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1.
Zhonghua Bing Li Xue Za Zhi ; 53(7): 697-701, 2024 Jul 08.
Artigo em Chinês | MEDLINE | ID: mdl-38955701

RESUMO

Objective: To investigate the clinicopathological and genetic features of confined placental mosaicism (CPM) and its effect on fetal intrauterine growth. Methods: Fourteen CPM cases of Haidian Maternal and Children Health Hospital were collected from May 2018 to March 2022. Clinicopathological examination on placental specimens and molecular genetic analysis were performed. Results: The age of the parturient women ranged from 27 to 34 years, with an average age of (30.0±3.54) years. The gestational weeks ranged from 35+1 to 41+2 weeks. There were 4 premature births and 10 term births, among which 6 were female and 8 were male fetuses. Nine cases (9/14) had adverse pregnancy outcomes, including 7 cases of fetal growth restriction. The weight of CPM placenta decreased, with 6 cases below the 10th percentile of weight standards and 5 cases between the 10th and 25th percentile. All 14 CPM placental specimens showed morphological changes of perfusion dysfunction to varying degrees, with mainly placental-maternal vascular malperfusion followed by placental-fetal vascular malperfusion. The mosaic chromosomes in different CPM cases varied, with 16-trisomy/monosomy mosaicism being the most common followed by 7-trisomy and 21-trisomy/monosomy mosaicism. The mosaic proportion was unequal in different parts of the same CPM placenta, with the mosaic proportion of umbilical cord, fetal membranes, fetal surface, maternal surface, and edge ranging from 1% to 70%. Conclusions: The mosaic chromosomes in different CPM cases vary, and the mosaic proportion is unequal in different parts of the same CPM placenta. The pathological morphology is mainly manifested as perfusion dysfunction, which can lead to adverse pregnancy outcomes such as fetal growth restriction and preterm birth.


Assuntos
Retardo do Crescimento Fetal , Mosaicismo , Placenta , Humanos , Gravidez , Feminino , Adulto , Placenta/patologia , Retardo do Crescimento Fetal/genética , Retardo do Crescimento Fetal/patologia , Resultado da Gravidez , Masculino , Doenças Placentárias/patologia , Doenças Placentárias/genética , Trissomia/genética , Recém-Nascido , Idade Gestacional
3.
Taiwan J Obstet Gynecol ; 63(4): 549-551, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-39004485

RESUMO

OBJECTIVE: We present low-level mosaic trisomy at amniocentesis in a pregnancy associated with cytogenetic discrepancy between cultured amniocytes and uncultured amniocytes, perinatal progressive decrease of the trisomy 7 cell line and a favorable fetal outcome. CASE REPORT: A 40-year-old, primigravid woman underwent amniocentesis at 16 weeks of gestation because of advanced maternal age. Amniocentesis revealed a karyotype of 46,XY in cultured amniocytes. Simultaneous array comparative genomic hybridization (aCGH) analysis on the DNA extracted from uncultured amniocytes revealed the result of arr (7) × 2-3, (X,Y) × 1, consistent with 24% mosaicism for trisomy 7. Polymorphic DNA marker analysis on the DNA extracted from the uncultured amniocytes and parental bloods excluded uniparental disomy (UPD) 7. Prenatal ultrasound findings were normal. She was referred for genetic counseling at 19 weeks of gestation. No repeat amniocentesis was suggested, and continuing the pregnancy was advised. At 22 weeks of gestation, the result of soluble fms-like tyrosine kinase-1 (sFlt-1)/placental growth factor (PlGF) = 6.1 (normal < 38). She did not have preeclampsia. At 39 weeks of gestation, a 3346-g male baby was delivered without any phenotypic abnormality. aCGH analysis on the DNA extracted from cord blood and placenta revealed the result of arr (1-22) × 2, (X,Y) × 1 with no genomic imbalance in all tissues. When follow-up at age three months, the baby was normal in development and phenotype. The peripheral blood had a karyotype of 46,XY, and interphase fluorescence in situ hybridization (FISH) analysis using the bacterial artificial chromosome (BAC) probes of chromosome 7 showed disomy 7 cells in all 102/102 cells. CONCLUSION: Low-level mosaic trisomy 7 at amniocentesis can be associated with cytogenetic discrepancy between cultured amniocytes and uncultured amniocytes, perinatal progressive decrease of the trisomy 7 cell line and a favorable fetal outcome.


