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1.
Zhejiang Da Xue Xue Bao Yi Xue Ban ; 49(5): 586-590, 2020 Oct 25.
Artigo em Chinês | MEDLINE | ID: mdl-33210484

RESUMO

OBJECTIVE: To perform gene mutation analysis in a patient with atypical clinical manifestations of tuberous sclerosis (TSC) for definite diagnosis. METHODS: Peripheral blood DNA was obtained from a patient with clinically suspected TSC and her parents, and all exons and their flanking sequences of TSC1 and TSC2 genes in the proband were sequenced by whole exome sequencing to determine the candidate pathogenic mutations. At the same time, Sanger sequencing was performed to verify the peripheral blood DNA of the patient and her parents. And the mosaic percentage of the mutation in the proband's somatic cells was detected by the droplet digital PCR method. RESULTS: A heterozygous nonsense mutation c.1096G>T (p.E366*) was identified in the exon 11 of the TSC2 gene, which only had a small mutation peak. A lower percentage of the mutation was found in the DNA of the patient than that in the public database, therefore the possibility of mosaicism might not be excluded. In addition, the droplet digital PCR method demonstrated that the proband was a c.1096G>T mutant mosaicism, and the mosaic percentage was 14%. CONCLUSIONS: The somatic mosaic mutation c.1096G>T (p.e366*) may be responsible for the phenotype of TSC in this patient. And the drop digital PCR is expected to be a diagnostic method for somatic cells mosaicism.


Assuntos
Mutação , Proteína 2 do Complexo Esclerose Tuberosa , Esclerose Tuberosa , Feminino , Humanos , Masculino , Mosaicismo , Esclerose Tuberosa/genética , Proteína 2 do Complexo Esclerose Tuberosa/genética , Sequenciamento Completo do Exoma
2.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(11): 1265-1268, 2020 Nov 10.
Artigo em Chinês | MEDLINE | ID: mdl-33179236

RESUMO

OBJECTIVE: To explore the genetic cause of a patient suspected for congenital ectodermal dysplasia with repeated hyperthermia and to assess the reproductive risk for his family. METHODS: Medical whole-exome sequencing (WES) were used to detect single-nucleotide variations and low-coverage massively parallel copy number variation sequencing (CNV-seq) were employed to verify suspected CNVs. PCR and real-time quantitative PCR were applied to confirm the deletion of EDA gene. RESULTS: The results of WES suggested that the patient carried a hemizygous deletion for chrX:69 243 016-69 395 730. CNV-seq indicated that the patient carried a deletion of approximately 0.12 Mb on Xq13.1, which encompassed the EDA gene. The PCR results confirmed that there was a hemizygous deletion of exons 3 to 8 of the EDA gene. The same deletion was not found in his mother. CONCLUSION: The congenital ectodermal dysplasia of the patient may be attributed to deletion of exons 3 to 8 of the EDA gene, which could be de novo or derive from germline mosaicism of his mother. The WES and CNV-seq are of great value for the diagnosis of rare diseases.


Assuntos
Variações do Número de Cópias de DNA , Displasia Ectodérmica , Sequenciamento Completo do Exoma , Displasia Ectodérmica/genética , Ectodisplasinas/genética , Éxons , Testes Genéticos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Mosaicismo , Deleção de Sequência
3.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(11): 1276-1279, 2020 Nov 10.
Artigo em Chinês | MEDLINE | ID: mdl-33179239

RESUMO

OBJECTIVE: To carry out prenatal diagnosis for a fetus with Pallister-killian syndrome (PKS). METHODS: The fetus was found to have limb malformations at 23rd gestational week. With informed consent from its parents, amniotic fluid sample was taken from the fetus and subjected to chromosomal karyotyping, chromosomal microarray analysis (CMA) and fluorescence in situ hybridization (FISH) assay. RESULTS: G-banding analysis suggested the fetus has a mos47,XY,+mar[55]/46,XY[10] karyotype. CMA analysis of the cultured amniocytes with CytoScan 750K microarray revealed a segmental tetrasomy duplication of 12p13.33p11.1. FISH confirmed a 70% mosaicism of tetrasomy 12p in the metaphase amniocytes with 12pter/12qter probes. CONCLUSION: Combined use of G-banding karyotyping, CMA and FISH analysis has enabled diagnosis of PKS in the fetus. Although short limb is a common feature of PKS, unequal femur length has not been reported previously, which has expanded the spectrum of PKS-associated limb abnormalities.


