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1.
PLoS Genet ; 15(5): e1008137, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31091232

RESUMO

When the fungus Candida albicans proliferates in the oropharyngeal cavity during experimental oropharyngeal candidiasis (OPC), it undergoes large-scale genome changes at a much higher frequency than when it grows in vitro. Previously, we identified a specific whole chromosome amplification, trisomy of Chr6 (Chr6x3), that was highly overrepresented among strains recovered from the tongues of mice with OPC. To determine the functional significance of this trisomy, we assessed the virulence of two Chr6 trisomic strains and a Chr5 trisomic strain in the mouse model of OPC. We also analyzed the expression of virulence-associated traits in vitro. All three trisomic strains exhibited characteristics of a commensal during OPC in mice. They achieved the same oral fungal burden as the diploid progenitor strain but caused significantly less weight loss and elicited a significantly lower inflammatory host response. In vitro, all three trisomic strains had reduced capacity to adhere to and invade oral epithelial cells and increased susceptibility to neutrophil killing. Whole genome sequencing of pre- and post-infection isolates found that the trisomies were usually maintained. Most post-infection isolates also contained de novo point mutations, but these were not conserved. While in vitro growth assays did not reveal phenotypes specific to de novo point mutations, they did reveal novel phenotypes specific to each lineage. These data reveal that during OPC, clones that are trisomic for Chr5 or Chr6 are selected and they facilitate a commensal-like phenotype.


Assuntos
Candida albicans/genética , Candidíase Bucal/genética , Orofaringe/microbiologia , Animais , Candida albicans/metabolismo , Candidíase/genética , Modelos Animais de Doenças , Células Epiteliais , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Neutrófilos , Fenótipo , Trissomia/genética , Virulência
2.
Z Geburtshilfe Neonatol ; 223(5): 297-303, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31132797

RESUMO

We aimed to configure impaired/altered metabolomic profiles of pregnant women carrying Down syndrome (DS) fetuses. The study involved 21 and 32 pregnant women with DS and euploid fetuses, respectively, as determined by prenatal screening and diagnosis as part of an antenatal care program. Metabolomic analyses were carried out using gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-quadrupole time-of-flight mass spectrometry (LC-qTOF-MS) methods. A total of 95 metabolites were identified. GC-MS analysis indicated that levels of 2-hydroxybutyric acid, benzoic acid, nonanoic acid, 3-hydroxybutyric acid, and 2-ketoisocaproic acid were increased in the DS group, where beta-alanine, threonic acid, oxalic acid, alpha-tocopherol, uracil, 2-piperidone, and creatinine were decreased. However, LC-qTOF-MS analysis showed that lipid-related metabolites were decreased in women carrying DS fetuses, whereas creatine, N4-phosphoagmatine, citrate, 2,5-dioxopentanoate, 2-furoate, pyruvate, and fructose levels were increased. Pathway analysis was also performed using metabolites whose levels were significantly altered (p<0.05) between the groups, and the findings indicated that the biosynthesis pathways of aminoacyl-tRNA and "valine-leucine-isoleucine", and metabolism pathways of "glycine-serine-threonine", nitrogen, "alanine-aspartate-glutamate", propanoate, glycerophospholipid, cysteine, methionine, and phenylalanine were significantly altered. Our findings indicate a special type of metabolic status/syndrome in pregnant women with Down syndrome fetuses. It could be speculated that altered metabolic status might influence both gametogenesis and embryogenesis. Down syndrome is a complex genetic disorder that is important to detect prenatally, but may also be prevented by taking necessary precautions prior to pregnancy.


Assuntos
Síndrome de Down , Cromatografia Gasosa-Espectrometria de Massas/métodos , Metabolômica , Diagnóstico Pré-Natal , Biomarcadores/sangue , Síndrome de Down/sangue , Síndrome de Down/diagnóstico , Feminino , Feto , Humanos , Metabolômica/métodos , Gravidez , Diagnóstico Pré-Natal/métodos , Trissomia/diagnóstico , Trissomia/genética
3.
Cytogenet Genome Res ; 158(2): 74-82, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31141803

RESUMO

Deletion of distal 9p is associated with a rare clinical condition characterized by dysmorphic features, developmental delay, and ambiguous genitalia. The phenotype shows variable expressivity and is related to the size of the deletion. 8q24 duplication has been reported in only few cases to date, all showing dysmorphic features and mild psychomotor developmental delay. A case of chromosomal aberration involving a 9p terminal deletion with an 8q duplication has never been reported. Here, we describe a child with a female phenotype, male karyotype, dysmorphic features, ambiguous genitalia, and developmental delay. In order to assess the cause of the patient's phenotype, conventional karyotyping, FISH, and a chromosomal microarray analysis were performed on the patient and her parents. The cytogenetic and molecular analysis revealed an unbalanced chromosomal aberration with a duplication in the long arm of chromosome 8 at 8q24.11q24.3 associated with a distal deletion in the short arm of chromosome 9 at 9p24.3p24.1, derived from a maternal balanced translocation. We compared the clinical picture of our patient with other similar cases reported in the literature and found that some clinical findings, such as strabismus, symphalangism of the first finger, and cubitus valgus, have never been previously associated with 9p deletion or 8q duplication expanding the phenotypic range of this condition. This study is aimed to better define the clinical history and prognosis of patients with this rare chromosomal aberration.


