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1.
Zhongguo Dang Dai Er Ke Za Zhi ; 25(1): 38-45, 2023 Jan 15.
Artigo em Chinês | MEDLINE | ID: mdl-36655662

RESUMO

OBJECTIVES: To study the clinical features and prognosis of high hyperdiploid (HHD) childhood acute lymphoblastic leukemia (ALL). METHODS: A retrospective analysis was performed on the medical data of 1 414 children who were newly diagnosed with ALL and were admitted to five hospitals in Fujian Province of China from April 2011 to December 2020. According to karyotype, they were divided into two groups: HHD (n=172) and non-HHD (n=1 242). The clinical features and treatment outcome were compared between the two groups, and the factors influencing the prognosis were further explored. RESULTS: Among the 1 414 children with ALL, 172 (12.16%) had HHD. Compared with the non-HHD group, the HHD group had significantly lower proportions of children with risk factors for poor prognosis at diagnosis (age of onset ≥10 years or <1 year, white blood cell count ≥50×109/L, and T-cell phenotype) or positive fusion genes (TEL-AML1, BCR-ABL1, E2A-PBX1, and MLL gene rearrangement) (P<0.05). The HHD group had a significantly higher proportion of children with minimal residual disease (MRD) <0.01% at the end of induction chemotherapy (P<0.05). The 10-year event-free survival (EFS) rate and overall survival (OS) rate in the HHD group were significantly higher than those in the non-HHD group (P<0.05). The univariate analysis showed that the number of chromosomes of 58-66, trisomy of chromosome 10, trisomy of chromosome 17, bone marrow MRD <1% on day 15 or 19 of induction chemotherapy, and bone marrow MRD <0.01% on day 33 or 46 of induction chemotherapy were associated with a higher EFS rate (P<0.05), and trisomy of chromosome 10 was associated with a higher OS rate (P<0.05). The multivariate Cox analysis showed that trisomy of chromosome 17 was closely associated with a high EFS rate (P<0.05). CONCLUSIONS: The ALL children with HHD have few risk factors for poor prognosis at diagnosis and often have good prognosis. The number of chromosomes and trisomy of specific chromosomes are associated with prognosis in these children.


Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras , Trissomia , Criança , Humanos , Estudos Retrospectivos , Prognóstico , Resultado do Tratamento , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Neoplasia Residual , Intervalo Livre de Doença
2.
Am J Speech Lang Pathol ; 32(1): 287-297, 2023 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-36603546

RESUMO

PURPOSE: This study aimed to describe speech sound development in a group of 18-month-old children with sex chromosome trisomies (SCTs), compared with a group of typically developing (TD) peers. Concurrent and longitudinal relationships between speech sound abilities and lexical development were examined. METHOD: A group of 76 children aged 18 months, 38 children prenatally diagnosed with SCTs (12 with XXY, 12 with XYY, and 14 with XXX) and 38 TD children, participated in the study. From video recordings of semistructured naturalistic parent-child play sessions, quantitative and qualitative measures of speech sound development were collected (e.g., the number of consonants, type and place of articulation, and syllable structures used), and group differences were observed. The relationships between the number of consonants produced and vocabulary size at 18 and 24 months were assessed. RESULTS: At 18 months, children with SCTs used a significantly lower number of consonants than TD children. Qualitatively, children with SCTs used significantly fewer articulatory complex consonants (fricative/affricates) and a more restricted inventory of syllable structures. The number of consonants used was significantly correlated with lexical development at 18 months. Moreover, in the SCTs group (but not in the TD group), the children with lower speech sound development at 18 months showed a significantly smaller vocabulary growth between 18 and 24 months than those with higher speech-sound development. CONCLUSIONS: Toddlers with SCTs showed a significantly delayed speech sound development pattern rather than an atypical one. Children with SCTs with low speech sound development also showed lower vocabulary growth between 18 and 24 months of age. These results can be clinically relevant for follow-up and treatment planning for children with SCTs.


