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1.
Med. infant ; 26(2): 92-98, Junio 2019. tab, ilus
Artigo em Espanhol | LILACS | ID: biblio-1009182

RESUMO

Introducción: El síndrome de deleción 22q11.2, también llamado síndrome Velo-Cardio-Facial (VCFS/del22q11.2) o síndrome de DiGeorge, es una entidad causada por una anomalía cromosómica, deleción en la región q11.2 (brazo largo) del cromosoma 22. Se trata de una enfermedad multisistémica de expresión variable que afecta el aparato cardiovascular, la inmunidad, las funciones endocrinológicas, la cavidad oral, el desarrollo neurocognitivo, con una expresión facial particular. La prevalencia estimada es de 1:2000/4000. Objetivos: Identificar y describir las cardiopatías congénitas más frecuentemente asociadas a pacientes con síndrome de microdeleción 22q11.2. Materiales y métodos: Estudio descriptivo, transversal y retrospectivo que analiza los pacientes con diagnóstico de microdeleción 22q11.2 atendidos en el Hospital Garrahan desde Octubre de 1998 hasta Febrero 2018. El criterio diagnóstico fueron signos clínicos compatibles y la presencia de la microdeleción 22q11.2 por técnica de FISH o MLPA. Resultados: Población: 321 pacientes, 151 Femeninos (47%) 170 Masculinos (53%). Rango etario: 0 a 197 meses (1 día a 16,4 años). Mediana de edad al diagnóstico clínico: 31 meses. El 74,4% (239/321) de los pacientes evaluados con microdeleción 22q11.2 tuvieron cardiopatías congénitas asociadas a facies peculiar. Las cardiopatías congénitas más frecuentemente asociadas fueron conotroncales. De los pacientes con cardiopatías congénitas el 68,6% requirió cirugía cardiovascular. Fallecieron 24 pacientes (10%) con cardiopatías congénitas asociadas y en el 93% la causa de muerte estuvo relacionada a la afección cardiológica. Conclusiones: Los pacientes con microdeleción 22q11.2 se asocian con un alto porcentaje de cardiopatías congénitas, la gran mayoría son complejas (conotroncales) y requieren resolución quirúrgica en los primeros años de vida. Es de vital importancia la evaluación multidisciplinaria de este grupo especial de pacientes con cardiopatía asociada a otras alteraciones extra cardíacas para el diagnóstico precoz y tratamiento oportuno (AU)


Introduction: 22q11.2 deletion syndrome, also called velocardiofacial syndrome (VCFS/del22q11.2) or DiGeorge syndrome, is a condition caused by chromosomal abnormality, a deletion in the q11.2 region (long arm) of chromosome 22. VCFS is a multisystem disease of variable expression that affects the cardiovascular, immune, and endocrine systems, the oral cavity, neurocognitive development, and is associated with specific facial features. The estimated prevalence is 1:2000/4000. Objectives: To identify and describe the most common congenital heart defects associated with 22q11.2 micro-deletion syndrome. Materials and methods: Descriptive, cross-sectional, and retrospective study analyzing patients diagnosed with a 22q11.2 microdeletion seen at Garrahan Hospital from October 1998 to February 2018. Diagnostic criteria were compatible clinical signs and the presence of a 22q11.2 microdeletion identified by FISH or MLPA. Results: Population: 321 patients, 151 female (47%) and 170 Male (53%). Age range: 0 to 197 months (1 day to 16.4 years). Median age at clinical diagnosis: 31 months. Overall, 74.4% (239/321) of patients with a 22q11.2 microdeletion had congenital heart defects associated with a peculiar facies. The most commonly associated congenital heart defects were conotruncal. Of the patients with congenital heart defects, 68.6% required cardiovascular surgery. Of the patients with congenital heart defects 24 patients died (10%) and in 93% the cause of death was related to the heart disease (p 0.002). Conclusions: A high percentage of patients with a 22q11.2 microdeletion have congenital heart defects, which are complex (conotruncal) in the majority, requiring surgical treatment in the first years of life. Multidisciplinary evaluation of this special group of patients with heart defects associated with other extracardiac disorders is essential for an early diagnosis and timely treatment (AU)