Assuntos
Cromossomos Humanos Par 9/genética , Deficiências do Desenvolvimento/genética , Disgenesia Gonadal 46 XY/genética , Trissomia/genética , Deleção Cromossômica , Mapeamento Cromossômico , Cromossomos Humanos Par 8/genética , Feminino , Humanos
4.
Cytogenet Genome Res ; 157(4): 220-226, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30939474

RESUMO

Trisomy 18p is a rarely observed chromosomal aberration. Only 31 cases have previously been described in the literature. Trisomy 18p is associated with mild to moderate phenotypic anomalies and intellectual disability. Here, we report on a pregnant woman in whom noninvasive prenatal testing indicated a high risk of fetal trisomy 18. Prenatal diagnosis and karyotyping of the parents were performed and demonstrated that both the mother and the fetus had a derivative chromosome 15 with a segment of unknown origin. Chromosomal microarray analysis and FISH revealed a 14.9-Mb duplication of 18p and detected 3 centromeres of chromosome 18. To our knowledge, this is the first study reporting trisomy 18p due to an unbalanced translocation of 18p onto chromosome 15q showing 2-generation transmission. The results suggest that trisomy 18p can be considered a euchromatic variant.


Assuntos
Cromossomos Humanos Par 15/genética , Deficiência Intelectual/genética , Diagnóstico Pré-Natal/métodos , Trissomia/genética , Cromossomos Humanos Par 18/genética , Feminino , Humanos , Hibridização in Situ Fluorescente , Análise de Sequência com Séries de Oligonucleotídeos , Gravidez , Translocação Genética , Adulto Jovem
5.
High Blood Press Cardiovasc Prev ; 26(2): 143-144, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30806948

RESUMO

Trisomy of the short arm of chromosome 12 is a rare genetic disease characterised by dysmorphic features, mental retardation, behavioural disorders, seizures predisposition and other congenital abnormalities. Arterial hypertension is not a characteristic feature of 12p trisomy, although congenital heart defects are reported. In this case report, we present a young patient with incomplete trisomy 12p, analysing some characteristics of this disease that have not been previously described in literature.


Assuntos
Pressão Sanguínea/genética , Dislipidemias/complicações , Hipertensão/genética , Trissomia/genética , Adolescente , Anti-Hipertensivos/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Cromossomos Humanos Par 12/genética , Dislipidemias/sangue , Dislipidemias/diagnóstico , Dislipidemias/tratamento farmacológico , Predisposição Genética para Doença , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hipertensão/diagnóstico , Hipertensão/tratamento farmacológico , Hipertensão/fisiopatologia , Lipídeos/sangue , Masculino , Fenótipo , Medição de Risco , Fatores de Risco , Resultado do Tratamento , Trissomia/diagnóstico
6.
J Assist Reprod Genet ; 36(4): 749-757, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30739229

RESUMO

PURPOSE: To clarify the associations of the maternal age, history of miscarriage, and embryonic/fetal size at miscarriage with the frequencies and profiles of cytogenetic abnormalities detected in spontaneous early miscarriages. METHODS: Miscarriages before 12 weeks of gestation, whose karyotypes were evaluated by G-banding between May 1, 2005, and May 31, 2017, were included in this study. The relationships between their karyotypes and clinical findings were assessed using trend or chi-square/Fisher's exact tests and multivariate logistic analyses. RESULTS: Three hundred of 364 miscarriage specimens (82.4%) had abnormal karyotypes. An older maternal age was significantly associated with the frequency of abnormal karyotype (ptrend < 0.001), particularly autosomal non-viable and viable trisomies (ptrend 0.001 and 0.025, respectively). Women with ≥ 2 previous miscarriages had a significantly lower possibility of miscarriages with abnormal karyotype than women with < 2 previous miscarriages (adjusted odds ratio [aOR], 0.48; 95% confidence interval [95% CI], 0.27-0.85). Although viable trisomy was observed more frequently in proportion to the increase in embryonic/fetal size at miscarriage (ptrend < 0.001), non-viable trisomy was observed more frequently in miscarriages with an embryonic/fetal size < 10 mm (aOR, 2.41; 95% CI, 1.27-4.58), but less frequently in miscarriages with an embryonic/fetal size ≥ 20 mm (aOR, 0.01; 95% CI, 0.00-0.07) than in anembryonic miscarriages. CONCLUSIONS: The maternal age, history of miscarriage, and embryonic/fetal size at miscarriage may be independently associated with the frequencies or profiles of cytogenetic abnormalities in early miscarriages.


