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1.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(9): 938-942, 2019 Sep 10.
Artigo em Chinês | MEDLINE | ID: mdl-31515795

RESUMO

OBJECTIVE: To explore the influence of uniparental disomy (UPD) on bipartite and tripartite paternity testing. METHODS: Two cases of paternity testing were analyzed by multiplex amplification and capillary electrophoresis typing. Suspected UPD was verified by using single nucleotide polymorphism array (SNP array). Parental power index was calculated by using a bipartite or tripartite model. RESULTS: The two cases were found to harbor respectively three short tandem repeats on chromosome 2 and two short tandem repeats on chromosome 15. SNP array verified that both cases were of UPD. Case 1 had a parental power index of 122274987565.23 by a tripartite model, while case 2 had a parental power index of 13500.8463 by a bipartite model. Based on the technical specification, the conclusions supported a biological parent-child relationship in both cases. CONCLUSION: UPD may lead to misjudgment of paternity testing. The possibility of UPD should be considered when certain loci which do not conform to Mendelian inheritance have aggregated to one chromosome.


Assuntos
Paternidade , Dissomia Uniparental/genética , Cromossomos Humanos Par 2/genética , Humanos , Repetições de Microssatélites , Polimorfismo de Nucleotídeo Único
2.
Cytogenet Genome Res ; 157(4): 197-202, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30991391

RESUMO

Uniparental disomy (UPD) is a rare type of chromosomal aberration that has sometimes been detected in paternity testing. We examined a 3-person family (father, mother, daughter) first by using short tandem repeat markers, which revealed 4 markers, TPOX, D2S1338, D2S1772, and D2S441, on chromosome 2 that were not transmitted in a Mendelian style. We then performed whole genome sequencing (WGS) to determine the range of the UPD. Chromosome 2 in the daughter showed a complete paternal UPD. To the best of our knowledge, this is the 4th case of complete paternal UPD of chromosome 2 with no clinical phenotype. Our study suggests that WGS, when performed to enhance the accuracy and reliability of parentage testing, can provide a powerful method to detect an UPD.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Repetições de Microssatélites , Dissomia Uniparental/diagnóstico , Sequenciamento Completo do Genoma/métodos , Adolescente , Cromossomos Humanos Par 2/genética , Pai , Feminino , Humanos , Masculino , Mães , Linhagem , Dissomia Uniparental/genética
3.
Clin Epigenetics ; 11(1): 35, 2019 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-30808399

RESUMO

BACKGROUND: Genome-wide studies have begun to link subtle variations in both allelic DNA methylation and parent-of-origin genetic effects with early development. Numerous reports have highlighted that the placenta plays a critical role in coordinating fetal growth, with many key functions regulated by genomic imprinting. With the recent description of wide-spread polymorphic placenta-specific imprinting, the molecular mechanisms leading to this curious polymorphic epigenetic phenomenon is unknown, as is their involvement in pregnancies complications. RESULTS: Profiling of 35 ubiquitous and 112 placenta-specific imprinted differentially methylated regions (DMRs) using high-density methylation arrays and pyrosequencing revealed isolated aberrant methylation at ubiquitous DMRs as well as abundant hypomethylation at placenta-specific DMRs. Analysis of the underlying chromatin state revealed that the polymorphic nature is not only evident at the level of allelic methylation, but DMRs can also adopt an unusual epigenetic signature where the underlying histones are biallelically enrichment of H3K4 methylation, a modification normally mutually exclusive with DNA methylation. Quantitative expression analysis in placenta identified two genes, GPR1-AS1 and ZDBF2, that were differentially expressed between IUGRs and control samples after adjusting for clinical factors, revealing coordinated deregulation at the chromosome 2q33 imprinted locus. CONCLUSIONS: DNA methylation is less stable at placenta-specific imprinted DMRs compared to ubiquitous DMRs and contributes to privileged state of the placenta epigenome. IUGR-associated expression differences were identified for several imprinted transcripts independent of allelic methylation. Further work is required to determine if these differences are the cause IUGR or reflect unique adaption by the placenta to developmental stresses.