Assuntos
Linguagem Infantil , Fonética , Humanos , Criança , Lactente , Trissomia/diagnóstico , Medida da Produção da Fala , Cromossomos Sexuais , Fala
3.
J Appl Genet ; 64(1): 125-134, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36586055

RESUMO

Partial 16p trisomy syndrome is a rare disorder typically characterized by psychomotor retardation, prenatal and postnatal growth deficiency, cleft palate, and facial dysmorphism, with some patients also presenting with heart defects and urogenital anomalies. Pure 16p13.3 duplications usually occur de novo, while those duplications that associate with partial monosomy result rather from parental chromosomal translocations. Due to the large size of the aberrations, the majority of patients are identified by standard chromosome analysis. In all published cases, the minimal-causative duplicated region encompasses the CREBBP gene. Here, we report on the patient presenting with psychomotor retardation, femoral hypoplasia, and some features of the partial 16p trisomy syndrome, who carries a complex de novo terminal 16p13.3 microduplication with an overlapping region of amplification without translocation or associated monosomy. In contrast to the previously reported cases, the duplicated region of the patient does not involve CREBBP and other neighboring genes; still, the observed pattern of dysmorphic features of the index is characteristic of the described syndrome. Based on the animal studies and other published cases, we discuss the possible role of the PDK1 and IGFALS genes in the development of limb anomalies, while IFT140 could contribute both to the observed femoral phenotype and heart abnormalities in the patient. To the best of our knowledge, we present a proband harboring the smallest terminal 16p13.3 duplication of the size below 3 Mb. Therefore, our proband with her detailed phenotypic description may be helpful for clinicians who consult patients with this syndrome.


Assuntos
Anormalidades Múltiplas , Cardiopatias Congênitas , Gravidez , Feminino , Humanos , Trissomia/genética , Anormalidades Múltiplas/genética , Deleção Cromossômica , Cardiopatias Congênitas/genética , Síndrome , Translocação Genética
5.
Hum Genomics ; 16(1): 64, 2022 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-36457118

RESUMO

BACKGROUND: Aneuploidies are the most common chromosomal abnormality and the main genetic cause of adverse pregnancy outcomes. Since numerous studies have focused on common trisomies, relatively little is known about the association between phenotypic findings and rare autosomal aneuploidies (RAAs). We conducted a retrospective study of 48,904 cases for chromosomal microarray analysis in a large tertiary referral center and reported the overall frequencies, clinical manifestations, and outcomes of prenatal RAAs. RESULTS: A total of 90 RAAs were detected, of which 83 cases were mosaic trisomies and 7 were non-mosaic trisomies. Chromosomes 16, 22, and 9 were identified as the major chromosomes involving RAAs. The four predominant indications for prenatal diagnosis in our RAA cases were RAA-positive in noninvasive prenatal screening, advanced maternal age, ultrasound abnormalities, and high-risk for serum prenatal screening. Cardiovascular defects were the most frequently observed structural abnormalities, followed by musculoskeletal anomalies. Increased nuchal translucency and persistent left superior vena cava, the major soft marker abnormalities involved, were also observed in our RAA cases. Clinical outcomes were available for all RAAs, with 63 induced abortions and 27 live births recorded. CONCLUSIONS: Variable phenotypes and outcomes were observed, which were highly heterogeneous in cases of prenatal RAAs. Thus, a cautious and comprehensive strategy should be implemented during prenatal counseling for RAAs.


Assuntos
Resultado da Gravidez , Trissomia , Feminino , Gravidez , Humanos , Estudos Retrospectivos , Veia Cava Superior , Análise em Microsséries , Fenótipo , Aneuploidia , Cromossomos Humanos Par 16
6.
Epigenetics Chromatin ; 15(1): 39, 2022 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-36463299

RESUMO

Intellectual disability is a well-known hallmark of Down Syndrome (DS) that results from the triplication of the critical region of human chromosome 21 (HSA21). Major studies were conducted in recent years to gain an understanding about the contribution of individual triplicated genes to DS-related brain pathology. Global transcriptomic alterations and widespread changes in the establishment of neural lineages, as well as their differentiation and functional maturity, suggest genome-wide chromatin organization alterations in trisomy. High Mobility Group Nucleosome Binding Domain 1 (HMGN1), expressed from HSA21, is a chromatin remodeling protein that facilitates chromatin decompaction and is associated with acetylated lysine 27 on histone H3 (H3K27ac), a mark correlated with active transcription. Recent studies causatively linked overexpression of HMGN1 in trisomy and the development of DS-associated B cell acute lymphoblastic leukemia (B-ALL). HMGN1 has been shown to antagonize the activity of the Polycomb Repressive Complex 2 (PRC2) and prevent the deposition of histone H3 lysine 27 trimethylation mark (H3K27me3), which is associated with transcriptional repression and gene silencing. However, the possible ramifications of the increased levels of HMGN1 through the derepression of PRC2 target genes on brain cell pathology have not gained attention. In this review, we discuss the functional significance of HMGN1 in brain development and summarize accumulating reports about the essential role of PRC2 in the development of the neural system. Mechanistic understanding of how overexpression of HMGN1 may contribute to aberrant brain cell phenotypes in DS, such as altered proliferation of neural progenitors, abnormal cortical architecture, diminished myelination, neurodegeneration, and Alzheimer's disease-related pathology in trisomy 21, will facilitate the development of DS therapeutic approaches targeting chromatin.


