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1.
Allergol. immunopatol ; 49(1): 95-100, ene.-feb. 2021. tab
Artigo em Inglês | IBECS | ID: ibc-199231

RESUMO

INTRODUCTION AND OBJECTIVES: The purpose of this study was to evaluate patients diagnosed with 22q11.2 deletion syndrome and determine the clues directing to diagnosis and evaluation of immunological findings for excellent management of the disease. MATERIAL AND METHODS: Thirty-three pediatric patients with 22q11.2 deletion syndrome diag­nosed between 1998 and 2019 at Pediatric Immunology Division of Ege University Faculty of Medicine and SBU Izmir Dr Behcet Uz Children's Education and Research Hospital were evaluated. RESULTS: This study includes the largest case series reported from Turkey. Congenital car­diac anomalies were the most common pathology associated with the syndrome (90.9%). Hypocalcemic symptoms were observed in 13 patients (40%). Twenty-two of the 33 (66.6%) patients were diagnosed before two years of age. Autoimmune diseases, dysmorphic facial findings, recurrent infections, growth retardation, and speech impairment were other clues for diagnosis in older patients. Clinical spectrum and immunological abnormalities of this syn­drome are quite variable. All T-cell subset counts were less than 5th percentile below median by age in one patient (3%) and 10 patients had normal all T-cell subset counts (30.3%). Overall, 69.6% of the patients had normal IgG, IgA, and IgM levels and two patients had panhypogam­maglobulinemia. Recurrent infections were revealed in 75.7% of the patients during follow-up. CONCLUSIONS: Presence of cardiac anomaly is more helpful in the diagnosis, especially under two years of age. Patients with immunologically high or standard risk did not show any differ­ence in terms of numbers and severity of infections and autoimmunity


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Assuntos
Humanos , Masculino , Feminino , Pré-Escolar , Síndrome da Deleção 22q11/diagnóstico , Síndromes de Imunodeficiência/epidemiologia , Síndromes de Imunodeficiência/imunologia , Transtornos Cromossômicos/epidemiologia , Cromossomos Humanos Par 22 , Síndrome da Deleção 22q11/imunologia , Doenças do Sistema Imunitário/diagnóstico , Doenças do Sistema Imunitário/imunologia , Testes Imunológicos , Técnicas Imunológicas/métodos , Doenças Autoimunes/diagnóstico , Doenças Autoimunes/imunologia
2.
Medicine (Baltimore) ; 99(40): e22532, 2020 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-33019458

RESUMO

RATIONALE: Small supernumerary marker chromosomes (sSMC) are structurally abnormal chromosomes, which can be detected in patients with developmental retardation, infertile problems, and prenatal fetus. We report 3 adult female with fertility problems carrying sSMC(14/22) and aim to explore the correlation between sSMC(14/22) and fertility problems in women. PATIENT CONCERNS: Three Chinese female patients were referred for infertility consultation in our hospital. DIAGNOSES: The karyotype of these 3 patients were 47, XX, +mar. The chromosome microarray analysis (CMA) detected various chromosomal duplications and deletions in the 3 cases: a 0.49Mb gain of 5q32 for case 1; a 0.54Mb gain of 14q32.33 and a 1.83Mb gain of 16p11.2 for case 2; a 0.37Mb loss of 13q21.2q21.31 and a 0.12Mb gain of Xp11.2 for case 3. Fluorescence in situ hybridization (FISH) using the specific probes for chromosomes 13/21, 14/22, and 15 was applied to identify the origination of these sSMC, which were all finally identified as sSMC(14/22). INTERVENTIONS: Case 1 underwent the artificial reproductive technology to get her offspring and finally delivered a healthy male infant at 39 weeks. Case 2 did not plan to choose in vitro fertilization (IVF) to get offspring. Case 3 refused to do assisted reproductive technology. OUTCOMES: The genotype-phenotype correlation of sSMC(14/22) remain unclear. However, the existence of sSMC(14/22) might negatively affect the fertility ability in sSMC female carriers. LESSONS: The combined application of traditional banding technique and molecular cytogenetic techniques can better identify more details of sSMC. For sSMC carriers with fertility problems, they could get their offsprings through assisted reproductive technologies after comprehensive fertility assessment.