Assuntos
Transtornos Cromossômicos/diagnóstico , Diagnóstico Pré-Natal , Transtornos Cromossômicos/genética , Cromossomos Humanos Par 12/genética , Feminino , Feto , Humanos , Hibridização in Situ Fluorescente , Mosaicismo , Gravidez
4.
Medicine (Baltimore) ; 99(40): e22223, 2020 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-33019396

RESUMO

RATIONALE: Mixed gonadal dysgenesis is a rare disorder of sex development, and typically contains a mosaic 45,X/46,XY karyotype. PATIENT CONCERNS: We reported here a case of a 42-year-old man with infertility for 6 years and inability to ejaculate during intercourse. DIAGNOSIS: Physical examination confirmed that the external genitalia was male. The right testis of this patient was resected and the left testis had intrascrotal calcification. Hormone test showed that the level of follicle-stimulating hormone was 20.14 IU/L (normal range, 1.27-19.26 IU/L). No deletion or mutation was found on the sex-determining region Y. H&E staining revealed seminiferous tubule dysgenesis. The karyotyping in peripheral blood and testicular tissue was 45,X/46,XY and 45,X/47,XYY/46,XY, respectively. Based on these results, the patient was diagnosed with 45,X/46,XY or 45,X/47,XYY/46,XY mosaicism and gonadal dysgenesis. INTERVENTIONS: In vitro fertilization and embryo transfer technology were used to help his wife to achieve pregnancy. OUTCOMES: A normal baby boy was born at 36 weeks of gestation with a karyotype 46, XY. LESSONS: We reported a rare case of a karyotype 45,X/46,XY in blood cells and 45,X/47, XYY/46,XY in testicular tissue. In vitro fertilization and embryo transfer technology can help to achieve pregnancy.


Assuntos
Disgenesia Gonadal Mista/genética , Injeções de Esperma Intracitoplásmicas/métodos , Adulto , Feminino , Disgenesia Gonadal Mista/complicações , Disgenesia Gonadal Mista/diagnóstico , Humanos , Infertilidade Masculina/etiologia , Masculino , Mosaicismo , Gravidez , Resultado da Gravidez , Recuperação Espermática
5.
Medicine (Baltimore) ; 99(35): e21949, 2020 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-32871942

RESUMO

RATIONALE: Rhabdomyoma is the most common type of fetal heart tumors and 50% to 60% of cardiac rhabdomyomas are associated with tuberous sclerosis complex (TSC). TSC is characterized by hamartomas in multiple organ systems including the brain, heart, skin, lungs, and kidneys, resulting in complications such as learning difficulties, epilepsy, behavioral problems, and renal failure. The etiological diagnosis of Rhabdomyoma is very important. PATIENT CONCERNS: A 22-year-old G2P0 woman chose to terminate the pregnancy at 24 + 4 weeks of gestation because of the presence of a cardiac space-occupying lesion in the fetus. DIAGNOSES: The pathological diagnosis of cardiac neoplasm tissue was cardiac rhabdomyoma, but the etiology was unknown. INTERVENTIONS: Targeted exome capture, next-generation sequencing (NGS) and sanger sequencing were performed on peripheral blood lymphocytes and paternal sperm. OUTCOMES: Targeted exome capture sequencing revealed a novel heterozygous variant (NM_000548, c.2294delC) in the tuberous sclerosis 2 (TSC2) gene. Sanger sequencing of maternal blood samples showed no mutation at this locus, however, suspected low level mosaicism was observed in paternal blood samples. Deep NGS analysis showed that about 7% paternal alleles from peripheral blood leucocytes and 20% paternal alleles from sperm carried the mutation consistent with somatic and germinal mosaicism. LESSONS: For fetuses suspected of TSC, when pathogenic mutations are detected in the tuberous sclerosis 1 (TSC1) or TSC2 gene, it is recommended that the parents should be screened by deep NGS and their germ cells are screened as well if necessary, which would help to predict the risk of TSC recurrence in the next pregnancy.


