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1.
BMC Pregnancy Childbirth ; 24(1): 93, 2024 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-38297236

RESUMO

BACKGROUND: To evaluate the clinical significance of noninvasive prenatal testing (NIPT) for detecting fetal sex chromosome aneuploidies (SCAs) in Korean pregnant women. METHODS: We retrospectively analyzed NIPT data from 9,176 women with singleton pregnancies referred to the CHA Biotech genome diagnostics center. Cell-free fetal DNA (cffDNA) was extracted from maternal peripheral blood, and high-throughput massively parallel sequencing was conducted. Subsequently, the positive NIPT results for SCA were validated via karyotype and chromosomal microarray analyses. RESULTS: Overall, 46 cases were SCA positive after NIPT, including 20, 12, 8, and 6 for Turner, triple X, Klinefelter, and Jacob syndromes, respectively. Among 37 women with invasive prenatal diagnosis, 19 had true positive NIPT results. The overall positive predictive value (PPV) of NIPT for detecting SCAs was 51.35%. The PPV was 18.75% for Turner, 88.89% for triple X, 71.43% for Klinefelter, and 60.00% for Jacob's syndromes. NIPT accuracy for detecting sex chromosome trisomies was higher than that for sex chromosome monosomy (P = 0.002). No significant correlation was observed between fetal SCA incidence and maternal age (P = 0.914), except for the borderline significance of Jacob's syndrome (P = 0.048). No significant differences were observed when comparing NIPT and karyotyping validation for fetal SCA according to pregnancy characteristics. CONCLUSION: Our data suggest that NIPT can reliably screen for SCAs, and it performed better in predicting sex chromosome trisomies compared with monosomy X. No correlation was observed between maternal age and fetal SCA incidence, and no association was observed between different pregnancy characteristics. The accuracy of these findings requires improvements; however, our study provides an important reference for clinical genetic counseling and further management. Larger scale studies, considering confounding factors, are required for accurate evaluation.


Assuntos
Teste Pré-Natal não Invasivo , Transtornos dos Cromossomos Sexuais , Trissomia , Cariótipo XYY , Feminino , Gravidez , Humanos , Estudos Retrospectivos , Gestantes , Aneuploidia , Aberrações dos Cromossomos Sexuais , Diagnóstico Pré-Natal/métodos , Cromossomos Sexuais/genética , República da Coreia
2.
Orphanet J Rare Dis ; 18(1): 110, 2023 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-37161533

RESUMO

Hemophilia is an inherited bleeding disorder caused by deficiency of a specific coagulation factor. Factor VIII deficiency is responsible for hemophilia A while factor IX deficiency is responsible for hemophilia B. As per the 2020 annual global survey by the World Federation of Hemophilia, only 1828 Thai hemophiliacs have been registered to the national healthcare system. The reason for the low number is the underdiagnosis which is a major concern in the real-world practice among Asian countries. In Thailand, most hemophiliacs are diagnosed by general practitioners, pediatricians or internists at rural hospitals and are referred to hemophilia specialists at the Hemophilia Treatment Centers (HTCs). Despite the challenges pertaining to infrastructure and cost of treatment, Thailand has progressed substantially in providing the required hemophilia care, as evidenced by an evolution in acquiring and sharing knowledge as well as collaborative efforts among multiple stakeholders over the past three decades. In this letter-to-the-editor, the authors have summarized the practices for and challenges faced with hemophilia management in Thailand.


Assuntos
Clínicos Gerais , Hemofilia A , Hemofilia B , Medicina , Transtornos dos Cromossomos Sexuais , Humanos , Hemofilia A/terapia , Tailândia
3.
Mol Genet Genomics ; 298(3): 693-708, 2023 May.
Artigo em Inglês | MEDLINE | ID: mdl-37004560