Assuntos
Humanos , Recém-Nascido , Lactente , Pré-Escolar , Criança , Adolescente , Cromossomos Humanos Par 22/genética , Deleção Cromossômica , Síndrome de DiGeorge/diagnóstico , Síndrome de DiGeorge/genética , Cardiopatias Congênitas/diagnóstico , Cardiopatias Congênitas/genética , Tetralogia de Fallot/etiologia , Tetralogia de Fallot/genética , Estudos Transversais , Estudos Retrospectivos , Cardiopatias Congênitas/cirurgia , Comunicação Interventricular/etiologia , Comunicação Interventricular/genética
2.
Int J Mol Sci ; 20(7)2019 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-30959806

RESUMO

Abstract: Deciphering the code of cis-regulatory element (CRE) is one of the core issues of current biology. As an important category of CRE, enhancers play crucial roles in gene transcriptional regulations in a distant manner. Further, the disruption of an enhancer can cause abnormal transcription and, thus, trigger human diseases, which means that its accurate identification is currently of broad interest. Here, we introduce an innovative concept, i.e., abelian complexity function (ACF), which is a more complex extension of the classic subword complexity function, for a new coding of DNA sequences. After feature selection by an upper bound estimation and integration with DNA composition features, we developed an enhancer prediction model with hybrid abelian complexity features (HACF). Compared with existing methods, HACF shows consistently superior performance on three sources of enhancer datasets. We tested the generalization ability of HACF by scanning human chromosome 22 to validate previously reported super-enhancers. Meanwhile, we identified novel candidate enhancers which have supports from enhancer-related ENCODE ChIP-seq signals. In summary, HACF improves current enhancer prediction and may be beneficial for further prioritization of functional noncoding variants.


Assuntos
Biologia Computacional/métodos , Sequências Reguladoras de Ácido Nucleico/genética , Algoritmos , Sequência de Bases , Cromossomos Humanos Par 22/genética , Doença/genética , Elementos Facilitadores Genéticos , Entropia , Éxons/genética , Humanos , Íntrons/genética , Regiões Promotoras Genéticas/genética
3.
Morphologie ; 103(341 Pt 2): 116-121, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30885456

RESUMO

The 6p terminal deletions are rare and usually early diagnosed because of their association with eye and cranio-facial anomalies, particularly as part of Axenfeld-Rieger syndrome in relation with the haploinsufficiency of FOXC1 gene. Deletions in the 22q11 region are frequent, highly correlated with DiGeorge syndrome also named CATCH22, and may be associated with many clinical features of various severities. We report a 31-year-old man with an unbalanced 45,XY,der(6)t(6;22)(p25;q11.2),-22 karyotype leading to monosomies in both 6p25 and 22q11 regions, confirmed by FISH and array-CGH. The length of the deletions was respectively 770 Kb for 6pter and 2.9 Mb for 22q11. This karyotype was discovered at adult age following problems of fertility. The chromosomal formula was unexpected, regarding the patient's medical history and clinical features. This case makes a great example of the difficulties to correlate genotype and phenotype, and furthermore demonstrates the complexity of genetic counselling even in a case with two different chromosomal unbalances.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 22/genética , Cromossomos Humanos Par 6/genética , Fenótipo , Translocação Genética , Adulto , Humanos , Infertilidade Masculina/genética , Cariotipagem , Masculino
4.
Transl Psychiatry ; 9(1): 15, 2019 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-30710087

RESUMO

The 22q11.2 deletion is a strong, but insufficient, "first hit" genetic risk factor for schizophrenia (SZ). We attempted to identify "second hits" from the entire genome in a unique multiplex 22q11.2 deletion syndrome (DS) family. Bioinformatic analysis of whole-exome sequencing and comparative-genomic hybridization array identified de novo and inherited, rare and damaging variants, including copy number variations, outside the 22q11.2 region. A specific 22q11.2-haplotype was associated with psychosis. The interaction of the identified "second hits" with the 22q11.2 haploinsufficiency may affect neurodevelopmental processes, including neuron projection, cytoskeleton activity, and histone modification in 22q11.2DS-ralated psychosis. A larger load of variants, involved in neurodevelopment, in combination with additional molecular events that affect sensory perception, olfactory transduction and G-protein-coupled receptor signaling may account for the development of 22q11.2DS-related SZ. Comprehensive analysis of multiplex families is a promising approach to the elucidation of the molecular pathophysiology of 22q11.2DS-related SZ with potential relevance to treatment.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 22/genética , Herança Multifatorial , Esquizofrenia/genética , Adulto , Variações do Número de Cópias de DNA , Feminino , Expressão Gênica/fisiologia , Haplótipos , Humanos , Relação entre Gerações , Masculino , Síndrome , Sequenciamento Completo do Exoma
5.
Cytogenet Genome Res ; 158(1): 32-37, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30799418

