RESUMO
PURPOSE: The molecular mechanism of breast and/or ovarian cancer susceptibility remains unclear in the majority of patients. While germline mutations in the regulatory non-coding regions of BRCA1 and BRCA2 genes have been described, screening has generally been limited to coding regions. The aim of this study was to evaluate the contribution of BRCA1/2 non-coding variants. METHODS: Four BRCA1/2 non-coding regions were screened using high-resolution melting analysis/Sanger sequencing or next-generation sequencing on DNA extracted from index cases with breast and ovarian cancer predisposition (3926 for BRCA1 and 3910 for BRCA2). The impact of a set of variants on BRCA1/2 gene regulation was evaluated by site-directed mutagenesis, transfection, followed by Luciferase gene reporter assay. RESULTS: We identified a total of 117 variants and tested twelve BRCA1 and 8 BRCA2 variants mapping to promoter and intronic regions. We highlighted two neighboring BRCA1 promoter variants (c.-130del; c.-125C > T) and one BRCA2 promoter variants (c.-296C > T) inhibiting significantly the promoter activity. In the functional assays, a regulating region within the intron 12 was found with the same enhancing impact as within the intron 2. Furthermore, the variants c.81-3980A > G and c.4186-2022C > T suppress the positive effect of the introns 2 and 12, respectively, on the BRCA1 promoter activity. We also found some variants inducing the promoter activities. CONCLUSION: In this study, we highlighted some variants among many, modulating negatively the promoter activity of BRCA1 or 2 and thus having a potential impact on the risk of developing cancer. This selection makes it possible to conduct future validation studies on a limited number of variants.
Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Genes BRCA1 , Genes BRCA2 , Síndrome Hereditária de Câncer de Mama e Ovário/genética , Adulto , Idoso , Estudos de Coortes , Biologia Computacional , Feminino , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Íntrons/genética , Pessoa de Meia-Idade , Linhagem , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas/genética , Regiões não Traduzidas/genéticaRESUMO
We aimed to investigate the cost-effectiveness of a 2000-gene-expression profiling (GEP) test to help identify the primary tumor site when clinicopathological diagnostic evaluation was inconclusive in patients with cancer of unknown primary (CUP). We built a decision-analytic-model to project the lifetime clinical and economic consequences of different clinical management strategies for CUP. The model was parameterized using follow-up data from the Manitoba Cancer Registry, cost data from Manitoba Health administrative databases and secondary sources. The 2000-GEP-based strategy compared to current clinical practice resulted in an incremental cost-effectiveness ratio (ICER) of $44,151 per quality-adjusted life years (QALY) gained. The total annual-budget impact was $36.2 million per year. A value-of-information analysis revealed that the expected value of perfect information about the test's clinical impact was $4.2 million per year. The 2000-GEP test should be considered for adoption in CUP. Field evaluations of the test are associated with a large societal benefit.