Assuntos
Metilação de DNA , Retardo do Crescimento Fetal/genética , Perfilação da Expressão Gênica/métodos , Placenta/química , Cromossomos Humanos Par 2/genética , Ilhas de CpG , Proteínas de Ligação a DNA/genética , Feminino , Retardo do Crescimento Fetal/metabolismo , Regulação da Expressão Gênica , Impressão Genômica , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Histonas/metabolismo , Humanos , Linhagem , Gravidez
4.
Clin Epigenetics ; 11(1): 3, 2019 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-30616679

RESUMO

BACKGROUND: The term pseudohypoparathyroidism (PHP) describes disorders derived from resistance to the parathyroid hormone. Albright hereditary osteodystrophy (AHO) is a disorder with several physical features that can occur alone or in association with PHP. The subtype 1B, classically associated with resistance to PTH and TSH, derives from the epigenetic dysregulation of the GNAS locus. Patients showing features of AHO were described, but no explanation for such phenotypic heterogeneity is available. An AHO-like phenotype was associated with the loss of genetic information stored in chromosome 2q37, making this genomic region an interesting object of study as it could contain modifier genes involved in the development of AHO features in patients with GNAS imprinting defects. The present study aimed to screen a series of 65 patients affected with GNAS imprinting defects, with or without signs of AHO, for the presence of 2q37 deletions in order to find genes involved in the clinical variability. RESULTS: The molecular investigations performed on our cohort of patients with GNAS imprinting defects identified two overlapping terminal deletions of the long arm of chromosome 2. The smaller deletion was of approximately 3 Mb and contained 38 genes, one or more of which is potentially involved in the clinical presentation. Patients with the deletions were both affected by a combination of the most pathognomic AHO-like features, brachydactyly, cognitive impairment and/or behavioural defects. Our results support the hypothesis that additional genetic factors besides GNAS methylation defects are involved in the development of a complex phenotype in the subgroup of patients showing signs of AHO. CONCLUSIONS: For the first time, the present work describes PHP patients with hormone resistance and AHO signs simultaneously affected by GNAS imprinting defects and 2q37 deletions. Although further studies are needed to confirm the cause of these two rare molecular alterations and to identify candidate genes, this finding provides novel interesting clues for the identification of factors involved in the still unexplained clinical variability observed in PHP1B.


Assuntos
Cromograninas/genética , Deleção Cromossômica , Cromossomos Humanos Par 2/genética , Subunidades alfa Gs de Proteínas de Ligação ao GTP/genética , Pseudo-Hipoparatireoidismo/genética , Resistência a Medicamentos , Feminino , Estudos de Associação Genética , Heterogeneidade Genética , Impressão Genômica , Humanos , Masculino , Fenótipo , Pseudo-Hipoparatireoidismo/sangue , Tireotropina/sangue
5.
Stem Cell Res ; 34: 101377, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30616144

RESUMO

Skin fibroblasts from a patient with developmental delay and chromosome 2p25.3 deletion syndrome were reprogrammed into induced pluripotent stem cells (iPSCs) and the clonal stem cell line ICAGi001-A (iTAF9-11) was established. ICAGi001-A pluripotency was demonstrated in vitro by three germ layer differentiation capacity. This line is a good model for studying of the developmental delay and brain disorder.