Assuntos
Aberrações Cromossômicas , Cromossomos Humanos Par 14/genética , Cromossomos Humanos Par 22/genética , Infertilidade Feminina/genética , Adulto , China , Duplicação Cromossômica , Análise Citogenética , Feminino , Humanos , Hibridização in Situ Fluorescente , Cariótipo
3.
PLoS Genet ; 16(8): e1008915, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32776928

RESUMO

Sequences homologous to human herpesvirus 6 (HHV-6) are integrated within the nuclear genome of about 1% of humans, but it is not clear how this came about. It is also uncertain whether integrated HHV-6 can reactivate into an infectious virus. HHV-6 integrates into telomeres, and this has recently been associated with polymorphisms affecting MOV10L1. MOV10L1 is located on the subtelomere of chromosome 22q (chr22q) and is required to make PIWI-interacting RNAs (piRNAs). As piRNAs block germline integration of transposons, piRNA-mediated repression of HHV-6 integration has been proposed to explain this association. In vitro, recombination of the HHV-6 genome along its terminal direct repeats (DRs) leads to excision from the telomere and viral reactivation, but the expected "solo-DR scar" has not been described in vivo. Here we screened for integrated HHV-6 in 7,485 Japanese subjects using whole-genome sequencing (WGS). Integrated HHV-6 was associated with polymorphisms on chr22q. However, in contrast to prior work, we find that the reported MOV10L1 polymorphism is physically linked to an ancient endogenous HHV-6A variant integrated into the telomere of chr22q in East Asians. Unexpectedly, an HHV-6B variant has also endogenized in chr22q; two endogenous HHV-6 variants at this locus thus account for 72% of all integrated HHV-6 in Japan. We also report human genomes carrying only one portion of the HHV-6B genome, a solo-DR, supporting in vivo excision and possible viral reactivation. Together these results explain the recently-reported association between integrated HHV-6 and MOV10L1/piRNAs, suggest potential exaptation of HHV-6 in its coevolution with human chr22q, and clarify the evolution and risk of reactivation of the only intact (non-retro)viral genome known to be present in human germlines.


Assuntos
Genoma Humano , Herpesvirus Humano 6/genética , Integração Viral , Grupo com Ancestrais do Continente Asiático/genética , Cromossomos Humanos Par 22/genética , Evolução Molecular , Mutação em Linhagem Germinativa , Humanos , Polimorfismo de Nucleotídeo Único , RNA Interferente Pequeno/genética
4.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(8): 867-870, 2020 Aug 10.
Artigo em Chinês | MEDLINE | ID: mdl-32761597

RESUMO

OBJECTIVE: To explore the genetic basis for a child with developmental delay and mental retardation. METHODS: Chromosomal karyotype of the child was analyzed by G-, C- and N-banding techniques. Her genome DNA was analyzed with single nucleotide polymorphisms array (SNP array). The result was validated by fluorescence quantitative polymerase chain reaction (PCR). RESULTS: The karyotype of the child was ascertained as 46,XX,r(22)(p12q13). SNP array has revealed a deletion of approximately 1.4 Mb at 22q13.33 (49 802 963-51 197 766). The deletion has encompassed the SHANK3, a crucial gene for the development of nervous system. Fluorescence quantitative PCR has confirmed the deletion of exons 7, 19 and 22 of the SHANK3 gene. CONCLUSION: The phenotype of the patient may be attributed to the microdeletion at 22q13.33. Cytogenetic methods combined with SNP array and fluorescence quantitative PCR can identify aberrant chromosomes and provide accurate information for the clinical diagnosis and genetic counseling.


Assuntos
Análise Citogenética , Deficiências do Desenvolvimento/genética , Deficiência Intelectual , Criança , Bandeamento Cromossômico , Deleção Cromossômica , Cromossomos Humanos Par 22 , Feminino , Humanos , Deficiência Intelectual/genética , Cariotipagem , Polimorfismo de Nucleotídeo Único
5.
Hematol Oncol ; 38(4): 607-610, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32602167
6.
Sci Rep ; 10(1): 12235, 2020 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-32699385