RESUMO

Disorders of sexual development (DSD) are an abnormal congenital conditions associated with atypical development of the urogenital tract and external genital structures. The steroidogenic acute regulatory (STAR) gene, associated with congenital lipoid adrenal hyperplasia (CLAH), is included in the targeted gene panel for the DSD diagnosis. Therefore, the genetic alterations of the STAR gene and their molecular effect were examined in the CLAH patients affected with DSD. Ten different Iranian families including twelve male pseudo-hermaphroditism patients with CLAH phenotype were studied using genetic linkage screening and STAR gene sequencing in the linked families to the STAR locus. Furthermore, the structural, dynamical, and functional impacts of the variants on the STAR in silico were analyzed. Sanger sequencing showed the pathogenic variant p.A218V in STAR gene, as the first report in Iranian population. Moreover, modeling and simulation analysis were performed using tools such as radius of gyration, root mean square deviation (RMSD), root mean square fluctuation (RMSF), and molecular docking showed that p.A218V variant affects the residues interaction in cholesterol-binding site and the proper folding of STAR through increasing H-bound and the amount of α-Helix, deceasing total flexibility and changing fluctuations in some residues, resulting in reduced steroidogenic activity of the STAR protein. The study characterized the structural and functional changes of STAR caused by pathogenic variant p.A218V. It leads to limited cholesterol-binding activity of STAR, ultimately leading to the CLAH disease. Molecular dynamics simulation of STAR variants could help explain different clinical manifestations of CLAH disease.


Assuntos
Hiperplasia Suprarrenal Congênita , Fosfoproteínas , Humanos , Masculino , Hiperplasia Suprarrenal Congênita/genética , Hiperplasia Suprarrenal Congênita/diagnóstico , Irã (Geográfico) , Simulação de Acoplamento Molecular , Mutação , Fosfoproteínas/genética , Transtornos dos Cromossomos Sexuais/genética , Transtorno 46,XY do Desenvolvimento Sexual/genética
4.
Nature ; 615(7954): 900-906, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36922585

RESUMO

Sex chromosome disorders severely compromise gametogenesis in both males and females. In oogenesis, the presence of an additional Y chromosome or the loss of an X chromosome disturbs the robust production of oocytes1-5. Here we efficiently converted the XY chromosome set to XX without an additional Y chromosome in mouse pluripotent stem (PS) cells. In addition, this chromosomal alteration successfully eradicated trisomy 16, a model of Down's syndrome, in PS cells. Artificially produced euploid XX PS cells differentiated into mature oocytes in culture with similar efficiency to native XX PS cells. Using this method, we differentiated induced pluripotent stem cells from the tail of a sexually mature male mouse into fully potent oocytes, which gave rise to offspring after fertilization. This study provides insights that could ameliorate infertility caused by sex chromosome or autosomal disorders, and opens the possibility of bipaternal reproduction.


Assuntos
Engenharia Genética , Técnicas In Vitro , Oócitos , Cromossomo X , Animais , Feminino , Masculino , Camundongos , Oócitos/metabolismo , Oócitos/fisiologia , Cromossomo X/genética , Cromossomo Y/genética , Células-Tronco Pluripotentes/metabolismo , Síndrome de Down/genética , Síndrome de Down/terapia , Fertilização , Infertilidade/terapia , Homossexualidade Masculina , Transtornos dos Cromossomos Sexuais/complicações , Transtornos dos Cromossomos Sexuais/genética , Transtornos dos Cromossomos Sexuais/terapia , Engenharia Genética/métodos
5.
J Neurodev Disord ; 15(1): 8, 2023 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-36803654