Assuntos
Deleção Cromossômica , Transtornos Cromossômicos/genética , Cromossomos Humanos Par 2/genética , Fibroblastos/patologia , Células-Tronco Pluripotentes Induzidas/patologia , Pele/patologia , Linhagem Celular , Pré-Escolar , Feminino , Humanos
6.
Mol Genet Genomic Med ; 7(4): e00591, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30697976

RESUMO

BACKGROUND: Platelet-derived growth factor receptor beta (PDGFRB) rearrangement has been reported in a number of patients with chronic eosinophilic leukemia (CEL), B-acute lymphoblastic leukemia, myeloproliferative neoplasms, and juvenile myelomonocytic leukemia. Here, we report a case of CEL carrying a novel fusion gene involving PDGFRB and GRIP and coiled-coil domain containing 2 (GCC2). PATIENT AND METHODS: A 54-year-old man presenting with a cough and dyspnea was diagnosed with acute eosinophilic pneumonia. Cytogenetic analysis of the bone marrow revealed the presence of t(2;5)(q37;q31). Fluorescence in situ hybridization analysis in the peripheral blood leukocytes revealed the presence of a split signal at PDGFRB gene. Imatinib treatment was effective, and disappearance of t(2;5)(q37;q31) in the bone marrow was confirmed after three months of imatinib therapy. Whole-genome sequencing was performed in peripheral blood leukocytes collected before imatinib therapy. RESULTS: A novel fusion gene between exon 22 of GCC2 and exon 12 of PDGFRB was detected and the presence of GCC2-PDGFRB was confirmed by PCR. CONCLUSION: This is the first case report demonstrating the GCC2 gene as a partner of PDGFRB in the pathogenesis of CEL.


Assuntos
Biomarcadores Tumorais/genética , Proteínas da Matriz do Complexo de Golgi/genética , Síndrome Hipereosinofílica/genética , Leucemia/genética , Proteínas de Fusão Oncogênica/genética , Receptor beta de Fator de Crescimento Derivado de Plaquetas/genética , Células da Medula Óssea/metabolismo , Células da Medula Óssea/patologia , Cromossomos Humanos Par 2/genética , Cromossomos Humanos Par 5/genética , Humanos , Síndrome Hipereosinofílica/patologia , Leucemia/patologia , Masculino , Pessoa de Meia-Idade , Fusão Oncogênica , Translocação Genética
7.
Blood Adv ; 2(24): 3637-3647, 2018 12 26.
Artigo em Inglês | MEDLINE | ID: mdl-30578281

RESUMO

Red blood cell (RBC) transfusion remains a critical therapeutic intervention in sickle cell disease (SCD); however, the apparent propensity of some patients to regularly develop RBC alloantibodies after transfusion presents a significant challenge to finding compatible blood for so-called alloimmunization responders. Predisposing genetic loci have long been thought to contribute to the responder phenomenon, but to date, no definitive loci have been identified. We undertook a genome-wide association study of alloimmunization responder status in 267 SCD multiple transfusion recipients, using genetic estimates of ancestral admixture to bolster our findings. Analyses revealed single nucleotide polymorphisms (SNPs) on chromosomes 2 and 5 approaching genome-wide significance (minimum P = 2.0 × 10-8 and 8.4 × 10-8, respectively), with local ancestry analysis demonstrating similar levels of admixture in responders and nonresponders at implicated loci. Association at chromosome 5 was nominally replicated in an independent cohort of 130 SCD transfusion recipients, with meta-analysis surpassing genome-wide significance (rs75853687, P meta = 6.6 × 10-9), and this extended to individuals forming multiple (>3) alloantibodies (P meta = 9.4 × 10-5). The associated variant is rare outside of African populations, and orthogonal genome-wide haplotype analyses, contingent on local ancestry, revealed genome-wide significant sharing of a ∼60-kb haplotype of African ancestry at the chromosome 5 locus (Bayes Factor = 4.95). This locus overlaps a putative cis-acting enhancer predicted to regulate transcription of ADRA1B and the lncRNA LINC01847, both members of larger ontologies associated with immune regulation. Our findings provide potential insights to the pathophysiology underlying the development of alloantibodies and implicate non-RBC ancestry-limited loci in the susceptibility to alloimmunization.