Assuntos
Síndrome de Down , Proteína HMGN1 , Humanos , Síndrome de Down/genética , Complexo Repressor Polycomb 2/genética , Trissomia , Histonas , Lisina , Encéfalo , Cromatina/genética
7.
Am J Hum Genet ; 109(12): 2126-2140, 2022 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-36459979

RESUMO

Chromosome gains are detrimental for the development of the human embryo. As such, autosomal trisomies almost always result in spontaneous abortion, and the rare embryos surviving until live birth suffer from a plethora of pathological defects. There is no treatment currently available to ameliorate the consequences of trisomies, such as Down syndrome (trisomy of chromosome 21). Identifying the source of the phenotypes observed in cells with extra chromosomes is crucial for understanding the underlying molecular causes of trisomy syndromes. Although increased expression of the genes localized on the extra chromosome triggers several pathological phenotypes, an alternative model suggests that global, aneuploidy-associated changes in cellular physiology also contribute to the pathology. Here, we compare the molecular consequences of trisomy syndromes in vivo against engineered cell lines carrying various chromosome gains in vitro. We point out several phenotypes that are shared by variable trisomies and, therefore, might be caused by the presence of an extra chromosome per se, independent of its identity. This alternative view may provide useful insights for understanding Down syndrome pathology and open additional opportunities for diagnostics and treatments.


Assuntos
Síndrome de Down , Trissomia , Feminino , Gravidez , Humanos , Trissomia/genética , Síndrome de Down/genética , Aberrações Cromossômicas , Cromossomos Humanos Par 21 , Aneuploidia
8.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 39(12): 1402-1405, 2022 Dec 10.
Artigo em Chinês | MEDLINE | ID: mdl-36453968

RESUMO

OBJECTIVE: To explore the genetic etiology of a child featuring recurrent oral ulcer. METHODS: Clinical data of the child was collected. Whole exome sequencing was carried out for her. Candidate variant was verified by low-coverage massive parallel copy number variation sequencing (CNV-seq) of the family trio. RESULTS: The child, a 6-year-old girl, has featured recurrent fever and ulcers of the oral mucosa, vulvar and perianal regions. No pathogenic variant was found by whole exome sequencing. However, analysis of chromosome copy number variation using the whole exome sequencing data has revealed mosaicism of trisomy 8. CNV-seq assay has verified the variant in the child, with the percentage of mosaicism being 73%. No abnormality was found in neither of her parents. CONCLUSION: A case of mosaicism trisomy 8 with recurrent oral ulcer as the first symptom was diagnosed, which has enriched the phenotypic data of trisomy 8 syndrome.


Assuntos
Úlceras Orais , Trissomia , Humanos , Criança , Feminino , Trissomia/genética , Cromossomos Humanos Par 8/genética , Variações do Número de Cópias de DNA , Mosaicismo
9.
BMC Med Genomics ; 15(1): 266, 2022 12 21.
Artigo em Inglês | MEDLINE | ID: mdl-36544206

RESUMO

BACKGROUND: Down syndrome (DS) is caused by the presence of an extra copy of full or partial human chromosome 21 (Hsa21). Partial (segmental) trisomy 21 (PT21) is the duplication of only a delimited region of Hsa21 and can be associated or not to DS: the study of PT21 cases is an invaluable model for addressing genotype-phenotype correlation in DS. Previous works reported systematic reanalyses of 132 subjects with PT21 and allowed the identification of a 34-kb highly restricted DS critical region (HR-DSCR) as the minimal region whose duplication is shared by all PT21 subjects diagnosed with DS. METHODS: We report clinical data and cytogenetic analysis of two children with PT21, one with DS and the other without DS. Moreover, we performed a systematic bibliographic search for any new PT21 report. RESULTS: Clinical and cytogenetic analyses of the two PT21 children have been reported: in Case 1 the duplication involves the whole long arm of Hsa21, except for the last 2.7 Mb, which are deleted as a consequence of an isodicentric 21: the HR-DSCR is within the duplicated regions and the child is diagnosed with DS. In Case 2 the duplication involves 7.1 Mb of distal 21q22, with a deletion of 2.1 Mb of proximal 20p, as a consequence of an unbalanced translocation: the HR-DSCR is not duplicated and the child presents with psychomotor development delay but no clinical signs of DS. Furthermore, two PT21 reports recently published (named Case 3 and 4) have been discussed: Case 3 has DS diagnosis, nearly full trisomy for Hsa21 and a monosomy for the 21q22.3 region. Case 4 is a baby without DS and a 0.56-Mb duplication of 21q22.3. Genotype-phenotype correlation confirmed the presence of three copies of the HR-DSCR in all DS subjects and two copies in all non-DS individuals. CONCLUSIONS: The results presented here are fully consistent with the hypothesis that the HR-DSCR is critically associated with DS diagnosis. No exception to this pathogenetic model was found. Further studies are needed to detect genetic determinants likely located in the HR-DSCR and possibly responsible for core DS features, in particular intellectual disability.


