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1.
Cytogenet Genome Res ; 160(6): 309-315, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32599602

RESUMO

Warburg micro syndrome (WARBM) is a rare autosomal recessive disorder characterized by microcephaly, cortical dysplasia, intellectual disability, ocular abnormalities, spastic diplegia, and microgenitalia. WARBM has 4 subtypes arising from pathogenic variants in 4 genes (RAB18, RAB3GAP1, RAB3GAP2, and TBC1D20). Here, we report on a patient with a homozygous pathogenic c.665delC (p.Pro222HisfsTer30) variant in the RAB3GAP1 gene identified by whole-exome sequencing (WES) analyses. Only his father was a heterozygous carrier, and homozygosity mapping analysis of the WES data revealed large loss-of-heterozygosity regions in both arms of chromosome 2, interpreted as uniparental isodisomy. This uniparental disomy pattern could be due to paternal meiosis I nondisjunction because of the preserved heterozygosity in the pericentromeric region. This report provides novel insights, including a rare form of UPD, usage of homozygosity mapping analysis for the evaluation of isodisomy, and the first reported case of WARBM1 as a result of uniparental isodisomy.


Assuntos
Anormalidades Múltiplas/genética , Catarata/congênito , Cromossomos Humanos Par 2/genética , Córnea/anormalidades , Homozigoto , Hipogonadismo/genética , Deficiência Intelectual/genética , Microcefalia/genética , Atrofia Óptica/genética , Dissomia Uniparental/genética , Sequenciamento Completo do Exoma , Adolescente , Adulto , Catarata/genética , Feminino , Humanos , Lactente , Perda de Heterozigosidade/genética , Masculino , Pais , Polimorfismo de Nucleotídeo Único/genética , Proteínas rab3 de Ligação ao GTP/genética
2.
Am J Hum Genet ; 106(4): 453-466, 2020 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-32197076

RESUMO

Identity-by-descent (IBD) segments are a useful tool for applications ranging from demographic inference to relationship classification, but most detection methods rely on phasing information and therefore require substantial computation time. As genetic datasets grow, methods for inferring IBD segments that scale well will be critical. We developed IBIS, an IBD detector that locates long regions of allele sharing between unphased individuals, and benchmarked it with Refined IBD, GERMLINE, and TRUFFLE on 3,000 simulated individuals. Phasing these with Beagle 5 takes 4.3 CPU days, followed by either Refined IBD or GERMLINE segment detection in 2.9 or 1.1 h, respectively. By comparison, IBIS finishes in 6.8 min or 7.8 min with IBD2 functionality enabled: speedups of 805-946× including phasing time. TRUFFLE takes 2.6 h, corresponding to IBIS speedups of 20.2-23.3×. IBIS is also accurate, inferring ≥7 cM IBD segments at quality comparable to Refined IBD and GERMLINE. With these segments, IBIS classifies first through third degree relatives in real Mexican American samples at rates meeting or exceeding other methods tested and identifies fourth through sixth degree pairs at rates within 0.0%-2.0% of the top method. While allele frequency-based approaches that do not detect segments can infer relationship degrees faster than IBIS, the fastest are biased in admixed samples, with KING inferring 30.8% fewer fifth degree Mexican American relatives correctly compared with IBIS. Finally, we ran IBIS on chromosome 2 of the UK Biobank dataset and estimate its runtime on the autosomes to be 3.3 days parallelized across 128 cores.


Assuntos
Análise de Sequência/métodos , Alelos , Cromossomos Humanos Par 2/genética , Frequência do Gene/genética , Genoma Humano/genética , Humanos , Modelos Genéticos , Polimorfismo de Nucleotídeo Único/genética
4.
Eur Child Adolesc Psychiatry ; 29(9): 1301-1310, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31865460

RESUMO

Alterations in fear learning/generalization are considered to be relevant mechanisms engendering the development of anxiety disorders being the most prevalent mental disorders. Although anxiety disorders almost exclusively have their first onset in childhood and adolescence, etiological research focuses on adult individuals. In this study, we evaluated findings of a recent meta-analysis of genome-wide association studies in adult anxiety disorders with significant associations of four single nucleotide polymorphisms (SNPs) in a large cohort of 347 healthy children (8-12 years) characterized for dimensional anxiety. We investigated the modulation of anxiety parameters by these SNPs in a discriminative fear conditioning and generalization paradigm in the to-date largest sample of children. Results extended findings of the meta-analysis showing a genomic locus on 2p21 to modulate anxious personality traits and arousal ratings. These SNPs might, thus, serve as susceptibility markers for a shared risk across pathological anxiety, presumably mediated by alterations in arousal.