Assuntos
Amniocentese , Cromossomos Humanos Par 7 , Hibridização Genômica Comparativa , Mosaicismo , Trissomia , Dissomia Uniparental , Humanos , Gravidez , Feminino , Mosaicismo/embriologia , Trissomia/diagnóstico , Trissomia/genética , Adulto , Cromossomos Humanos Par 7/genética , Dissomia Uniparental/diagnóstico , Dissomia Uniparental/genética , Recém-Nascido , Linhagem Celular , Células Cultivadas , Resultado da Gravidez/genética
5.
J Neurodev Disord ; 16(1): 39, 2024 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-39014349

RESUMO

BACKGROUND: Sleep disturbances are a prevalent and complex comorbidity in neurodevelopmental disorders (NDDs). Dup15q syndrome (duplications of 15q11.2-13.1) is a genetic disorder highly penetrant for NDDs such as autism and intellectual disability and it is frequently accompanied by significant disruptions in sleep patterns. The 15q critical region harbors genes crucial for brain development, notably UBE3A and a cluster of gamma-aminobutyric acid type A receptor (GABAAR) genes. We previously described an electrophysiological biomarker of the syndrome, marked by heightened beta oscillations (12-30 Hz) in individuals with Dup15q syndrome, akin to electroencephalogram (EEG) alterations induced by allosteric modulation of GABAARs. Those with Dup15q syndrome exhibited increased beta oscillations during the awake resting state and during sleep, and they showed profoundly abnormal NREM sleep. This study aims to assess the translational validity of these EEG signatures and to delve into their neurobiological underpinnings by quantifying sleep physiology in chromosome-engineered mice with maternal (matDp/ + mice) or paternal (patDp/ + mice) inheritance of the full 15q11.2-13.1-equivalent duplication, and mice with duplication of just the UBE3A gene (Ube3a overexpression mice; Ube3a OE mice) and comparing the sleep metrics with their respective wildtype (WT) littermate controls. METHODS: We collected 48-h EEG/EMG recordings from 35 (23 male, 12 female) 12-24-week-old matDp/ + , patDp/ + , Ube3a OE mice, and their WT littermate controls. We quantified baseline sleep, sleep fragmentation, spectral power dynamics during sleep states, and recovery following sleep deprivation. Within each group, distinctions between Dup15q mutant mice and WT littermate controls were evaluated using analysis of variance (ANOVA) and student's t-test. The impact of genotype and time was discerned through repeated measures ANOVA, and significance was established at p < 0.05. RESULTS: Our study revealed that across brain states, matDp/ + mice mirrored the elevated beta oscillation phenotype observed in clinical EEGs from individuals with Dup15q syndrome. Time to sleep onset after light onset was significantly reduced in matDp/ + and Ube3a OE mice. However, NREM sleep between Dup15q mutant and WT littermate mice remained unaltered, suggesting a divergence from the clinical presentation in humans. Additionally, while increased beta oscillations persisted in matDp/ + mice after 6-h of sleep deprivation, recovery NREM sleep remained unaltered in all groups, thus suggesting that these mice exhibit resilience in the fundamental processes governing sleep-wake regulation. CONCLUSIONS: Quantification of mechanistic and translatable EEG biomarkers is essential for advancing our understanding of NDDs and their underlying pathophysiology. Our study of sleep physiology in the Dup15q mice underscores that the beta EEG biomarker has strong translational validity, thus opening the door for pre-clinical studies of putative drug targets, using the biomarker as a translational measure of drug-target engagement. The unaltered NREM sleep may be due to inherent differences in neurobiology between mice and humans. These nuanced distinctions highlight the complexity of sleep disruptions in Dup15q syndrome and emphasize the need for a comprehensive understanding that encompasses both shared and distinct features between murine models and clinical populations.


Assuntos
Cromossomos Humanos Par 15 , Modelos Animais de Doenças , Eletroencefalografia , Animais , Camundongos , Cromossomos Humanos Par 15/genética , Masculino , Feminino , Transtornos do Sono-Vigília/genética , Transtornos do Sono-Vigília/fisiopatologia , Sono/fisiologia , Sono/genética , Trissomia/fisiopatologia , Trissomia/genética , Aberrações Cromossômicas , Deficiência Intelectual
6.
Pathology ; 56(5): 671-680, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38852040

