RESUMO
Marfan syndrome (MFS) is an autosomal dominant connective-tissue disorder characterized by skeletal, ocular and cardiovascular defects of highly variable expressivity. The diagnosis relies solely on clinical criteria requiring anomalies in at least two systems. By excluding the chromosome 15 disease locus, fibrillin 1 (FBN1), in a large French family with typical cardiovascular and skeletal anomalies, we raised the issue of genetic heterogeneity in MFS and the implication of a second locus (MFS2). Linkage analyses, performed in this family, have localized MFS2 to a region of 9 centiMorgans between D3S1293 and D3S1283, at 3p24.2-p25. In this region, the highest lod score was found with D3S2336, of 4.89 (theta = 0.05). By LINKMAP analyses, the most probable position for the second locus in MFS was at D3S2335.
Assuntos
Cromossomos Humanos Par 3 , Síndrome de Marfan/genética , Proteínas dos Microfilamentos/genética , Adulto , Sequência de Bases , Mapeamento Cromossômico , Feminino , Fibrilina-1 , Fibrilinas , Haplótipos/genética , Humanos , Escore Lod , Masculino , Síndrome de Marfan/classificação , Proteínas dos Microfilamentos/classificação , Repetições Minissatélites , Dados de Sequência Molecular , LinhagemRESUMO
Providing valid risk estimates of a genetic disease with variable age of onset is a major challenge for prevention strategies. When data are obtained from pedigrees ascertained through affected individuals, an adjustment for ascertainment bias is necessary. This article focuses on ascertainment through at least one affected and presents an estimation method based on maximum likelihood, called the Proband's phenotype exclusion likelihood or PEL for estimating age-dependent penetrance using disease status and genotypic information of family members in pedigrees unselected for family history. We studied the properties of the PEL and compared with another method, the prospective likelihood, in terms of bias and efficiency in risk estimate. For that purpose, family samples were simulated under various disease risk models and under various ascertainment patterns. We showed that, whatever the genetic model and the ascertainment scheme, the PEL provided unbiased estimates, whereas the prospective likelihood exhibited some bias in a number of situations. As an illustration, we estimated the disease risk for transthyretin amyloid neuropathy from a French sample and a Portuguese sample and for BRCA1/2 associated breast cancer from a sample ascertained on early-onset breast cancer cases.
Assuntos
Doenças Genéticas Inatas/genética , Fatores Etários , Neuropatias Amiloides/genética , Viés , Neoplasias da Mama/genética , França , Genes BRCA1 , Genes BRCA2 , Humanos , Funções Verossimilhança , Modelos Genéticos , Modelos Estatísticos , Linhagem , Fenótipo , Portugal , Pré-Albumina/genética , RiscoRESUMO
BACKGROUND AND PURPOSE: Familial amyloid polyneuropathy (FAP) type I is a severe autosomal dominant inherited neuropathy associated with mutations in the transthyretin (TTR) gene. Significant phenotypic variability is seen amongst families with distinct geographic origin, especially regarding penetrance and age of onset. The aim of this study was to estimate the penetrance of FAP in Brazilian families. METHODS: Twenty-two distinct families were ascertained through genetically confirmed index cases and included in this study. Genealogical and clinical data were obtained from a total of 623 individuals, including 126 affected by FAP. In 15 families, TTR genotyping was performed in all available relatives (n = 86), after informed written consent. Seven families did not consent for genetic testing, but agreed to provide clinical and genealogical data. Penetrance was estimated using a previously described method based on survival analysis and corrected for ascertainment bias. RESULTS: Mean age of onset in our sample was 34.5 years, with a significant earlier onset in males (31.1 vs. 35.9, P < 0.0001). The penetrance of FAP in our sample was estimated as 83% (95% CI: 66-99) after 60 years. CONCLUSION: Our results provide new information on FAP in Brazilian patients and may be helpful in the genetic counseling of this population.