Assuntos
Doenças Fetais/genética , Neoplasias Cardíacas/genética , Rabdomioma/genética , Proteína 2 do Complexo Esclerose Tuberosa/genética , Feminino , Doenças Fetais/diagnóstico por imagem , Neoplasias Cardíacas/diagnóstico por imagem , Humanos , Mosaicismo , Gravidez , Rabdomioma/diagnóstico por imagem , Ultrassonografia Pré-Natal , Adulto Jovem
6.
Clin Dermatol ; 38(4): 408-420, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32972600

RESUMO

Genodermatoses are inherited disorders presenting with cutaneous manifestations with or without the involvement of other systems. The majority of these disorders, particularly in cases that present with a cutaneous patterning, may be explained in the context of genetic mosaicism. Despite the barriers to the genetic analysis of mosaic disorders, next-generation sequencing has led to a substantial progress in understanding their pathogenesis, which has significant implications for the clinical management and genetic counseling. Advances in paired and deep sequencing technologies in particular have made the study of mosaic disorders more feasible. In this review, we provide an overview of genetic mosaicism as well as mosaic cutaneous disorders and the techniques required to study them.


Assuntos
Mosaicismo , Dermatopatias Genéticas/diagnóstico , Dermatopatias Genéticas/genética , Feminino , Aconselhamento Genético , Testes Genéticos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Fenótipo , Dermatopatias Genéticas/etiologia , Dermatopatias Genéticas/patologia
7.
Pediatrics ; 146(4)2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32938777

RESUMO

BACKGROUND AND OBJECTIVES: Genetic testing is recommended for individuals with autism spectrum disorder (ASD). Pathogenic yield varies by clinician and/or patient characteristics. Our objectives were to determine the pathogenic yield of genetic testing, the variability in rate of pathogenic results based on subject characteristics, and the percentage of pathogenic findings resulting in further medical recommendations in toddlers with a Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition diagnosis of ASD. METHODS: We conducted a retrospective chart review of 500 toddlers, 18 to 36 months, diagnosed with Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition ASD (mean age: 25.8 months, 79% male). Subject demographics, medical and neuropsychological characteristics, and genetic test results were abstracted. Genetic results were divided into negative or normal, variants of unknown significance, and pathogenic. Subject characteristics were compared across results. Manual chart review determined if further recommendations were made after pathogenic results. RESULTS: Over half of subjects (59.8%, n = 299) completed genetic testing, and of those, 36 (12.0%) had pathogenic findings. There were no significant differences in Bayley Scales of Infant Development cognitive (P = .112), language (P = .898), or motor scores (P = .488) among children with negative or normal findings versus a variant of unknown significance versus pathogenic findings. Medical recommendations in response to the genetic finding were made for 72.2% of those with pathogenic results. CONCLUSIONS: Our findings reinforce the importance of genetic testing for toddlers diagnosed with ASD given the 12% yield and lack of phenotypic differences between subjects with and without pathogenic findings. The majority of pathogenic results lead to further medical recommendations.