RESUMO

Flow cytometry can be applied in the detection of fluorescence in situ hybridisation (FISH) signals to efficiently analyse chromosomal aberrations. However, such interphase chromosome (IC) Flow-FISH protocols are currently limited to detecting a single colour. Furthermore, combining IC Flow-FISH with conventional multicolour flow cytometry is difficult because the DNA-denaturation step in FISH assay also disrupts cellular integrity and protein structures, precluding subsequent antigen-antibody binding and hindering concurrent labeling of surface antigens and FISH signals. We developed a working protocol for concurrent multicolour flow cytometry detection of nuclear IC FISH signals and cell surface markers. The protocol was validated by assaying sex chromosome content of blood cells, which was indicative of chimerism status in patients who had received sex-mismatched allogeneic haematopoietic stem cell transplants (allo-HSCT). The method was also adapted to detect trisomy 12 in chronic lymphocytic leukaemia (CLL) subjects. We first demonstrated the feasibility of this protocol in detecting multiple colours and concurrent nuclear and surface signals with high agreement. In clinical validation experiments, chimerism status was identified in clinical samples (n=56) using the optimised IC Flow-FISH method; the results tightly corresponded to those of conventional slide-based FISH (R2=0.9649 for XX cells and 0.9786 for XY cells). In samples from patients who received sex-mismatched allo-HSCT, individual chimeric statuses in different lineages could be clearly distinguished with high flexibility in gating strategies. Furthermore, in CLL samples with trisomy 12, this method could demonstrate that enriched trisomy 12 FISH signal was present in B cells rather than in T cells. Finally, by performing combined labelling of chromosome 12, X chromosome, and surface markers, we could detect rare residual recipient CLL cells with trisomy 12 after allo-HSCT. This adaptable protocol for multicolour and lineage-specific IC Flow-FISH advances the technique to allow for its potential application in various clinical contexts where conventional FISH assays are currently being utilised.


Assuntos
Citometria de Fluxo , Hibridização in Situ Fluorescente , Interfase , Leucemia Linfocítica Crônica de Células B , Humanos , Hibridização in Situ Fluorescente/métodos , Citometria de Fluxo/métodos , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/diagnóstico , Leucemia Linfocítica Crônica de Células B/patologia , Feminino , Masculino , Transplante de Células-Tronco Hematopoéticas , Trissomia/diagnóstico , Trissomia/genética , Pessoa de Meia-Idade , Cromossomos Humanos Par 12/genética
7.
Mol Genet Genomic Med ; 12(6): e2479, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38860502

RESUMO

BACKGROUND: As a screening method, inaccuracies in noninvasive prenatal screening (NIPS) exist, which are often attributable to biological factors. One such factor is the history of transplantation. However, there are still limited reports on such NIPS cases. METHODS: We report an NIPS case of a pregnant woman who had received a stem cell transplant from a male donor. To determine the karyotype in the woman's original cell, we performed chromosome microarray analysis (CMA) on her postnatal blood and oral mucosa. To comprehensively estimate the cell-free DNA (cfDNA) composition, we further performed standard NIPS procedures on the postnatal plasma. Moreover, we reviewed all published relevant NIPS case reports about pregnant women with transplantation history. RESULTS: NIPS showed a low-risk result for common trisomies with a fetal fraction of 65.80%. CMA on maternal white blood cells showed a nonmosaic male karyotype, while the oral mucosa showed a nonmosaic female karyotype. The proportion of donor's cfDNA in postnatal plasma was 94.73% based on the Y-chromosome reads ratio. The composition of cfDNA in maternal plasma was estimated as follows: prenatally, 13.60% maternal, 65.80% donor, and 20.60% fetal/placental, whereas postnatally, 5.27% maternal and 94.73% donor. CONCLUSIONS: This study expanded our understanding of the influence of stem cell transplantation on NIPS, allowing us to optimize NIPS management for these women.


Assuntos
Ácidos Nucleicos Livres , Teste Pré-Natal não Invasivo , Humanos , Feminino , Gravidez , Masculino , Adulto , Ácidos Nucleicos Livres/genética , Ácidos Nucleicos Livres/sangue , Teste Pré-Natal não Invasivo/métodos , Transplante de Células-Tronco , Doadores de Tecidos , Trissomia/genética
8.
Genes (Basel) ; 15(6)2024 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-38927714