Assuntos
Feto Abortado/patologia , Aborto Espontâneo/genética , Citogenética , Trissomia/genética , Cariótipo Anormal , Aborto Espontâneo/patologia , Adulto , Aneuploidia , Vilosidades Coriônicas/patologia , Aberrações Cromossômicas , Transtornos Cromossômicos/diagnóstico , Transtornos Cromossômicos/genética , Transtornos Cromossômicos/patologia , Feminino , Feto/patologia , Humanos , Cariótipo , Cariotipagem , Idade Materna , Mosaicismo , Gravidez , Estudos Retrospectivos , Trissomia/patologia
7.
Mol Biol Rep ; 46(2): 1931-1940, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30710232

RESUMO

The aim of the study was to characterize the type of aneuploidy present in the hybrid Urochloa ruziziensis × Urochloa decumbens and to confirm the origin of the additional chromosomes through comparative analysis of the hybrid and parental karyotypes. C and CMA banding techniques were used for chromosome differentiation. The parental genotypes showed 36 chromosomes. The hybrid presented plants with 36 + 2 chromosomes and plants with 36 + 1 chromosomes. Urochloa ruziziensis (4x) presented four chromosomes with CMA and C bands co-located in the terminal position. In U. decumbens, four chromosomes presented terminal CMA bands, eight chromosomes were distinguished by C banding with pericentromeric and terminal bands, one chromosome with terminal band at both ends and one chromosome presented one C terminal band. For the hybrid, CMA bands were found on five chromosomes and C bands on seven chromosomes, all in terminal position. Aneuploidy was identified in pairs 3' and 4' in the hybrid plants with 36 + 2 chromosomes, characterizing it as double trisomy. The karyotype of hybrid plants with 36 + 1 chromosomes indicated elimination of the additional chromosome identified in pair 4' and maintenance of trisomy on pair 3'. The comparative analysis of karyotypes indicates that the additional chromosomes that characterize the trisomy were inherited from U. ruziziensis (artificial tetraploid).


Assuntos
Quimera/genética , Poaceae/genética , Aneuploidia , Cromossomos de Plantas/genética , Transferência Genética Horizontal/genética , Genótipo , Cariotipagem/métodos , Plantas/genética , Poaceae/metabolismo , Poliploidia , Trissomia/genética
8.
Orphanet J Rare Dis ; 14(1): 16, 2019 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-30642344

RESUMO

BACKGROUND: Knowledge on the prevalence of sex chromosome abnormalities (SCAs) is limited, and delayed diagnosis or non-diagnosis of SCAs are a continuous concern. We aimed to investigate change over time in incidence, prevalence and age at diagnosis among Turner syndrome (TS), Klinefelter syndrome (KS), Triple X syndrome (Triple X) and Double Y syndrome (Double Y). METHODS: This study is a nationwide cohort study in a public health care system. The Danish Cytogenetic Central Registry (DCCR) holds information on all karyotypes performed in Denmark since 1961. We identified all individuals in the DCCR with a relevant SCA during 1961-2014; TS: n = 1156; KS: n = 1235; Triple X: n = 197; and Double Y: n = 287. From Statistics Denmark, which holds an extensive collection of data on the Danish population, complete data concerning dates of death and migrations in and out of Denmark were retrieved for all individuals. RESULTS: The prevalence among newborns was as follows: TS: 59 per 100,000 females; KS: 57 per 100,000 males; Triple X: 11 per 100,000 females; and Double Y: 18 per 100,000 males. Compared with the expected number among newborns, all TS, 38% of KS, 13% of Triple X, and 18% of Double Y did eventually receive a diagnosis. The incidence of TS with other karyotypes than 45,X (P < 0.0001), KS (P = 0.02), and Double Y (P = 0.03) increased during the study period whereas the incidence of 45,X TS decreased (P = 0.0006). The incidence of Triple X was stable (P = 0.22). CONCLUSIONS: The prevalence of TS is higher than previously identified, and the karyotypic composition of the TS population is changing. Non-diagnosis is extensive among KS, Triple X and Double Y, whereas all TS seem to become diagnosed. The diagnostic activity has increased among TS with other karyotypes than 45,X as well as among KS and Double Y.