RESUMO

This report describes a newborn girl presenting with some of the common features of DiGeorge syndrome/velocardiofacial syndrome (DGS/VCFS), including hypocalcemia, atrial septal defect, and aortic stenosis. Several genetic tests were carried out to determine the origin of the clinical phenotype. MLPA was initially performed followed by aCGH, cytogenetic analysis, and FISH. Cytogenetic analysis of the proband's parents was also done. MLPA revealed a deletion in 22q11.1q11.2 spanning from the cat eye syndrome region to the most commonly deleted region in DGS/VCFS patients. The size of the deletion as defined by aCGH was 3.2 Mb. The karyotype of the proband was 45,XX,der(1)t(1;22)(p36.3;q11.2)dn,-22, the karyotypes of the parents were normal. FISH analysis showed that the 22q11 deletion occurred in the der(1). No loss or gain of chromosomal material was evident for chromosome 1, as confirmed by MLPA, aCGH, and FISH. Unbalanced translocations resulting in DGS are relatively rare, with limited reports in the literature. To our knowledge, this is the second case involving chromosome 1 and the first one with breakpoints in 1p36 and 22q11.2. This case also emphasizes the importance of combining diagnostic methods to better understand a given genetic abnormality.


Assuntos
Síndrome da Deleção 22q11/genética , Cromossomos Humanos Par 1/genética , Cromossomos Humanos Par 22/genética , Deleção de Sequência , Translocação Genética/genética , Cariótipo Anormal , Cromossomos Humanos Par 1/ultraestrutura , Cromossomos Humanos Par 22/ultraestrutura , Hibridização Genômica Comparativa , Síndrome de DiGeorge/genética , Feminino , Humanos , Hibridização in Situ Fluorescente , Recém-Nascido , Técnicas de Amplificação de Ácido Nucleico , Síndrome
7.
Mol Genet Genomic Med ; 7(2): e00507, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30614210

RESUMO

BACKGROUND: Chromosome 22q11.2 is susceptible to genomic rearrangements and the most frequently reported involve deletions and duplications between low copy repeats LCR22A to LCR22D. Atypical nested deletions and duplications are rarer and can provide a valuable opportunity to investigate the dosage effects of a smaller subset of genes within the 22q11.2 genomic disorder region. METHODS: We describe thirteen individuals from six families, each with atypical nested duplications within the central 22q11.2 region between LCR22B and LCR22D. We then compared the molecular and clinical data for patients from this study and the few reported atypical duplication cases, to the cases with larger typical duplications between LCR22A and LCR22D. Further, we analyzed genes with the nested region to identify candidates highly enriched in human brain tissues. RESULTS: We observed that atypical nested duplications are heterogeneous in size, often familial, and associated with incomplete penetrance and highly variable clinical expressivity. We found that the nested atypical duplications are a possible risk factor for neurodevelopmental phenotypes, particularly for autism spectrum disorder (ASD), speech and language delay, and behavioral abnormalities. In addition, we analyzed genes within the nested region between LCR22B and LCR22D to identify nine genes (ZNF74, KLHL22, MED15, PI4KA, SERPIND1, CRKL, AIFM3, SLC7A4, and BCRP2) with enriched expression in the nervous system, each with unique spatiotemporal patterns in fetal and adult brain tissues. Interestingly, PI4KA is prominently expressed in the brain, and this gene is included either partially or completely in all of our subjects. CONCLUSION: Our findings confirm variable expressivity and incomplete penetrance for atypical nested 22q11.2 duplications and identify genes such as PI4KA to be directly relevant to brain development and disorder. We conclude that further work is needed to elucidate the basis of variable neurodevelopmental phenotypes and to exclude the presence of a second disorder. Our findings contribute to the genotype-phenotype data for atypical nested 22q11.2 duplications, with implications for genetic counseling.


Assuntos
Anormalidades Múltiplas/genética , Transtorno do Espectro Autista/genética , Duplicação Cromossômica/genética , Deficiências do Desenvolvimento/genética , Síndrome de DiGeorge/genética , Penetrância , Anormalidades Múltiplas/patologia , Adolescente , Adulto , Transtorno do Espectro Autista/patologia , Criança , Pré-Escolar , Cromossomos Humanos Par 22/genética , Deficiências do Desenvolvimento/patologia , Síndrome de DiGeorge/patologia , Feminino , Humanos , Masculino , Linhagem , Fenótipo , Duplicações Segmentares Genômicas , Síndrome
8.
Hum Genet ; 138(1): 93-103, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30627818

