genética , Duplicação Cromossômica/genética , Cromossomos Humanos Par 13/genética , Doenças Fetais/genética , Diagnóstico Pré-Natal , Cromossomos em Anel , Tetrassomia/genética , Adulto , Centrômero/genética , Bandeamento Cromossômico , Feminino , Doenças Fetais/diagnóstico , Feto/metabolismo , Humanos , Hibridização in Situ Fluorescente , Cariotipagem , Polimorfismo de Nucleotídeo Único/genética , Gravidez
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