Assuntos
Síndrome de Down , Deficiência Intelectual , Criança , Humanos , Síndrome de Down/genética , Síndrome de Down/patologia , Trissomia , Deficiência Intelectual/genética , Estudos de Associação Genética , Cromossomos Humanos Par 21/genética , Fenótipo
10.
Zhonghua Fu Chan Ke Za Zhi ; 57(12): 900-906, 2022 Dec 25.
Artigo em Chinês | MEDLINE | ID: mdl-36562223

RESUMO

Objective: To evaluate the effect of noninvasive prenatal testing (NIPT) as first-line screening in fetal chromosome aneuploidy screening practice, and to provide evidence for the prevention and control strategy of birth defects. Methods: Since July 2019, Hebei province had carried out the NIPT project providing first-line screening for eligible pregnant women in the area (except for those who were not applicable). Pregnant women with high risk received genetic counseling, prenatal diagnosis and intervention guidance. Low risk and false-positive ones received continuous detection and moved to prenatal diagnosis center for counseling and diagnosis if abnormities were discovered. All pregnant women were followed up to learn about pregnancy outcomes and newborn health status. Detection results and clinical data of pregnant women participating the NIPT project from July 2019 to July 2020 were collected. The detection results and effect of NIPT were analyzed. Results: (1) Basic information of the screened population: A total of 424 330 pregnant women were screened, and 423 596 were successfully detected, with a success rate of 99.83% (423 596/424 330). The age of pregnant women was (28.8±4.5) years old; the gestational age of screening was (16.6±2.3) weeks; the proportion of advanced-age pregnant women (≥35 years old) was 10.18% (43 132/423 596); in vitro fertilization-embryo transfer (IVF-ET) rate was 1.58% (6 713/423 596); the twin rate was 1.38% (5 849/423 596); the proportion of primipara was 34.23% (144 977/423 596). (2) Screening results and detection performance: totally, 325, 73 and 20 pregnant women were diagnosed with trisomy 21, 18 and 13; the sensitivity were 99.39%, 100.00% and 100.00%; the specificity were 99.98%, 99.99% and 99.98%; the positive predictive value were 75.76%, 68.87% and 21.51%, respectively. Besides, 249 190 pregnant women were received supplementary reports as well, and 255, 10 and 9 were confirmed for sex chromosome aneuploidy, other autosomal aneuploidy and deletion/duplication syndrome; the positive predictive value were 37.78%, 6.06% and 32.14%, respectively. The sensitivity of NIPT for target trisomy (trisomy 21, 18 and 13) screening in advanced-age, IVF-ET and twin pregnant women were 99.29%, 100.00% and 90.00%, respectively; the specificity were 99.93% for all; the positive predictive value were 82.25%, 61.54% and 69.23%, respectively. Conclusions: NIPT has a significant effect and good performance in the first-line screening of fetal chromosome aneuploidy in the whole population, which might provide reference for the improvement of birth defect prevention and control strategy.


Assuntos
Transtornos Cromossômicos , Síndrome de Down , Recém-Nascido , Gravidez , Feminino , Humanos , Adulto Jovem , Adulto , Lactente , Síndrome de Down/diagnóstico , Estudos Retrospectivos , Diagnóstico Pré-Natal/métodos , Transtornos Cromossômicos/diagnóstico , Transtornos Cromossômicos/epidemiologia , Trissomia , Aneuploidia
11.
Acta Med Okayama ; 76(6): 645-650, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36549766

RESUMO

We used biomathematics to describe and compare cerebellar growth in normally developing and trisomy 18 Japanese fetuses. This retrospective study included 407 singleton pregnancies with fetuses at 14-39 weeks of gestation and 33 fetuses with trisomy 18 at 17-35 weeks. We used ultrasonography to measure fetal transverse cerebellar diameter (TCD) and anteroposterior cerebellar diameter (APCD). We hypothesized that cerebellar growth is proportional to cerebellar length at any given time point. We determined the formula L(t) ≒Keat+r, where e is Napier's number, t is time, L is cerebellar length, and a, K, and r are constants. We then obtained regression functions for each TCD and APCD in all fetuses. The regression equations for TCD and APCD values in normal fetuses, expressed as exponential functions, were TCD(t)=27.85e0.02788t-28.62 (mm) (adjusted R2=0.997), and APCD(t)=324.29e0.00286t-322.62 (mm) (adjusted R2=0.995). These functions indicated that TCD and APCD grew at constant rates of 2.788%/week and 0.286%/week, respectively, throughout gestation. TCD (0.0153%/week) and APCD (0.000430%/week) grew more slowly in trisomy 18 fetuses. This study demonstrates the potential of biomathematics in clinical research and may aid in biological understanding of fetal cerebellar growth.