RESUMO

BACKGROUND: Recurrent gene dosage disorders impart substantial risk for psychopathology. Yet, understanding that risk is hampered by complex presentations that challenge classical diagnostic systems. Here, we present a suite of generalizable analytic approaches for parsing this clinical complexity, which we illustrate through application to XYY syndrome. METHOD: We gathered high-dimensional measures of psychopathology in 64 XYY individuals and 60 XY controls, plus additional interviewer-based diagnostic data in the XYY group. We provide the first comprehensive diagnostic description of psychiatric morbidity in XYY syndrome and show how diagnostic morbidity relates to functioning, subthreshold symptoms, and ascertainment bias. We then map behavioral vulnerabilities and resilience across 67 behavioral dimensions before borrowing techniques from network science to resolve the mesoscale architecture of these dimensions and links to observable functional outcomes. RESULTS: Carriage of an extra Y-chromosome increases risk for diverse psychiatric diagnoses, with clinically impactful subthreshold symptomatology. Highest rates are seen for neurodevelopmental and affective disorders. A lower bound of < 25% of carriers are free of any diagnosis. Dimensional analysis of 67 scales details the profile of psychopathology in XYY, which survives control for ascertainment bias, specifies attentional and social domains as the most impacted, and refutes stigmatizing historical associations between XYY and violence. Network modeling compresses all measured symptom scales into 8 modules with dissociable links to cognitive ability, adaptive function, and caregiver strain. Hub modules offer efficient proxies for the full symptom network. CONCLUSIONS: This study parses the complex behavioral phenotype of XYY syndrome by applying new and generalizable analytic approaches for analysis of deep-phenotypic psychiatric data in neurogenetic disorders.


Assuntos
Transtornos dos Cromossomos Sexuais , Cariótipo XYY , Humanos , Masculino , Transtornos dos Cromossomos Sexuais/diagnóstico , Cognição , Fenótipo
6.
Br J Haematol ; 200(1): 23-34, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-35869698

RESUMO

Some non-factor products that work by facilitating the coagulation pathway (emicizumab) and blocking the anticoagulant pathway (fitusiran, concizumab and marstacimab) for patients with haemophilia (H) have been developed, and clinical trials using these products are currently ongoing. Prophylaxis using non-factor products by subcutaneous administration provides marked reductions of bleeding episodes in patients with HA or HB, regardless of the presence of inhibitor. Emicizumab has already been approved globally. Emicizumab alters the phenotype of patients with HA from severe to mild by maintaining trough levels of equivalent factor VIII activity (15-20 iu/dl). Phase 3 clinical trials and long-term observations assessing emicizumab revealed tolerable safety and efficacy. However, thrombotic events have occurred in patients receiving these non-factor products. Furthermore, monitoring of the haemostatic function of these products with concomitant therapy is also required in clinical practice. These products have promising haemostatic efficiency, but wider clinical experience is needed to provide optimal therapeutic strategies in the future.


Assuntos
Anticorpos Biespecíficos , Hemofilia A , Hemostáticos , Transtornos dos Cromossomos Sexuais , Humanos , Hemofilia A/complicações , Fator VIII/uso terapêutico , Hemostasia , Coagulação Sanguínea , Hemostáticos/uso terapêutico , Transtornos dos Cromossomos Sexuais/complicações
7.
Br J Haematol ; 200(2): 229-239, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-35999026

RESUMO

A phase 1b/2, three-month study of marstacimab, a human monoclonal antibody targeting tissue factor pathway inhibitor (TFPI), was conducted in participants with haemophilia A or B, with or without inhibitors. Participants assigned to four cohorts received escalating weekly doses based on inhibitor status (without inhibitors: 300 mg, a single 300-mg loading dose with subsequent 150-mg doses, or 450 mg; with inhibitors: 300 mg). Safety outcomes were treatment-emergent adverse events (TEAEs), injection site reactions, clinical and laboratory parameter changes. Efficacy was assessed by annualised bleeding rates (ABRs). Pharmacokinetics and pharmacodynamics (PD) were also evaluated. Among 26 treated participants [haemophilia A without inhibitor, n = 16 (61.5%); haemophilia A with inhibitor, n = 7 (26.9%); haemophilia B, n = 3 (11.5%)], 24 completed the study. Overall, 80.8% experienced TEAEs. ABR during treatment was significantly reduced versus an external on-demand control group (p < 0.0001) and versus pretreatment ABR (p < 0.0001), with significant reductions observed across all dose cohorts. Marstacimab exposure generally increased in a dose-related manner, with steady-state concentration reached by day 57. Changes in pharmacodynamic biomarkers occurred across all dose cohorts. Marstacimab was safe and well tolerated. Clinically meaningful reductions in ABR and treatment-related changes for all PD biomarkers indicated effective targeting of TFPI. (Clinicaltrials.gov identifier, NCT02974855).