RESUMO

Mosaicism for autosomal trisomy is uncommon in clinical practice. However, despite its rarity among both prenatally and postnatally diagnoses, there are a large number of characterized and published cases. Surprisingly, in contrast to regular trisomies, no attempts at systematic analyses of mosaic carriers' demographics were undertaken. This is the first study aimed to address this gap. For that, we have screened more than eight hundred publications on mosaic trisomies, reviewing data including gender and clinical status of mosaic carriers, maternal age and reproductive history. In total, 596 publications were eligible for analysis, containing data on 948 prenatal diagnoses, including true fetal mosaicism (TFM) and confined placental mosaicism (CPM), and on 318 cases of postnatally detected mosaicism (PNM). No difference was found in maternal age between normal pregnancy outcomes with appropriate birth weight and those with intrauterine growth restriction. Unexpectedly, a higher proportion of advanced maternal ages (AMA) was found in normal outcomes compared to abnormal ones (abnormal fetus or newborn) and fetal losses, 73% vs. 56% and 50%, p = 0.0015 and p = 0.0011, correspondingly. Another intriguing finding was a higher AMA proportion in mosaic carriers with concomitant uniparental disomy (UPD) for chromosomes 7, 14, 15, and 16 compared to carriers with biparental disomy (BPD) (72% vs. 58%, 92% vs. 55%, 87% vs. 78%, and 65% vs. 24%, correspondingly); overall figures were 78% vs. 48%, p = 0.0026. Analysis of reproductive histories showed a very poor reporting but almost two-fold higher rate of mothers reporting a previous fetal loss from PNM cohort (in which almost all patients were clinically abnormal) compared to mothers from the TFM and CPM cohorts (with a large proportion of normal outcomes), 30% vs. 16%, p = 0.0072. The occurrence of a previous pregnancy with a chromosome abnormality was 1 in 13 in the prenatal cohort and 1 in 16 in the postnatal cohort, which are five-fold higher compared to published studies on non-mosaic trisomies. We consider the data obtained in this study to be preliminary despite the magnitude of the literature reviewed since reporting of detailed data was mostly poor, and therefore, the studied cohorts do not represent "big data". Nevertheless, the information obtained is useful both for clinical genetic counseling and for modeling further studies.


Assuntos
Mosaicismo , Trissomia , Cromossomos Humanos , Idade Materna , Humanos , Feminino , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Masculino , Gravidez , Resultado da Gravidez , Diploide
9.
Taiwan J Obstet Gynecol ; 63(3): 418-421, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38802211

RESUMO

OBJECTIVE: Herein, we present a case of mosaic trisomy 6 detected by amniocentesis. CASE REPORT: Amniocentesis (G-banding) was performed at 17 weeks of gestation; the results were 47,XY,+6[3]/46,XY[12]. Fetal screening ultrasonography showed no morphological abnormalities, and the parents desired to continue the pregnancy. The infant was delivered vaginally at 39 weeks' gestation. The male infant weighed 3002 g at birth with no morphological abnormalities. G-banding karyotype analysis performed on the infant's peripheral blood revealed 46,XY[20]. FISH analysis revealed trisomy signals on chromosome 6 in 1-4 out of 100 cells from the placenta. The single nucleotide polymorphism microarray of the umbilical cord blood revealed no abnormalities. Methylation analysis of umbilical cord blood revealed no abnormalities in PLAGL1. No disorders were observed at one year of age. CONCLUSION: When amniocentesis reveals chromosomal mosaicism, it is essential to provide a thorough fetal ultrasound examination and careful genetic counseling to support the couples' decision-making.


Assuntos
Amniocentese , Cromossomos Humanos Par 6 , Mosaicismo , Trissomia , Humanos , Mosaicismo/embriologia , Feminino , Gravidez , Trissomia/genética , Trissomia/diagnóstico , Masculino , Adulto , Cromossomos Humanos Par 6/genética , Recém-Nascido , Ultrassonografia Pré-Natal , Cariotipagem , Hibridização in Situ Fluorescente
11.
BMC Pregnancy Childbirth ; 24(1): 338, 2024 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-38702634

RESUMO

OBJECTIVE: This study aims to perform a prenatal genetic diagnosis of a high-risk fetus with trisomy 7 identified by noninvasive prenatal testing (NIPT) and to evaluate the efficacy of different genetic testing techniques for prenatal diagnosis of trisomy mosaicism. METHODS: For prenatal diagnosis of a pregnant woman with a high risk of trisomy 7 suggested by NIPT, karyotyping and chromosomal microarray analysis (CMA) were performed on an amniotic fluid sample. Low-depth whole-genome copy number variation sequencing (CNV-seq) and fluorescence in situ hybridization (FISH) were used to clarify the results further. In addition, methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) was performed to analyze the possibility of uniparental disomy(UPD). RESULTS: Amniotic fluid karyotype analysis revealed a 46, XX result. Approximately 20% mosaic trisomy 7 was detected according to the CMA result. About 16% and 4% of mosaicism was detected by CNV-seq and FISH, respectively. MS-MLPA showed no methylation abnormalities. The fetal ultrasound did not show any detectable abnormalities except for mild intrauterine growth retardation seen at 39 weeks of gestation. After receiving genetic counseling, the expectant mother decided to continue the pregnancy, and follow-up within three months of delivery was normal. CONCLUSION: In high-risk NIPT diagnosis, a combination of cytogenetic and molecular genetic techniques proves fruitful in detecting low-level mosaicism. Furthermore, the exclusion of UPD on chromosome 7 remains crucial when NIPT indicates a positive prenatal diagnosis of trisomy 7.