Assuntos
Biomarcadores Tumorais/genética , Técnicas de Apoio para a Decisão , Perfilação da Expressão Gênica/economia , Custos de Cuidados de Saúde , Neoplasias Primárias Desconhecidas/economia , Neoplasias Primárias Desconhecidas/genética , Transcriptoma , Orçamentos , Análise Custo-Benefício , Árvores de Decisões , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica , Predisposição Genética para Doença , Humanos , Manitoba , Cadeias de Markov , Modelos Econômicos , Neoplasias Primárias Desconhecidas/patologia , Neoplasias Primárias Desconhecidas/terapia , Fenótipo , Valor Preditivo dos Testes , Prognóstico , Anos de Vida Ajustados por Qualidade de Vida , Sistema de Registros , Fatores de TempoRESUMO
OBJECTIVE: We estimated the frequency of occult gynecologic primary tumours (gpts) in patients with metastatic cancer from an uncertain primary and evaluated the effect on disease management and overall survival (os). METHODS: We used Manitoba administrative health databases to identify all patients initially diagnosed with metastatic cancer during 2002-2011. We defined patients as having an "occult" primary tumour if the primary was classified at least 6 months after the initial diagnosis. Otherwise, we considered patients to have "obvious" primaries. We then compared clinicopathologic and treatment characteristics and 2-year os for women with occult and with obvious gpts. We used Cox regression adjustment and propensity score methods to assess the effect on os of having an occult gpt. RESULTS: Among the 5953 patients diagnosed with metastatic cancer, occult primary tumours were more common in women (n = 285 of 2552, 11.2%) than in men (n = 244 of 3401, 7.2%). In women, gpts were the most frequent occult primary tumours (n = 55 of 285, 19.3%). Compared with their counterparts having obvious gpts, women with occult gpts (n = 55) presented with similar histologic and metastatic patterns but received fewer gynecologic diagnostic examinations during diagnostic work-up. Women with occult gpts were less likely to undergo surgery, waited longer for radiotherapy, and received a lesser variety of chemotherapeutic agents. Having an occult compared with an obvious gpt was associated with decreased os (hazard ratio: 1.62; 95% confidence interval: 1.2 to 2.35). Similar results were observed in adjusted analyses. CONCLUSIONS: In women with metastatic cancer from an uncertain primary, gpts constitute the largest clinical entity. Accurate diagnosis of occult gpts early in the course of metastatic cancer might lead to more effective treatment decisions and improved survival outcomes.
RESUMO
Despite extensive analyses on the centromere and its associated proteins, detailed studies of centromeric DNA structure have provided limited information about its topography in condensed chromatin. We have developed a method with correlative fluorescence light microscopy and atomic force microscopy that investigates the physical and structural organization of α-satellite DNA sequences in the context of its associated protein, CENP-B, on human metaphase chromosome topography. Comparison of centromeric DNA and protein distribution patterns in fixed homologous chromosomes indicates that CENP-B and α-satellite DNA are distributed distinctly from one another and relative to observed centromeric ridge topography. Our approach facilitates correlated studies of multiple chromatin components comprising higher-order structures of human metaphase chromosomes.
Assuntos
Proteína B de Centrômero/metabolismo , Centrômero/metabolismo , DNA Satélite/metabolismo , Linhagem Celular Tumoral , Centrômero/genética , Proteína B de Centrômero/genética , Cromatina/genética , Cromatina/metabolismo , Cromossomos Humanos Par 17/genética , Cromossomos Humanos Par 17/metabolismo , Sondas de DNA/metabolismo , DNA Satélite/genética , Imunofluorescência , Humanos , Hibridização in Situ Fluorescente/métodos , Linfócitos/citologia , Metáfase , Microscopia de Força Atômica , Fixação de Tecidos/métodosRESUMO
Introduction: Patients with cancer of unknown primary (cup) have pathologically confirmed metastatic tumours with unidentifiable primary tumours. Currently, very little is known about the relationship between the treatment of patients with cup and their survival outcomes. Thus, we compared oncologic treatment and survival outcomes for patients in Ontario with cup against those for a cohort of patients with metastatic cancer of known primary site. Methods: Using the Ontario Cancer Registry and the Same-Day Surgery and Discharge Abstract databases maintained by the Canadian Institute for Health Information, we identified all Ontario patients diagnosed with metastatic cancer between 1 January 2000 and 31 December 2005. Ontario Health Insurance Plan treatment records were linked to identify codes for surgery, chemotherapy, or therapeutic radiation related to oncology. Multivariable Cox regression models were constructed, adjusting for histology, age, sex, and comorbidities. Results: In 45,347 patients (96.3%), the primary tumour site was identifiable, and in 1743 patients (3.7%), cup was diagnosed. Among the main tumour sites, cup ranked as the 6th largest. The mean Charlson score was significantly higher (p < 0.0001) in patients with cup (1.88) than in those with a known primary (1.42). Overall median survival was 1.9 months for patients with cup compared with 11.9 months for all patients with a known-primary cancer. Receipt of treatment was more likely for patients with a known primary site (n= 35,012, 77.2%) than for those with cup (n = 891, 51.1%). Among patients with a known primary site, median survival was significantly higher for treated than for untreated patients (19.0 months vs. 2.2 months, p < 0.0001). Among patients with cup, median survival was also higher for treated than for untreated patients (3.6 months vs. 1.1 months, p < 0.0001). Conclusions: In Ontario, patients with cup experience significantly lower survival than do patients with metastatic cancer of a known primary site. Treatment is associated with significantly increased survival both for patients with cup and for those with metastatic cancer of a known primary site.