Assuntos
Hemofilia A , Transtornos dos Cromossomos Sexuais , Humanos , Hemofilia A/tratamento farmacológico , Hemofilia A/induzido quimicamente , Anticorpos Monoclonais Humanizados/efeitos adversos , Lipoproteínas
8.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 39(7): 763-767, 2022 Jul 10.
Artigo em Chinês | MEDLINE | ID: mdl-35810438

RESUMO

OBJECTIVE: To explore the genetic basis for a child with mental retardation. METHODS: The child was subjected to chromosomal microarray analysis (CMA) and targeted capture next-generation sequencing for the exons of genes related to genetic and metabolic diseases. Candidate variants were verified by Sanger sequencing of the child and his parents. RESULTS: CMA suggested that the child has a 47,XYY karyotype. Next-generation sequencing revealed that the child has harbored compound heterozygous variants of the AUH gene, including c.677G>A (p.R226H) and c.373C>T (p.R125W), which were respectively inherited from his parents. Based on the American college of Medical Genetics and Genomics (ACMG) standards and guidelines, the c.677G>A (P.r226h) variant was predicted as variant of uncertain significance (PM2+PP4+PP3), whilst the c.373C>T (P.R125W) variant was predicted as likely pathogenic (PM1+PM2+PP3+PP4). CONCLUSION: The child had XYY syndrome in conjunct with 3-methylglutaenedioic aciduria type I due to biallelic pathogenic variants of the AUH gene.


Assuntos
Transtornos dos Cromossomos Sexuais , Cariótipo XYY , Criança , Testes Genéticos , Humanos , Masculino , Mutação
10.
BMC Urol ; 22(1): 16, 2022 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-35109852

RESUMO

BACKGROUND: The incidence of 47, XYY syndrome in live-born male infants is 1/1000. Due to its variable clinical symptoms, the diagnosis is easy to miss. The incidence of congenital bilateral absence of the vas deferens (CBAVD) in infertile men is 1-2%. The main cause is the mutation of CFTR and ADGAG2 genes. CASE PRESENTATION: The patient was a 33-year-old man who visited a doctor 5 years ago due to infertility. The investigation revealed that the patient's secondary sexual characteristics, testicular, and penis development were normal, and there was no gynecomastia, but the bilateral vas deferens and epididymis were not palpable. Transrectal ultrasound showed that the left seminal vesicle was missing, and the right seminal vesicle was atrophied. No abnormality was observed in Y chromosome microdeletion. Karyotype analysis indicated that the patient was 46, XY/47, XYY mosaic. Genetic testing found heterozygous mutations at two sites of CFTR (c263T > G and c2249C > T). CONCLUSIONS: Herein, we report the rare case of a male patient with clinical manifestations of infertility, chromosome 46, XY/47, XXY mosaic type, simultaneously manifested as the absence of bilateral vas deferens. Two pathogenic heterozygous CFTR gene mutations were found. Given the low genetic risk of the disease, we recommend that patients undergo intracytoplasmic sperm injection (ICSI) for fertility assessment.


Assuntos
Transtornos dos Cromossomos Sexuais/diagnóstico , Ducto Deferente/anormalidades , Cariótipo XYY/diagnóstico , Adulto , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Heterozigoto , Humanos , Infertilidade Masculina/genética , Infertilidade Masculina/terapia , Cariotipagem , Masculino , Mutação , Transtornos dos Cromossomos Sexuais/diagnóstico por imagem , Injeções de Esperma Intracitoplásmicas , Ultrassonografia , Cariótipo XYY/diagnóstico por imagem
12.
Mutat Res Rev Mutat Res ; 788: 108389, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34893154