Assuntos
Transtornos de Ansiedade/psicologia , Cromossomos Humanos Par 2/genética , Medo/psicologia , Generalização Psicológica/fisiologia , Polimorfismo de Nucleotídeo Único/genética , Criança , Feminino , Técnicas de Genotipagem , Humanos , Masculino
5.
Nat Commun ; 10(1): 4920, 2019 10 29.
Artigo em Inglês | MEDLINE | ID: mdl-31664034

RESUMO

Familial Adult Myoclonic Epilepsy (FAME) is characterised by cortical myoclonic tremor usually from the second decade of life and overt myoclonic or generalised tonic-clonic seizures. Four independent loci have been implicated in FAME on chromosomes (chr) 2, 3, 5 and 8. Using whole genome sequencing and repeat primed PCR, we provide evidence that chr2-linked FAME (FAME2) is caused by an expansion of an ATTTC pentamer within the first intron of STARD7. The ATTTC expansions segregate in 158/158 individuals typically affected by FAME from 22 pedigrees including 16 previously reported families recruited worldwide. RNA sequencing from patient derived fibroblasts shows no accumulation of the AUUUU or AUUUC repeat sequences and STARD7 gene expression is not affected. These data, in combination with other genes bearing similar mutations that have been implicated in FAME, suggest ATTTC expansions may cause this disorder, irrespective of the genomic locus involved.


Assuntos
Proteínas de Transporte/genética , Cromossomos Humanos Par 2/genética , Expansão das Repetições de DNA , Epilepsias Mioclônicas/genética , Íntrons , Adolescente , Adulto , Criança , Pré-Escolar , Mapeamento Cromossômico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Adulto Jovem
6.
Nat Commun ; 10(1): 3927, 2019 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-31477735

RESUMO

The duration of pregnancy is influenced by fetal and maternal genetic and non-genetic factors. Here we report a fetal genome-wide association meta-analysis of gestational duration, and early preterm, preterm, and postterm birth in 84,689 infants. One locus on chromosome 2q13 is associated with gestational duration; the association is replicated in 9,291 additional infants (combined P = 3.96 × 10-14). Analysis of 15,588 mother-child pairs shows that the association is driven by fetal rather than maternal genotype. Functional experiments show that the lead SNP, rs7594852, alters the binding of the HIC1 transcriptional repressor. Genes at the locus include several interleukin 1 family members with roles in pro-inflammatory pathways that are central to the process of parturition. Further understanding of the underlying mechanisms will be of great public health importance, since giving birth either before or after the window of term gestation is associated with increased morbidity and mortality.


Assuntos
Cromossomos Humanos Par 2/genética , Citocinas/genética , Feto/metabolismo , Genoma Humano/genética , Polimorfismo de Nucleotídeo Único , Feminino , Estudo de Associação Genômica Ampla , Idade Gestacional , Humanos , Recém-Nascido , Gravidez , Nascimento Prematuro/genética
7.
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
8.
Arch Dermatol Res ; 311(10): 735-740, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31435740

RESUMO

Primary hyperhidrosis is a condition characterized by excessive sweating. The estimated prevalence is between 0.6 and 4.4%, and it can have economic, psychological, and social consequences for affected individuals. Family and genetic studies have suggested a genetic component in the inheritance of the disease. In this review, we summarize the current literature on genetic disposition to primary hyperhidrosis. We Identified 20 studies on Pubmed and Embase in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Probands reported a positive family history in 5.7-65% of cases, and the inheritance appeared to be either autosomal dominant or recessive. Individuals with palmoplantar phenotypes and a positive family history had a younger age of onset. Genetic linkage and genome-wide association studies have identified loci on chromosome 2, 14, and 16. However, the evidence is heterogeneous and limited. It seems that primary hyperhidrosis is polygenically inherited, and considering the impairment, further data to understand the genetic etiology of the disease are needed.