Assuntos
Ultrassonografia Pré-Natal , Feminino , Gravidez , Humanos , Síndrome da Trissomía do Cromossomo 18 , Idade Gestacional , Estudos Retrospectivos , Feto/diagnóstico por imagem , Trissomia
12.
Genes (Basel) ; 13(12)2022 11 29.
Artigo em Inglês | MEDLINE | ID: mdl-36553513

RESUMO

It is well known that first-trimester miscarriages are associated with chromosome abnormalities, with numerical chromosome abnormalities being the ones most commonly detected. Conventional karyotyping is still considered the gold standard in the analysis of products of conception, despite the extended use of molecular genetic techniques. However, conventional karyotyping is a laborious and time-consuming method, with a limited resolution of 5-10 Mb and hampered by maternal cell contamination and culture failure. The aim of our study was to assess the type and frequency of chromosomal abnormalities detected by conventional karyotyping in specimens of sporadic first-trimester miscarriages in a Romanian cohort, using QF-PCR to exclude maternal cell contamination. Long-term cultures were established and standard protocols were applied for cell harvesting, slide preparation, and GTG banding. All samples with 46,XX karyotype were tested for maternal cell contamination by QF-PCR, comparing multiple microsatellite markers in maternal blood with cell culture and tissue samples. Out of the initial 311 specimens collected from patients with sporadic first-trimester miscarriages, a total of 230 samples were successfully analyzed after the exclusion of 81 specimens based on unsuitable sampling, culture failure, or QF-PCR-proven maternal cell contamination. Chromosome abnormalities were detected in 135 cases (58.7%), with the most common type being single autosomal trisomy (71/135-52.6%), followed by monosomy (monosomy X being the only one detected, 24/135-17.8%), and polyploidy (23/135-17.0%). The subgroup analysis based on maternal age showed a statistically significant higher rate of single trisomy for women aged 35 years or older (40.3%) compared to the young maternal age group (26.1%) (p = 0.029). In conclusion, the combination of conventional karyotyping and QF-PCR can lead to an increased chromosome abnormality detection rate in first-trimester miscarriages. Our study provides reliable information for the genetic counseling of patients with first-trimester miscarriages, and further large-scale studies using different genetic techniques are required.


Assuntos
Aborto Espontâneo , Trissomia , Gravidez , Humanos , Feminino , Primeiro Trimestre da Gravidez/genética , Aborto Espontâneo/genética , Estudos Retrospectivos , Estudos de Coortes , Romênia , Aberrações Cromossômicas , Cariotipagem , Análise Citogenética , Reação em Cadeia da Polimerase/métodos
13.
Genes (Basel) ; 13(12)2022 12 16.
Artigo em Inglês | MEDLINE | ID: mdl-36553656

RESUMO

The scope of cell-free DNA (cfDNA) testing was expanded to the genome, which allowed screening for rare chromosome anomalies (RCAs). Since the efficiency of the test for RCAs remains below the common aneuploidies, there is a debate on the usage of expanded tests. This study focuses on the confirmatory and follow-up data of cases with positive cfDNA testing for RCAs and cases with screen-negative results in a series of 912 consecutive cases that underwent invasive testing following cfDNA testing. Chorion villus sampling (CVS), amniocentesis (AS), fetal blood sampling, and term placenta samples were investigated using classical cytogenetic and molecular cytogenetic techniques. Out of 593 screen-positive results, 504 (85%) were for common aneuploidies, 40 (6.7%) for rare autosomal trisomies (RATs), and 49 (8.3%) for structural chromosome anomalies (SAs). Of the screen-positives for RATs, 20 cases were evaluated only in fetal tissue, and confined placental mosaicism (CPM) could not be excluded. Among cases with definitive results (n = 20), the rates of true positives, placental mosaics, and false positives were 35%, 45%, and 10%, respectively. Among screen-positives for SAs, 32.7% were true positives. The confirmation rate was higher for duplications than deletions (58.3% vs. 29.4%). The rate of chromosomal abnormality was 10.9% in the group of 256 screen-negatives with pathological ultrasound findings. This study provides further data to assess the efficiency of expanded cfDNA testing for RATs and SAs. The test efficiency for cfDNA seems to be higher for duplications than for deletions, which is evidence of the role of expert ultrasound in identifying pregnancies at increased risk for chromosome anomalies, even in pregnancies with screen-negatives. Furthermore, we discussed the efficiency of CVS vs. AC in screen-positives for RATs.