RESUMO

As human life expectancy increases substantially and aging is the primary risk factor for most chronic diseases, there is an urgent need for advancing the development of post-genomic era biomarkers that can be used for disease prediction and early detection (DPED). Mosaic loss of Y chromosome (LOY) is the state of nullisomy Y in sub-groups of somatic cells acquired from different post-zygotic development stages and onwards throughout the lifespan. Multiple large-cohort based epidemiology studies have found that LOY in blood cells is a significant risk factor for future mortality and various diseases in males. Many features intrinsic to LOY analysis may be leveraged to enhance its use as a non-invasive, sensitive, reliable, high throughput-biomarker for DPED. Here, we review the emerging literatures in LOY studies and highlight ten strengths for using LOY as a novel biomarker for genomics-driven DPED diagnostics. Meanwhile, the current limitations in this area are also discussed. We conclude by identifying some important knowledge gaps regarding the consequences of malsegregation of the Y chromosome and propose further steps that are required before clinical implementation of LOY. Taken together, we think that LOY has substantial potential as a biomarker for DPED, despite some hurdles that still need to be addressed before its integration into healthcare becomes acceptable.


Assuntos
Cromossomos Humanos Y/genética , Monossomia , Teste Pré-Natal não Invasivo/métodos , Transtornos dos Cromossomos Sexuais/genética , Diagnóstico Precoce , Feminino , Humanos , Masculino , Transtornos dos Cromossomos Sexuais/diagnóstico
14.
Taiwan J Obstet Gynecol ; 60(4): 778-780, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34247825

RESUMO

OBJECTIVE: We present mosaic Xq duplication, or 46,X,der(X)dup(X)(q22.1q22.2)dup(X)(q25q22.3)/46,XX at amniocentesis in a pregnancy with a favorable outcome. CASE REPORT: A 40-year-old woman underwent amniocentesis at 16 weeks of gestation because of advanced maternal age. Amniocentesis revealed a result of 46,X,der(X)dup(X)(q22.1q22.2)dup(X)(q25q22.3)[7]/46,XX[20]. Simultaneous array comparative genomic hybridization (aCGH) analysis on the DNA extracted from uncultured amniocytes revealed the result of arr (1-22, X) × 2. Cytogenetic analysis on maternal blood revealed a karyotype of 46,XX. At 22 weeks of gestation, she underwent repeat amniocentesis which revealed a karyotype of 46,XX in 22/22 colonies of cultured amniocytes and an aCGH result of (1-22, X) × 2 in the uncultured amniocytes. Prenatal ultrasound findings were unremarkable. The parents decided to continue the pregnancy, and a healthy female baby was delivered at 39 weeks of gestation with a body weight of 3510 g and a body length of 49 cm. The cord blood had a karyotype of 46,X,der(X)dup(X)(q22.1q22.2)dup(X)(q25q22.3)[3]/46,XX[37]. At age two months, interphase fluorescence in situ hybridization (FISH) analysis on buccal mucosal cells showed Xq duplication signals in 1.25% (1/80 cells), compared with 0% (0/90 cells) in the normal control. At age nine months, the neonate had normal physical and psychomotor development. Her body weight was 9.6 Kg (85th - 97th centile), and body length was 72 cm (50th - 85th centile). Cytogenetic analysis of peripheral blood revealed a karyotype of 46,X,der(X)dup(X) (q22.1q22.2)dup(X)(q25q22.3)[1]/46,XX[39]. Interphase FISH analysis on 100 buccal mucosal cells revealed no abnormal signal. CONCLUSION: In case of mosaicism for an Xq duplication with a normal euploid cell line at amniocentesis, the in-vitro culture process of amniocytes may cause over-estimation of the mosaic level for the aberrant chromosome because of culture artifacts, and the abnormal cell line can decline after birth.


Assuntos
Nascido Vivo/genética , Mosaicismo/embriologia , Transtornos dos Cromossomos Sexuais/diagnóstico , Trissomia/diagnóstico , Adulto , Amniocentese , Cromossomos Humanos X/genética , Hibridização Genômica Comparativa , Análise Citogenética , Feminino , Humanos , Hibridização in Situ Fluorescente , Lactente , Recém-Nascido , Cariótipo , Gravidez , Aberrações dos Cromossomos Sexuais/embriologia , Transtornos dos Cromossomos Sexuais/embriologia , Transtornos dos Cromossomos Sexuais/genética , Trissomia/genética
15.
Clin Epigenetics ; 13(1): 136, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34210361