Assuntos
Cromossomos Humanos Par 7 , Variações do Número de Cópias de DNA , Hibridização in Situ Fluorescente , Cariotipagem , Mosaicismo , Trissomia , Dissomia Uniparental , Humanos , Feminino , Mosaicismo/embriologia , Gravidez , Hibridização in Situ Fluorescente/métodos , Cromossomos Humanos Par 7/genética , Trissomia/diagnóstico , Trissomia/genética , Cariotipagem/métodos , Adulto , Dissomia Uniparental/diagnóstico , Dissomia Uniparental/genética , Diagnóstico Pré-Natal/métodos , Análise em Microsséries/métodos , Teste Pré-Natal não Invasivo/métodos , Reação em Cadeia da Polimerase Multiplex/métodos , Líquido Amniótico
12.
Blood Cancer Discov ; 5(4): 276-297, 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38713018

RESUMO

Despite advances in understanding the genetic abnormalities in myeloproliferative neoplasms (MPN) and the development of JAK2 inhibitors, there is an urgent need to devise new treatment strategies, particularly for patients with triple-negative (TN) myelofibrosis (MF) who lack mutations in the JAK2 kinase pathway and have very poor clinical outcomes. Here we report that MYC copy number gain and increased MYC expression frequently occur in TN-MF and that MYC-directed activation of S100A9, an alarmin protein that plays pivotal roles in inflammation and innate immunity, is necessary and sufficient to drive development and progression of MF. Notably, the MYC-S100A9 circuit provokes a complex network of inflammatory signaling that involves numerous hematopoietic cell types in the bone marrow microenvironment. Accordingly, genetic ablation of S100A9 or treatment with small molecules targeting the MYC-S100A9 pathway effectively ameliorates MF phenotypes, highlighting the MYC-alarmin axis as a novel therapeutic vulnerability for this subgroup of MPNs. Significance: This study establishes that MYC expression is increased in TN-MPNs via trisomy 8, that a MYC-S100A9 circuit manifest in these cases is sufficient to provoke myelofibrosis and inflammation in diverse hematopoietic cell types in the BM niche, and that the MYC-S100A9 circuit is targetable in TN-MPNs.


Assuntos
Calgranulina B , Cromossomos Humanos Par 8 , Transtornos Mieloproliferativos , Proteínas Proto-Oncogênicas c-myc , Trissomia , Cromossomos Humanos Par 8/genética , Humanos , Trissomia/genética , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Calgranulina B/genética , Calgranulina B/metabolismo , Transtornos Mieloproliferativos/genética , Transtornos Mieloproliferativos/metabolismo , Transtornos Mieloproliferativos/patologia , Animais , Camundongos , Mielofibrose Primária/genética , Mielofibrose Primária/patologia , Mielofibrose Primária/metabolismo , Transdução de Sinais/genética
13.
Prenat Diagn ; 44(8): 953-958, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38801227

RESUMO

OBJECTIVE: To evaluate the performance of prenatal screening for common autosomal trisomies in twin pregnancies through the use of rolling-circle replication (RCR)-cfDNA as a first-tier test. METHOD: Prospective multicenter study. Women who underwent prenatal screening for trisomy (T) 21, 18 and 13 between January 2019 and March 2022 in twin pregnancies were included. Patients were included in two centers. The primary endpoint was the rate of no-call results in women who received prenatal screening for common autosomal trisomies by RCR-cfDNA at the first attempt, compared to that in prospectively collected samples from 16,382 singleton pregnancies. The secondary endpoints were the performance indices of the RCR-cfDNA. RESULTS: 862 twin pregnancies underwent screening for T21, T18 and T13 by RCR-cfDNA testing at 10-33 weeks' gestation. The RCR-cfDNA tests provided a no-call result from the first sample obtained from the patients in 107 (0.7%) singleton and 17 (2.0%) twin pregnancies. Multivariable regression analysis demonstrated that significant independent predictors of test failure were twin pregnancy and in vitro fertilization conception. All cases of T21 (n = 20/862; 2.3%), T18 (n = 4/862; 0.5%) and T13 (n = 1/862; 0.1%) were correctly detected by RCR-cfDNA (respectively, 20, 4 and 1 cases). Sensitivity was 100% (95% CI, 83.1%-100%), 100% (95% CI 39.8%-100%) and 100% (95% CI 2.5%-100%) for T21, T18 and T13, respectively, in twin pregnancies. CONCLUSION: The RCR-cfDNA test appears to have good accuracy with a low rate of no-call results in a cohort of twin pregnancies for the detection of the most frequent autosomal trisomies.


