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1.
Nature ; 571(7763): 107-111, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31217582

RESUMO

Large-scale genome sequencing is poised to provide a substantial increase in the rate of discovery of disease-associated mutations, but the functional interpretation of such mutations remains challenging. Here we show that deletions of a sequence on human chromosome 16 that we term the intestine-critical region (ICR) cause intractable congenital diarrhoea in infants1,2. Reporter assays in transgenic mice show that the ICR contains a regulatory sequence that activates transcription during the development of the gastrointestinal system. Targeted deletion of the ICR in mice caused symptoms that recapitulated the human condition. Transcriptome analysis revealed that an unannotated open reading frame (Percc1) flanks the regulatory sequence, and the expression of this gene was lost in the developing gut of mice that lacked the ICR. Percc1-knockout mice displayed phenotypes similar to those observed upon ICR deletion in mice and patients, whereas an ICR-driven Percc1 transgene was sufficient to rescue the phenotypes found in mice that lacked the ICR. Together, our results identify a gene that is critical for intestinal function and underscore the need for targeted in vivo studies to interpret the growing number of clinical genetic findings that do not affect known protein-coding genes.


Assuntos
Diarreia/congênito , Diarreia/genética , Elementos Facilitadores Genéticos/genética , Regulação da Expressão Gênica no Desenvolvimento , Genes , Intestinos/fisiologia , Deleção de Sequência/genética , Animais , Cromossomos Humanos Par 16/genética , Modelos Animais de Doenças , Feminino , Genes Reporter , Loci Gênicos/genética , Humanos , Masculino , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Linhagem , Fenótipo , Ativação Transcricional , Transcriptoma/genética , Transgenes/genética
2.
Cytogenet Genome Res ; 157(4): 213-219, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30974445

RESUMO

Patients with childhood acute myeloid leukemia (AML) with complex karyotypes (CKs) have a dismal outcome. However, for patients with a KMT2A rearrangement (KMT2A-r), the prognosis appears to depend on the fusion partner gene rather than the karyotype structure. Thus, a precise characterization of KMT2A-r and the fusion partner genes, especially in CKs, is of interest for managing AML. We describe the clinical and molecular features of a child who presented with a large abdominal mass, AML, and a new CK, involving chromosomes 11, 16, and 19 leading to a KMT2A-MLLT1 fusion and 2 extra copies of the ELL gene, thus resulting in the concurrent overexpression of MLLT1 and ELL. Molecular cytogenetic studies defined the karyotype as 47,XY,der(11)t(11;16)(q23.3;p11.2),der(16)t(16;19)(p11.2;p13.3),der(19)t(11;19)(q23.3;p13.3),+der(19)t(16;19)(16pter→p11.2::19p13.3→19q11::19p11→19p13.3::16p11.2→16pter). Array CGH revealed a gain of 30.5 Mb in the 16p13.3p11.2 region and a gain of 18.1 Mb in the 19p13.3p12 region. LDI-PCR demonstrated the KMT2A-MLLT1 fusion. Reverse sequence analysis showed that the MLLT1 gene was fused to the 16p11.2 region. RT-qPCR quantification revealed that ELL and MLLT1 were overexpressed (4- and 10-fold, respectively). In summary, this is a pediatric case of AML presenting a novel complex t(11;16;19) variant with overexpression of ELL and MLLT1.