Assuntos
Afro-Americanos/genética , Anemia Falciforme/patologia , Cromossomos Humanos Par 5/genética , Isoanticorpos/sangue , Alelos , Anemia Falciforme/genética , Anemia Falciforme/imunologia , Cromossomos Humanos Par 2/genética , Loci Gênicos , Estudo de Associação Genômica Ampla , Genótipo , Haplótipos , Humanos , Polimorfismo de Nucleotídeo Único , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Receptores Adrenérgicos alfa 1/genética , Receptores Adrenérgicos alfa 1/metabolismo
8.
Tohoku J Exp Med ; 245(3): 187-191, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-30012910

RESUMO

Campomelic dysplasia (CD) is a skeletal dysplasia characterized by shortened and bowed long bones, airway instability, the potential for disorders of sexual differentiation (DSD), and Pierre Robin Sequence (PRS) with cleft palate, midface hypoplasia and laryngotrachemomalacia. CD is caused by alterations in the Sex-determining region of the Y chromosome (SRY)-related-box 9 (SOX9), which has important roles in tissue and sexual differentiation. The SOX9 gene and the enhancer regions of SOX9 are located at chromosome 17q24.3. We report a 6-year-old phenotypically female referred to our department because of precocious puberty. The patient was born with Tetralogy of Fallot (TOF) and PRS. Skeletal X-ray examination showed only 11 pairs of ribs and bilateral bowed radiuses. Endocrine evaluations showed that increased levels of serum testosterone, and chromosomal analysis revealed a 46, XY, t(2;17)(p15;q24.2) karyotype. The patient was diagnosed with peripheral precocious puberty caused by over-secretion of testosterone by gonadoblastoma originating from dysgenetic gonads with Y-chromosome-related DSD. Multiple somatic abnormalities and DSD indicated that the patient might have CD. Laparoscopy revealed bilateral dysgenetic gonads, and these were removed in the successive operation to prevent malignant transformation and virilization, caused by dysgenetic gonads with Y chromosomal materials. It is highly suggestive that the chromosomal translocation of 17q 24.2 may cause DSD and multiple somatic abnormalities, including CD, although the identified 17q breakpoint was located outside of known SOX9 enhancer regions. Thus, a hitherto unknown enhancer may be present at 17q24.2. This is the first reported case of CD with a translocation breakpoint at 17q24.2.


Assuntos
Anormalidades Múltiplas/genética , Cromossomos Humanos Par 17/genética , Cromossomos Humanos Par 2/genética , Gônadas/anormalidades , Translocação Genética , Criança , Endoscopia , Feminino , Hormônios/sangue , Humanos
10.
J Genet ; 97(1): 311-317, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29666350

RESUMO

We describe a newborn female with a de novo duplication of chromosomes 2q31.2 and 2q37.3, and a de novo monosomy 9p24.3. The clinical findings of this patient include congenital heart defects, dysmorphic facial features, hypotonia, feeding difficulties and microcephaly. Ultrasonographic prenatal findings were negative for foetal malformations. Only a mild pyelectasis was reported. This is the first report of molecular cytogenetic characterization of a partial trisomy 2q31.2-37.3 with monosomy 9p24.3.


Assuntos
Cromossomos Humanos Par 2/genética , Cromossomos Humanos Par 9/genética , Monossomia/genética , Trissomia/genética , Duplicação Cromossômica , Humanos , Recém-Nascido , Cariotipagem
11.
Clin Dysmorphol ; 27(2): 27-30, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29315086

RESUMO

Heterozygous microdeletions of chromosome 2p21 encompassing only the SIX2 gene have been described in two families to date. The clinical phenotype comprised autosomal-dominant inherited frontonasal dysplasia with ptosis in one family. In the second family, conductive hearing loss was the major clinical feature described; however, the affected persons also had ptosis. Here, we present a large family combining all three predescribed features of SIX2 gene deletion. The phenotype in four affected family members in three generations consisted of bilateral congenital ptosis, epicanthus inversus, frontonasal dysplasia with broad nasal bridge and hypertelorism, frontal bossing and large anterior fontanel in childhood, narrow ear canals, and mild conductive hearing loss with onset in childhood. Thus, the phenotypic spectrum of SIX2 haploinsufficiency is widened. Moreover, 2p21 microdeletions with SIX2 haploinsufficiency appear to lead to a recognizable phenotype with facial features resembling blepharophimosis-ptosis-epicanthus inversus syndrome.