Assuntos
Loci Gênicos/genética , Predisposição Genética para Doença , Hiperidrose/genética , Idade de Início , Cromossomos Humanos Par 14/genética , Cromossomos Humanos Par 16/genética , Cromossomos Humanos Par 2/genética , Estudo de Associação Genômica Ampla , Humanos , Hiperidrose/epidemiologia , Anamnese , Prevalência
10.
Acta Otolaryngol ; 139(10): 870-875, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31403828

RESUMO

Background: Deletions of the interstitial 2q36 are uncommon and associated with varying phenotypes. However, the list of currently known phenotypes is still far complete for an understanding of the interstitial 2q36 deletion syndrome characteristics. Aims/Objectives: To identify the genetic and clinical characterization of a 6-year-old male patient suffering from a severe form of syndromic hearing loss, with brachydactyly family history. Material and Methods: We performed conventional cytogenetic analysis on the peripheral blood lymphocytes and whole exome sequencing and SNP array analysis on DNA samples from the family. Results: The proband showed signs such as bilateral sensorineural deafness, ocular hypertelorism, flat facial profile and several decayed teeth, slightly ulnar deviation of the hands, single transverse palmar crease, short stature and intellectual disability. Through cytogenetic and molecular genetic analysis, we discovered that the syndromic hearing loss was the result of a de novo 5.175-Mb microdeletion at chromosome 2q36.1q36.3 whose breakpoints had been precisely mapped by us. Conclusions and Significance: Our study warns that auditory assessment should be evaluated even if the patient with 2q36 deletion syndrome is not obviously presenting hearing loss. In addition, a comprehensive molecular genetics diagnosis involving multiple methods is important to support accurate genetic characterization of this syndrome.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 2/genética , Perda Auditiva Neurossensorial/genética , Criança , Humanos , Masculino , Linhagem , Síndrome
12.
BMJ Case Rep ; 12(5)2019 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-31133547

RESUMO

Several genes located within the chromosome 8p11.21 region are associated with movement disorders including SLC20A2 and THAP1. SLC20A2 is one of four genes associated with primary familial brain calcification, a syndrome that also includes movement disorders, cognitive decline and psychiatric issues. THAP1 is associated with dystonia type 6, a dominantly inherited dystonia with variable expression. In addition, several reports in the French-Canadian population have described microdeletions within the 8p11.2 region presenting with dystonia-plus syndromes including brain calcifications. This case report describes a 12-year-old boy with brain calcifications and generalised dystonia associated with a deletion in the 8p11.2 region detected via single nucleotide polymorphism microarray. This report emphasises the importance of obtaining a microarray analysis in diagnosing movement disorders and suggests that this copy number variant may be an under-recognised cause of dystonia and brain calcifications.


Assuntos
Encefalopatias/genética , Encefalopatias/patologia , Distonia/diagnóstico , Malformações do Sistema Nervoso/genética , Proteínas Reguladoras de Apoptose , Calcinose/diagnóstico por imagem , Calcinose/patologia , Criança , Cromossomos Humanos Par 2/genética , Proteínas de Ligação a DNA , Distonia/genética , Deleção de Genes , Haploinsuficiência/genética , Heterozigoto , Humanos , Masculino , Análise em Microsséries/métodos , Transtornos dos Movimentos/genética , Malformações do Sistema Nervoso/diagnóstico por imagem , Malformações do Sistema Nervoso/patologia , Polimorfismo de Nucleotídeo Único , Proteínas Cotransportadoras de Sódio-Fosfato Tipo III
13.
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
14.
Int J Hematol ; 110(1): 107-114, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30963474