RESUMO

The 22q11.2 deletion syndrome (22q11.2DS) is caused by recurrent hemizygous deletions of chromosome 22q11.2. The phenotype of the syndrome is complex and varies widely among individuals. Little is known about the role of the different genes located in 22q11.2, and we hypothesized that genetic risk factors lying elsewhere in the genome might contribute to the phenotype. Here, we present the whole-genome gene expression data of 11 patients with approximately 3 Mb deletions. Apart from the hemizygous genes mapped to the 22q11.2 region, the TUBA8 and GNAZ genes, neighboring the deleted interval but in normal copy number, showed altered expression. When genes mapped to other chromosomes were considered in the gene expression analysis, a genome-wide dysregulation was observed, with increased or decreased expression levels. The enriched pathways of these genes were related to immune response, a deficiency that is frequently observed in 22q11.2DS patients. We also used the hypothesis-free weighted gene co-expression network analysis (WGCNA), which revealed the co-expression gene network modules with clear connection to mechanisms associated with 22q11.2DS such as immune response and schizophrenia. These findings, combined with the traditional gene expression profile, can be used for the identification of potential pathways and genes not previously considered to be related to the 22q11.2 deletion syndrome.


Assuntos
Biomarcadores/análise , Deleção Cromossômica , Cromossomos Humanos Par 22/genética , Síndrome de DiGeorge/genética , Subunidades alfa de Proteínas de Ligação ao GTP/genética , Tubulina (Proteína)/genética , Estudos de Casos e Controles , Regulação para Baixo , Seguimentos , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Fenótipo , Prognóstico
9.
Hong Kong Med J ; 25(1): 6-12, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30655461

RESUMO

INTRODUCTION: The aim of the present study was to calculate the prevalence of chromosomal abnormalities among antenatally diagnosed congenital heart diseases (CHDs), and the prevalence of 22q11.2 deletion in those with conotruncal CHDs versus isolated non-conotruncal CHDs. METHODS: All patients with antenatal ultrasound finding of fetal CHDs in two obstetric units in a 5-year period were retrospectively reviewed. Detected CHDs were classified as conotruncal if the malformation involved either the aortic outflow tract or the pulmonary outflow tract; otherwise they were classified as non-conotruncal. Karyotyping, fluorescence in situ hybridisation for 22q11.2 deletion (22q11FISH), and array comparative genomic hybridisation (aCGH) results were retrieved from patient medical records. The primary outcome was prevalence of chromosomal abnormalities in CHDs. The secondary outcomes were prevalence of 22q11.2 deletion and its prevalence in conotruncal versus non-conotruncal CHDs. RESULTS: A total of 254 Chinese patients were diagnosed to have fetal CHDs. In all, 50 (19.7%) were found to have chromosomal abnormalities with seven (2.8%) patients having 22q11.2 deletion, of whom all seven had conotruncal CHDs and none had non-conotruncal CHDs (P<0.05). Conventional karyotyping detected 35 (70%) cases of the chromosomal abnormalities. The 22q11FISH detected three cases of 22q11.2 deletion; aCGH was performed to detect four cases of 22q11.2 deletion and eight other cases of copy number variations. CONCLUSION: Our results suggest that invasive testing for karyotyping is recommended for fetal CHDs. Although the prevalence of 22q11.2 deletion was low, testing for 22q11.2 deletion should be offered for conotruncal CHDs.


Assuntos
Síndrome da Deleção 22q11/epidemiologia , Síndrome da Deleção 22q11/genética , Cromossomos Humanos Par 22/genética , Doenças Fetais/genética , Cardiopatias Congênitas/genética , Adulto , Hibridização Genômica Comparativa , Variações do Número de Cópias de DNA , Feminino , Doenças Fetais/epidemiologia , Cardiopatias Congênitas/epidemiologia , Hong Kong/epidemiologia , Humanos , Hibridização in Situ Fluorescente , Recém-Nascido , Cariotipagem , Gravidez , Resultado da Gravidez , Prevalência , Estudos Retrospectivos , Ultrassonografia Pré-Natal
10.
Spine Deform ; 7(2): 262-266, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30660220