Assuntos
Histona-Lisina N-Metiltransferase/genética , Leucemia Mieloide Aguda/genética , Proteína de Leucina Linfoide-Mieloide/genética , Proteínas de Neoplasias/genética , Proteínas Nucleares/genética , Fatores de Transcrição/genética , Fatores de Elongação da Transcrição/genética , Translocação Genética , Criança , Cromossomos Humanos Par 11/genética , Cromossomos Humanos Par 16/genética , Cromossomos Humanos Par 19/genética , Humanos , Cariótipo , Masculino , Proteínas de Fusão Oncogênica/genética , Regulação para Cima
3.
Int J Mol Sci ; 20(5)2019 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-30836598

RESUMO

Chromosome 16 is one of the most gene-rich chromosomes of our genome, and 10% of its sequence consists of segmental duplications, which give instability and predisposition to rearrangement by the recurrent mechanism of non-allelic homologous recombination. Microarray technologies have allowed for the analysis of copy number variations (CNVs) that can contribute to the risk of developing complex diseases. By array comparative genomic hybridization (CGH) screening of 1476 patients, we detected 27 cases with CNVs on chromosome 16. We identified four smallest regions of overlapping (SROs): one at 16p13.11 was found in seven patients; one at 16p12.2 was found in four patients; two close SROs at 16p11.2 were found in twelve patients; finally, six patients were found with atypical rearrangements. Although phenotypic variability was observed, we identified a male bias for Childhood Apraxia of Speech associated to 16p11.2 microdeletions. We also reported an elevated frequency of second-site genomic alterations, supporting the model of the second hit to explain the clinical variability associated with CNV syndromes. Our goal was to contribute to the building of a chromosome 16 disease-map based on disease susceptibility regions. The role of the CNVs of chromosome 16 was increasingly made clear in the determination of developmental delay. We also found that in some cases a second-site CNV could explain the phenotypic heterogeneity by a simple additive effect or a pejorative synergistic effect.


Assuntos
Anormalidades Múltiplas/genética , Cromossomos Humanos Par 16/genética , Hibridização Genômica Comparativa , Deficiências do Desenvolvimento/genética , Anormalidades Múltiplas/classificação , Anormalidades Múltiplas/fisiopatologia , Adolescente , Adulto , Criança , Pré-Escolar , Aberrações Cromossômicas , Deleção Cromossômica , Variações do Número de Cópias de DNA/genética , Deficiências do Desenvolvimento/classificação , Deficiências do Desenvolvimento/fisiopatologia , Feminino , Recombinação Homóloga/genética , Humanos , Lactente , Recém-Nascido , Cariótipo , Masculino , Fenótipo , Duplicações Segmentares Genômicas/genética , Adulto Jovem
4.
Ann Hematol ; 98(5): 1149-1157, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30759270

RESUMO

t(8;16)(p11.2;p13.3)/KAT6A-CREBBP is a rare recurrent cytogenetic abnormality associated with acute myeloid leukemia (AML). We report 15 cases with t(8;16)(p11.2;p13.3). All patients were adult and had AML: 13 women and 2 men, with a median age of 50 years. Ten patients had a history of malignancy and received cytotoxic therapies before therapy-related AML (t-AML), and five patients had de novo AML. All cases of AML showed monoblastic (n = 12) or myelomonocytic (n = 3) differentiation. Hemophagocytosis was observed in seven patients. All patients had t(8;16) in the stemline: seven had t(8;16) as the sole abnormality, two had one additional abnormality, and six had a complex karyotype. KAT6A/CREBBP rearrangement was confirmed by fluorescence in situ hybridization in 13 patients who had material available for analysis. All patients received induction chemotherapy, and 11 achieved complete remission after first induction. At the time of last follow-up, nine patients (eight t-AML and one de novo AML) died and six were alive, with a median overall survival of 18.2 months. The patients with de novo AML and/or patients with non-complex karyotype showed an "undefined" overall survival. We conclude that t(8;16)(p11.2;p13.3) commonly exhibits monoblastic or myelomonocytic differentiation and commonly arises in patients with a history of cancer treated with cytotoxic therapies. Patients with de novo AML with t(8;16) or t-AML with t(8;16) without adverse prognostic factors (e.g., complex karyotype) have a good outcome.