Assuntos
Neuropatias Amiloides Familiares/genética , Penetrância , Pré-Albumina/genética , Adulto , Fatores Etários , Idade de Início , Idoso , Brasil , Família , Feminino , Humanos , Funções Verossimilhança , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Análise de Sequência de DNA , Fatores Sexuais , Análise de Sobrevida , Adulto JovemRESUMO
We have performed an extensive analysis of TP53 in 474 French families suggestive of Li-Fraumeni syndrome (LFS), including 232 families fulfilling the Chompret criteria. We identified a germline alteration of TP53 in 82 families (17%), in 67/232 of the families fulfilling the Chompret criteria (29%) and in 15/242 which did not fulfil these criteria (6%). Most of the alterations corresponded to missense mutations (67%), and we identified in four families genomic deletions removing the entire TP53 locus, the promoter and the non-coding exon 1, or exons 2-10. These results represent a definitive argument demonstrating that LFS results from TP53 haplodeficiency. The mean ages of tumour onset were significantly different between patients harbouring TP53 missense mutations and other types of alterations, missense mutations being associated with a 9 year earlier tumour onset. These results confirm that missense mutations not only inactivate p53 but also have an additional oncogenic effect. Germline alterations of TP53 that lead exclusively to loss of function are therefore associated with a later age of tumour onset and the presence of such mutations should be considered in atypical LFS families with tumours diagnosed after 40 years.
Assuntos
Genes p53 , Predisposição Genética para Doença , Síndrome de Li-Fraumeni/genética , Feminino , França , Deleção de Genes , Humanos , Masculino , Mutação de Sentido Incorreto , Neoplasias/genética , LinhagemRESUMO
We have previously shown that patients with renal fibromuscular dysplasia (FMD) have asymptomatic carotid lesions and that familial forms may occur. The objective of this study was to test whether carotid lesions could be detected in relatives of familial cases. High-resolution echotracking of the carotid artery was performed in 47 relatives of 13 cases from six families. This non-invasive investigation led to a semiquantitative arterial score that was compared with that obtained for 47 controls matched for age and sex and that for 125 sporadic cases. Familial resemblance was tested by using a generalized estimating equation approach taking into account the clustering of scores in families. As expected, FMD cases had a significantly higher score than controls (4.02 vs 2.52, P<10(-5)). Familial cases were not significantly different from sporadic cases. Of interest, the 47 apparently healthy relatives of familial cases had also a high carotid score (4.17), very significantly higher than that of controls (2.52, P<10(-5)) even though lower than the corresponding index FMD cases (4.81, P=0.01). Segregation analysis showed that 52% of the descendants of subjects with a score >4 had a score >4, a proportion consistent with autosomal-dominant transmission of the trait. Altogether these results strengthen the hypothesis of renal FMD being a systemic arterial disease and argue for a familial resemblance that may be due to a major genetic effect. The carotid score obtained by high-resolution echotracking may provide a non-invasive surrogate marker for renal FMD of potential value for use in linkage strategies on large pedigrees.
Assuntos
Doenças das Artérias Carótidas/genética , Artéria Carótida Primitiva/patologia , Displasia Fibromuscular/genética , Obstrução da Artéria Renal/genética , Adulto , Idoso , Análise de Variância , Doenças das Artérias Carótidas/complicações , Estudos de Casos e Controles , Análise por Conglomerados , Feminino , Displasia Fibromuscular/complicações , França , Predisposição Genética para Doença , Humanos , Hipertensão/etiologia , Hipertensão/genética , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo , Curva ROC , Análise de Regressão , Obstrução da Artéria Renal/complicações , Projetos de Pesquisa , Análise de Sobrevida , Túnica Íntima/patologia , Túnica Média/patologiaRESUMO
Li-Fraumeni syndrome, resulting from p53 (TP53) germline mutations, represents one of the most devastating genetic predispositions to cancer. Recently, the MDM2 SNP309 (T-->G variation) was shown to be associated with accelerated tumour formation in p53 mutation carriers. The impact of the common p53 codon 72 polymorphism on cancer risk remains controversial. We therefore investigated the effect of these two polymorphisms in 61 French carriers of the p53 germline mutation. The mean age of tumour onset in MDMD2 SNP309 G allele carriers (19.6 years) was significantly different from that observed in patients homozygous for the T allele (29.9 years, p<0.05). For the p53 codon 72 polymorphism, the mean age of tumour onset in Arg allele carriers (21.8 years) was also different from that of Pro/Pro patients (34.4 years, p<0.05). We observed a cumulative effect of both polymorphisms because the mean ages of tumour onset in carriers of the MDM2G and p53Arg alleles (16.9 years) and those with the MDM2T/T and p53Pro/Pro genotypes (43 years) were clearly different (p<0.02). Therefore, our results confirm the impact of the MDM2 SNP309 G allele on the age of tumour onset in germline p53 mutation carriers, and suggest that this effect may be amplified by the p53 72Arg allele. Polymorphisms affecting p53 degradation therefore represent one of the rare examples of modifier genetic factors identified to date in mendelian predispositions to cancer.