Assuntos
Blefaroptose/genética , Anormalidades Craniofaciais/genética , Face/anormalidades , Perda Auditiva Condutiva/genética , Proteínas de Homeodomínio/genética , Proteínas do Tecido Nervoso/genética , Blefaroptose/fisiopatologia , Criança , Pré-Escolar , Cromossomos Humanos Par 2/genética , Hibridização Genômica Comparativa , Anormalidades Craniofaciais/fisiopatologia , Face/fisiopatologia , Feminino , Predisposição Genética para Doença , Haploinsuficiência , Perda Auditiva Condutiva/fisiopatologia , Heterozigoto , Humanos , Lactente , Masculino , Mutação , Linhagem , Fenótipo
12.
Int Braz J Urol ; 44(4): 785-793, 2018 Jul-Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29219278

RESUMO

OBJECTIVE: To explore the clinical features of carriers of chromosome 2 translocations, enabling informed genetic counseling of these patients. MATERIALS AND METHODS: Eighty-two male carriers of a translocation who were infertile or receiving fertility counseling were recruited. Cytogenetic analyses were performed using G-banding. A search of PubMed was performed to determine whether the identified translocations on chromosome 2 are involved in male infertility. The relationships of translocation breakpoints with male infertility and recurrent pregnancy loss were analyzed. RESULTS: Of the 82 translocation carriers, 9 (11%) were carriers of a chromosome 2 translocation. Four cases had oligozoospermia or infertility, while five had normal semen. In an analysis of the literature, 55 patients who were carriers of chromosome 2 translocations were also reviewed. Breakpoints at 2p13 and 2q31 were observed in six patients each, and were the most common. Breakpoints at 2p23, 2p13, 2p11.2, 2q31, and 2q37 were associated to both pre-gestational and gestational infertility, while other breakpoints were associated with gestational infertility. CONCLUSIONS: All breakpoints at chromosome 2 were correlated with gestational infertility. Carriers of chromosome 2 translocations should therefore receive counseling to continue with natural conception and use of different technologies available via assisted reproductive technology, such as preimplantation genetic diagnosis.


Assuntos
Cromossomos Humanos Par 2/genética , Infertilidade Masculina/genética , Translocação Genética/genética , Pontos de Quebra do Cromossomo , Análise Citogenética , Feminino , Triagem de Portadores Genéticos , Aconselhamento Genético , Humanos , Masculino , Gravidez , Resultado da Gravidez , Padrões de Referência , Análise do Sêmen
13.
Pediatr Hematol Oncol ; 35(7-8): 434-441, 2018 Oct - Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30776935

RESUMO

Extraskeletal myxoid chondrosarcoma (EMC), a soft-tissue sarcoma with unique clinicopathologic features and characteristic chromosomal translocations, is extremely rare in the pediatric population. We, herein, present the case of a 7-year-old boy with profound microcytic hypochromic anemia, poor weight gain and a mid-thoracic paraspinal mass that was identified as EMC. Systemic manifestations of localized, nonmetastatic EMC have never been described in the pediatric population, yet our patient's anemia and poor weight gain resolved after successful surgical resection of the tumor, suggesting that localized EMC can present with systemic manifestations. The tumor also contained a novel t(2;22)(q34;q12) translocation involving the EWSR1 gene, which is consistent with additional reports suggesting that a growing list of translocations can drive formation of, and potential new management strategies for, EMC.