Assuntos
Proteína de Ligação a CREB , Cromossomos Humanos Par 16 , Cromossomos Humanos Par 8 , Histona Acetiltransferases , Leucemia Mieloide Aguda , Proteínas de Fusão Oncogênica , Translocação Genética , Adulto , Proteína de Ligação a CREB/genética , Proteína de Ligação a CREB/metabolismo , Cromossomos Humanos Par 16/genética , Cromossomos Humanos Par 16/metabolismo , Cromossomos Humanos Par 8/genética , Cromossomos Humanos Par 8/metabolismo , Feminino , Histona Acetiltransferases/genética , Histona Acetiltransferases/metabolismo , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Estudos Retrospectivos
5.
Hum Genet ; 138(2): 199-210, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30671673

RESUMO

In this study, we investigated low-frequency and rare variants associated with blood pressure (BP) by focusing on a linkage region on chromosome 16p13. We used whole genome sequencing (WGS) data obtained through the NHLBI Trans-Omics for Precision Medicine (TOPMed) program on 395 Cleveland Family Study (CFS) European Americans (CFS-EA). By analyzing functional coding variants and non-coding rare variants with CADD score > 10 residing within the chromosomal region in families with linkage evidence, we observed 25 genes with nominal statistical evidence (burden or SKAT p < 0.05). One of the genes is RBFOX1, an evolutionarily conserved RNA-binding protein that regulates tissue-specific alternative splicing that we previously reported to be associated with BP using exome array data in CFS. After follow-up analysis of the 25 genes in ten independent TOPMed studies with individuals of European, African, and East Asian ancestry, and Hispanics (N = 29,988), we identified variants in SLX4 (p = 2.19 × 10-4) to be significantly associated with BP traits when accounting for multiple testing. We also replicated the associations previously reported for RBFOX1 (p = 0.007). Follow-up analysis with GTEx eQTL data shows SLX4 variants are associated with gene expression in coronary artery, multiple brain tissues, and right atrial appendage of the heart. Our study demonstrates that linkage analysis of family data can provide an efficient approach for detecting rare variants associated with complex traits in WGS data.


Assuntos
Pressão Sanguínea/genética , Cromossomos Humanos Par 16/genética , Exoma , Ligação Genética , Variação Genética , Genoma Humano , Sequenciamento de Nucleotídeos em Larga Escala , Processamento Alternativo/genética , Feminino , Seguimentos , Estudo de Associação Genômica Ampla , Humanos , Masculino , Fatores de Processamento de RNA/genética , Recombinases/genética
6.
Neuron ; 101(4): 648-661.e4, 2019 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-30679017

RESUMO

Distinct genetic forms of autism are hypothesized to share a common increase in excitation-inhibition (E-I) ratio in cerebral cortex, causing hyperexcitability and excess spiking. We provide a systematic test of this hypothesis across 4 mouse models (Fmr1-/y, Cntnap2-/-, 16p11.2del/+, Tsc2+/-), focusing on somatosensory cortex. All autism mutants showed reduced feedforward inhibition in layer 2/3 coupled with more modest, variable reduction in feedforward excitation, driving a common increase in E-I conductance ratio. Despite this, feedforward spiking, synaptic depolarization, and spontaneous spiking were largely normal. Modeling revealed that E and I conductance changes in each mutant were quantitatively matched to yield stable, not increased, synaptic depolarization for cells near spike threshold. Correspondingly, whisker-evoked spiking was not increased in vivo despite detectably reduced inhibition. Thus, elevated E-I ratio is a common circuit phenotype but appears to reflect homeostatic stabilization of synaptic drive rather than driving network hyperexcitability in autism.