RESUMO

Double-hit lymphoma is typically categorized as "high-grade B-cell lymphoma, with MYC and BCL2 and/or BCL6 rearrangements", but in infrequent cases in which terminal deoxynucleotidyl transferase (TdT) expression is positive, it is categorized as B-lymphoblastic lymphoma (B-LBL). BCL2 rearrangements are usually caused by t(14;18)(q32;q21); variant translocations are very rare. Here, we describe an unusual case of double-hit pancreatic B-LBL with a variant translocation t(2;18)(p11;q21). A 69-year-old man was admitted because of an abdominal mass. Computed tomography scans demonstrated a diffusely enlarged pancreas and massive ascites. Cell block preparations of ascites cells revealed marked proliferation of blastic lymphoid cells positive for CD19, CD10, CD79a, PAX5, and TdT, indicating a diagnosis of B-LBL. G-banding and spectral karyotyping showed 45,XY,+X,t(2;18)(p11;q21),-4,der(5)t(1;5)(q12;p15),der(6)t(6;21)(q21;q?),t(8;14)(q24;q32),-15. Fluorescence in situ hybridization detected split BCL2 and IGH/MYC fusion signals. Almost all ascites cells were diffusely and strongly positive for MYC and BCL2. The patient died of progressive disease 20 days after admission. To our knowledge, this is the first reported case of MYC and BCL2 double-hit B-LBL with t(2;18)(p11;q21). High coexpression of MYC by t(8;14) and BCL2 by t(2;18) may be implicated in the development of B-LBL. Furthermore, double-hit B-LBL may be associated with a less favorable outcome compared with typical B-LBL.


Assuntos
Linfoma de Células B/genética , Neoplasias Pancreáticas/genética , Translocação Genética/genética , Idoso , Cromossomos Humanos Par 18/genética , Cromossomos Humanos Par 2/genética , Evolução Fatal , Genes myc , Variação Genética , Humanos , Masculino , Proteínas Proto-Oncogênicas c-bcl-2/genética
15.
Am J Med Genet A ; 179(5): 782-791, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30848064

RESUMO

The 2q37 deletion syndrome, also described in the literature as brachydactyly-mental retardation syndrome (MIM 600430), is caused by deletion or haploinsufficiency of the HDAC4 gene, which encodes the histone deacetylase 4 protein. Although the most commonly described hallmark features of the 2q37 deletion syndrome include brachydactyly type E, developmental delay, obesity, autistic features, and craniofacial or skeletal dysmorphism, a literature review of 101 published cases plus two newly reported individuals indicates that there is a high degree of variability in the presence of some of the features that are considered the most characteristic of the syndrome: overweight and obesity (34%), cognitive-behavioral issues (79%), dysmorphic craniofacial features (86%), and type E brachydactyly (48%). These features overlap with other neurodevelopmental conditions, including Smith-Magenis syndrome (SMS), and may be incompletely penetrant or demonstrate variable expressivity, depending on the specific chromosomal anomaly. With the advent of fluorescence in situ hybridization (FISH), array-based comparative genomic hybridization, and next-generation DNA sequencing, more detailed molecular diagnoses are possible than in years past, enabling refined characterization of the genotype-phenotype correlation for subjects with 2q37 deletions. In addition, investigations into molecular and gene expression networks are expanding in neurodevelopmental conditions, and we surveyed HDAC4 downstream gene expression by quantitative real-time polymerase chain reaction, further implicating HDAC4 in its role in the regulation of RAI1. Correlation of clinical data defining the impact on downstream gene expression and the potential clinical associations across neurodevelopment will improve our understanding of these complex conditions and potentially lead to common therapeutic approaches.