Assuntos
Condrossarcoma , Cromossomos Humanos Par 22/genética , Cromossomos Humanos Par 2/genética , Proteína EWS de Ligação a RNA , Translocação Genética , Criança , Condrossarcoma/genética , Condrossarcoma/metabolismo , Condrossarcoma/patologia , Humanos , Masculino , Proteína EWS de Ligação a RNA/genética , Proteína EWS de Ligação a RNA/metabolismo
14.
Pediatr Hematol Oncol ; 35(7-8): 407-414, 2018 Oct - Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30806137

RESUMO

Rhabdomyosarcoma (RMS) represents the most common soft tissue sarcoma in the pediatric age group. While RMS has been traditionally classified on the basis of its histological appearance (with embryonal and alveolar being most common), it is now clear that the PAX-FOXO1 fusion product drives prognosis. We report here a case of pelvic embryonal RMS in a 3-month-old male who was subsequently found to have developed brain metastases during the course of chemotherapy. Cytogenetic analysis of the brain metastases at the time of autopsy as well as next-generation sequencing analysis revealed a reciprocal translocation involving the SH3 domain containing ring finger 3 gene (SH3RF3, on chromosome 2q13) and the Lipase C gene (LIPC, on chromosome 15q21.3). Due to the poor quality of the pretreatment and postresection samples, cytogenetics and NGS analysis looking for the presence of this balanced translocation in these specimens could not be performed. To the authors' knowledge, this translocation has never been described in RMS. Further studies are needed to determine the biological and clinical implications of this novel translocation.


Assuntos
Cromossomos Humanos Par 15/genética , Cromossomos Humanos Par 2/genética , Rabdomiossarcoma Embrionário/genética , Translocação Genética , Proteína Forkhead Box O1/genética , Humanos , Lactente , Lipase/genética , Masculino , Proteínas de Fusão Oncogênica/genética , Fatores de Transcrição Box Pareados/genética , Rabdomiossarcoma Embrionário/patologia , Ubiquitina-Proteína Ligases/genética
15.
Cytogenet Genome Res ; 153(3): 117-124, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29268249

RESUMO

We report on a prenatally diagnosed unusual case of inverted terminal duplication of the short arm of chromosome 2, leading to interstitial telomeric sequences (ITSs) and partial trisomy 2p. To our knowledge, there are only 4 further cases of pure partial trisomy 2p reported prenatally. Here, the mother was referred at 22 weeks of gestation for isolated fetal congenital heart malformation at ultrasound. The karyotype of amniotic fluid cells displayed a large duplication of the short arm of chromosome 2 that was further investigated by array-CGH, which detected a 1-copy gain of 43.75 Mb in chromosome 2 at 2p21p25.3. FISH confirmed the presence of an inverted duplication in the short arm of chromosome 2 involving the region 2p21pter and revealed the presence of ITSs at the breakpoint in chromosome 2p21. This report contributes to the prenatal description of the syndrome. We also discuss the possible mechanisms leading to this duplication and the formation of ITSs which are rarely described in constitutional rearrangements.


Assuntos
Cromossomos Humanos Par 2/genética , Doenças Fetais/genética , Diagnóstico Pré-Natal , Telômero/genética , Trissomia/genética , Bandeamento Cromossômico , Hibridização Genômica Comparativa , Feminino , Doenças Fetais/diagnóstico , Humanos , Hibridização in Situ Fluorescente , Gravidez , Trissomia/diagnóstico
16.
J Proteome Res ; 16(12): 4340-4351, 2017 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-28891297