Assuntos
Transtorno Autístico/fisiopatologia , Potenciais Somatossensoriais Evocados , Potenciais Pós-Sinápticos Excitadores , Potenciais Pós-Sinápticos Inibidores , Córtex Somatossensorial/fisiopatologia , Animais , Transtorno Autístico/genética , Cromossomos Humanos Par 16/genética , Proteína do X Frágil de Retardo Mental/genética , Humanos , Masculino , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Proteínas do Tecido Nervoso/genética , Córtex Somatossensorial/fisiologia , Proteína 2 do Complexo Esclerose Tuberosa/genética
8.
Mol Genet Genomic Med ; 7(3): e549, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30632303

RESUMO

BACKGROUND: Intestinal malrotation is a potentially life-threatening congenital anomaly due to the risk of developing midgut volvulus. The reported incidence is 0.2%-1% and both apparently hereditary and sporadic cases have been reported. Intestinal malrotation is associated with a few syndromes with known genotype but the genetic contribution in isolated intestinal malrotation has not yet been reported. Rare copy number variants (CNVs) have been implicated in many congenital anomalies, and hence we sought to investigate the potential contribution of rare CNVs in intestinal malrotation. METHODS: Analysis of array comparative genomic hybridization (aCGH) data from 47 patients with symptomatic intestinal malrotation was performed. RESULTS: We identified six rare CNVs in five patients. Five CNVs involved syndrome loci: 7q11.23 microduplication, 16p13.11 microduplication, 18q terminal deletion, HDAC8 (Cornelia de Lange syndrome type 5 and FOXF1) as well as one intragenic deletion in GALNT14, not previously implicated in human disease. CONCLUSION: In the present study, we identified rare CNVs contributing pathogenic or potentially pathogenic alleles in five patients with syndromic intestinal malrotation, suggesting that CNV screening is indicated in intestinal malrotation with associated malformations or neurological involvements. In addition, we identified intestinal malrotation in two known syndromes (Cornelia de Lange type 5 and 18q terminal deletion syndrome) that has not previously been associated with gastrointestinal malformations.


Assuntos
Variações do Número de Cópias de DNA , Síndrome de Lange/genética , Anormalidades do Sistema Digestório/genética , Volvo Intestinal/genética , Síndrome de Williams/genética , Adolescente , Adulto , Idoso , Alelos , Criança , Pré-Escolar , Cromossomos Humanos Par 16/genética , Cromossomos Humanos Par 18/genética , Síndrome de Lange/diagnóstico por imagem , Síndrome de Lange/patologia , Anormalidades do Sistema Digestório/diagnóstico por imagem , Anormalidades do Sistema Digestório/patologia , Feminino , Humanos , Lactente , Recém-Nascido , Volvo Intestinal/diagnóstico por imagem , Volvo Intestinal/patologia , Masculino , Pessoa de Meia-Idade , Síndrome de Williams/diagnóstico por imagem , Síndrome de Williams/patologia
9.
Transl Psychiatry ; 9(1): 8, 2019 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-30664628

RESUMO

Deletion and duplication of 16p11.2 (BP4-BP5) have been associated with an increased risk of intellectual disability and psychiatric disorder. This is the first study to compare the frequency of a broad spectrum of psychiatric disorders in children with 16p11.2 deletion and duplication. We aimed to evaluate (1) the nature and prevalence of psychopathology associated with copy number variation (CNV) in children with 16p11.2 by comparing deletion and duplication carriers with family controls; (2) whether deletion and duplication carriers differ in frequency of psychopathology. 217 deletion carriers, 77 deletion family controls, 114 duplication carriers, and 32 duplication family controls participated in the study. Measures included standardized research diagnostic instruments. Deletion carriers had a higher frequency of any psychiatric disorder (OR = 8.9, p < 0.001), attention deficit hyperactivity disorder (ADHD) (OR = 4.0, p = 0.01), and autism spectrum disorder (ASD) (OR = 39.9, p = 0.01) than controls. Duplication carriers had a higher frequency of any psychiatric diagnosis (OR = 5.3, p = 0.01) and ADHD (OR = 7.0, p = 0.02) than controls. The prevalence of ASD in child carriers of deletions and duplications was similar (22% versus 26%). Comparison of the two CNV groups indicated a higher frequency of ADHD in children with the duplication than deletion (OR = 2.7, p = 0.04) as well as a higher frequency of overall psychiatric disorders (OR = 2.8, p = 0.02) and psychotic symptoms (OR = 4.7, p = 0.02). However, no differences between deletion and duplications carriers in the prevalence of ASD were found. Both deletion and duplication are associated with an increased risk of psychiatric disorder, supporting the importance of early recognition, diagnosis, and intervention in these groups.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/genética , Transtorno do Espectro Autista/genética , Duplicação Cromossômica , Cromossomos Humanos Par 16/genética , Deleção de Sequência , Adolescente , Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico , Transtorno do Espectro Autista/diagnóstico , Estudos de Casos e Controles , Criança , Pré-Escolar , Variações do Número de Cópias de DNA , Feminino , Heterozigoto , Humanos , Masculino
10.
Br J Haematol ; 184(3): 337-347, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30592296