Assuntos
Metástase Neoplásica/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Ontário , Resultado do TratamentoRESUMO
BACKGROUND: Nucleotide variants in several genes for lipid and methionine metabolism influence the risk of premature atherosclerosis. Ten percent of single nucleotide substitutions in these genes involve mRNA splice sites. The effects of some of these changes on splicing and on phenotypic severity are not inherently obvious. METHODS AND RESULTS: Using an information theory-based model, we measured the individual information content (R(i), in bits) of splice sites adjacent to 289 mutations (including 31 splice-site mutations) in the atherosclerosis candidate genes APOAII, APOB, APOCII, APOE, CBS, CETP, LCAT, LIPA, LDLR, and LPL. The predictions of information analysis were then corroborated by published mRNA analyses. The R(i) values of mutant sites were consistent with either complete (n=17) or partial (n=8) inactivation of these sites. Seven mutations were predicted to activate cryptic splice sites. Predicted inactive mutant sites were associated with either "average" or "severe" dyslipidemia and commensurate reductions in protein levels or activity, whereas mutations expected to exhibit residual splicing had average or "mild" effects on lipid and protein expression. CONCLUSIONS: Information analysis of splice-junction variants in atherosclerosis candidate genes distinguishes inactive from leaky splice sites and identifies activated cryptic sites. Predicted changes in splicing were related to phenotypic severity.
Assuntos
Arteriosclerose/genética , Genes , Splicing de RNA , Substituição de Aminoácidos , Arteriosclerose/metabolismo , Análise Mutacional de DNA , Regulação da Expressão Gênica , Predisposição Genética para Doença , Humanos , Hiperlipidemias/complicações , Hiperlipidemias/genética , Teoria da Informação , Metabolismo dos Lipídeos , Metionina/metabolismo , Modelos Genéticos , Fenótipo , Mutação Puntual , Biossíntese de Proteínas , RNA Mensageiro/metabolismo , Fatores de Risco , Índice de Gravidade de DoençaRESUMO
Mutations in the human ABCR gene have been associated with the autosomal recessive Stargardt disease (STGD), retinitis pigmentosa (RP19), and cone-rod dystrophy (CRD) and have also been found in a fraction of age-related macular degeneration (AMD) patients. The ABCR gene is a member of the ATP-binding cassette (ABC) transporter superfamily and encodes a rod photoreceptor-specific membrane protein. The cytogenetic location of the ABCR gene was refined to 1p22.3-1p22.2. The intron/exon structure was determined for the ABCR gene from overlapping genomic clones. ABCR spans over 100kb and comprises 50 exons. Intron/exon splice site sequences are presented for all exons and analyzed for information content (Ri). Nine splice site sequence variants found in STGD and AMD patients are evaluated as potential mutations. The localization of splice sites reveals a high degree of conservation between other members of the ABC1 subfamily, e.g. the mouse Abc1 gene. Analysis of the 870-bp 5' upstream of the transcription start sequence reveals multiple putative photoreceptor-specific regulatory elements including a novel retina-specific transcription factor binding site. These results will be useful in further mutational screening of the ABCR gene in various retinopathies and for determining the substrate and/or function of this photoreceptor-specific ABC transporter.
Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Genes/genética , Processamento Alternativo/genética , Sequência de Bases , Sítios de Ligação/genética , Sequência Conservada/genética , DNA/química , DNA/genética , Evolução Molecular , Éxons/genética , Humanos , Íntrons/genética , Dados de Sequência Molecular , Mutação/genética , Regiões Promotoras Genéticas/genética , RNA Mensageiro/química , RNA Mensageiro/genética , Análise de Sequência de DNARESUMO
The atypical presentation of CATCH 22 raises several important concerns. First, in this patient, as in others, the heart defects were found in association with subtle facial abnormalities but with few of the other criteria normally seen in CATCH 22. This association alone may be sufficient to raise suspicion that an interstitial 22q11 deletion may be present. Second, the incidence of chromosome 22 deletions in parents of children with a 22q11 deletion (25%) suggests that siblings or subsequent fetuses may also be at risk. Parents with subtle or unusual manifestations of CATCH 22 may be unaware of their potential carrier status. Finally, the recognition of chromosomal mosaicism in this patient may have been fortuitous, as cytogenetic studies of leukocytes from other individuals with a mosaic karyotype may sometimes fail to reveal a 22q11 deletion that is present in cardiac tissues. Molecular cytogenetic analysis of cardiac specimens that are removed during routine surgical procedures may be warranted in appropriate clinical situations.
Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 22/genética , Face/anormalidades , Cardiopatias Congênitas/genética , Síndrome do Coração Esquerdo Hipoplásico/genética , Mosaicismo , Evolução Fatal , Feminino , Humanos , Recém-Nascido , Recém-Nascido Pequeno para a Idade Gestacional , Fenótipo , SíndromeRESUMO
Transesophageal echocardiographic findings and their effect on disease management were evaluated in 216 patients with suspected cardiovascular source of emboli. Clinical and transesophageal echocardiographic findings were useful in defining pretest probability for finding a probable cardiovascular source of emboli on transesophageal echocardiography.
Assuntos
Doenças Cardiovasculares/complicações , Doenças Cardiovasculares/diagnóstico por imagem , Ecocardiografia Transesofagiana , Embolia e Trombose Intracraniana/diagnóstico por imagem , Embolia e Trombose Intracraniana/etiologia , Adulto , Idoso , Diagnóstico Diferencial , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Valor Preditivo dos TestesRESUMO
PURPOSE: Congenital cataracts constitute a morphologically and genetically heterogeneous group of diseases that are a major cause of childhood blindness. Autosomal Dominant Zonular Cataracts with Sutural Opacities (CCZS) have been mapped to chromosome 17q11-q12 near the betaA3A1-crystallin gene (CRYBA1). The betaA3A1-crystallin gene was investigated as the causative gene for the cataracts. METHODS: The betaA3/A1-crystallin gene was sequenced in affected and control individuals. Base changes were confirmed and assayed in additional family members and controls using NlaIII restriction digestion of PCR amplified DNA sequences. Base changes were assessed for their effects on splicing by information analysis. RESULTS: The cataracts are associated with a sequence change in the 5' (donor) splice site of intron 3: GC(g->a)tgagt. The sequence change also creates a new NlaIII site. This base change cosegregates with the cataracts in this family, being present in every affected individual. Conversely, this base change was not seen in 140 chromosomes examined in 70 unaffected and unrelated individuals. Information theory mutational analysis shows that the base change lowers the information content of the splice site from 6.0 to -6.8 bits, so that splicing would not be expected to occur at the altered site. CONCLUSIONS: Taken together, these observations suggest that the observed mutation might be causally related to the cataracts in this family.
Assuntos
Catarata/genética , Cristalinas/genética , Sequência de Aminoácidos , Sequência de Bases , Catarata/congênito , Feminino , Ligação Genética , Humanos , Masculino , Dados de Sequência Molecular , Mutação , Linhagem , Reação em Cadeia da Polimerase , Splicing de RNA , Análise de Sequência , Cadeia A de beta-CristalinaRESUMO
Maternal uniparental disomy of chromosome 21 [upd(21)mat] was found previously in a normal female and in 2 cases of early embryonic failure. We present a phenotypically normal child with upd(21)mat due to a de novo der(21;21)(q10;10). This finding suggests that chromosome 21 is not imprinted in the maternal germline.