RESUMO

The present study is a contribution to the "neXt50 challenge", a coordinated effort across C-HPP teams to identify the 50 most tractable missing proteins (MPs) on each chromosome. We report the targeted search of 38 theoretically detectable MPs from chromosomes 2 and 14 in Triton X-100 soluble and insoluble sperm fractions from a total of 15 healthy donors. A targeted mass-spectrometry-based strategy consisting of the development of LC-PRM assays (with heavy labeled synthetic peptides) targeting 92 proteotypic peptides of the 38 selected MPs was used. Out of the 38 selected MPs, 12 were identified with two or more peptides and 3 with one peptide after extensive SDS-PAGE fractionation of the two samples and with overall low-intensity signals. The PRM data are available via ProteomeXchange in PASSEL (PASS01013). Further validation by immunohistochemistry on human testes sections and cytochemistry on sperm smears was performed for eight MPs with antibodies available from the Human Protein Atlas. Deep analysis of human sperm still allows the validation of MPs and therefore contributes to the C-HPP worldwide effort. We anticipate that our results will be of interest to the reproductive biology community because an in-depth analysis of these MPs may identify potential new candidates in the context of human idiopathic infertilities.


Assuntos
Proteoma/análise , Espermatozoides/química , Anticorpos , Cromossomos Humanos Par 14/genética , Cromossomos Humanos Par 2/genética , Histocitoquímica , Humanos , Imuno-Histoquímica , Masculino , Octoxinol , Espectrometria de Massas em Tandem , Testículo/química
17.
PLoS Genet ; 13(8): e1006957, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28859103

RESUMO

Deletions at chromosome 2p25.3 are associated with a syndrome consisting of intellectual disability and obesity. The smallest region of overlap for deletions at 2p25.3 contains PXDN and MYT1L. MYT1L is expressed only within the brain in humans. We hypothesized that single nucleotide variants (SNVs) in MYT1L would cause a phenotype resembling deletion at 2p25.3. To examine this we sought MYT1L SNVs in exome sequencing data from 4, 296 parent-child trios. Further variants were identified through a genematcher-facilitated collaboration. We report 9 patients with MYT1L SNVs (4 loss of function and 5 missense). The phenotype of SNV carriers overlapped with that of 2p25.3 deletion carriers. To identify the transcriptomic consequences of MYT1L loss of function we used CRISPR-Cas9 to create a knockout cell line. Gene Ontology analysis in knockout cells demonstrated altered expression of genes that regulate gene expression and that are localized to the nucleus. These differentially expressed genes were enriched for OMIM disease ontology terms "mental retardation". To study the developmental effects of MYT1L loss of function we created a zebrafish knockdown using morpholinos. Knockdown zebrafish manifested loss of oxytocin expression in the preoptic neuroendocrine area. This study demonstrates that MYT1L variants are associated with syndromic obesity in humans. The mechanism is related to dysregulated expression of neurodevelopmental genes and altered development of the neuroendocrine hypothalamus.


Assuntos
Regulação da Expressão Gênica/genética , Hipotálamo/fisiologia , Deficiência Intelectual/genética , Proteínas do Tecido Nervoso/genética , Obesidade/genética , Fatores de Transcrição/genética , Adulto , Animais , Sistemas CRISPR-Cas , Linhagem Celular , Criança , Deleção Cromossômica , Cromossomos Humanos Par 2/genética , Feminino , Técnicas de Inativação de Genes , Humanos , Hipotálamo/metabolismo , Hipotálamo/patologia , Deficiência Intelectual/fisiopatologia , Masculino , Mutação , Obesidade/fisiopatologia , Polimorfismo de Nucleotídeo Único/genética , Peixe-Zebra
19.
PLoS Genet ; 13(7): e1006871, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28715450