RESUMO

The scenario of paediatric acute myeloid leukaemia (AML), particularly non-Down syndrome acute megakaryoblastic leukaemia (non-DS-AMKL), has been recently revolutionized by the advent of large-scale, genomic sequencing technologies. In this changing landscape, a significantly relevant discovery has been represented by the identification of the CBFA2T3-GLIS2 fusion gene, which is the result of a cryptic inversion of chromosome 16. It is the most frequent chimeric oncogene identified to date in non-DS-AMKL, although it seems not to be exclusively restricted to the French-American-British M7 subgroup. The CBFA2T3-GLIS2 fusion gene characterizes a subtype of leukaemia that is specific to paediatrics, having never been identified in adults. It characterizes an extremely aggressive leukaemia, as the presence of this fusion is associated with a grim outcome in almost all of the case series reported, with overall survival rates ranging between 15% and 30%. Although the molecular basis that underlies this leukaemia subtype is still far from being completely elucidated, unique functional properties induced by CBFA2T3-GLIS2 in the leukaemogenesis driving process have been recently identified. We here review the peculiarities of CBFA2T3-GLIS2-positive AML, describing its intriguing clinical and biological behaviour and providing some challenging targeting opportunities.


Assuntos
Cromossomos Humanos Par 16 , Fatores de Transcrição Kruppel-Like , Leucemia Mieloide Aguda , Proteínas de Fusão Oncogênica , Proteínas Repressoras , Proteínas Supressoras de Tumor , Adolescente , Animais , Criança , Pré-Escolar , Cromossomos Humanos Par 16/genética , Cromossomos Humanos Par 16/metabolismo , Intervalo Livre de Doença , Feminino , Humanos , Lactente , Recém-Nascido , Fatores de Transcrição Kruppel-Like/genética , Fatores de Transcrição Kruppel-Like/metabolismo , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/terapia , Masculino , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Taxa de Sobrevida , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo
11.
Genes Chromosomes Cancer ; 57(10): 522-524, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30107050

RESUMO

We present a leukemia case that exhibits a chromosomal translocation t(11;16)(q23;q23), which results in the expression of a novel KMT2A fusion gene. This novel fusion, KMT2A-USP10, was found in a relapse of acute myeloid leukaemia M5a. USP10 belongs to a protein family that deubiquitinates a distinct set of target proteins, and thus, increases the steady state protein levels of its target subproteome. One of the USP10 targets is TP53. Wildtype TP53 is usually rescued from proteasomal degradation by USP10. As most KMT2A leukemias display wildtype p53 alleles, one might argue that the disruption of an USP10 allele can be classified as a pro-oncogenic event.