Assuntos
Aberrações Cromossômicas/genética , Cromossomos Humanos Par 21/genética , Adulto , Feminino , Marcadores Genéticos , Impressão Genômica , Genótipo , Humanos , Lactente , Masculino , Fenótipo , Polimorfismo de Fragmento de Restrição , Diagnóstico Pré-NatalRESUMO
Neurologic abnormalities have been described only once previously in a child with Weissenbacher-Zweymüller syndrome (WZS), a rare skeletal dysplasia, evident neonatally. We report on identical twin male infants with skeletal findings typical of WZS, including small size at birth, proximal limb shortness, mid face hypoplasia, and myopia. In addition, twin B had a parieto occipital encephalocele while twin A had a meningocele at the same location. Twin B has had significant delays in development and hearing loss.
Assuntos
Doenças em Gêmeos/genética , Defeitos do Tubo Neural/genética , Osteocondrodisplasias/genética , Gêmeos Monozigóticos , Pré-Escolar , Encefalocele/complicações , Encefalocele/genética , Humanos , Masculino , Meningocele/complicações , Meningocele/genética , Miopia/complicações , Miopia/genética , Defeitos do Tubo Neural/complicações , Osteocondrodisplasias/complicações , Fenótipo , SíndromeRESUMO
Brothers were affected with severe congenital contractures, multiple cutaneous manifestations of ectodermal dysplasia, cleft lip/palate, and psychomotor and growth impairment. High resolution prometaphase chromosomes were normal. Molecular studies of DNA markers, closely flanking the X-linked hypohidrotic ectodermal dysplasia locus, did not show evidence of a submicroscopic deletion from the Xq12-q13 region. The parents and a normal sister exhibited none of these findings. This constellation of anomalies appears to represent a unique AR or XLR syndrome.
Assuntos
Anormalidades Múltiplas/genética , Fenda Labial/genética , Fissura Palatina/genética , Contratura/congênito , Deficiências do Desenvolvimento/genética , Displasia Ectodérmica/genética , Feminino , Aconselhamento Genético , Ligação Genética , Humanos , Recém-Nascido , Masculino , Linhagem , Síndrome , Cromossomo XRESUMO
We report on our findings of 4 patients with mosaicism for a deletion of chromosome 15, most commonly associated with Prader-Willi syndrome (PWS). We examined a series of typical and atypical PWS patients in order to identify cytogenetically undetected deletions, using fluorescence in situ hybridization. In 4 of the patients analyzed we detected a deletion in 14-60% of peripheral blood leukocytes, using four commercially available probes. Our results indicate that mosaicism may play a role in the etiology of some PWS cases. These findings may be especially useful in patients who display discrepancies between clinical phenotype and established diagnostic criteria. Methylation and microsatellite polymorphism analyses of 2 patients with low-level mosaicism failed to identify the deletion. We propose that fluorescence in situ hybridization is the most effective method for detecting somatic mosaicism, since a large number of cells can be individually examined for the presence or absence of a specific deletion.
Assuntos
Mosaicismo , Síndrome de Prader-Willi/genética , Adolescente , Adulto , Deleção Cromossômica , Mapeamento Cromossômico , Cromossomos Humanos Par 15 , Feminino , Humanos , Hibridização in Situ Fluorescente , Masculino , Fenótipo , Síndrome de Prader-Willi/patologiaRESUMO
Individuals with a ring 15 chromosome [r(15)] and those with Russell-Silver syndrome have short stature, developmental delay, triangular face, and clinodactyly. To assess whether the apparent phenotypic overlap of these conditions reflects a common genetic cause, the extent of deletions in chromosome 15q was determined in 5 patients with r(15), 1 patient with del 15q26.1-qter, and 5 patients with Russell-Silver syndrome. All patients with Russell-Silver syndrome were diploid for genetic markers in distal 15q, indicating that Russell-Silver syndrome in these individuals was unlikely to be related to the expression of single alleles at these or linked genetic loci. At least 3 distinct sites of chromosome breakage close to the telomere were found in the r(15) and del 15q25.1-qter patients, with 1 r(15) patient having both a terminal and an interstitial deletion. Although the patient with del 15q25.1-qter exhibited the largest deletion and the most profound growth retardation, the degree of growth impairment among the r(15) patients was not correlated with the size of the deleted interval. Rather, the parental origin of the ring chromosome in several patients was associated with phenotypes that are also seen in patients with either Prader-Willi (PWS) or Angelman (AS) syndromes, conditions that result from uniparental expression of genes on chromosome 15. In fact, unequal representation of chromosome 15 alleles in 1 patient with r(15) suggests the possibility that a mosaic karyotype composed of the constitutional cell line and cell line(s) possibly deficient in the ring chromosome might be present. The PWS-like or AS-like phenotypes could be explained by postzygotic loss of the ring chromosome, leading to uniparental inheritance of the intact chromosome in some tissues of r(15) patients.