RESUMO

The most prevalent microdeletion in humans occurs at 22q11.2, a region rich in chromosome-specific low copy repeats (LCR22s). The structure of this region has defied elucidation due to its size, regional complexity, and haplotype diversity, and is not well represented in the human genome reference. Most individuals with 22q11.2 deletion syndrome (22q11.2DS) carry a de novo hemizygous deletion of ~ 3 Mbp occurring by non-allelic homologous recombination (NAHR) mediated by LCR22s. In this study, optical mapping has been used to elucidate LCR22 structure and variation in 88 individuals in thirty 22q11.2DS families to uncover potential risk factors for germline rearrangements leading to 22q11.2DS offspring. Families were optically mapped to characterize LCR22 structures, NAHR locations, and genomic signatures associated with the deletion. Bioinformatics analyses revealed clear delineations between LCR22 structures in normal and deletion-containing haplotypes. Despite no explicit whole-haplotype predisposing configurations being identified, all NAHR events contain a segmental duplication encompassing FAM230 gene members suggesting preferred recombination sequences. Analysis of deletion breakpoints indicates that preferred recombinations occur between FAM230 and specific segmental duplication orientations within LCR22A and LCR22D, ultimately leading to NAHR. This work represents the most comprehensive analysis of 22q11.2DS NAHR events demonstrating completely contiguous LCR22 structures surrounding and within deletion breakpoints.


Assuntos
Cromossomos Humanos Par 22/genética , Síndrome de DiGeorge/genética , Recombinação Homóloga/genética , Duplicações Segmentares Genômicas/genética , Alelos , Deleção Cromossômica , Mapeamento Cromossômico/métodos , Feminino , Genoma Humano/genética , Haplótipos/genética , Humanos , Masculino
7.
Ann Biol Clin (Paris) ; 78(2): 187-190, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32319947

RESUMO

Acute myeloid leukemia (AML) with inv(16) is primarily associated with the eosinophilic LAM4 form belonging to the favorable prognosis group of AML. We report the case of an 18-year-old man with acute myeloid leukemia with unusual inversion of chromosome 16. Cytological, phenotypic and cytogenetic investigations showed a divergence from those in the literature. Indeed, the myelogram shows a medullary infiltration by elements blocked at the stage of myeloblates/promyelocytes, containing Auer rods grouped sometimes in fagots in blasts, promyelocytes and neutrophils. In view of this pathognomonic aspect, the diagnosis of AML type M3 is mentioned but quickly questioned by the results of immunophenotyping in favor of a maturing AML (M2). The karyotype and the FISH later objectify a recurrent anomaly "cytologically unexpected" inversion 16 (p13, q22) associated with trisomy 22.


Assuntos
Inversão Cromossômica , Cromossomos Humanos Par 16 , Leucemia Mieloide Aguda/diagnóstico , Adolescente , Cromossomos Humanos Par 22/genética , Citodiagnóstico , Análise Citogenética , Humanos , Imunofenotipagem , Cariotipagem , Leucemia Mieloide Aguda/complicações , Leucemia Mieloide Aguda/genética , Masculino , Trissomia/diagnóstico , Trissomia/genética
8.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(5): 532-534, 2020 May 10.
Artigo em Chinês | MEDLINE | ID: mdl-32335879

RESUMO

OBJECTIVE: To delineate the nature and origin of chromosomal aberration in a boy with mental retardation and multiple congenital deformities. METHODS: Chromosomal karyotypes of the proband and his parents were determined by routine G-banding analysis. Genomic DNA was also analyzed with single nucleotide polymorphism array (SNP array). RESULTS: The karyotype of the proband was 46,X,add(Y)(q11.23). No karyotypic abnormality was detected in either parent. SNP array has identified a de novo 21.6 Mb duplication at 22q12qter in the proband. CONCLUSION: The de novo 22q12qter duplication probably underlies the abnormalities in the proband.


Assuntos
Anormalidades Múltiplas , Cromossomos Humanos Par 22 , Trissomia , Anormalidades Múltiplas/genética , Adulto , Criança , Bandeamento Cromossômico , Cromossomos Humanos Par 22/genética , Feminino , Testes Genéticos , Humanos , Deficiência Intelectual/genética , Cariotipagem , Masculino
9.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(5): 555-558, 2020 May 10.
Artigo em Chinês | MEDLINE | ID: mdl-32335885

RESUMO

OBJECTIVE: To explore the genetic basis for an infant with multiple malformations including congenital heart disease and cleft palate. METHODS: The child and his parents were subjected to conventional chromosomal karyotyping and low-coverage massively parallel copy number variation sequencing (CNV-seq) analysis. RESULTS: The infant was found to have a 46,X,add(Y)(q11.23) karyotype, and his CNV-seq result was seq [hg19] 22q12.1q13.3 (29 520 001-51 180 000)× 3. His parents were found to be normal by both methods. CONCLUSION: The additional chromosomal material found on Yq, verified as duplication of 22q12.1-q13.3, may account for the abnormal phenotype in this infant. CNV-seq has provided a useful complement for the diagnosis and more accurate information for genetic counseling.