Assuntos
Histona-Lisina N-Metiltransferase/genética , Leucemia Mieloide Aguda/genética , Proteína de Leucina Linfoide-Mieloide/genética , Translocação Genética/genética , Ubiquitina Tiolesterase/genética , Adolescente , Cromossomos Humanos Par 11/genética , Cromossomos Humanos Par 16/genética , Humanos , Cariotipagem , Leucemia Mieloide Aguda/patologia , Masculino , Proteínas de Fusão Oncogênica/genética , Proteína Supressora de Tumor p53/genética
13.
Ann Hematol ; 97(10): 1775-1783, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29872884

RESUMO

Chromosome translocation t(16;21)(q24;q22)/RUNX1-RUNX1T3 is an infrequent but recurrent chromosomal abnormality identified in myeloid neoplasms, with only 25 cases have been reported to date. Here, we report eight cases (six women and two men) of myeloid neoplasms associated with t(16;21)(q24;q22): five with therapy-related myeloid neoplasms, two with relapsed acute myeloid leukemia (AML), and one with blast phase of chronic myeloid leukemia. Morphologic and immunophenotypic features include granulocytic dysplasia, blasts with prominent perinuclear hof, large orange-pink granules, long and slim Auer rods, and aberrant expression of CD19. Six patients received AML-based regimens, and five achieved complete remission after initial induction therapy. Our study suggests that myeloid neoplasm with t(16;21)/RUNX1-RUNX1T1 resembles AML with t(8;21)(q22;q22)/RUNX1-RUNX1T1, in regard to morphology, immunophenotype, and response to therapy. Therefore, the clinical management of AML with t(8;21) may provide the best model for patients with myeloid neoplasms with t(16;21).


Assuntos
Cromossomos Humanos Par 16/genética , Cromossomos Humanos Par 21/genética , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Leucemia Mieloide Aguda/genética , Transtornos Mieloproliferativos/genética , Proteínas de Fusão Oncogênica/genética , Proteína 1 Parceira de Translocação de RUNX1/genética , Proteínas Repressoras/genética , Translocação Genética , Proteínas Supressoras de Tumor/genética , Adulto , Idoso , Estudos de Coortes , Análise Mutacional de DNA , Feminino , Humanos , Imunofenotipagem , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Mimetismo Molecular , Transtornos Mieloproliferativos/diagnóstico , Transtornos Mieloproliferativos/patologia
15.
Pediatr Ann ; 47(5): e198-e203, 2018 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-29750287

RESUMO

This review summarizes common microdeletion and microduplication syndromes and highlights important updates in patient-care needs for people with these conditions (22q11.2, 7q11.23, 17p11.2, and 16p11.2). These conditions are in chromosomal "hotspots" and have an estimated prevalence of 1 in 1,000 to 1 in 25,000. Some conditions have possible increased or decreased genetic risk of schizophrenia (22q11.2 deletion and duplication), or risk of aortic dilation (7q11.23 duplication) versus aortic stenosis (7q11.23 deletion). Many of these conditions are associated with developmental delay, autism, and/or multiple congenital anomalies and would not be detected with a karyotype. Chromosomal microarray analysis will detect all these conditions with a single screening test, allowing for the appropriate diagnosis and management of these patients. [Pediatr Ann. 2018;47(5):e198-e203.].


Assuntos
Anormalidades Múltiplas , Transtorno Autístico , Deleção Cromossômica , Transtornos Cromossômicos , Duplicação Cromossômica , Síndrome de DiGeorge , Deficiência Intelectual , Síndrome de Smith-Magenis , Síndrome de Williams , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/terapia , Transtorno Autístico/diagnóstico , Transtorno Autístico/genética , Transtorno Autístico/terapia , Transtornos Cromossômicos/diagnóstico , Transtornos Cromossômicos/genética , Transtornos Cromossômicos/terapia , Duplicação Cromossômica/genética , Cromossomos Humanos Par 16/genética , Cromossomos Humanos Par 7 , Variações do Número de Cópias de DNA , Síndrome de DiGeorge/diagnóstico , Síndrome de DiGeorge/genética , Síndrome de DiGeorge/terapia , Testes Genéticos , Humanos , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Deficiência Intelectual/terapia , Síndrome de Smith-Magenis/diagnóstico , Síndrome de Smith-Magenis/genética , Síndrome de Smith-Magenis/terapia , Síndrome de Williams/diagnóstico , Síndrome de Williams/genética , Síndrome de Williams/terapia
16.
J Med Case Rep ; 12(1): 90, 2018 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-29609622