Assuntos
Transtorno do Espectro Autista/genética , Testes Genéticos/estatística & dados numéricos , Transtorno do Espectro Autista/diagnóstico , Transtornos Dismórficos Corporais/diagnóstico , Transtornos Dismórficos Corporais/genética , Pré-Escolar , Cromossomos Humanos 13-15 , Cognição , Manual Diagnóstico e Estatístico de Transtornos Mentais , Feminino , Proteína do X Frágil de Retardo Mental/genética , Deleção de Genes , Duplicação Gênica , Testes Genéticos/métodos , Humanos , Lactente , Desenvolvimento da Linguagem , Masculino , Análise em Microsséries , Mosaicismo , Destreza Motora , Mutação , Fenótipo , Encaminhamento e Consulta , Estudos Retrospectivos
8.
Adv Exp Med Biol ; 1298: 177-187, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32852734

RESUMO

Protocadherin-19 (PCDH19) pathogenic variants cause an infantile onset epilepsy syndrome called Girls Clustering Epilepsy due to the vast majority of affected individuals being female. This syndromic name was developed to foster early recognition and diagnosis in infancy. It has, however, sparked debate, as, there are rare males with postzygotic somatic, and therefore, mosaic, PCDH19 pathogenic variants with similar clinical features to females. Conversely, "transmitting" males with germline inherited PCDH19 variants are considered asymptomatic. To date, there has been no standardized neuropsychiatric assessment of males with PCDH19 pathogenic variants. Here, we studied 15 males with PCDH19 pathogenic variants (nine mosaic and six transmitting) aged 2 to 70 years. Our families completed a survey including standardized clinical assessments: Social Responsiveness Scale, Strengths and Difficulties Questionnaire, Behavior Rating Inventory of Executive Function, and Dimensional Obsessive-Compulsive Scale. We identified neuropsychiatric abnormalities in two males with germline PCDH19 possibly pathogenic variants. One had a prior history of a severe encephalopathic illness, which may have been unrelated. We also describe a non-penetrant somatic mosaic male with mosaicism confirmed in blood, but not identified in skin fibroblasts. Our data suggest that transmitting hemizygous males are generally unaffected, in contrast to males with postzygotic somatic mosaic variants who show a similar neuropsychiatric profile to females who are naturally mosaic, due to X-chromosome inactivation. The penetrance of PCDH19 pathogenic variants has been estimated to be 80%. Like females, not all mosaic males are affected. From our small sample, we estimate that males with mosaic PCHD19 pathogenic variants have a penetrance of 85%. With these insights into the male phenotypic spectrum of PCDH19 epilepsy, we propose the new term Clustering Epilepsy (CE). Both affected females and males typically present with infantile onset of clusters of seizures.


Assuntos
Caderinas/genética , Epilepsia , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Epilepsia/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mosaicismo , Mutação , Penetrância , Adulto Jovem
9.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(8): 839-842, 2020 Aug 10.
Artigo em Chinês | MEDLINE | ID: mdl-32761590

RESUMO

OBJECTIVE: To explore the mechanism of a false-negative result from karyotyping of chorionic villi cells for a trisomy 13 fetus featuring multiple malformations. METHODS: For a fetus with multiple malformations by ultrasonography and a 46,XY karyotype by chorionic villi analysis, amniocytes were further analyzed with quantitative fluorescence PCR (QF-PCR), G-banded karyotyping and chromosomal microarray analysis (CMA). Meanwhile, non-invasive prenatal testing (NIPT) was conducted on peripheral blood sample from the pregnant woman to determine the chromosomal composition of cytotrophoblast. After induction of labor, common aneuploidies in placenta and fetal tissue were also analyzed by QF-PCR. RESULTS: QF-PCR, chromosomal karyotyping and CMA analysis of the amniocytes all suggested complete trisomy 13 (47,XY,+13) in the fetus. NIPT also suggested existence of fetal trisomy 13. QF-PCR analysis of the placenta and fetal tissues revealed that cells derived from the maternal surface and right side of fetal surface harbored mosaic trisomy 13, while those derived from other sites of fetal surface of the placenta, umbilical cord, amniotic membrane and fetal muscle tissue harbored trisomy 13. CONCLUSION: Karyotyping of long-term cultured chorionic villus sample may give rise to false negative results due to placental mosaicism. To ensure accurate prenatal diagnosis, discordance between karyotyping of chorionic villi cells, fetal ultrasound and NIPT result should be verified by amniocentesis or cordocentesis and application of multiple cytogenetic and molecular techniques.