RESUMO

BACKGROUND: Equal dosage of X-linked genes between males and females is maintained by the X-inactivation of the second X chromosome in females through epigenetic mechanisms. Boys with aneuploidy of the X chromosome exhibit a host of symptoms such as low fertility, musculoskeletal anomalies, and cognitive and behavioral deficits that are presumed to be caused by the abnormal dosage of these genes. The objective of this pilot study is to assess the relationship between CpG methylation, an epigenetic modification, at several genes on the X chromosome and behavioral dysfunction in boys with supernumerary X chromosomes. RESULTS: Two parental questionnaires, the Behavior Rating Inventory of Executive Function (BRIEF) and Child Behavior Checklist (CBCL), were analyzed, and they showed expected differences in both internal and external behaviors between neurotypical (46,XY) boys and boys with 49,XXXXY. There were several CpGs in AR and MAOA of boys with 49,XXXXY whose methylation levels were skewed from levels predicted from having one active (Xa) and three inactive (Xi) X chromosomes. Further, methylation levels of multiple CpGs in MAOA showed nominally significant association with externalizing behavior on the CBCL, and the methylation level of one CpG in AR showed nominally significant association with the BRIEF Regulation Index. CONCLUSIONS: Boys with 49,XXXXY displayed higher levels of CpG methylation at regulatory intronic regions in X-linked genes encoding the androgen receptor (AR) and monoamine oxidase A (MAOA), compared to that in boys with 47,XXY and neurotypical boys. Our pilot study results suggest a link between CpG methylation levels and behavior in boys with 49,XXXXY.


Assuntos
Metilação de DNA/genética , Comportamento Problema/psicologia , Transtornos dos Cromossomos Sexuais/diagnóstico , Cariótipo XYY/diagnóstico , Aneuploidia , Pré-Escolar , Cromossomos Humanos X , Humanos , Lactente , Masculino , Projetos Piloto , Psicometria/instrumentação , Psicometria/métodos , Aberrações dos Cromossomos Sexuais , Transtornos dos Cromossomos Sexuais/epidemiologia , Transtornos dos Cromossomos Sexuais/genética , Transtornos dos Cromossomos Sexuais/psicologia , Inquéritos e Questionários , Cariótipo XYY/genética , Cariótipo XYY/psicologia
16.
Am J Med Genet A ; 185(11): 3236-3241, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34056828

RESUMO

An account is given of the introduction of human cytogenetics to the Division of Medical Genetics at Johns Hopkins Hospital, and the first 3 years' work of the chromosome diagnostic laboratory that was established at the time. Research on human sex chromosome disorders, including novel discoveries in the Turner and Klinefelter syndromes, is described together with original observations on chromosome behavior at mitosis. It is written in celebration of the centenary of the birth of Victor McKusick, the acknowledged father of Medical Genetics, who established the Division and had the foresight to ensure that it included the investigation of human chromosomes.


Assuntos
Citogenética/história , Síndrome de Klinefelter/genética , Transtornos dos Cromossomos Sexuais/genética , Síndrome de Turner/genética , Aberrações Cromossômicas , História do Século XX , Hospitais , Humanos , Síndrome de Klinefelter/diagnóstico , Síndrome de Klinefelter/história , Aberrações dos Cromossomos Sexuais , Transtornos dos Cromossomos Sexuais/diagnóstico , Transtornos dos Cromossomos Sexuais/história , Síndrome de Turner/diagnóstico , Síndrome de Turner/história
17.
J Gene Med ; 23(9): e3362, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33973298