Assuntos
Ácidos Nucleicos Livres , Gravidez de Gêmeos , Humanos , Feminino , Gravidez , Gravidez de Gêmeos/sangue , Gravidez de Gêmeos/genética , Adulto , Estudos Prospectivos , Ácidos Nucleicos Livres/análise , Ácidos Nucleicos Livres/sangue , Trissomia/diagnóstico , Trissomia/genética
14.
Eur J Obstet Gynecol Reprod Biol ; 298: 31-34, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38705011

RESUMO

OBJECTIVE: This study evaluated the BACs-on-Beads™ (BoBs) efficiency assay in detecting chromosomal anomalies in products of conception (POC) specimens associated with anembryonic pregnancy (AP) among Thai pregnant women. METHOD: Retrospective analysis applied the BoBs™ assay to examine AP samples from 2010 to 2022. The incidences of AP with chromosomal abnormalities were reported. RESULT: Assessment of villi from anembryonic pregnancy samples found normal chromosome complement in 50% of the cases, while the remainder showed chromosomal abnormalities. Trisomy 16 was found in 15% of the cases and trisomies 22, 15, and 19 in 9.6%, 3.8%, and 3.8%, respectively. Advanced maternal age was associated with a higher incidence of aneuploidy. CONCLUSION: The BoBs™ assay effectively detected diverse chromosomal abnormalities in villi samples from POC. The diagnostic utility of the BoBs™ assay was highlighted in identifying chromosomal irregularities in AP cases. Trisomy 16 possessed the most chromosomal abnormalities in the AP samples.


Assuntos
Aberrações Cromossômicas , Humanos , Feminino , Gravidez , Estudos Retrospectivos , Adulto , Tailândia/epidemiologia , Transtornos Cromossômicos/diagnóstico , Transtornos Cromossômicos/genética , Trissomia/diagnóstico , Trissomia/genética , Adulto Jovem
15.
Mol Genet Genomic Med ; 12(5): e2436, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38738460

RESUMO

BACKGROUND: Trisomy 20p is a rare genetic condition caused by a duplication of the short arm of chromosome 20. METHODS: We employed clinical observation and molecular genetic testing (SNP microarray), to study identical twin males with an unknown dysmorphic syndrome. We conducted a literature review of trisomy 20p and collated the clinical and molecular genetic findings on 20 affected subjects reported since 2000. RESULTS: Identical twin males, whose prenatal course was complicated by a twin-to-twin transfusion, manifested profound language and neurocognitive delays as well as distinctive facial dysmorphisms when evaluated at 2 years of age. SNP microarray identified identical duplications of 20p13 with no other chromosomal aberrations. A literature survey of 20p trisomy syndrome identified 20 other examples of this condition reported since 2000, which we collated with 33 summarized by Sidwell et al. (2000). Within the combined total of 55 affected individuals, we found a distinctive clinical phenotype that provides insight on the effects of abnormal dosage of genes in 20p13. These loci include FAM110A (OMIM 611393), ANGPT4 (OMIM 603705), RSPO4 (OMIM 610573), PSMF1 (OMIM 617858), SNPH (OMIM 604942), SDCBP2 (OMIM 617358), FKBP1A (OMIM 186945), TMEM74B, C20orf202, and RAD21L1 (OMIM 619533). Gene profiling highlighted that syntaphilin (SNPH) is highly expressed in mammalian brain, where it is considered critical for mitochondrial transport in neuronal axons, and to directly influence axonal morphogenesis and function. CONCLUSION: We propose that abnormal activity of syntaphilin engendered by the trisomy is primarily responsible for the language, neurocognitive, and gross motor delays reported in individuals with 20p trisomy. Additional studies, for example, characterization of cerebral organoids generated from affected patients may help to better understand this condition, and potentially suggest rational remedies to improve the lives of affected individuals and their families.


Assuntos
Trissomia , Humanos , Masculino , Trissomia/genética , Duplicação Cromossômica , Pré-Escolar , Gêmeos Monozigóticos/genética , Polimorfismo de Nucleotídeo Único
16.
Taiwan J Obstet Gynecol ; 63(3): 293-296, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38802190

RESUMO

Trisomy 7 is the most common observed type of rare autosomal trisomies (RATs) detected at expanded genome-wide non-invasive prenatal testing (NIPT). Genetic counseling of NIPT trisomy 7-positive pregnancies remains to be not easy because the parents may worry about the likelihood of adverse pregnancy outcomes, fetal abnormality and the necessity of invasive procedures for confirmation of fetal mosaic trisomy 7 and uniparental disomy (UPD) 7. This review provides a comprehensive information on the update issues concerning genetic counseling of NIPT trisomy 7-positive pregnancies.