Assuntos
Amostra da Vilosidade Coriônica , Cariotipagem , Diagnóstico Pré-Natal , Síndrome da Trissomia do Cromossomo 13/genética , Amniocentese , Feminino , Feto , Humanos , Cariótipo , Mosaicismo , Gravidez , Síndrome da Trissomia do Cromossomo 13/diagnóstico
10.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(9): 934-937, 2020 Sep 10.
Artigo em Chinês | MEDLINE | ID: mdl-32820502

RESUMO

OBJECTIVE: To apply single cell sequencing based on multiple annealing and looping amplification cycles (MALBAC) for the determination of the rate and type of mosaicisms of high-quality embryos at cleavage stage. METHODS: After thawing and removing of zona pellucida by enzymatic digestion, blastomeres were collected the high-quality embryos donated by couples whom had given birth to healthy offspring by intracytoplasmic sperm injection and embryo transfer. The whole genome of single cell was amplified and subjected to next generation sequencing. RESULTS: From a total of 23 embryos, 184 blastomeres were collected. 175 (95.1%) of the blastomeres were successfully sequenced, of which 100 (57.1%) were found to harbor chromosomal aneuploidies. Among the 23 embryos, 3 (13.0%) were diploid, 20 (87.0%) were mosaicisms, which included 5 (21.7%) aneuploid mosaicisms, 7 (30.4%) diploid-aneuploid mosaicisms, 5 (21.7%) abnormal mosaicisms, and 3 (13.0%) irregular segregations. CONCLUSION: There is a high rate of chromosomal mosaicisms in high-quality cleavage embryos. Mosaicisms of complex chromosomal abnormality or with high proportion of abnormal cells may be an important factor affecting the potential of embryonic development.


Assuntos
Testes Genéticos , Mosaicismo , Diagnóstico Pré-Implantação , Análise de Célula Única , Aneuploidia , Blastômeros , Hibridização Genômica Comparativa , Feminino , Fertilização In Vitro , Humanos , Gravidez
11.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(9): 1032-1035, 2020 Sep 10.
Artigo em Chinês | MEDLINE | ID: mdl-32820524

RESUMO

OBJECTIVE: To determine the size and origin of a small supernumerary marker chromosome (sSMC) identified in a patient featuring developmental retardation. METHODS: High-throughput sequencing for copy number variation (CNV-seq) was carried out to delineate the sSMC identified upon G-banded chromosomal karyotyping. The genotype-phenotype correlation was explored by database retrieval and literature analysis. RESULTS: The patient was found to have a karyotype of mos 47,XX,+mar[36]/46,XX[23]. CNV-seq has identified a 18 Mb duplication at 5p14.1-p12 (hg19: 27,399,261-46,083,784)x2.6 with a mosaicism rate of approximately 60%. CONCLUSION: Patients with mosaic partial trisomy 5p may have extensive clinical manifestations, and the ratio of trisomy 5p cells is correlated with clinical severity of this syndrome.


Assuntos
Síndrome do Miado do Gato , Mosaicismo , Trissomia , Cromossomos Humanos Par 5 , Síndrome do Miado do Gato/diagnóstico , Síndrome do Miado do Gato/genética , Variações do Número de Cópias de DNA , Feminino , Testes Genéticos , Humanos , Cariotipagem , Trissomia/diagnóstico , Trissomia/genética
12.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(9): 1036-1038, 2020 Sep 10.
Artigo em Chinês | MEDLINE | ID: mdl-32820525