Assuntos
Síndrome de Turner/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Cromossomos Humanos X/genética , Estudos de Coortes , Feminino , Humanos , Incidência , Lactente , Recém-Nascido , Cariotipagem , Síndrome de Klinefelter/genética , Masculino , Pessoa de Meia-Idade , Aberrações dos Cromossomos Sexuais , Transtornos dos Cromossomos Sexuais/genética , Transtornos do Cromossomo Sexual no Desenvolvimento Sexual/genética , Trissomia/genética , Cariótipo XYY/genética , Adulto Jovem
9.
J Pediatr Hematol Oncol ; 41(1): e57-e59, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29683949

RESUMO

Hemophagocytic lymphohistiocytosis (HLH) is a rare disease resulting in clinical and biochemical manifestations of extreme inflammation. Myelodysplastic syndrome (MDS) represents a heterogenous group of clonal hematopoietic disorders. The development of MDS is common in children with trisomy of chromosome 8. Here, we report a fatal case of 8-year-old girl who was admitted to the emergency department with status epilepticus, and later diagnosed with HLH associated with MDS and trisomy of chromosome 8. We believe this is the first reported case of HLH associated with MDS and trisomy 8 in a pediatric patient.


Assuntos
Linfo-Histiocitose Hemofagocítica/genética , Síndromes Mielodisplásicas/genética , Trissomia/genética , Criança , Cromossomos Humanos Par 8/genética , Evolução Fatal , Feminino , Humanos
10.
Congenit Anom (Kyoto) ; 59(2): 43-46, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29732662

Assuntos
Aneuploidia , Síndrome de Klinefelter/mortalidade , Transtornos do Cromossomo Sexual no Desenvolvimento Sexual/mortalidade , Transtornos dos Cromossomos Sexuais/mortalidade , Síndrome da Trissomía do Cromossomo 18/mortalidade , Cariótipo XYY/mortalidade , Cromossomos Humanos X/química , Cromossomos Humanos X/genética , Cromossomos Humanos Y/química , Permeabilidade do Canal Arterial/genética , Permeabilidade do Canal Arterial/mortalidade , Permeabilidade do Canal Arterial/patologia , Feminino , Cardiopatias Congênitas/genética , Cardiopatias Congênitas/mortalidade , Cardiopatias Congênitas/patologia , Comunicação Interatrial/genética , Comunicação Interatrial/mortalidade , Comunicação Interatrial/patologia , Comunicação Interventricular/genética , Comunicação Interventricular/mortalidade , Comunicação Interventricular/patologia , Humanos , Lactente , Recém-Nascido , Cariótipo , Síndrome de Klinefelter/genética , Síndrome de Klinefelter/patologia , Masculino , Aberrações dos Cromossomos Sexuais , Transtornos dos Cromossomos Sexuais/genética , Transtornos dos Cromossomos Sexuais/patologia , Transtornos do Cromossomo Sexual no Desenvolvimento Sexual/genética , Transtornos do Cromossomo Sexual no Desenvolvimento Sexual/patologia , Análise de Sobrevida , Trissomia/genética , Trissomia/patologia , Síndrome da Trissomía do Cromossomo 18/genética , Síndrome da Trissomía do Cromossomo 18/patologia , Cariótipo XYY/genética , Cariótipo XYY/patologia
11.
Int J Dev Neurosci ; 74: 56-60, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30217625

RESUMO

OBJECTIVE: To identify candidate genes for the clinical diagnosis of floppy infant syndrome (FIS) using single nucleotide polymorphism (SNP) array in a specific FIS family. METHODS: SNP array analysis of the whole chromosome copy number was performed in the proband (III1). Multiple polymerase chain reaction (PCR) combined with denaturing high-performance liquid chromatography (DHPLC) was used to validate the array data. RESULTS: A large 5.818182 Mb duplication (Xq13.1: 67987646-73805828), which encompasses 66 known genes, was found in III1. The start and end points of the duplication were confirmed with an SNP array. Duplicated genes with potential roles in central and/or peripheral nervous system development (HDAC8, PHKA1, TAF1, DLG3, KIF4A, IGBP1, PJA1, and SLC16A2) were confirmed by multiple PCR-DHPLC in III1. The patient's mother and grandmother carry duplications in these eight genes, but only on one X chromosome, while the patient's aunt does not carry any of the duplications. CONCLUSION: Based on the location of the eight candidate genes in Xq13.1, the large duplication found by SNP array does indeed exist and is predicted to be both novel and pathogenic. Moreover, we recommend SNP array as the first option for genetic diagnosis of both large-scale and rare/complicated diseases, such as FIS.