Assuntos
Anormalidades Múltiplas , Duplicação Cromossômica , Cromossomos Humanos Par 22 , Anormalidades Múltiplas/genética , Criança , Cromossomos Humanos Par 22/genética , Fissura Palatina/genética , Variações do Número de Cópias de DNA , Testes Genéticos , Cardiopatias Congênitas/genética , Humanos , Lactente , Cariotipagem
10.
Cancer Genet ; 243: 48-51, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32272434

RESUMO

Traditional cytogenetic testing methodologies, including conventional chromosome analysis and fluorescence in situ hybridization (FISH), are invaluable for the detection or recurrent genetic abnormalities in various hematologic malignancies. However, technological advances, including a novel next-generation sequencing technique termed mate-pair sequencing (MPseq), continue to revolutionize the field of cytogenetics by enabling the characterization of structural variants at a significantly higher resolution compared to traditional methodologies. To illustrate the power of MPseq, we present a 27-year-old male diagnosed with chronic myeloid leukemia in myeloid blast crisis with multiple chromosomal abnormalities observed in all 20 metaphases from a peripheral blood specimen, including t(9;22)(q34;q11.2) and t(4;11)(q12;p15). Suspicious of a novel NUP98/PDGFRA fusion [t(4;11)(q12;p15)], break-apart FISH probe sets for the PDGFRA (4q12) and NUP98 (11p15.4) gene regions were performed and were both positive in approximately 86% of 200 interphase nuclei. However, subsequent MPseq testing revealed breakpoints located within the NUP98 gene and within an intergenic region (4q12) located between the CHIC2 and PDGFRA genes, indicating this 4;11 translocation does not result in the predicted NUP98/PDGFRA gene fusion as inferred from FISH and conventional chromosome results. This case demonstrates the clinical utility of MPseq, particularly for characterizing novel gene fusion events which may ultimately identify a false-positive FISH result.


Assuntos
Crise Blástica/genética , Sequenciamento de Nucleotídeos em Larga Escala , Hibridização in Situ Fluorescente , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Proteínas de Fusão Oncogênica/isolamento & purificação , Adulto , Crise Blástica/diagnóstico , Aberrações Cromossômicas , Cromossomos Humanos Par 11/genética , Cromossomos Humanos Par 22/genética , Cromossomos Humanos Par 4/genética , Cromossomos Humanos Par 9/genética , Análise Citogenética , Progressão da Doença , Reações Falso-Positivas , Humanos , Masculino , Complexo de Proteínas Formadoras de Poros Nucleares/genética , Proteínas de Fusão Oncogênica/genética , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética
11.
Am J Hematol ; 95(6): 691-709, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32239758

RESUMO

DISEASE OVERVIEW: Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm with an incidence of 1-2 cases per 100 000 adults. It accounts for approximately 15% of newly diagnosed cases of leukemia in adults. DIAGNOSIS: CML is characterized by a balanced genetic translocation, t(9;22)(q34;q11.2), involving a fusion of the Abelson gene (ABL1) from chromosome 9q34 with the breakpoint cluster region (BCR) gene on chromosome 22q11.2. This rearrangement is known as the Philadelphia chromosome. The molecular consequence of this translocation is the generation of a BCR-ABL1 fusion oncogene, which in turn translates into a BCR-ABL oncoprotein. FRONTLINE THERAPY: Four tyrosine kinase inhibitors (TKIs), imatinib, nilotinib, dasatinib, and bosutinib are approved by the United States Food and Drug Administration for first-line treatment of newly diagnosed CML in chronic phase (CML-CP). Clinical trials with second generation TKIs reported significantly deeper and faster responses, but they had no impact on survival prolongation, likely because of the existence of highly effective salvage therapies for patients who have a cytogenetic relapse with frontline TKI. SALVAGE THERAPY: For CML post failure on frontline therapy, second-line options include second and third generation TKIs. Although potent and selective, these exhibit unique pharmacological profiles and response patterns relative to different patient and disease characteristics, such as patients' comorbidities, disease stage, and BCR-ABL1 mutational status. Patients who develop the T315I "gatekeeper" mutation display resistance to all currently available TKIs except ponatinib. Allogeneic stem cell transplantation remains an important therapeutic option for patients with CML-CP who have failed at least 2 TKIs, and for all patients in advanced phase disease. Even among older patients who have a cytogenetic relapse post failure on all TKIs, they can maintain long-term survival if they continue on a daily most effective/less toxic TKI, with or without the addition of non-TKI anti-CML agents (hydroxyurea, omacetaxine, azacitidine, decitabine, cytarabine, busulfan, others).


Assuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva , Inibidores de Proteínas Quinases/uso terapêutico , Cromossomos Humanos Par 22/genética , Cromossomos Humanos Par 9/genética , Ensaios Clínicos como Assunto , Intervalo Livre de Doença , Proteínas de Fusão bcr-abl/genética , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Monitorização Fisiológica , Inibidores de Proteínas Quinases/efeitos adversos , Taxa de Sobrevida , Translocação Genética
13.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(4): 405-409, 2020 Apr 10.
Artigo em Chinês | MEDLINE | ID: mdl-32219823

RESUMO

OBJECTIVE: To carry out genetic testing for 3 fetuses with abnormal prenatal screening. METHODS: Fetal ultrasound, karyotype analysis, single nucleotide polymorphism (SNP) array and fluorescence in situ hybridization were performed. RESULTS: Abnormalities of chromosome 22 were found with all 3 fetuses. Fetus 1 harbored a 7.1 Mb deletion in 22q13.2q13.33 region, which involved 54 OMIM genes including SHANK3 and FBLN1. Fetus 2 had a mosaicism karyotype, with 12% of cells harboring a 6.6 Mb deletion in 22q13.31q13.33, covering 48 OMIM genes such as SHANK3 and PPARA, and 5% of cells harboring a 26.1 Mb duplication in 22q11.1q13.2 involving 285 OMIM genes. Fetus 3 carried a tandem duplication of 1.7 Mb in 22q11.1q11.21, which involved 10 OMIM genes including CECR1, CECR2 and ATP6V1E1. No abnormality was found in the three couples by chromosomal karyotyping and SNP array analysis. CONCLUSION: The severity of diseases caused by chromosome 22 abnormalities not only depends on the range of the deletion or duplication, but is also closely related to chromosome structure, gene dose and genetic environment. Combined ultrasonography and various genetic testing techniques in prenatal diagnosis can greatly increase the detection rate of genetic diseases with substantial phenotypic variation.


Assuntos
Transtornos Cromossômicos/diagnóstico , Cromossomos Humanos Par 22/genética , Testes Genéticos , Cariotipagem , Diagnóstico Pré-Natal , Ultrassonografia Pré-Natal , Aberrações Cromossômicas , Deleção Cromossômica , Transtornos Cromossômicos/genética , Feminino , Feto , Humanos , Hibridização in Situ Fluorescente , Gravidez , Fatores de Transcrição
14.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(2): 175-177, 2020 Feb 10.
Artigo em Chinês | MEDLINE | ID: mdl-32034749

RESUMO

OBJECTIVE: To explore the genetic basis for a child featuring delayed language development. METHODS: The patient was subjected to conventional G-banding chromosomal karyotyping and single nucleotide polymorphism microarray (SNP array) analysis. RESULTS: The karyotype of the child was 46, XY, r(22)(p11.2q13). SNP array analysis has identified a hemizygous 1.67 Mb deletion at 22q13 (arr [Hg19]22q13.33 (49 531 302-51 197 766)×1). CONCLUSION: The child has carried a ring 22 in addition with a 22q13 microdeletion. The results may provide clues for her condition and genetic counseling for the family.


Assuntos
Aconselhamento Genético , Desenvolvimento da Linguagem , Polimorfismo de Nucleotídeo Único , Criança , Bandeamento Cromossômico , Deleção Cromossômica , Cromossomos Humanos Par 22 , Feminino , Humanos , Cariotipagem
15.
J Craniofac Surg ; 31(2): 428-431, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31917711