RESUMO

OBJECTIVE: To carry out prenatal diagnosis for a fetus with increased nuchal translucency (NT) and another fetus with non-invasive prenatal testing (NIPT) suggested reduced sex chromosomes by cytogenetic and molecular techniques. METHODS: Chromosomal karyotyping, single nucleotide polymorphism array (SNP-array) and fluorescence in situ hybridization (FISH) were applied for the diagnoses. Peripheral blood samples were also taken from their parents for chromosomal karyotyping and SNP-array analysis. RESULTS: Both fetuses showed a 46,X,+mar/45,X karyotype. SNP-array has detected a 22.0 Mb duplication at Yp11.31q11.223 and a 3.9 Mb microdeletion at Yq11.223q11.23 in fetus 1, and a 16.9 Mb duplication at Yp11.31q11.221 and a 8.1 Mb deletion at Yq11.222q11.23 in fetus 2. The results were confirmed by FISH. The parents of both fetuses were normal by chromosomal karyotyping and SNP-array. CONCLUSION: Combined use of various techniques can enable accurate prenatal diagnosis and genetic counseling.


Assuntos
Mosaicismo , Diagnóstico Pré-Natal , Cromossomos Humanos Y , Feminino , Feto , Humanos , Hibridização in Situ Fluorescente , Polimorfismo de Nucleotídeo Único , Gravidez
13.
Nat Commun ; 11(1): 3987, 2020 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-32778678

RESUMO

Aneuploidy, the presence of an abnormal number of chromosomes, is a major cause of early pregnancy loss in humans. Yet, the developmental consequences of specific aneuploidies remain unexplored. Here, we determine the extent of post-implantation development of human embryos bearing common aneuploidies using a recently established culture platform. We show that while trisomy 15 and trisomy 21 embryos develop similarly to euploid embryos, monosomy 21 embryos exhibit high rates of developmental arrest, and trisomy 16 embryos display a hypo-proliferation of the trophoblast, the tissue that forms the placenta. Using human trophoblast stem cells, we show that this phenotype can be mechanistically ascribed to increased levels of the cell adhesion protein E-CADHERIN, which lead to premature differentiation and cell cycle arrest. We identify three cases of mosaicism in embryos diagnosed as full aneuploid by pre-implantation genetic testing. Our results present the first detailed analysis of post-implantation development of aneuploid human embryos.


Assuntos
Aneuploidia , Implantação do Embrião/genética , Embrião de Mamíferos , Desenvolvimento Embrionário , Antígenos CD/genética , Caderinas/genética , Caderinas/metabolismo , Adesão Celular , Pontos de Checagem do Ciclo Celular , Linhagem da Célula , Segregação de Cromossomos , Cromossomos Humanos Par 16 , Cromossomos Humanos Par 21 , Feminino , Genes erbB-1/genética , Testes Genéticos , Humanos , Monossomia , Mosaicismo , Gravidez , Células-Tronco , Trissomia
15.
Nat Commun ; 11(1): 3375, 2020 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-32632155

RESUMO

Hybridization can drive speciation. We examine the hypothesis that Castanea henryi var. omeiensis is an evolutionary lineage that originated from hybridization between two near-sympatric diploid taxa, C. henryi var. henryi and C. mollissima. We produce a high-quality genome assembly for mollissima and characterize evolutionary relationships among related chestnut taxa. Our results show that C. henryi var. omeiensis has a mosaic genome but has accumulated divergence in all 12 chromosomes. We observe positive correlation between admixture proportions and recombination rates across the genome. Candidate barrier genomic regions, which isolate var. henryi and mollissima, are re-assorted in the hybrid lineage. We further find that the putative barrier segments concentrate in genomic regions with less recombination, suggesting that interaction between natural selection and recombination shapes the evolution of hybrid genomes during hybrid speciation. This study highlights that reassortment of parental barriers is an important mechanism in generating biodiversity.