Assuntos
Prolapso da Valva Mitral/genética , Polimorfismo de Nucleotídeo Único , Trissomia/genética , Cromossomos Humanos X/genética , Saúde da Família , Genoma Humano , Humanos , Masculino , Prolapso da Valva Mitral/complicações , Análise de Sequência com Séries de Oligonucleotídeos , Aberrações dos Cromossomos Sexuais
12.
Eur J Haematol ; 102(1): 63-69, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30218579

RESUMO

OBJECTIVE: We report cases of myelodysplastic syndrome/myeloproliferative neoplasms (MDS/MPN) with trisomy 8 associated with inflammatory and autoimmune diseases (IADs). METHOD: Data for 21 patients with trisomy 8-MDS/MPN and IADs were analyzed and compared to 103 patients with trisomy 8-MDS/MPN without IADs. RESULTS: The median age of MDS/MPN patients with IADs was 67 [59-80]. The IADs were Behçet's-like disease in 11 (52%) patients, inflammatory arthritis in 4 (19%) and Sjögren's syndrome, autoimmune hemolytic anemia, aseptic abscess, periarteritis nodosa, Sweet's syndrome and unclassified vasculitis in one patient each. Overall, 17/21 (81%) patients with IADs received treatment (88% with steroids), with complete and partial response in 7/17 (35%) and 8/17 (47%), respectively. The effect of MDS treatment on IADs could be assessed in seven patients receiving azacytidine: five achieved remission and two partial response. As compared with the 103 trisomy 8-MDS/MPN cases without IADs, those with IADs were more often non-European (P = 0.005) and had poor karyotype (P < 0.001). We found no difference in overall survival or acute myeloid leukemia progression between trisomy 8-associated MDS/MPN with and without IADs. CONCLUSION: The spectrum of IADs associated with trisomy 8-positive MDS/MPN is dominated by Behçet's-like disease. Steroid therapy is effective, but mostly sparing therapies are necessary. Azacytidine could be an effective alternative.


Assuntos
Inflamação/etiologia , Síndromes Mielodisplásicas/complicações , Síndromes Mielodisplásicas/genética , Trissomia/genética , Idoso , Idoso de 80 Anos ou mais , Doenças Autoimunes/diagnóstico , Doenças Autoimunes/etiologia , Estudos de Casos e Controles , Cromossomos Humanos Par 8/genética , Progressão da Doença , Feminino , Seguimentos , França , Humanos , Inflamação/diagnóstico , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/mortalidade , Doenças Mieloproliferativas-Mielodisplásicas/complicações , Doenças Mieloproliferativas-Mielodisplásicas/diagnóstico , Doenças Mieloproliferativas-Mielodisplásicas/genética , Doenças Mieloproliferativas-Mielodisplásicas/mortalidade , Prognóstico
13.
Ann Hematol ; 98(2): 423-435, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30368590

RESUMO

Activation-induced cytidine deaminase (AID) is a mutator enzyme essential for somatic hypermutation (SHM) and class switch recombination (CSR) during effective adaptive immune responses. Its aberrant expression and activity have been detected in lymphomas, leukemias, and solid tumors. In chronic lymphocytic leukemia (CLL) increased expression of alternatively spliced AID variants has been documented. We used real-time RT-PCR to quantify the expression of AID and its alternatively spliced transcripts (AIDΔE4a, AIDΔE4, AIDivs3, and AIDΔE3E4) in 149 CLL patients and correlated this expression to prognostic markers including recurrent chromosomal aberrations, the presence of complex karyotype, mutation status of the immunoglobulin heavy chain variable gene, and recurrent mutations. We report a previously unappreciated association between higher AID transcript levels and trisomy of chromosome 12. Functional analysis of AID splice variants revealed loss of their activity with respect to SHM, CSR, and induction of double-strand DNA breaks. In silico modeling provided insight into the molecular interactions and structural dynamics of wild-type AID and a shortened AID variant closely resembling AIDΔE4, confirming its loss-of-function phenotype.


Assuntos
Processamento Alternativo , Citidina Desaminase , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Leucemia Linfocítica Crônica de Células B , Modelos Biológicos , Proteínas de Neoplasias , Trissomia , Idoso , Animais , Cromossomos Humanos Par 12/enzimologia , Cromossomos Humanos Par 12/genética , Simulação por Computador , Citidina Desaminase/biossíntese , Citidina Desaminase/química , Citidina Desaminase/genética , Feminino , Humanos , Leucemia Linfocítica Crônica de Células B/enzimologia , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/patologia , Masculino , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Simulação de Dinâmica Molecular , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/química , Proteínas de Neoplasias/genética , Trissomia/genética , Trissomia/patologia
14.
Eur J Med Genet ; 62(6): 103533, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30171908

RESUMO

We present a case with discordant results in three prenatal screening methods, with additional genetic analyses. Non-invasive prenatal testing (NIPT) was performed on a 41-year-old Japanese woman at 10 weeks of gestation, and the result was positive for trisomy 18 with high accuracy. Amniocentesis was performed at 16 weeks of gestation. However, the result showed 47,XX,+mar[16]/47,XX,+18[2]. Fetal examination by ultrasound revealed no malformations. After termination of the pregnancy, we performed additional genetic analyses, and confirmed the presence of confined placental mosaicism (CPM). Furthermore, a small supernumerary marker chromosome (sSMC) was detected in fetal cells, which was derived de novo from the centromere of chromosome 18. Single nucleotide polymorphism array analysis revealed that fetal chromosome 18 was inherited with maternal uniparental disomy, with a relatively large copy-neutral loss of heterozygosity, including its centromere. Our genetic analyses strongly indicated the cause of result discrepancy in prenatal testing as incomplete trisomy 18 rescue leading to atypical CPM with a sSMC. These findings also offer insight into the mechanisms by which chromosomal aberrations form during human oogenesis and embryogenesis.