RESUMO

The 22q11.2 deletion syndrome affects approximately 1 in 4000 live births and involves cardiac defects, immunodeficiency, and endocrine disruption. The complexity of diagnosis and multifaceted care often leads to fragmented management in the short and long term. With the purpose of developing an effective multidisciplinary program, the authors aimed to identify the deficiencies in current screening and referral processes among the teams required in the care for patients with 22q11.2 deletion syndrome. A retrospective chart review was conducted at our institution between 2001 and 2016. Patients with confirmed 22q11.2 deletion diagnoses between the ages of 0 and 28 were included. A list of 15 relevant specialties that should evaluate patients with 22q11.2 deletion syndrome was created according to established guidelines. Patient medical and demographic information were collected and analyzed. A total of 270 patients were included. Mean age at diagnosis was 3.3 years. On average, patients visited 6 of 15 departments (1-14). Only 8.8% of patients visited >10 specialties. The majority were seen by Cardiology, Allergy and Immunology, Genetics, and Speech (57.4-87.8%). A minority were seen by Hematology and Oncology, Sleep Therapy, and Physical Therapy (13.3-16.3%). Only 34.1% encountered plastic surgery. Negative correlation (-0.128; P = 0.035) was demonstrated between patients' age at diagnosis and number of specialty teams encountered. This study highlights the current underutilization of services required to manage patients with 22q11.2 deletion syndrome. While screening guidelines have been established, implementation can be challenging as it requires efficient care coordination between teams. Moving forward, the authors believe that a multidisciplinary clinical approach to streamline patient care is necessary.


Assuntos
Síndrome da Deleção 22q11/terapia , Síndrome da Deleção 22q11/genética , Adolescente , Adulto , Criança , Pré-Escolar , Cromossomos Humanos Par 22 , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Programas de Rastreamento , Estudos Retrospectivos , Adulto Jovem
16.
J Assist Reprod Genet ; 37(1): 231-238, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31834537

RESUMO

PURPOSE: To assess the variability of meiotic segregation patterns in sperm of Robertsonian translocation (RobT) carrier t(21;22) and present effect on reproductive outcome. METHODS: Infertile couple enrolled in IVF/ICSI program. Sperm chromosomal segregation analysis was done using FISH; preimplantation genetic testing for aneuploids (PGT-A) was performed by NGS. RESULTS: Patients had a low fertilization rate and a negative outcome after the first IVF/ICSI cycle, so they were advised to do chromosomal aberration analysis before their next attempt. The second IVF/ICSI procedure resulted in pregnancy, and two blastocysts were cryopreserved. The NIFTY test has shown low risk for all tested trisomies, sex chromosomes aneuploidis, and deletion syndromes, so a healthy female child was born. During pregnancy, karyotypisation results revealed that the male partner is a RobT carrier t(21;22). Sperm segregation analysis of chromosomes 21 and 22 has shown six types of sperm chromosome sets. The majority of sperm cells had a normal/balanced RobT form of a haploid set of chromosomes (68.5-76%) called an "alternate." Sperm cells that had additional chromosome 21 or 22, or lack of chromosome 21 or 22, were present in 4-12%. PGT-A performed on two cryopreserved blastocysts revealed one embryo euploid and the other with the mosaic aneuploidy of chromosome 7 present in 50% of the cells. CONCLUSION: Infertile couples with a RobT male carrier who have semen comprising of normal/alternate form in the majority have a good prognosis of IVF/ICSI outcome. PGT is recommended because of the possible occurrence of viable trisomic embryos and potential interchromosomal effect.


Assuntos
Segregação de Cromossomos , Cromossomos Humanos Par 21/genética , Cromossomos Humanos Par 22/genética , Fertilização In Vitro/métodos , Infertilidade Masculina/terapia , Espermatozoides/patologia , Translocação Genética , Adulto , Portador Sadio , Feminino , Humanos , Infertilidade Masculina/genética , Infertilidade Masculina/patologia , Masculino , Gravidez , Taxa de Gravidez , Diagnóstico Pré-Implantação/métodos , Injeções de Esperma Intracitoplásmicas/métodos , Adulto Jovem
17.
J Clin Invest ; 130(3): 1479-1490, 2020 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-31805011