Assuntos
Diploide , Fagaceae/genética , Genoma de Planta/genética , Hibridização Genética , Mosaicismo , Ploidias , Algoritmos , Evolução Molecular , Fagaceae/classificação , Especiação Genética , Modelos Genéticos , Recombinação Genética , Seleção Genética , Especificidade da Espécie , Sequenciamento Completo do Genoma/métodos
16.
Medicine (Baltimore) ; 99(29): e20848, 2020 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-32702826

RESUMO

RATIONALE: Non-invasive prenatal testing (NIPT) is an accurate screening method with high specificity and sensitivity and a low false-positive rate of trisomy 21, 18, and 13. However, false-negative NIPT results could also limit the clinical application of NIPT. PATIENT CONCERNS: A 34-year-old primigravida woman who underwent NIPT at 16 + 3 weeks' gestation was identified as being at high risk for fetal trisomy X (47, XXX). Fetal cardiac defect and hand posture were observed during prenatal ultrasound examination at the 23rd week of gestation. DIAGNOSES: Amniocentesis conducted at the 24th week of gestation. Fetal karyotyping and FISH identified karyotype 48, XXX, + 18, which indicated that the NIPT failed to detect trisomy 18 in this case. INTERVENTIONS: The couple decided to terminate pregnancy at the 26th week of gestation and was willing to undergo further examinations. OUTCOMES: Discordant results between fetus with trisomy 18 and placenta with mosaic T18 were further identified with massive parallel sequencing, which might be due to that the fetal cell-free DNA in maternal plasma for NIPT that was assessed principally originated from the trophoblast cells. LESSONS: The presence of trisomy 18 mosaicism in the placenta might be the reason for the false-negative NIPT result in this case of double aneuploidy with 48, XXX, + 18, karyotype. Although the NIPT is a valuable screening method that has evident advantages in prenatal aneuploidy screening for certain chromosomal abnormalities compared to other methods, it is not a "diagnostic test" yet.


Assuntos
Aneuploidia , Testes Genéticos , Mosaicismo , Placenta , Diagnóstico Pré-Natal , Síndrome da Trissomía do Cromossomo 18/diagnóstico , Amniocentese , Reações Falso-Negativas , Feminino , Humanos , Cariótipo , Gravidez , Análise de Sequência de DNA
17.
Cytogenet Genome Res ; 160(5): 225-237, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32659775

RESUMO

Loss of chromosome Y (LOY) is a mosaic aneuploidy that can be detected mainly in blood samples of male individuals. Usually, LOY occurrence increases with chronological age in healthy men. Moreover, recently LOY has been reported in association with several diseases, such as cancer, where its frequency is even higher. The Y chromosome is one of the shortest chromosomes of the human karyotype, and it is crucial for correct male development. This chromosome has functions beyond the male reproductive system, and loss of its genes or even LOY can have consequences for the male body that are yet to be elucidated. Analyses of the Y chromosome are largely applied in forensic contexts such as paternity testing, ancestry studies, and sexual assault cases, among others. Thus, LOY can be a disadvantage, limiting laboratory methods and result interpretation. However, as an advantage, LOY detection could be used as a biological age biomarker due to its association with the aging process. The potential application of LOY as biomarker highlights the necessity to clarify the molecular mechanism behind its occurrence and its possible applications in both health and forensic studies.


Assuntos
Aneuploidia , Cromossomos Humanos Y/genética , Medicina Legal , Marcadores Genéticos/genética , Saúde , Mosaicismo , Envelhecimento/genética , Haplótipos/genética , Humanos , Masculino , Paternidade , Delitos Sexuais
18.
Am J Hum Genet ; 107(2): 325-329, 2020 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-32574563

RESUMO

Large copy-number variants (CNVs) are strongly associated with both developmental delay and cancer, but the type of disease depends strongly on when and where the mutation occurred, i.e., germline versus somatic. We used microarray data from UK Biobank to investigate the prevalence and penetrance of large autosomal CNVs and chromosomal aneuploidies using a standard CNV detection algorithm not designed for detecting mosaic variants. We found 160 individuals that carry >10 Mb copy number changes, including 56 with whole chromosome aneuploidies. Nineteen (12%) individuals had a diagnosis of Down syndrome or other developmental disorder, while 84 (52.5%) individuals had a diagnosis of hematological malignancies or chronic myeloproliferative disorders. Notably, there was no evidence of mosaicism in the blood for many of these large CNVs, so they could easily be mistaken for germline alleles even when caused by somatic mutations. We therefore suggest that somatic mutations associated with blood cancers may result in false estimates of rare variant penetrance from population biobanks.