Assuntos
Cromossomos Humanos Par 7 , Aconselhamento Genético , Teste Pré-Natal não Invasivo , Trissomia , Humanos , Feminino , Gravidez , Trissomia/diagnóstico , Trissomia/genética , Teste Pré-Natal não Invasivo/métodos , Cromossomos Humanos Par 7/genética , Dissomia Uniparental/diagnóstico , Dissomia Uniparental/genética , Testes Genéticos/métodos , Diagnóstico Pré-Natal/métodos
17.
Genes (Basel) ; 15(5)2024 04 28.
Artigo em Inglês | MEDLINE | ID: mdl-38790198

RESUMO

Genome-wide prenatal cell-free DNA (cfDNA) screening can be used to screen for a wide range of fetal chromosomal anomalies in pregnant patients. In this study, we describe our clinical experience with a genome-wide cfDNA assay in screening for common trisomies, sex chromosomal aneuploidies (SCAs), rare autosomal aneuploidies (RAAs), and copy-number variations (CNVs) in about 6000 patients over a three-year period at our hospital's Prenatal Diagnostic Unit in Spain. Overall, 204 (3.3%) patients had a high-risk call, which included 76 trisomy 21, 21 trisomy 18, 7 trisomy 13, 29 SCAs, 31 RAAs, 31 CNVs, and 9 cases with multiple anomalies. The diagnostic outcomes were obtained for the high-risk cases when available, allowing for the calculation of positive predictive values (PPVs). Calculated PPVs were 95.9% for trisomy 21, 77.8% for trisomy 18, 66.7% for trisomy 13, 10.7% for RAAs, and 10.7% for CNVs. Pregnancy and birth outcomes were also collected for the majority of RAA and CNV cases. Adverse perinatal outcomes for some of these cases included preeclampsia, fetal growth restriction, preterm birth, reduced birth weight, and major congenital structural abnormalities. In conclusion, our study showed strong performance for genome-wide cfDNA screening in a large cohort of pregnancy patients in Spain.


Assuntos
Ácidos Nucleicos Livres , Variações do Número de Cópias de DNA , Humanos , Feminino , Gravidez , Espanha , Ácidos Nucleicos Livres/genética , Ácidos Nucleicos Livres/sangue , Adulto , Diagnóstico Pré-Natal/métodos , Trissomia/genética , Trissomia/diagnóstico , Transtornos Cromossômicos/diagnóstico , Transtornos Cromossômicos/genética , Aneuploidia , Teste Pré-Natal não Invasivo/métodos
18.
Prenat Diagn ; 44(8): 946-952, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38622635

RESUMO

OBJECTIVE: Determine current analytical methods and number of cell-free (cf) DNA prenatal screening tests performed for common trisomies. METHODS: The College of American Pathologists 2022-B Noninvasive Prenatal Testing exercise was distributed in December 2022 to 93 participants in 22 countries. Supplemental questions included the number of tests performed in a recent month and the proportion of samples originating outside the United States (US). RESULTS: Eighty-three participants from three continents returned results; 74 (89%) were suitable for the analyses. Nine manufacturer/platform combinations were identified, most commonly Illumina/Nextseq (55%). The most common methodology was whole genome sequencing (76%). Annualized cfDNA tests were 2.80 million, with Asian, European and North American participants representing 10.6%, 6.5% and 82.9% of tests, respectively. When restricted to US in-country tests, the annualized rate was 2.18 million, with four of 20 participants testing 79.2%. Among 73 respondents, 63 (86%) were for-profit, eight (11%) were non-profit academic or government supported and the remaining two included hospital-based and private non-profit. Eighteen (25%) supported relevant academic training. CONCLUSION: In 2011, screening for common trisomies was based on serum/ultrasound markers with an estimated 2.96 million US pregnancies screened in 131 laboratories. In 2022, cfDNA-based screening was offered by 20 laboratories testing 2.18 million US pregnancies.