RESUMO

Race, specifically African ancestry, and obesity are important risk factors for uterine fibroids, and likely interact to provide the right conditions for fibroid growth. However, existing studies largely focus on the main-effects rather than their interaction. Here, we firstly provide evidence for interaction between categories of body mass index (BMI) and reported-race in relation to uterine fibroids. We then investigate whether the association between inferred local European ancestry and fibroid risk is modified by BMI in African American (AA) women in the Vanderbilt University Medical Center bio-repository (BioVU) (539 cases and 794 controls) and the Coronary Artery Risk Development in Young Adults study (CARDIA, 264 cases and 173 controls). We used multiple logistic regression to evaluate interactions between local European ancestry and BMI in relation to fibroid risk, then performed fixed effects meta-analysis. Statistical significance threshold for local-ancestry and BMI interactions was empirically estimated with 10,000 permutations (p-value = 1.18x10-4). Admixture mapping detected an association between European ancestry and fibroid risk which was modified by BMI (continuous-interaction p-value = 3.75x10-5) around ADTRP (chromosome 6p24); the strongest association was found in the obese category (ancestry odds ratio (AOR) = 0.51, p-value = 2.23x10-5). Evaluation of interaction between genotyped/imputed variants and BMI in this targeted region suggested race-specific interaction, present in AAs only; strongest evidence was found for insertion/deletion variant (6:11946435), again in the obese category (OR = 1.66, p-value = 1.72x10-6). We found nominal evidence for interaction between local ancestry and BMI at a previously reported region in chromosome 2q31-32, which includes COL5A2, and TFPI, an immediate downstream target of ADTRP. Interactions between BMI and SNPs (single nucleotide polymorphisms) found in this region in AA women were also detected in an independent European American population of 1,195 cases and 1,164 controls. Findings from our study provide an example of how modifiable and non-modifiable factors may interact to influence fibroid risk and suggest a biological role for BMI in fibroid etiology.


Assuntos
Grupo com Ancestrais do Continente Africano/genética , Índice de Massa Corporal , Leiomioma/genética , Polimorfismo de Nucleotídeo Único , Adolescente , Adulto , Estudos de Casos e Controles , Mapeamento Cromossômico , Cromossomos Humanos Par 2/genética , Cromossomos Humanos Par 6/genética , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Técnicas de Genotipagem , Humanos , Leiomioma/etnologia , Modelos Logísticos , Obesidade/complicações , Obesidade/genética , Estudos Prospectivos , Fatores de Risco , Adulto Jovem
20.
Clin Dysmorphol ; 26(4): 209-216, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28737552

RESUMO

In this study, we describe two patients with a recombinant chromosome secondary to a maternal intrachromosomal insertion. Patient 1 was a girl with dup(6)(p22.3p25.3). Patient 2 was a boy with dup(2)(q24.2q32.1). Both familial rearrangements were characterized by means of GTG-bands, fluorescence in-situ hybridization, and comparative genomic hybridization microarray analyses. Patient 1 had an ∼23 Mb gain that involved the bands 6p22.3-6p25.3. Patient 2 had an ∼23 Mb gain (cytobands 2q24.2-2q32.1) and a further ∼1.9 Mb gain of 2p16.2-p16.3. The phenotype of each patient was in agreement with the typical 6p duplication or 2q24.2q32.1 duplication syndrome. The compound macular lesion in patient 1 suggests that retinal anomalies may be a part of the 6p trisomy phenotype. Among the 70 intrachromosomal insertions compiled here (including 68 from the literature), four were submicroscopic unbalanced insertions inherited from a balanced carrier and 66 were detectable on banded chromosomes (with or without array comparative genomic hybridization or other high-resolution assessment) and therefore spanned at least 5 Mb. Pericentric insertions are found in most chromosomes, whereas the paracentric ones are mainly observed in large and medium chromosome arms. That the former outnumber the latter in almost a 2 : 1 ratio appears to be related to the technique of diagnosis, size of the insertion, and size of the involved chromosome. Regardless of the apparent excess of carrier mothers, carriers of an intrachromosomal insertion beget almost twice as many children with a duplication than with a deletion.


Assuntos
Duplicação Cromossômica/genética , Cromossomos Humanos Par 2/genética , Cromossomos Humanos Par 6/genética , Recombinação Genética/genética , Bandeamento Cromossômico , Hibridização Genômica Comparativa , Família , Evolução Fatal , Feminino , Humanos , Lactente , Cariotipagem , Masculino
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