RESUMO

BACKGROUND: The recurrent ∼ 600 kb 16p11.2 microdeletion is among the most commonly known genetic etiologies of autism spectrum disorder, overweightness, and related neurodevelopmental disorders. CASE PRESENTATION: Our patient is a 2-year-old white girl from the first pregnancy of a non-consanguineous healthy young white couple (father 33-years old and mother 29-years old). Our patient and her parents' DNA were analyzed by comparative genomic hybridization-array platform. Comparative genomic hybridization-array analysis highlighted a ∼ 600 kb deletion in 16p11.2 region. It has a segregant nature, since it was found in the mother and in her 2-year-old daughter. The microdeletion was confirmed by fluorescence in situ hybridization analysis. CONCLUSIONS: The presented clinical case is worthy of note since the observed microdeletion is often associated with a clinical phenotype tending to overweightness, but the proband (female) was hospitalized due to poor height and weight development, and anorexia. Moreover, the segregant nature of the observed genomic abnormality has to be noted, as well as the phenotypic variability between the mother and daughter. The case described here enriches the phenotypical spectrum linked to the 16p11.2 microdeletion. For these reasons, in the presence of a suspected genetic pathology it is fundamental to study the proband from the clinical point of view, to extend the clinical observation to the parents, and to provide a good family anamnesis. In this way, it is possible to reveal the presence of a familial genetic pathology whose phenotypical outcomes can be highly variable among the members of a family.


Assuntos
Transtorno Autístico/genética , Transtornos Cromossômicos/genética , Deficiências do Desenvolvimento/genética , Deficiência Intelectual/genética , Adulto , Transtorno Autístico/diagnóstico , Pré-Escolar , Deleção Cromossômica , Transtornos Cromossômicos/diagnóstico , Cromossomos Humanos Par 16/genética , Feminino , Humanos , Hibridização in Situ Fluorescente , Deficiência Intelectual/diagnóstico , Masculino , Pais , Fenótipo , Magreza/genética
17.
Gene ; 658: 146-151, 2018 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-29524577

RESUMO

INTRODUCTION: Obesity is a serious health problem that leads to low quality of life and early mortality. To the purpose of prevention and gene therapy for such a worldwide disease, genome wide association study is a powerful tool for finding SNPs associated with increased risk of obesity. To conduct an association analysis, kernel machine regression is a generalized regression method, has an advantage of considering the epistasis effects as well as the correlation between individuals due to unknown factors. MATERIALS AND METHODS: In this study, information of the people who participated in Tehran cardio-metabolic genetic study was used. They were genotyped for the chromosomal region, evaluation 986 variations located at 16q12.2; build 38hg. Kernel machine regression and single SNP analysis were used to assess the association between obesity and SNPs genotyped data. RESULTS: We found that associated SNP sets with obesity, were almost in the FTO (P = 0.01), AIKTIP (P = 0.02) and MMP2 (P = 0.02) genes. Moreover, two SNPs, i.e., rs10521296 and rs11647470, showed significant association with obesity using kernel regression (P = 0.02). CONCLUSION: In conclusion, significant sets were randomly distributed throughout the region with more density around the FTO, AIKTIP and MMP2 genes. Furthermore, two intergenic SNPs showed significant association after using kernel machine regression. Therefore, more studies have to be conducted to assess their functionality or precise mechanism.