RESUMO

STUDY DESIGN: Retrospective cohort study. OBJECTIVES: To investigate a possible linkage between idiopathic scoliosis (IS) and schizophrenia in an adolescent population. SUMMARY OF BACKGROUND DATA: There is an interesting link between schizophrenia and idiopathic scoliosis: schizophrenia is a disturbance of mental equilibrium, and scoliosis of physical equilibrium, both are multifactorial, genetically determined, start at a young age, and brain development is thought to play a role. Furthermore, both may be presenting symptoms of the genetic disorder 22q11 deletion syndrome. This study poses the question whether these two poorly understood disorders are related. METHODS: A retrospective cohort study was conducted and consisted of 3,702 Swedish adolescents, collected from the National Patient Register, that underwent inpatient care for IS during 1997-2015. These were matched by age, sex, and date of diagnosis to 370,200 controls, collected from Swedish population data, and then followed up in the National Patient Register to identify in- and outpatient care for schizophrenia diagnosis. Follow-up time was calculated from first IS diagnosis date until date of schizophrenia diagnosis or end of follow-up. Cox proportional regression analysis was performed to estimate hazard ratios (HRs) with 95% confidence intervals (CIs) for being diagnosed with schizophrenia. RESULTS: Over a median follow-up time of 9.5 years, 0.7% of patients with IS developed schizophrenia versus 0.5% of controls (p = .04). The risk of schizophrenia was significantly higher in patients with IS (HR, 1.52; 95% CI, 1.03-2.23). Using only hospitalized schizophrenia as event, the prevalence for schizophrenia was 0.5% versus 0.3% (p ≤.01; HR, 1.83; 95% CI, 1.17-2.84). CONCLUSION: This study suggests that patients with IS have increased risk of schizophrenia. Dissatisfaction with one's physical appearance might lead to psychological distress and provoke mental illness in predisposed persons. Alternatively, these two disorders may share a common genetic background. LEVEL OF EVIDENCE: Level 2B.


Assuntos
Esquizofrenia/etiologia , Escoliose/complicações , Adolescente , Cromossomos Humanos Par 22/genética , Estudos de Coortes , Feminino , Seguimentos , Deleção de Genes , Humanos , Masculino , Aparência Física , Prevalência , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Esquizofrenia/epidemiologia , Esquizofrenia/genética , Psicologia do Esquizofrênico , Escoliose/genética , Escoliose/psicologia , Síndrome , Fatores de Tempo
11.
Int J Hematol ; 109(6): 731-736, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30680670

RESUMO

A 67-year-old female was referred to our hospital with a sternal fracture in March 2008. She received a diagnosis of multiple myeloma (MM) BJP-κ type (ISS stage III). G-banding karyotype revealed 46, XX, t(11;22)(q23.3;q11.2) (Hubacek, Gene 592:193-9, 2016), which was later confirmed to be congenital. After repeated rounds of chemotherapy with bortezomib and lenalidomide, she obtained a very good partial response in August 2014, and she was followed up with no treatment. However, she relapsed in February 2016. At that time, fluorescence in situ hybridization identified del(13q) and t(4;14)(p16;q32), which are associated with a poor prognosis. Furthermore, PCR analysis showed that the chromosome 11 breakpoint was at the APOA5/APOA4 locus at 11q23.3, which is associated with malignancy, and that the chromosome 22 breakpoint was at the SEPT5 intron 1 locus, which also plays a role in leukemogenesis through formation of a fusion gene with MLL. Although she was treated with three further lines of therapy, she died from disease progression in August 2017. Synergism between t(11;22) and t(4;14) may have induced the double-refractory phenotype to proteasome inhibitor and lenalidomide, at least during the chemorefractory phase. We present a biological analysis of this case and a review of the literature.


Assuntos
Aberrações Cromossômicas , Cromossomos Humanos Par 11/genética , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/genética , Proteínas de Fusão Oncogênica/genética , Idoso , Bortezomib/uso terapêutico , Cromossomos Humanos Par 14/genética , Cromossomos Humanos Par 22/genética , Cromossomos Humanos Par 4/genética , Progressão da Doença , Quimioterapia Combinada , Evolução Fatal , Feminino , Humanos , Lenalidomida/uso terapêutico
12.
Immunol Rev ; 287(1): 186-201, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30565249

RESUMO

Chromosome 22q11.2 deletion syndrome is the most common microdeletion syndrome in humans. The effects are protean and highly variable, making a unified approach difficult. Nevertheless, commonalities have been identified and white papers with recommended evaluations and anticipatory guidance have been published. This review will cover the immune system in detail and discuss both the primary features and the secondary features related to thymic hypoplasia. A brief discussion of the other organ system involvement will be provided for context. The immune system, percolating throughout the body can impact the function of other organs through allergy or autoimmune disease affecting organs in deleterious manners. Our work has shown that the primary effect of thymic hypoplasia is to restrict T cell production. Subsequent homeostatic proliferation and perhaps other factors drive a Th2 polarization, most obvious in adulthood. This contributes to atopic risk in this population. Thymic hypoplasia also contributes to low regulatory T cells and this may be part of the overall increased risk of autoimmunity. Collectively, the effects are complex and often age-dependent. Future goals of improving thymic function or augmenting thymic volume may offer a direct intervention to ameliorate infections, atopy, and autoimmunity.