Assuntos
Ácidos Nucleicos Livres , Transtornos Cromossômicos , Gravidez , Feminino , Humanos , Diagnóstico Pré-Natal/métodos , Ácidos Nucleicos Livres/genética , Placenta , Transtornos Cromossômicos/diagnóstico , Transtornos Cromossômicos/genética , Trissomia/diagnóstico , Trissomia/genética , Aneuploidia , Mosaicismo , Análise Citogenética
14.
Int J Mol Sci ; 23(23)2022 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-36499318

RESUMO

The risk of chromosomal abnormalities in the child increases with increasing maternal age. Although non-invasive prenatal testing (NIPT) is a safe and effective prenatal screening method, the accuracy of the test results needs to be improved owing to various testing conditions. We attempted to achieve a more accurate and robust prediction of chromosomal abnormalities by combining multiple methods. Here, three different methods, namely standard Z-score, normalized chromosome value, and within-sample reference bin, were used for 1698 reference and 109 test samples of whole-genome sequencing. The logistic regression model combining the three methods achieved a higher accuracy than any single method. In conclusion, the proposed method offers a promising approach for increasing the reliability of NIPT.


Assuntos
Aberrações Cromossômicas , Diagnóstico Pré-Natal , Gravidez , Feminino , Criança , Humanos , Reprodutibilidade dos Testes , Diagnóstico Pré-Natal/métodos , Idade Materna , Trissomia , Aneuploidia
15.
F1000Res ; 11: 571, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36567683

RESUMO

Background: Autism is diagnosed on the basis of social and non-social behavioural features that are assumed to cluster together, and assumed to be distinct from other aspects of development, such as language ability. It is unclear, however, if these assumptions are valid. This study presents a novel approach to answering this question by investigating whether correlations between autism features are similar for groups selected on behavioural versus genetic diagnosis. Methods: The autism phenotype was assessed by diagnostic interview in young people aged 7 to 14 diagnosed with autism ( N=61) or sex chromosome trisomy (SCT; N=49). Data were analysed by confirmatory factor analysis and MANOVA. Results: Autism features showed a similar factor structure and were distinct from language ability in both groups. However, the SCT group was more likely to show clinically-significant difficulties in just some aspects of autism and a lower level of non-social autism features for their social-communication disabilities. Conclusions: We suggest the group differences emerged because autism diagnostic criteria do not map exactly on the autism phenotype as it manifests "naturally". Conventional diagnostic criteria for autism miss those with uneven profiles of difficulty and those with relatively low levels of restricted and repetitive behaviours and interests.


Assuntos
Transtorno Autístico , Humanos , Transtorno Autístico/diagnóstico , Transtorno Autístico/genética , Trissomia/diagnóstico , Trissomia/genética , Fenótipo , Cromossomos Sexuais/genética , Comunicação
16.
J Transl Med ; 20(1): 536, 2022 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-36401256

RESUMO

BACKGROUND: Chromosomal aneuploidy is the most common birth defect. However, the developmental mechanism and gene expression profile of fetuses with chromosomal aneuploidy are relatively unknown, and the maternal immune changes induced by fetal aneuploidy remain unclear. The inability to obtain the placenta multiple times in real-time is a bottleneck in research on aneuploid pregnancies. Plasma cell-free DNA (cfDNA) carries the gene expression profile information of its source cells and may be used to evaluate the development of fetuses with aneuploidy and the immune changes induced in the mother owing to fetal aneuploidy. METHODS: Here, we carried out whole-genome sequencing of the plasma cfDNA of 101 pregnant women carrying a fetus with trisomy (trisomy 21, n = 42; trisomy 18, n = 28; trisomy 13, n = 31) based on non-invasive prenatal testing (NIPT) screening and 140 normal pregnant women to identify differential genes according to the cfDNA nucleosome profile in the region around the transcription start sites (TSSs). RESULTS: The plasma cfDNA promoter profiles were found to differ between aneuploid and euploid pregnancies. A total of 158 genes with significant differences were identified, of which 43 genes were upregulated and 98 genes were downregulated. Functional enrichment and signaling pathway analysis were performed based on Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases found that these signal pathways were mainly related to the coordination of developmental signals during embryonic development, the control of cell growth and development, regulation of neuronal survival, and immune regulation, such as the MAPK, Hippo, TGF-ß, and Rap1 signaling pathways, which play important roles in the development of embryonic tissues and organs. Furthermore, based on the results of differential gene analysis, a total of 14 immune-related genes with significant differences from the ImmPort database were collected and analyzed. These significantly different immune genes were mainly associated with the maintenance of embryonic homeostasis and normal development. CONCLUSIONS: These results suggest that the distribution characteristics of cfDNA nucleosomes in maternal plasma can be used to reflect the status of fetal development and changes of the immune responses in trisomic pregnancies. Overall, our findings may provide research ideas for non-invasive detection of the physiological and pathological states of other diseases.