Assuntos
Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Histona Desacetilases/genética , Penetrância , Fenótipo , Proteínas Repressoras/genética , Deleção Cromossômica , Cromossomos Humanos Par 2/genética , Deficiências do Desenvolvimento/genética , Feminino , Expressão Gênica , Humanos , Lactente , Deficiência Intelectual/genética , Masculino , Mutação
16.
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
17.
Am J Med Genet B Neuropsychiatr Genet ; 180(3): 213-222, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30779416

RESUMO

We previously identified bipolar disorder (BD) susceptibility loci on 8q24, 14q32, and 2q12-14 in a genome-wide nonparametric linkage screen in a Latino cohort. We now perform a fine mapping analysis using a dense map of additional SNPs to identify BD susceptibility genes within these regions. One thousand nine hundred and thirty-eight individuals with Latino ancestry (880 individuals with BD Type I or Schizoaffective, Bipolar Type) from 416 Latino pedigrees from the United States, Mexico, Costa Rica, and Guatemala were genotyped with 3,074 SNPs to provide dense coverage of the 8q24 (11.5 cM), 14q32 (7.5 cM), and 2q12-14 (6.5 cM) chromosomal loci. Single-marker association tests in the presence of linkage were performed using the LAMP software. The top linkage peak (rs7834818; LOD = 5.08, p = 3.30E - 5) and associated single marker (rs2280915, p = 2.70E - 12) were located within FBXO32 on 8q24. On chromosome 2, the top linkage peak (rs6750326; LOD = 5.06, p = 3.50E - 5) and associated single marker (rs11887088, p = 2.90E - 6) were located in intragenic regions near ACTR3 and DPP10. None of the additional markers in the region around chromosome 14q32 met significance levels for linkage or association. We identified six SNPs on 2q12-q14 and one SNP in FBXO32 on 8q24 that were significantly associated with BD in this Latino cohort.


Assuntos
Transtorno Bipolar/genética , Cromossomos Humanos Par 2/genética , Transtornos Psicóticos/genética , Proteína 3 Relacionada a Actina/genética , Proteína 3 Relacionada a Actina/metabolismo , Adulto , Transtorno Bipolar/psicologia , Mapeamento Cromossômico/métodos , Costa Rica , Dipeptidil Peptidases e Tripeptidil Peptidases/genética , Dipeptidil Peptidases e Tripeptidil Peptidases/metabolismo , Feminino , Ligação Genética/genética , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Genótipo , Guatemala , Hispano-Americanos/genética , Humanos , Escore Lod , Masculino , México , Pessoa de Meia-Idade , Proteínas Musculares/genética , Proteínas Musculares/metabolismo , Polimorfismo de Nucleotídeo Único/genética , Transtornos Psicóticos/psicologia , Proteínas Ligases SKP Culina F-Box/genética , Proteínas Ligases SKP Culina F-Box/metabolismo , Estados Unidos
18.
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
19.
Clin Pharmacol Ther ; 106(1): 219-227, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30648747

RESUMO

Anastrozole is a widely prescribed aromatase inhibitor for the therapy of estrogen receptor positive (ER+) breast cancer. We performed a genome-wide association study (GWAS) for plasma anastrozole concentrations in 687 postmenopausal women with ER+ breast cancer. The top single-nucleotide polymorphism (SNP) signal mapped across SLC38A7 (rs11648166, P = 2.3E-08), which we showed to encode an anastrozole influx transporter. The second most significant signal (rs28845026, P = 5.4E-08) mapped near ALPPL2 and displayed epistasis with the SLC38A7 signal. Both of these SNPs were cis expression quantitative trait loci (eQTL)s for these genes, and patients homozygous for variant genotypes for both SNPs had the highest drug concentrations, the highest SLC38A7 expression, and the lowest ALPPL2 expression. In summary, our GWAS identified a novel gene encoding an anastrozole transporter, SLC38A7, as well as epistatic interaction between SNPs in that gene and SNPs near ALPPL2 that influenced both the expression of the transporter and anastrozole plasma concentrations.


Assuntos
Fosfatase Alcalina/genética , Anastrozol/farmacocinética , Inibidores da Aromatase/farmacocinética , Epistasia Genética/genética , Anastrozol/sangue , Anastrozol/uso terapêutico , Inibidores da Aromatase/sangue , Inibidores da Aromatase/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Cromossomos Humanos Par 16/genética , Cromossomos Humanos Par 2/genética , Feminino , Proteínas Ligadas por GPI/genética , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Polimorfismo de Nucleotídeo Único , Pós-Menopausa , Receptores Estrogênicos/biossíntese
20.
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
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