Assuntos
Cromossomos Humanos Par 22/genética , Síndrome de DiGeorge/genética , Deleção de Sequência/genética , Linfócitos T/imunologia , Timo/patologia , Animais , Autoimunidade , Diferenciação Celular , Humanos , Hipersensibilidade Imediata , Infecção
13.
J Clin Immunol ; 39(1): 65-74, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30569262

RESUMO

PURPOSE: Immunodeficiency is one of the key features of 22q11.2 deletion syndrome (del), and it is seen in approximately 75% of the patients. The degree of immunodeficiency varies widely, from no circulating T cells to normal T cell counts. It has been hypothesized that the low number of T cells may at least in part be due to increased apoptosis of T cells. Increased spontaneous T cell apoptosis has been reported in one patient with 22q11.2del, but this has not been further investigated. METHODS: A national cohort of patients with a proven heterozygous deletion of chromosome 22q11.2 diagnosed by FISH or MLPA and a group of age and sex matched controls were studied. Spontaneous and activation-induced apoptosis, in addition to FAS expression on lymphocytes, were measured using flow cytometry. Serum levels of FASL were analyzed using ELISA. RESULTS: There was no increased spontaneous apoptosis in patients with 22q11.2del. Upon activation, anti-FAS-induced apoptosis was significantly increased in patients compared to those in controls, while there was no difference in activation induced cell death or activated cell autonomous death. We also found a significant increase in expression of FAS on freshly isolated lymphocytes from patients, while there was no difference in serum levels of FASL. Patients with congenital heart defects (CHD) had significantly higher serum levels of FASL compared to non-CHD patients. CONCLUSION: We have shown increased FAS expression on lymphocytes from patients with 22q11.2del as well as increased levels of FASL in patients with CHD. Those changes may contribute to the pathophysiology of the 22q11.2del.


Assuntos
Apoptose/imunologia , Cromossomos Humanos Par 22/genética , Síndrome de DiGeorge/genética , Síndrome de DiGeorge/imunologia , Linfócitos T/imunologia , Receptor fas/genética , Adolescente , Criança , Pré-Escolar , Cromossomos Humanos Par 22/imunologia , Feminino , Humanos , Masculino
14.
PLoS One ; 13(12): e0209096, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30557369

RESUMO

Genome-wide association studies (GWAS) have identified greater than 30 variants associated with ovarian cancer, but most of these variants were investigated in European populations. Here, we integrated GWAS and subsequent functional analyses to identify the genetic variants with potential regulatory effects. We conducted GWAS for ovarian cancer using 681 Japanese cases and 17,492 controls and found that rs137672 on 22q13.1 exhibited a strong association with a P-value of 1.05 × 10(-7) and an odds ratio of 0.573 with a 95% confidence interval of 0.466-0.703. In addition, three previously reported SNPs, i.e., rs10088218, rs9870207 and rs1400482, were validated in the Japanese population (P < 0.05) with the same risk allele as noted in previous studies. Functional studies including regulatory feature analysis and electrophoretic mobility shift assay (EMSA) revealed two regulatory SNPs in 22q13.1, rs2072872 and rs6509, that affect the binding affinity to some nuclear proteins in ovarian cancer cells. The plausible regulatory proteins whose motifs could be affected by the allele changes of these two SNPs were also proposed. Moreover, the protective G allele of rs6509 was associated with a decreased SYNGR1 expression level in normal ovarian tissues. Our findings elucidated the regulatory variants in 22q13.1 that are associated with ovarian cancer risk.