Assuntos
Anormalidades Múltiplas/genética , Cromossomos Humanos Par 15 , Transtornos do Crescimento/genética , Cromossomos em Anel , Adolescente , Criança , Pré-Escolar , Deleção Cromossômica , Feminino , Dosagem de Genes , Genótipo , Humanos , Lactente , Masculino , Linhagem , Receptor IGF Tipo 1/genética , SíndromeRESUMO
Acute leukemia in Down syndrome (DS) is often associated with additional changes in the number or structure of chromosome 21. We present two DS patients whose leukemic karyotypes were associated with changes in chromosome 21 ploidy. Patient 1 developed acute lymphocytic leukemia (type L1); disomy for chromosome 21 was evident in all blast cells examined. Loss of the paternal chromosome in the leukemic clone produced maternal uniparental disomy with isodisomy over a 25-cM interval. The second patient had acute monoblastic leukemia (type M5) with tetrasomy 21 in all leukemic cells. DNA polymorphism analysis showed duplicate paternal chromosomes in the constitutional genotype. The maternal chromosome was subsequently duplicated in the leukemic clone. The distinct inheritance patterns of chromosome 21 in the blast cells of these patients would appear to indicate that leukemogenesis occurred by different genetic mechanisms in each individual.
Assuntos
Aberrações Cromossômicas , Cromossomos Humanos Par 21 , Síndrome de Down/complicações , Síndrome de Down/genética , Leucemia Monocítica Aguda/complicações , Leucemia Monocítica Aguda/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Pré-Escolar , DNA de Neoplasias/genética , Feminino , Genótipo , Humanos , Polimorfismo GenéticoRESUMO
To assess whether sleep abnormalities are related to the genetic abnormalities in Prader-Willi Syndrome (PWS), we performed polysomnographic studies (nighttime and daytime) and determined the chromosome 15 genotypes in eight patients with PWS. Four patients demonstrated sleep onset REM periods (SOREM), and five met the objective polysomnographic criteria for severe or moderate excessive daytime sleepiness (EDS). Three of the four patients with SOREM displayed a paternally derived deletion of chromosome 15q11-q13, whereas the fourth exhibited maternal uniparental heterodisomy in this chromosomal region (UPD). Two of the four patients that did not display SOREM carried paternally derived deletions; the remaining two demonstrated UPD. Four of the five patients with EDS displayed paternal deletions, and the fifth exhibited UPD. One of three patients without evidence of EDS demonstrated paternal deletion; the remaining two showed UPD. Although neither EDS nor SOREM was not consistently associated with a specific genetic abnormality, these phenotypes may be more common in patients with paternal deletions than in those UPD. Sleep abnormalities in PWS cannot be explained by a single genetic model.