Assuntos
Ácidos Nucleicos Livres , Nucleossomos , Humanos , Feminino , Gravidez , Nucleossomos/genética , Nucleossomos/metabolismo , Transcriptoma , Aneuploidia , Feto/metabolismo , Trissomia , Ácidos Nucleicos Livres/genética
17.
Pediatr Rheumatol Online J ; 20(1): 104, 2022 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-36401314

RESUMO

BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening condition of immune dysregulation primarily driven by the cytokine interferon gamma. It can be either a genetic or acquired disorder associated with infection, malignancy, and rheumatologic disorders. Trisomy 21 can express a wide range of phenotypes which include immune dysregulation and shares inherent pathophysiology with a group of disorders termed interferonopathies. Knowledge of this overlap in seemingly unrelated conditions could provide a basis for future research, and most importantly, alternative therapeutic interventions in acute life threatening clinical scenarios. Herein, we describe two patients with trisomy 21 presenting with HLH that was refractory to conventional treatment. Both patients were successfully managed with novel interventions targeting the interferon pathway. CASE PRESENTATION: We describe a 17-month-old male and 15-month-old female with trisomy 21 presenting with a myriad of signs and symptoms including fever, rash, cytopenias, and hyperferritinemia, both ultimately diagnosed with HLH. Each had relapsing, refractory HLH over time requiring several admissions to the hospital receiving conventional high dose corticosteroids and interleukin-1 inhibition therapy. Successful steroid-free remission was achieved after targeting interferon inhibition with emapalumab induction followed by long-term maintenance on baricitinib. CONCLUSION: To our knowledge, these are the first reported cases of relapsed, refractory HLH in patients with trisomy 21 successfully treated with emapalumab and transitioned to a steroid-sparing regimen with oral baricitinib for maintenance therapy. Trisomy 21 autoimmunity and HLH are both thought to be driven by interferon gamma. Targeting therapy toward interferon signaling in both HLH and autoimmunity in trisomy 21 may have potential therapeutic benefits. Further investigation is needed to determine if trisomy 21 may predispose to the development of HLH given this common pathway.


Assuntos
Azetidinas , Síndrome de Down , Linfo-Histiocitose Hemofagocítica , Masculino , Feminino , Humanos , Interferons , Síndrome de Down/complicações , Interferon gama , Azetidinas/uso terapêutico , Trissomia , Linfo-Histiocitose Hemofagocítica/complicações , Linfo-Histiocitose Hemofagocítica/tratamento farmacológico , Linfo-Histiocitose Hemofagocítica/diagnóstico , Antivirais/uso terapêutico
18.
Genes (Basel) ; 13(11)2022 11 03.
Artigo em Inglês | MEDLINE | ID: mdl-36360264

RESUMO

A vanishing twin (VT) occurs in up to 30% of early diagnosed twin pregnancies and is associated with an increased risk of fetal aneuploidy. Here, we describe our experience in a large VT population of 847 patients that underwent noninvasive prenatal testing (NIPT) for common fetal trisomies over a three-year period. All patients underwent an ultrasound examination prior to NIPT. Two comparison populations were included, namely, the singleton (n = 105,560) and the viable multiple gestation pregnancy samples (n = 9691) collected over the same period. All NIPT samples in the VT population received a result, of which 14 were high-risk for trisomy 21 (1.6%), nine for trisomy 18 (1.1%), and six for trisomy 13 (0.7%). Diagnostic testing confirmed the presence of trisomy 21 in 6/12 samples, giving a positive predictive value of 50%. One trisomy 18 case and no trisomy 13 cases were confirmed. The time between fetal demise and NIPT sampling did not appear to affect the number of true- or false-positive cases. In conclusion, NIPT is an effective screening method for trisomy 21 in the surviving fetus(es) in VT pregnancies. For trisomies 18 and 13, a positive NIPT should be interpreted carefully and ultrasound monitoring is preferrable over invasive diagnostic testing.