Assuntos
Ácidos Nucleicos Livres , Teste Pré-Natal não Invasivo , Humanos , Ácidos Nucleicos Livres/análise , Ácidos Nucleicos Livres/sangue , Feminino , Gravidez , Teste Pré-Natal não Invasivo/métodos , Teste Pré-Natal não Invasivo/estatística & dados numéricos , Diagnóstico Pré-Natal/métodos , Diagnóstico Pré-Natal/estatística & dados numéricos , Trissomia/diagnóstico , Trissomia/genética , Testes para Triagem do Soro Materno/estatística & dados numéricos , Testes para Triagem do Soro Materno/métodos
19.
Genes (Basel) ; 15(4)2024 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-38674386

RESUMO

Down syndrome (DS) is the most common form of inherited intellectual disability caused by trisomy of chromosome 21, presenting with intellectual impairment, craniofacial abnormalities, cardiac defects, and gastrointestinal disorders. The Ts65Dn mouse model replicates many abnormalities of DS. We hypothesized that investigation of the cerebral cortex of fluoxetine-treated trisomic mice may provide proteomic signatures that identify therapeutic targets for DS. Subcellular fractionation of synaptosomes from cerebral cortices of age- and brain-area-matched samples from fluoxetine-treated vs. water-treated trisomic and euploid male mice were subjected to HPLC-tandem mass spectrometry. Analysis of the data revealed enrichment of trisomic risk genes that participate in regulation of synaptic vesicular traffic, pre-synaptic and post-synaptic development, and mitochondrial energy pathways during early brain development. Proteomic analysis of trisomic synaptic fractions revealed significant downregulation of proteins involved in synaptic vesicular traffic, including vesicular endocytosis (CLTA, CLTB, CLTC), synaptic assembly and maturation (EXOC1, EXOC3, EXOC8), anterograde axonal transport (EXOC1), neurotransmitter transport to PSD (SACM1L), endosomal-lysosomal acidification (ROGDI, DMXL2), and synaptic signaling (NRXN1, HIP1, ITSN1, YWHAG). Additionally, trisomic proteomes revealed upregulation of several trafficking proteins, involved in vesicular exocytosis (Rab5B), synapse elimination (UBE3A), scission of endocytosis (DBN1), transport of ER in dendritic spines (MYO5A), presynaptic activity-dependent bulk endocytosis (FMR1), and NMDA receptor activity (GRIN2A). Chronic fluoxetine treatment of Ts65Dn mice rescued synaptic vesicular abnormalities and prevented abnormal proteomic changes in adult Ts65Dn mice, pointing to therapeutic targets for potential treatment of DS.


Assuntos
Síndrome de Down , Fluoxetina , Proteômica , Vesículas Sinápticas , Animais , Fluoxetina/farmacologia , Camundongos , Síndrome de Down/metabolismo , Síndrome de Down/tratamento farmacológico , Síndrome de Down/genética , Síndrome de Down/patologia , Masculino , Proteômica/métodos , Vesículas Sinápticas/metabolismo , Vesículas Sinápticas/efeitos dos fármacos , Modelos Animais de Doenças , Proteoma/metabolismo , Córtex Cerebral/metabolismo , Córtex Cerebral/efeitos dos fármacos , Sinaptossomos/metabolismo , Sinaptossomos/efeitos dos fármacos , Trissomia/genética
20.
Genes (Basel) ; 15(4)2024 04 07.
Artigo em Inglês | MEDLINE | ID: mdl-38674397

RESUMO

The mosaic form of Edwards syndrome affects 5% of all children with Edwards syndrome. The clinical phenotype is highly variable, ranging from the full spectrum of trisomy 18 to the normal phenotype. The purpose of this publication was to present the therapeutic process in an 18-month-old girl with the mosaic form of Edwards syndrome and hepatoblastoma, against the background of other cases of simultaneous occurrence of this syndrome and hepatoblastoma described so far. It appears that this particular group of patients with hepatoblastoma and Edwards syndrome can have good outcomes, provided they do not have life-threatening cardiac or other severe defects. Due to the prematurity of our patient and the defects associated with Edwards syndrome, the child required constant multidisciplinary care, but Edwards syndrome itself was not a reason to discontinue therapy for a malignant neoplasm of the liver. Regular abdominal ultrasound examination, along with AFP testing, may be helpful in the early detection of liver tumors in children with Edwards syndrome.


Assuntos
Hepatoblastoma , Neoplasias Hepáticas , Síndrome da Trissomía do Cromossomo 18 , Humanos , Hepatoblastoma/genética , Hepatoblastoma/terapia , Feminino , Lactente , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Síndrome da Trissomía do Cromossomo 18/genética , Síndrome da Trissomía do Cromossomo 18/complicações , Mosaicismo , Trissomia/genética , Resultado do Tratamento , Cromossomos Humanos Par 18/genética
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