Assuntos
Cromossomos Humanos Par 18/genética , Cariótipo , Mosaicismo , Placenta/citologia , Trissomia/genética , Adulto , Feminino , Humanos , Placenta/metabolismo , Polimorfismo de Nucleotídeo Único , Gravidez , Trissomia/patologia
15.
J Clin Lab Anal ; 33(2): e22663, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30259573

RESUMO

BACKGROUND: Trisomy 22 mosaicism is a rare autosomal anomaly with survival compatibility. Recognition of the complete trisomy 22 which is incompatible with life from the mosaic form is critical for genetic counseling. Affected mosaic cases have prevalent clinical presentations such as webbed neck, developmental delay, abnormal ears, cardiac disorders, and microcephaly. Phenotype of these patients is milder than full chromosomal aneuploidy, and the severity of the phenotype depends on the count of trisomic cells. We describe a 4-year-old boy with mosaic trisomy 22 from healthy parents and no family history of any genetic disorders in the pedigree. METHOD AND RESULTS: The patient had determined dysmorphic clinical features including facial asymmetry, cleft palate, gastroenteritis, hydronephrosis, developmental delay, genital anomalies, dysplastic toenails, flattened nasal bridge, congenital heart defect, hearing loss, cryptorchidism, and hypotonic muscle. He is the first reported with hypothyroidism and larynx wall thickness in worldwide and the first with atrial septal defect (ASD) from Iran. Chromosomal analyses using G-banding indicated a de novo Mos 47,XY,+22(6)/46,XY(44) karyotype with no other chromosomal structural changes. CONCLUSIONS: Our observations confirm the importance of cytogenetic analyses for determining the cause of congenital anomalies and provide a useful genetic counseling. In addition, due to the fact that some of mosaic trisomy 22 features are unavoidable such as CHD and general hypotrophy, we suggest including echocardiography test for early diagnosis during the clinical assessment.


Assuntos
Transtornos Cromossômicos , Comunicação Interatrial , Trissomia , Dissomia Uniparental , Cariótipo Anormal , Pré-Escolar , Transtornos Cromossômicos/complicações , Transtornos Cromossômicos/diagnóstico , Transtornos Cromossômicos/genética , Transtornos Cromossômicos/patologia , Cromossomos Humanos Par 22/genética , Comunicação Interatrial/complicações , Comunicação Interatrial/diagnóstico , Comunicação Interatrial/genética , Comunicação Interatrial/patologia , Humanos , Hipotireoidismo/complicações , Masculino , Mosaicismo , Trissomia/diagnóstico , Trissomia/genética , Trissomia/patologia , Dissomia Uniparental/diagnóstico , Dissomia Uniparental/genética , Dissomia Uniparental/patologia
16.
Prenat Diagn ; 39(2): 88-99, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30575063

RESUMO

OBJECTIVE: Cell-free DNA (cfDNA) fragments in maternal plasma contain DNA damage and may negatively impact the sensitivity of noninvasive prenatal testing (NIPT). However, some of these DNA damages are potentially reparable. We aimed to recover these damaged cfDNA molecules using PreCR DNA repair mix. METHODS: cfDNA was extracted from 20 maternal plasma samples and was repaired and sequenced by the Illumina platform. Size profiles and fetal DNA fraction changes of repaired samples were characterized. Targeted sequencing of chromosome Y sequences was used to enrich fetal cfDNA molecules following repair. Single-molecule real-time (SMRT) sequencing platform was employed to characterize long (>250 bp) cfDNA molecules. NIPT of five trisomy 21 samples was performed. RESULTS: Size profiles of repaired libraries were altered, with significantly increased long (>250 bp) cfDNA molecules. Single nucleotide polymorphism (SNP)-based analyses showed that both fetal- and maternal-derived cfDNA molecules were enriched by the repair. Fetal DNA fractions in maternal plasma showed a small but consistent (4.8%) increase, which were contributed by a higher increment of long fetal cfDNA molecules. z-score values were improved in NIPT of all trisomy 21 samples. CONCLUSION: Plasma DNA repair recovers and enriches long cfDNA molecules of both fetal and maternal origins in maternal plasma.