Assuntos
Cromossomos Humanos Par 16/genética , Análise Mutacional de DNA/métodos , Obesidade/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Adulto , Idoso , Dioxigenase FTO Dependente de alfa-Cetoglutarato/genética , Proteínas Reguladoras de Apoptose/genética , Glicemia/metabolismo , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla/métodos , Humanos , Irã (Geográfico) , Desequilíbrio de Ligação , Lipídeos/sangue , Masculino , Metaloproteinase 2 da Matriz/genética , Pessoa de Meia-Idade , Obesidade/sangue , Polimorfismo de Nucleotídeo Único
18.
Psychiatry Clin Neurosci ; 72(4): 245-254, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29430824

RESUMO

AIM: Schizophrenia (SZ) and bipolar disorder (BD) have been known to share genetic and environmental risk factors, and complex gene-environmental interactions may contribute to their pathophysiology. In contrast to high genetic overlap between SZ and BD, as revealed by genome-wide association studies, the extent of epigenetic overlap remains largely unknown. In the present study, we explored whether SZ and BD share epigenetic risk factors in the same manner as they share genetic components. METHODS: We performed DNA methylation analyses of the CpG sites in the top five candidate regions (FAM63B, ARHGAP26, CTAGE11P, TBC1D22A, and intergenic region [IR] on chromosome 16) reported in a previous methylome-wide association study (MWAS) of SZ, using whole blood samples from subjects with BD and controls. RESULTS: Among the five candidate regions, the CpG sites in FAM63B and IR on chromosome 16 were significantly hypomethylated in the samples from subjects with BD as well as those from subjects with SZ. On the other hand, the CpG sites in TBC1D22A were hypermethylated in the samples from subjects with BD, in contrast to hypomethylation in the samples from subjects with SZ. CONCLUSION: Hypomethylation of FAM63B and IR on chromosome 16 could be common epigenetic risk factors for SZ and BD. Further comprehensive epigenetic studies for BD, such as MWAS, will uncover the extent of similarity and uniqueness of epigenetic alterations.


Assuntos
Antipsicóticos/farmacologia , Transtorno Bipolar/genética , Metilação de DNA/efeitos dos fármacos , Metilação de DNA/genética , Epigênese Genética/genética , Estudo de Associação Genômica Ampla , Risperidona/farmacologia , Esquizofrenia/genética , Adulto , Animais , Antipsicóticos/administração & dosagem , Callithrix , Cromossomos Humanos Par 16/genética , DNA Intergênico/genética , Feminino , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Risperidona/administração & dosagem , Ubiquitina Tiolesterase/genética
19.
Mol Genet Genomic Med ; 6(3): 441-445, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29441698

RESUMO

BACKGROUND AND PURPOSE: A recurrent duplication of chromosome 16p13.1 was associated with aortic dissection as well as with cervical artery dissection. We explore the segregation of this duplication in a family with familial aortic disease. METHODS: Whole exome sequencing (WES) analysis was performed in a patient with a family history of aortic diseases and ischemic stroke due to an aortic dissection extending into both carotid arteries. RESULTS: The index patient, his affected father, and an affected sister of his father carried a large duplication of region 16p13.1, which was also verified by quantitative PCR. The duplication was also found in clinically asymptomatic sister of the index patient. WES did not detect pathogenic variants in a predefined panel of 11 genes associated with aortic disease, but identified rare deleterious variants in 14 genes that cosegregated with the aortic phenotype. CONCLUSIONS: The cosegregation of duplication 16p13.1 with the aortic phenotype in this family suggested a causal relationship between the duplication and aortic disease. Variants in known candidate genes were excluded as disease-causing in this family, but cosegregating variants in other genes might modify the contribution of duplication 16p13.1 on aortic disease.


Assuntos
Aneurisma Dissecante/genética , Aneurisma da Aorta Torácica/genética , Adulto , Idoso , Aorta/fisiologia , Doenças da Aorta/genética , Doenças da Aorta/fisiopatologia , Estruturas Cromossômicas/genética , Cromossomos Humanos Par 16/genética , Bases de Dados Genéticas , Exoma , Família , Feminino , Duplicação Gênica/genética , Predisposição Genética para Doença/genética , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Linhagem , Fenótipo , Sequenciamento Completo do Exoma/métodos
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