RESUMO

BACKGROUNDDICER1 is the only miRNA biogenesis component associated with an inherited tumor syndrome, featuring multinodular goiter (MNG) and rare pediatric-onset lesions. Other susceptibility genes for familial forms of MNG likely exist.METHODSWhole-exome sequencing of a kindred with early-onset MNG and schwannomatosis was followed by investigation of germline pathogenic variants that fully segregated with the disease. Genome-wide analyses were performed on 13 tissue samples from familial and nonfamilial DGCR8-E518K-positive tumors, including MNG, schwannomas, papillary thyroid cancers (PTCs), and Wilms tumors. miRNA profiles of 4 tissue types were compared, and sequencing of miRNA, pre-miRNA, and mRNA was performed in a subset of 9 schwannomas, 4 of which harbor DGCR8-E518K.RESULTSWe identified c.1552G>A;p.E518K in DGCR8, a microprocessor component located in 22q, in the kindred. The variant identified is a somatic hotspot in Wilms tumors and has been identified in 2 PTCs. Copy number loss of chromosome 22q, leading to loss of heterozygosity at the DGCR8 locus, was found in all 13 samples harboring c.1552G>A;p.E518K. miRNA profiling of PTCs, MNG, schwannomas, and Wilms tumors revealed a common profile among E518K hemizygous tumors. In vitro cleavage demonstrated improper processing of pre-miRNA by DGCR8-E518K. MicroRNA and RNA profiling show that this variant disrupts precursor microRNA production, impacting populations of canonical microRNAs and mirtrons.CONCLUSIONWe identified DGCR8 as the cause of an unreported autosomal dominant mendelian tumor susceptibility syndrome: familial multinodular goiter with schwannomatosis.FUNDINGCanadian Institutes of Health Research, Compute Canada, Alex's Lemonade Stand Foundation, the Mia Neri Foundation for Childhood Cancer, Cassa di Sovvenzioni e Risparmio fra il Personale della Banca d'Italia, and the KinderKrebsInitiative Buchholz/Holm-Seppensen.


Assuntos
Predisposição Genética para Doença , Bócio Nodular/genética , Mutação de Sentido Incorreto , Proteínas de Neoplasias/genética , Neurilemoma/genética , Neurofibromatoses/genética , Proteínas de Ligação a RNA/genética , Neoplasias Cutâneas/genética , Substituição de Aminoácidos , Criança , Cromossomos Humanos Par 22/genética , Feminino , Dosagem de Genes , Estudo de Associação Genômica Ampla , Bócio Nodular/patologia , Células HEK293 , Humanos , Masculino , Neurilemoma/patologia , Neurofibromatoses/patologia , Neoplasias Cutâneas/patologia , Sequenciamento Completo do Exoma
18.
Cancer Genet ; 240: 66-72, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31794935

RESUMO

Ependymomas are neuroepithelial tumors that differentiate along the ependymal cell lineage, a lining of the ventricles of the brain and the central canal of the spinal cord. They are rare in adults, but account for around 9% of brain tumors in children, where they usually have an aggressive course. Efficient stratification could lead to improved care but remains a challenge even in the genomic era. Recent studies proposed a multivariate classification system based on tumor location, age, and broad genomic findings like global patterns of methylation and copy number variants (CNVs). This system shows improved prognostic utility, but is relatively impractical in the routine clinical setting because it necessitates multiple diagnostic tests. We analyzed 13 intracranial grade II and III ependymoma specimens on a DNA microarray to identify discrete CNVs that could support the existing classification. The loss of chr22 and the gain of 5p15.31 were common throughout our cohort (6 and 11 cases, respectively). Other CNVs correlated well with the previously proposed classification system. For example, gains of chr20 were unique to PF-EPN-B tumors of the posterior fossa and may differentiate them from PF-EPN-A. Given the ease of detecting CNVs using multiple, clinically validated methods, these CNVs should be further studied to confirm their diagnostic and prognostic utility, for incorporation into clinical testing algorithms.


Assuntos
Biomarcadores Tumorais/genética , Variações do Número de Cópias de DNA , Ependimoma/diagnóstico , Neoplasias Infratentoriais/diagnóstico , Neoplasias Supratentoriais/diagnóstico , Adulto , Criança , Pré-Escolar , Cromossomos Humanos Par 20/genética , Cromossomos Humanos Par 22/genética , Cromossomos Humanos Par 5/genética , Fossa Craniana Posterior/patologia , Diagnóstico Diferencial , Ependimoma/genética , Ependimoma/mortalidade , Ependimoma/patologia , Estudos de Viabilidade , Feminino , Humanos , Lactente , Neoplasias Infratentoriais/genética , Neoplasias Infratentoriais/mortalidade , Neoplasias Infratentoriais/patologia , Masculino , Gradação de Tumores , Análise de Sequência com Séries de Oligonucleotídeos , Prognóstico , Intervalo Livre de Progressão , Estudos Retrospectivos , Neoplasias Supratentoriais/genética , Neoplasias Supratentoriais/mortalidade , Neoplasias Supratentoriais/patologia
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