Assuntos
Ácidos Nucleicos Livres/sangue , Reparo do DNA/fisiologia , Feto/metabolismo , Mães , Análise Mutacional de DNA/métodos , Feminino , Técnicas de Genotipagem/métodos , Humanos , Testes para Triagem do Soro Materno/métodos , Análise em Microsséries , Polimorfismo de Nucleotídeo Único , Gravidez , Primeiro Trimestre da Gravidez/sangue , Terceiro Trimestre da Gravidez/sangue , Diagnóstico Pré-Natal/métodos , Trissomia/diagnóstico , Trissomia/genética
17.
Expert Rev Mol Diagn ; 19(2): 189-196, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30582381

RESUMO

OBJECTIVES: This study was aimed to report the clinical characteristics of fetal chromosomal aneuploidy diseases using noninvasive prenatal testing (NIPT) in twin pregnancies and analyze the results in terms of chorionicity, conception, and fetal fraction. METHODS: A total of 1160 women with twin pregnancies were recruited from 1 October 2015, to 1 August 2017. Next-generation sequencing technology was used to detect fetal aneuploidies, such as trisomy 21, trisomy 18, trisomy 13 and trisomy X. RESULTS: Aneuploidy was detected using NIPT in 26 fetuses, among which 18 fetal aneuploidies occurred in only one fetus of the twins. The rate of aneuploidy was 1.3% for dichorionic diamniotic twins and 0.5% for monochorionic diamniotic twins, respectively. The rate of aneuploidy was 1.2% for spontaneous pregnancy group and 1.1% for assisted reproductive technologies group. CONCLUSION: In this study, detection of trisomy 21, trisomy 18, trisomy 13, and X abnormality in twin pregnancies was confirmed to be accurate. The aneuploidies mostly occurred in only one fetus of the twins, and trisomy 21 was the most common type. The prenatal diagnostic standard for NIPT in singleton pregnancies could perform well in twin pregnancies, which means NIPT can be popularized as routine prenatal screening in twin pregnancies.


Assuntos
Síndrome de Down , Doenças Fetais , Gravidez de Gêmeos , Diagnóstico Pré-Natal , Aberrações dos Cromossomos Sexuais , Transtornos do Cromossomo Sexual no Desenvolvimento Sexual , Síndrome da Trissomia do Cromossomo 13 , Síndrome da Trissomía do Cromossomo 18 , Trissomia , Cromossomos Humanos X/genética , Síndrome de Down/diagnóstico , Síndrome de Down/genética , Feminino , Doenças Fetais/diagnóstico , Doenças Fetais/genética , Testes Genéticos , Humanos , Gravidez , Transtornos do Cromossomo Sexual no Desenvolvimento Sexual/diagnóstico , Transtornos do Cromossomo Sexual no Desenvolvimento Sexual/genética , Trissomia/diagnóstico , Trissomia/genética , Síndrome da Trissomia do Cromossomo 13/diagnóstico , Síndrome da Trissomia do Cromossomo 13/genética , Síndrome da Trissomía do Cromossomo 18/diagnóstico , Síndrome da Trissomía do Cromossomo 18/genética
18.
Prenat Diagn ; 39(2): 116-123, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30578730

RESUMO

OBJECTIVES: To compare the frequency of abnormal genetic diagnoses spanning a period before and after the availability of chromosomal microarray analysis (CMA). We hypothesised that microarray would provide additional clinically relevant information in cases of isolated hypoplastic nasal bone. METHOD: Fetuses with ultrasound-detected hypoplastic nasal bone (absent or <2.5th percentile in length) between 16 and 37 weeks' gestation over a 10-year period were analysed retrospectively. RESULTS: A total of 118 cases of hypoplastic nasal bone met the inclusion criteria. A pathogenic or potentially pathogenic karyotype was detected more frequently in the era where CMA was available (31/60, 52% vs 19/58, 33%). Of these, 25 cases (42%) had common aneuploidies, and six cases (10%) had clinically relevant copy number variants (CNVs). A clinically relevant CNV was detected in two fetuses that presented with isolated hypoplastic nasal bone on initial ultrasound. CONCLUSION: In addition to its known association with trisomy 21, a hypoplastic nasal bone may be an objective marker of facial dysmorphism associated with clinically relevant CNVs. Our results support consideration of invasive testing with microarray for pregnancies in which a hypoplastic nasal bone has been diagnosed on ultrasound irrespective of a low-risk screening result for common chromosomal abnormalities.