Assuntos
Genes p53 , Predisposição Genética para Doença , Síndrome de Li-Fraumeni/genética , Polimorfismo de Nucleotídeo Único , Proteínas Proto-Oncogênicas c-mdm2/genética , Adolescente , Adulto , Idade de Início , Análise Mutacional de DNA , Progressão da Doença , Feminino , Frequência do Gene , Mutação em Linhagem Germinativa , Heterozigoto , Humanos , Síndrome de Li-Fraumeni/diagnóstico , Síndrome de Li-Fraumeni/epidemiologia , Masculino , Pessoa de Meia-Idade , Fatores de RiscoRESUMO
BACKGROUND: Little is known about compliance with colonoscopy as a screening method in first-degree relatives of patients with large adenomas. Aims To evaluate the compliance with screening colonoscopy among this population, and its determinants. METHODS: Data were obtained from the family part of the GEADE study, a study on genetic factors of colorectal adenomas. Index cases were 306 patients with adenomas > or = 10 mm. All living first-degree relatives aged 40-75 who could be contacted by the index case were asked to undergo a colonoscopy, unless they had had one in the previous 5 years. RESULTS: Among 674 eligible relatives, 56 had had a colonoscopy within the preceding 5 years and 114 underwent a screening colonoscopy resulting in a compliance with screening colonoscopy of 18%. This was not related to most characteristics of index cases. Compliance was significantly lower when the index case lived in the Greater Paris area than when he/she lived in other areas (12% vs. 21%). It was higher in siblings (18%) and offspring (23%) than in parents (9%) and in relatives under 55 years old (22%) than in relatives aged 55 and over (15%). CONCLUSIONS: Compliance with colonoscopy was low in first-degree relatives of patients with large adenomas. The reasons for this should be determined and appropriate strategies developed to increase compliance.
Assuntos
Adenoma/diagnóstico , Colonoscopia/estatística & dados numéricos , Neoplasias Colorretais/diagnóstico , Cooperação do Paciente/estatística & dados numéricos , Adenoma/genética , Adulto , Idoso , Neoplasias Colorretais/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , LinhagemRESUMO
To test Knudson's hypothesis that two successive mutations are involved in retinoblastoma, we studied the data on 899 cases. Some of the findings appeared to differ from those that might be expected if Knudson's hypothesis were correct. Certain criticisms of Knudson's methodology and model were suggested. Alternative explanations proposed were 1) the role of the sequence in which mutations occur, and 2) the possibility of three mutational events.
Assuntos
Modelos Biológicos , Neoplasias/etiologia , Retinoblastoma/genética , Adolescente , Fatores Etários , Criança , Pré-Escolar , Características da Família , Células Germinativas , Humanos , Lactente , Recém-Nascido , Matemática , Mutação , Neoplasias Primárias MúltiplasRESUMO
We have undertaken a routine investigation of the p53 status for all the children treated at our institution either affected by multiple tumors or whose family displays at least one second degree relative or less, affected by cancer before the age of 45 years. We report here on the first set of ten such families, eight of which were identified through a proband with sarcoma. p53 exons 5 to 8 have been sequenced following polymerase chain reaction amplification performed on DNA isolated from total blood. A missense mutation affecting codons 248, 273, and 282 was identified in three families. The mutation was inherited in these three families and was detected in unaffected members. In seven families no mutation was detected in exons 5 to 8.