Assuntos
Variações do Número de Cópias de DNA/genética , Hematopoese/genética , Adulto , Idoso , Alelos , Aneuploidia , Bancos de Espécimes Biológicos , Cromossomos/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mosaicismo , Mutação/genética , Penetrância , Reino Unido
19.
Nat Commun ; 11(1): 2958, 2020 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-32528010

RESUMO

The high incidence of aneuploidy in the embryo is considered the principal cause for low human fecundity. However, the prevalence of aneuploidy dramatically declines as pregnancy progresses, with the steepest drop occurring as the embryo completes implantation. Despite the fact that the plasticity of the embryo in dealing with aneuploidy is fundamental to normal development, the mechanisms responsible for eliminating aneuploid cells are unclear. Here, using a mouse model of chromosome mosaicism, we show that aneuploid cells are preferentially eliminated from the embryonic lineage in a p53-dependent process involving both autophagy and apoptosis before, during and after implantation. Moreover, we show that diploid cells in mosaic embryos undertake compensatory proliferation during the implantation stages to confer embryonic viability. Together, our results indicate a close link between aneuploidy, autophagy, and apoptosis to refine the embryonic cell population and ensure only chromosomally fit cells proceed through development of the fetus.


Assuntos
Aneuploidia , Apoptose/fisiologia , Autofagia/fisiologia , Animais , Apoptose/genética , Autofagia/genética , Proliferação de Células/genética , Proliferação de Células/fisiologia , Diploide , Implantação do Embrião , Embrião de Mamíferos/metabolismo , Embriologia , Desenvolvimento Embrionário/fisiologia , Feminino , Imunofluorescência , Camadas Germinativas/metabolismo , Camundongos , Mosaicismo
20.
Anticancer Res ; 40(6): 3423-3427, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32487640

RESUMO

BACKGROUND: Neurofibromatosis type 1 (NF1) is an autosomal dominant hereditary disease with complete penetrance and a very variable phenotype. Recent research has shown that postzygotic NF1 gene mutations occur to a far greater extent than previously thought. The phenotype of affected individuals reflects the time of somatic mutation and the phenotype is correspondingly diverse. This report describes histological and genetic findings in a case of mosaic NF1, the clinical control of which documents almost stationary skin findings over a period of 9 years. CASE REPORT: The 55-year-old female first presented for advice on a strip of nodular skin tumours of the calf skin. She had no hallmarks of NF1. It was only 9 years later that she had the skin tumours removed, all of which were partially diffuse and partially plexiform neurofibroma. The genetic examination showed an atypical large deletion of the NF1 gene in the skin tumours, but not in overlying skin or blood. CONCLUSION: Segmental NF1 is a distinct type of mosaic/somatic NF1 mutation. The phenotype of diffuse and plexiform skin neurofibromas can resemble cutaneous neurofibroma. Surgical therapy for segmental neurofibromatosis does not differ from the concepts for treating nerve sheath tumours in NF1 patients with a germline NF1 mutation.


Assuntos
Mosaicismo , Neurofibroma Plexiforme/diagnóstico , Neurofibroma Plexiforme/genética , Neurofibromatose 1/diagnóstico , Neurofibromatose 1/genética , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/genética , Biópsia , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Testes Genéticos , Humanos , Perna (Membro)/patologia , Pessoa de Meia-Idade
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