Assuntos
Cromossomos Humanos Par 15 , Síndrome de Prader-Willi/genética , Síndrome de Prader-Willi/fisiopatologia , Transtornos do Sono-Vigília/genética , Sono/genética , Adolescente , Adulto , Criança , Mapeamento Cromossômico , Ritmo Circadiano , Feminino , Deleção de Genes , Marcadores Genéticos , Genótipo , Humanos , Masculino , Variações Dependentes do Observador , Polimorfismo Genético , Respiração , Sono/fisiologia , Sono REMRESUMO
Attention deficit disorder (ADHD) is a complex biobehavioral phenotype which affects up to 8% of the general population and often impairs social, academic, and job performance. Its origins are heterogeneous, but a significant genetic component is suggested by family and twin studies. The murine strain, coloboma, displays a spontaneously hyperactive phenotype that is responsive to dextroamphetamine and has been proposed as a genetic model for ADHD. Coloboma is a semi-dominant mutation that is caused by a hemizygous deletion of the SNAP-25 and other genes on mouse chromosome 2q. To test the possibility that the human homolog of the mouse coloboma gene(s) could be responsible for ADHD, we have carried out linkage studies with polymorphic markers in the region syntenic to coloboma (20p11-p12). Five families in which the pattern of inheritance of ADHD appears to be autosomal dominant were studied. Segregation analysis of the traits studied suggested that the best fitting model was a sex-influenced, single gene, Mendelian pattern. Several genetic models were evaluated based on estimates of penetrance, phenocopy rate, and allele frequency derived from our patient population and those of other investigators. No significant linkage was detected between the disease locus and markers spanning this chromosome 20 interval.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/genética , Camundongos Mutantes/genética , Adolescente , Adulto , Idoso , Animais , Criança , Pré-Escolar , Feminino , Ligação Genética , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Modelos Estatísticos , LinhagemRESUMO
Hemizygous deletion of 3p25-pter is associated with a phenotype of profound growth failure, microcephaly, characteristic facial changes, and mental retardation. Since the severity may be quite variable, we have studied 3 cases of del 3p25-pter to define the clinical manifestations and the critical chromosome region for phenotypic expression. The patient we now report died at age 6 months and provided an opportunity for a detailed necropsy analysis for only the second time in a del(3p) patient. He had marked hypoplasia of all organs, hypomyelination of white matter, and multiple renal cortical microcysts. Ordered genomic markers from the distal regions of chromosome 3p aided in determining the parent of origin of each deletion and in defining the boundaries of the deleted chromosomal segments. The deleted markers distal to the RAF1 oncogene in 2 of the 3 patients were consistently hemizygous. One patient had an interstitial deletion based on evidence of diploid inheritance of one of the most distal loci (D3S17). Available genetic linkage maps suggest that the deletion spans at least 19 centimorgans (cM).
Assuntos
Anormalidades Múltiplas/genética , Deleção Cromossômica , Cromossomos Humanos Par 3 , Face/anormalidades , Insuficiência de Crescimento/genética , Feminino , Humanos , Hibridização in Situ Fluorescente , Recém-Nascido , Deficiência Intelectual/genética , Cariotipagem , Masculino , Microcefalia/genética , Linhagem , Fenótipo , Polimorfismo de Fragmento de RestriçãoRESUMO
Recent studies have identified a new class of Prader-Willi syndrome (PWS) and Angelman syndrome (AS) patients who have biparental inheritance, but neither the typical deletion nor uniparental disomy (UPD) or translocation. However, these patients have uniparental DNA methylation throughout 15q11-q13, and thus appear to have a mutation in the imprinting process for this region. Here we describe detailed clinical findings of five AS imprinting mutation patients (three families) and two PWS imprinting mutation patients (one new family). All these patients have essentially the classical clinical phenotype for the respective syndrome, except that the incidence of microcephaly is lower in imprinting mutation AS patients than in deletion AS patients. Furthermore, imprinting mutation AS and PWS patients do not typically have hypopigmentation, which is commonly found in patients with the usual large deletion. Molecular diagnosis of these cases is initially achieved by DNA methylation analyses of the DN34/ZNF127, PW71 (D15S63), and SNRPN loci. The latter two probes have clear advantages in the simple molecular diagnostic analysis of PWS and AS patients with an imprinting mutation, as has been found for typical deletion or UPD PWS and AS cases. With the recent finding of inherited microdeletions in PWS and AS imprinting mutation families, our studies define a new class of these two syndromes. The clinical and molecular identification of these PWS and AS patients has important genetic counseling consequences.