Assuntos
Síndrome de Down , Teste Pré-Natal não Invasivo , Gravidez , Feminino , Humanos , Trissomia/diagnóstico , Trissomia/genética , Síndrome de Down/diagnóstico , Síndrome de Down/genética , Síndrome da Trissomía do Cromossomo 18/diagnóstico , Síndrome da Trissomía do Cromossomo 18/genética , Diagnóstico Pré-Natal/métodos , Síndrome da Trissomia do Cromossomo 13/diagnóstico , Síndrome da Trissomia do Cromossomo 13/genética
19.
BMC Med Genomics ; 15(1): 224, 2022 10 31.
Artigo em Inglês | MEDLINE | ID: mdl-36316743

RESUMO

BACKGROUND: To date, only twenty-one cases diagnosed postnatally with mosaic trisomy 12 have been reported. The most frequent phenotypic manifestations are developmental delay, dysmorphic facial features, congenital heart defects, digital alterations, and pigmentary disorders. In the present report, detailed clinical and genetic profiles of three unrelated new patients with mosaic trisomy 12 are described and compared with previously reported cases. CASE PRESENTATION: In the present report, we include the clinical, cytogenetic, and molecular description of three Mexican patients diagnosed postnatally with mosaic trisomy 12. At phenotypic level, the three patients present with developmental delay, dysmorphic facial features, congenital heart defects and skin pigmentary anomalies. Particularly, patient 1 showed unique eye alterations as bilateral distichiasis, triple rows of upper lashes, and digital abnormalities. In patient 2 redundant skin, severe hearing loss, and hypotonia were observed, and patient 3 presented with hypertelorism and telecanthus. Hyperpigmentation with disseminated pigmentary anomalies is a common trait in all of them. The cytogenetic study was carried out under the strict criteria of analysis, screening 50-100 metaphases from three different tissues, showing trisomy 12 mosaicism in at least one of the three different tissues analyzed. With SNParray, the presence of low-level mosaic copy number variants not previously detected by cytogenetics, and uniparental disomy of chromosome 12, was excluded. STR markers allowed to confirm the absence of uniparental disomy as well as to know the parental origin of supernumerary chromosome 12. CONCLUSIONS: The detailed clinical, cytogenetic, and molecular description of these three new patients, contributes with relevant information to delineate more accurately a group of patients that show a heterogeneous phenotype, although sharing the same chromosomal alteration. The possibility of detecting mosaic trisomy 12 is directly associated with the sensitivity of the methodology applied to reveal the low-level chromosomal mosaicism, as well as with the possibility to perform the analysis in a suitable tissue.


Assuntos
Transtornos Cromossômicos , Trissomia , Humanos , Trissomia/genética , Mosaicismo , Dissomia Uniparental/diagnóstico , Dissomia Uniparental/genética , Transtornos Cromossômicos/genética , Análise Citogenética
20.
Medicine (Baltimore) ; 101(43): e31559, 2022 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-36316914

RESUMO

INTRODUCTION: Myeloid sarcoma (MS) is an extramedullary tumor that consists of myeloblasts and rarely involves the female reproductive organs. Intestinal Behçet's disease (BD) is a chronic, inflammatory illness that is often associated with myelodysplastic syndrome (MDS). When MDS is diagnosed, some patients with intestinal BD experience synchronous gastrointestinal flares. CASE PRESENTATION: We report the case of a 49-year-old woman who presented with vaginal bleeding and an incidentally identified MS in the uterine cervix. Subsequent bone marrow biopsy showed simultaneous MDS without chromosomal abnormalities. This is the first reported case of concomitant MS, myelodysplastic disease, and intestinal BD. CONCLUSIONS: The accurate diagnosis of MSs that develop at non-predominant sites is crucial for a positive patient prognosis. MDS should be suspected in patients with a history of intestinal BD diagnosed with MS.


Assuntos
Síndrome de Behçet , Enteropatias , Síndromes Mielodisplásicas , Sarcoma Mieloide , Neoplasias do Colo do Útero , Humanos , Feminino , Pessoa de Meia-Idade , Síndrome de Behçet/complicações , Síndrome de Behçet/diagnóstico , Síndrome de Behçet/patologia , Sarcoma Mieloide/complicações , Sarcoma Mieloide/diagnóstico , Neoplasias do Colo do Útero/complicações , Neoplasias do Colo do Útero/diagnóstico , Trissomia , Síndromes Mielodisplásicas/complicações , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/patologia , Enteropatias/complicações , Enteropatias/diagnóstico
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