RESUMO

OBJECTIVE: The present study aimed to evaluate the efficacy of a non-invasive prenatal test (NIPT) in the detection of the sex chromosome aneuploidies (SCAs) at our prenatal diagnosis centre. METHODS: Among a cohort of 34,717 pregnancies, maternal plasma samples from our prenatal diagnosis centre were subject to analysis of SCAs using NIPT detection. Pregnant women with NIPT positive results of SCAs were recommended to undergo an invasive prenatal diagnosis (i.e. karyotyping and fluorescence in situ hybridization) to validate the prediction value of NIPT. RESULTS: From 34,717 clinical pregnancies, 229 (0.66%) pregnancies were identified with SCAs. Of these, 78 (34.1%) cases were positive for 45,X and 151 (65.9%) cases comprised a sex chromosome trisomy. Of the 229 positive NIPT results, 193 (84.3%) cases had accepted an invasive diagnosis involving karyotyping analysis of the amniotic fluid, which confirmed 67 cases (34.7%) as true positive, as well as 126 cases (65.3%) as false positive. The positive predictive values were 23.07%, 50%, 36% and 27.27% respectively. The remaining 36 (15.7%) cases declined a prenatal diagnosis. The termination rates of 45,X, 47,XXY, 47,XXX and 47,XYY were 20.5%,46%,12.9% and 11.5% respectively. CONCLUSIONS: NIPT demonstrated a lower accuracy in predicting monosomy X than sex chromosome trisomies. After invasive testing, the fetal chromosome with 45,X and 47,XXY were terminated more often than those with 47,XXX, 47,XYY. Because NIPT is a screening test, false positive/negative cases exist, and pre- and post-test counselling is essential for informing patients about the benefits and limitations of the test. Confirmatory testing of abnormal results is recommended prenatally or after birth, and the importance of confirmatory testing and benefits of early diagnosis should be addressed.


Assuntos
Aneuploidia , Testes Genéticos/métodos , Teste Pré-Natal não Invasivo/métodos , Diagnóstico Pré-Natal/métodos , Aberrações dos Cromossomos Sexuais , Transtornos dos Cromossomos Sexuais/diagnóstico , Adolescente , Adulto , China , Feminino , Humanos , Hibridização in Situ Fluorescente , Cariotipagem/métodos , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Gravidez , Resultado da Gravidez , Estudos Retrospectivos , Transtornos dos Cromossomos Sexuais/genética , Adulto Jovem
18.
Neuroreport ; 32(7): 541-547, 2021 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-33850088

RESUMO

BACKGROUND: 47,XYY syndrome (XYY) is a male sex chromosome disorder where subjects have one X chromosome and two copies of the Y chromosome. XYY is associated with a physical phenotype and carries increased risk of neurodevelopmental disorders such as autism spectrum disorder (ASD). Imbalance of excitation and inhibition has been proposed as a putative biological basis of disorders such as ASD [1-3] and several studies have reported atypical brain γ-aminobutyric acid (GABA) levels in this population. Given the male preponderance in the prevalence of ASD, the unique presence of the Y chromosome in males leads to the intriguing possibility of investigating boys with XYY syndrome as a model of excess Y-chromosome genes. METHOD: In this study, we investigated the associations of genotype and clinical phenotype with levels of GABA, estimated by regionally localized edited magnetic resonance spectroscopy in boys with 47, XYY syndrome compared to age-matched typically developing (XY) peers. RESULTS: Overall, we observed a decrease in GABA levels in XYY vs. XY, which appeared more significant in the left compared to the right hemisphere. There was no additional significant modulation of GABA levels in XYY according to presence/absence of ASD diagnosis. Interestingly, a positive correlation between bilateral GABA levels and testosterone levels was observed in pubescent XY boys that was not observed in XYY. CONCLUSION: The inhibitory neurotransmitter GABA appears to be reduced in boys with 47,XYY, especially in the left hemisphere. Further, the typical association between GABA and testosterone levels, observed in older typically developing control boys was not evident in boys with 47,XYY.


Assuntos
Transtornos dos Cromossomos Sexuais/metabolismo , Lobo Temporal/metabolismo , Cariótipo XYY/metabolismo , Ácido gama-Aminobutírico/metabolismo , Adolescente , Criança , Humanos , Espectroscopia de Ressonância Magnética , Masculino , Transtornos dos Cromossomos Sexuais/diagnóstico por imagem , Lobo Temporal/diagnóstico por imagem , Cariótipo XYY/diagnóstico por imagem
19.
Ophthalmic Genet ; 42(3): 320-325, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33719903