Assuntos
Cromossomos Humanos Par 22/genética , Variação Genética , Estudo de Associação Genômica Ampla , Neoplasias Ovarianas/genética , Idoso , Alelos , Estudos de Casos e Controles , Feminino , Técnicas de Genotipagem , Humanos , Japão , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único
15.
Cytogenet Genome Res ; 156(4): 185-190, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30566958

RESUMO

The AT-rich repeat on chromosome 22q11.2 is known to be involved in the recurrent constitutional t(11;22)(q23;q11.2). Segregation of this translocation has been reported in several hundred families, but a de novo translocation event has been identified in only 8 cases, and everytime the translocation originated in paternal germ-line chromosomes. Further, de novo t(11;22) rearrangements have been detected in the sperm of healthy males, leading to the hypothesis that it occurs somewhere along the meiosis-spermatogenesis pathway. This report describes a woman whose constitutional karyotype revealed mosaicism for the recurrent t(11;22) and the subsequent testing performed to determine the origin of the translocation event. Karyotype analysis, translocation-specific PCR, human identity testing, and a SNP genotyping array were performed to detect mosaicism and/or chimerism. As a result, the SNP genotyping array revealed no evidence for mosaicism in genomic DNA beyond mosaicism for the balanced t(11;22). Human identity testing and the SNP genotyping array ruled out chimerism. PCR of the translocation breakpoint followed by sequencing confirmed that the translocation had occurred at the typical t(11;22) breakpoints. In conclusion, these results indicate that the translocation occurred post-fertilization, providing the first evidence of a de novo t(11;22)(q23;q11.2) occurring in a maternal mitotic environment.


Assuntos
Cromossomos Humanos Par 11/genética , Cromossomos Humanos Par 22/genética , Translocação Genética , Aborto Espontâneo/genética , Adulto , Feminino , Humanos , Cariótipo , Mosaicismo , Síndrome do Ovário Policístico/genética , Análise de Sequência de DNA
16.
Nat Commun ; 9(1): 5356, 2018 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-30559385

RESUMO

Large copy number variants (CNVs) in the human genome are strongly associated with common neurodevelopmental, neuropsychiatric disorders such as schizophrenia and autism. Here we report on the epigenomic effects of the prominent large deletion CNVs on chromosome 22q11.2 and on chromosome 1q21.1. We use Hi-C analysis of long-range chromosome interactions, including haplotype-specific Hi-C analysis, ChIP-Seq analysis of regulatory histone marks, and RNA-Seq analysis of gene expression patterns. We observe changes on all the levels of analysis, within the deletion boundaries, in the deletion flanking regions, along chromosome 22q, and genome wide. We detect gene expression changes as well as pronounced and multilayered effects on chromatin states, chromosome folding and on the topological domains of the chromatin, that emanate from the large CNV locus. These findings suggest basic principles of how such large genomic deletions can alter nuclear organization and affect genomic molecular activity.


Assuntos
Encéfalo/crescimento & desenvolvimento , Cromatina/metabolismo , Dosagem de Genes/genética , Transtornos Mentais/genética , Linhagem Celular , Cromatina/genética , Cromossomos Humanos Par 1/genética , Cromossomos Humanos Par 22/genética , Genoma Humano/genética , Humanos
17.
Medicine (Baltimore) ; 97(44): e12762, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30383631

RESUMO

RATIONALE: The balanced translocation t(8;21;22)(q22;q22;q11.2) is not reported previously, although t(8;21)(q22;q22) is seen in approximately 7% of adults and most frequent abnormality in children with newly diagnosed acute myeloid leukemia (AML). AML-associated hemophagocytic lymphohistiocytosis (HLH) is a rare event, reported only of limited numbers. The present study reports a very rare case of t(8;21;22)(q22;q22;q11.2) with AML, not reported previously, and developed HLH at the same time. PATIENT CONCERNS AND DIAGNOSIS: A 15-year-old girl presented with a history of bleeding gums and high fever, leukocytosis, anemia, and thrombocytopenia. While waiting the result of bone marrow aspirate, the HLH-associated examinations were abnormal. Bone marrow aspirate showed a hypercellular marrow with 1% myeloblasts. The cytogenetic and molecular studies revealed the presence of abnormal karyotype-46, XX, t(8;21;22)(q22;q22;q11.2) and RUNX1-RUNX1T1 fusion gene. Genetic detections of HLH showed heterozygous genetic variants in lysosomal trafficking regulator (LYST). Hence, she was diagnosed with AML with t(8;21;22)(q22;q22;q11.2) and HLH. INTERVENTIONS AND OUTCOMES: All HLH clinical symptoms disappeared after the 4 weeks treatment of HLH. Then the patient received standard AML induction chemotherapy and the leukemia relapsed after 2 cycles of high-dosed consolidation therapy. Eventually, the patient received emergent paternal haploidentical hematopoietic stem cell transplantation based on the complex variant translocation, leukemia replased state and HLH with compound heterozygotes mutation, and achieved sustained remission with RUNX1-RUNX1T1 negative for more than 1 year. LESSONS: Patients with some specific recurrent cytogenetic abnormalities should be diagnosed with AML regardless of the blast count, for example t(8;21). We should improve the understanding of complex variant translocations. HLH-related genetic mutations were not only found in primary HLH, but also in second HLH.