Assuntos
Aberrações Cromossômicas/embriologia , Anormalidades Craniofaciais/diagnóstico , Variações do Número de Cópias de DNA , Análise em Microsséries , Osso Nasal/anormalidades , Adulto , Transtornos Cromossômicos/diagnóstico , Transtornos Cromossômicos/embriologia , Variações do Número de Cópias de DNA/genética , Feminino , Testes Genéticos/métodos , Idade Gestacional , Humanos , Osso Nasal/diagnóstico por imagem , Gravidez , Segundo Trimestre da Gravidez , Terceiro Trimestre da Gravidez , Diagnóstico Pré-Natal/métodos , Estudos Retrospectivos , Trissomia/diagnóstico , Trissomia/genética , Ultrassonografia Pré-Natal
19.
Prenat Diagn ; 39(2): 100-106, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30586157

RESUMO

OBJECTIVE: To evaluate the reasons for nonreportable cell-free DNA (cfDNA) results in noninvasive prenatal testing (NIPT), we retrospectively studied maternal characteristics and other details associated with the results. METHODS: A multicenter retrospective cohort study in pregnant women undergoing NIPT by massively parallel sequencing (MPS) with failed cfDNA tests was performed between April 2013 and March 2017. The women's data and MPS results were analyzed in terms of maternal characteristics, test performance, fetal fraction (FF), z scores, anticoagulation therapy, and other details of the nonreportable cases. RESULTS: Overall, 110 (0.32%) of 34 626 pregnant women had nonreportable cfDNA test results after an initial blood sampling; 22 (20.0%) cases had a low FF (<4%), and 18 (16.4%) cases including those with a maternal malignancy, were found to have altered genomic profile. Approximately half of the cases with nonreportable results had borderline z score. Among the women with nonreportable results because of altered genomic profile, the success rate of retesting using a second blood sampling was relatively low (25.0%-33.3%). Thirteen (11.8%) of the women with nonreportable results had required hypodermic heparin injection. CONCLUSIONS: The classification of nonreportable results using cfDNA analysis is important to provide women with precise information and to reduce anxiety during pregnancy.


Assuntos
Testes Genéticos/métodos , Sequenciamento de Nucleotídeos em Larga Escala , Diagnóstico Pré-Natal/métodos , Projetos de Pesquisa , Trissomia/diagnóstico , Adulto , Reações Falso-Negativas , Feminino , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Sequenciamento de Nucleotídeos em Larga Escala/normas , Sequenciamento de Nucleotídeos em Larga Escala/estatística & dados numéricos , Humanos , Valor Preditivo dos Testes , Gravidez , Primeiro Trimestre da Gravidez/sangue , Primeiro Trimestre da Gravidez/genética , Segundo Trimestre da Gravidez/sangue , Segundo Trimestre da Gravidez/genética , Reprodutibilidade dos Testes , Projetos de Pesquisa/normas , Projetos de Pesquisa/estatística & dados numéricos , Estudos Retrospectivos , Fatores de Risco , Trissomia/genética
20.
Neuropsychopharmacology ; 44(1): 9-21, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30127341

RESUMO

The study of sexual dimorphism in psychiatric and neurodevelopmental disorders is challenging due to the complex interplay of diverse biological, psychological, and social factors. Males are more susceptible to neurodevelopmental disorders including intellectual disability, autism spectrum disorder, and attention-deficit activity disorder. Conversely, after puberty, females are more prone to major depressive disorder and anxiety disorders compared to males. One major biological factor contributing to sex differences is the sex chromosomes. First, the X and Y chromosomes have unique and specific genetic effects as well as downstream gonadal effects. Second, males have one X chromosome and one Y chromosome, while females have two X chromosomes. Thus, sex chromosome constitution also differs between the sexes. Due to this complexity, determining genetic and downstream biological influences on sexual dimorphism in humans is challenging. Sex chromosome aneuploidies, such as Turner syndrome (X0) and Klinefelter syndrome (XXY), are common genetic conditions in humans. The study of individuals with sex chromosome aneuploidies provides a promising framework for studying sexual dimorphism in neurodevelopmental and psychiatric disorders. Here we will review and contrast four syndromes caused by variation in the number of sex chromosomes: Turner syndrome, Klinefelter syndrome, XYY syndrome, and XXX syndrome. Overall we describe an increased rate of attention-deficit hyperactivity disorder and autism spectrum disorder, along with the increased rates of major depressive disorder and anxiety disorders in one or more of these conditions. In addition to contributing unique insights about sexual dimorphism in neuropsychiatric disorders, awareness of the increased risk of neurodevelopmental and psychiatric disorders in sex chromosome aneuploidies can inform appropriate management of these common genetic disorders.


Assuntos
Síndrome de Klinefelter/genética , Transtornos Mentais/genética , Caracteres Sexuais , Transtornos do Cromossomo Sexual no Desenvolvimento Sexual/genética , Transtornos dos Cromossomos Sexuais/genética , Cromossomos Sexuais , Trissomia/genética , Síndrome de Turner/genética , Cariótipo XYY/genética , Cromossomos Humanos X/genética , Feminino , Humanos , Síndrome de Klinefelter/psicologia , Masculino , Transtornos Mentais/psicologia , Aberrações dos Cromossomos Sexuais , Transtornos dos Cromossomos Sexuais/psicologia , Transtornos do Cromossomo Sexual no Desenvolvimento Sexual/psicologia , Síndrome de Turner/psicologia , Cariótipo XYY/psicologia
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