RESUMO

Purpose: To describe a family with presumed SOX2 gonadosomatic mosaicism diagnosed upon ophthalmic examination of the proband's mother.Methods: The family underwent comprehensive ophthalmic and physical examination. Variant detection was performed using trio exome analysis on peripheral leukocyte DNA from blood and saliva samples. Variant segregation analysis was performed using a custom panel NGS sequencing. An identified variant in the SOX2 gene was confirmed in the proband by Sanger sequencing.Results: We report an individual with bilateral microphthalmia, developmental delay, hearing loss, and dysmorphic features. Her mother was found to have asymptomatic forme fruste uveal coloboma affecting her anterior segment. Her father, aunt, and sisters were unaffected. Trio exome sequence analysis showed an apparent de novo heterozygous deletion in the proband, NM_003106.3:c.70_89del, NP_003097.1:p.(Asn24Argfs*65), classified as pathogenic. Testing of the other family members' peripheral blood and saliva was negative for this variant. The iris transillumination abnormalities in the proband's mother supports a gonadosomatic mosaicism scenario.Conclusions: The results from this family underscore the importance of performing detailed evaluations of the parents of apparently sporadically affected individuals with heritable ophthalmic disorders. The identification of mildly affected individuals could substantially alter recurrence risks.


Assuntos
Microftalmia/diagnóstico , Mosaicismo , Fatores de Transcrição SOXB1/genética , Transtornos dos Cromossomos Sexuais/diagnóstico , Adulto , Anormalidades Craniofaciais/diagnóstico , Anormalidades Craniofaciais/genética , Deficiências do Desenvolvimento/diagnóstico , Deficiências do Desenvolvimento/genética , Feminino , Perda Auditiva/diagnóstico , Perda Auditiva/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Recém-Nascido , Masculino , Microftalmia/genética , Linhagem , Transtornos dos Cromossomos Sexuais/genética , Sequenciamento do Exoma
20.
J Neurodev Disord ; 13(1): 12, 2021 03 22.
Artigo em Inglês | MEDLINE | ID: mdl-33752588

RESUMO

BACKGROUND: Disorders of gene dosage can significantly increase risk for psychopathology, but outcomes vary greatly amongst carriers of any given chromosomal aneuploidy or sub-chromosomal copy number variation (CNV). One potential path to advance precision medicine for neurogenetic disorders is modeling penetrance in probands relative to observed phenotypes in their non-carrier relatives. Here, we seek to advance this general analytic framework by developing new methods in application to XYY syndrome-a sex chromosome aneuploidy that is known to increase risk for psychopathology. METHODS: We analyzed a range of cognitive and behavioral domains in XYY probands and their non-carrier family members (n = 58 families), including general cognitive ability (FSIQ), as well as continuous measures of traits related to autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD). Proband and relative scores were compared using covariance, regression and cluster analysis. Comparisons were made both within and across traits. RESULTS: Proband scores were shifted away from family scores with effect sizes varying between 0.9 and 2.4 across traits. Only FSIQ and vocabulary scores showed a significant positive correlation between probands and their non-carrier relatives across families (R2 ~ 0.4). Variability in family FSIQ also cross-predicted variability in proband ASD trait severity. Cluster analysis across all trait-relative pairings revealed that variability in parental psychopathology was more weakly coupled to their XYY versus their euploid offspring. CONCLUSIONS: We present a suite of generalizable methods for modeling variable penetrance in aneuploidy and CNV carriers using family data. These methods update estimates of phenotypic penetrance for XYY and suggest that the predictive utility of family data is likely to vary for different traits and different gene dosage disorders. TRIAL REGISTRATIONS: ClinicalTrials.gov NCT00001246 , "89-M-0006: Brain Imaging of Childhood Onset Psychiatric Disorders, Endocrine Disorders and Healthy Controls." Date of registry: 01 October 1989.


Assuntos
Transtornos dos Cromossomos Sexuais , Cariótipo XYY , Adolescente , Adulto , Transtorno do Espectro Autista , Criança , Pré-Escolar , Variações do Número de Cópias de DNA , Família , Humanos , Masculino , Adulto Jovem
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