Assuntos
Leucemia Mieloide Aguda/genética , Linfo-Histiocitose Hemofagocítica/genética , Translocação Genética/genética , Adolescente , Antineoplásicos/uso terapêutico , Cromossomos Humanos Par 21/genética , Cromossomos Humanos Par 22/genética , Cromossomos Humanos Par 8/genética , Feminino , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Leucemia Mieloide Aguda/complicações , Leucemia Mieloide Aguda/terapia , Linfo-Histiocitose Hemofagocítica/complicações , Linfo-Histiocitose Hemofagocítica/terapia
18.
Medicine (Baltimore) ; 97(42): e12875, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30335005

RESUMO

RATIONALE: Variant Philadelphia chromosome translocations involving chromosomes other than chromosomes 9 and 22 have been reported in 5% to 10% of patients with chronic myeloid leukemia (CML). Here, a case of CML with a t (9, 22, 16) (q34; q11; p13) translocation, which has never been described, is reported. PATIENT CONCERNS: A 59-year-old female with dry cough, referred to our hospital, exhibited hepatosplenomegaly, high basophil count, and high platelet count at admission without any other known chronic diseases. DIAGNOSES: The patient was diagnosed with CML with the translocation t (9;22;16) (q34; q11; p13). The patient was treated with imatinib, a first-generation tyrosine kinase inhibitor (TKI), discontinuously, achieving a complete hematological response for 7 years. Since November 8, 2017, the patient had recurrent fever, and her platelet count rose to 1422 × 10/L. Subsequently, the E279K mutation in the BCR-ABL kinase region was detected. OUTCOMES: According to a previous report, this mutation confers sensitivity to nilotinib, a second-generation TKI. In the end, the patient received treatment with nilotinib and showed a complete hematological response. LESSONS: The present study reports a rare case of CML with Ph chromosome and a t (9;22;16) (q34; q11; p13) translocation. For such cases about CML with variant Philadelphia chromosome translocations or BCR-ABL kinase region mutation, TKI may still be valuable.


Assuntos
Antineoplásicos/administração & dosagem , Mesilato de Imatinib/administração & dosagem , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Pirimidinas/administração & dosagem , Translocação Genética/genética , Cromossomos Humanos 16-18/genética , Cromossomos Humanos Par 22/genética , Cromossomos Humanos Par 9/genética , Feminino , Humanos , Pessoa de Meia-Idade , Mutação , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/genética , Cromossomo Filadélfia
19.
Bull Cancer ; 105(11): 1094-1101, 2018 Nov.
Artigo em Francês | MEDLINE | ID: mdl-30297237

RESUMO

Dematofibrosarcoma protuberans (DFSP) are very rare (1 to 4 incident cases per million of inhabitants). The local spreading of DFSP is underestimated. The histological diagnosis is challenging but we now know a specific marker (translocation t(17;22)(q22;q13) (COL1A1;PDGFB)). The risk of metastatic relapse is low (and related to fibrosarcoma component); the risk of local relapse depends on the quality of surgery. Management of localized DFSP is based on large resection with meticulous analysis of margins (with or without Mohs microsurgery). Advanced stages not amenable to surgery or metastatic DFSP (with presence of COL1A1;PDGFB) are best treated with imatinib. Locally advanced DFSP potentially amenable to curative intent surgery could be treated with imatinib as neo-adjuvant treatment. The management of these tumours requires multidisciplinary expertise.


Assuntos
Dermatofibrossarcoma , Doenças Raras , Neoplasias Cutâneas , Cromossomos Humanos Par 17/genética , Cromossomos Humanos Par 22/genética , Colágeno Tipo I/genética , Dermatofibrossarcoma/diagnóstico por imagem , Dermatofibrossarcoma/genética , Dermatofibrossarcoma/patologia , Dermatofibrossarcoma/terapia , Marcadores Genéticos , Humanos , Recidiva Local de Neoplasia , Proteínas Proto-Oncogênicas c-sis/genética , Doenças Raras/diagnóstico por imagem , Doenças Raras/genética , Doenças Raras/patologia , Doenças Raras/terapia , Neoplasias Cutâneas/diagnóstico por imagem , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/terapia , Translocação Genética
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