Assuntos
Genes p53/genética , Neoplasias/genética , Adolescente , Adulto , Alelos , Arginina/genética , Sequência de Bases , Criança , Pré-Escolar , Éxons/genética , Saúde da Família , Feminino , Células Germinativas/fisiologia , Glicina/genética , Humanos , Lactente , Síndrome de Li-Fraumeni/genética , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Mutação , Linhagem , Sarcoma/genéticaRESUMO
Germline p53 mutations have been detected in approximately half of the families affected by the Li-Fraumeni syndrome (LFS), in which they are believed to represent the genetic status predisposing to multiple cancers. Failure to detect mutations in the other half of LFS families suggests that sequence analysis, which has been limited to the p53 gene coding region, have overlooked other genetic events lying outside of this region or/and that alterations in other gene(s) than p53 may also lead to the syndrome. In this report, we present the evidence that a single base pair deletion in the p53 coding sequence, leading to premature signal termination of translation, generates a null allele by preventing transport of mutant allele mRNAs into the cytoplasm. This allelic exclusion which confers a status of unizygote vis-à-vis the wild-type p53 gene to individuals who carry the mutant allele, leads to predisposition to multiple cancers in a Li-Fraumeni family. Thus, the loss of the wild-type p53 allele appears as the rate limiting step in tumor induction.
Assuntos
Alelos , Genes p53 , Mutação em Linhagem Germinativa , Síndrome de Li-Fraumeni/genética , Biossíntese de Proteínas , Sequência de Bases , Feminino , Humanos , Masculino , Dados de Sequência Molecular , Linhagem , Splicing de RNA , RNA Mensageiro/genética , Células Tumorais CultivadasRESUMO
Although a few familial forms of congenital hypothyroidism (CH) due to thyroid dysgenesis (TD) have been reported, this disorder is usually considered to be sporadic. Recently, we reported that 2% of CH patients with TD have a positive familial history. The aim of this study was to describe the clinical characteristics of these familial cases and to compare them with sporadic cases. We used the French national population-based registry of the first 19-yr screening program, which included 14,416,428 screened neonates with a 100% recovery rate. Familial history of CH with TD was investigated by means of a questionnaire sent to the pediatricians (n = 592) who provided ongoing clinical care for the 4049 CH patients detected during this period, including 2863 CH cases due to TD. Information was obtained from 73% of these pediatricians who were following up 2472 CH patients with TD (86%). In all, 67 patients with a positive family history of CH with TD were referred, belonging to 32 multiplex families (i.e. including at least 2 affected members). Families were identified with ectopic gland (n = 12), athyreosis (n = 7), or both (n = 13). Comparison of familial with isolated cases showed a similar etiological diagnosis distribution of CH (40% vs. 33% for athyreosis and 60% vs. 67% for ectopic thyroid gland, respectively), whereas a significantly lower predominance of females was found in familial than in isolated cases (1.4 vs. 2.7; P < 0.03). Extrathyroidal congenital malformations were found with a similarly higher incidence in familial and isolated CH populations compared with the general population (respectively, 9% and 8.2% vs. 2.5%). In conclusion, although familial cases represent a minority of cases of congenital hypothyroidism caused by thyroid dysgenesis, they were observed in a significantly higher proportion (>15-fold) than would be expected from chance alone. This familial clustering, including athyreosis and ectopic thyroid gland, strongly suggests that genetic factors could be involved in thyroid dysgenesis with a common underlying mechanism for both etiological groups. Moreover, the high proportion of extrathyroidal congenital malformations in a population affected by CH due to TD suggests that the potential genetic factors involved in thyroid gland organogenesis are also involved in the development of other organs.
Assuntos
Hipotireoidismo Congênito , Glândula Tireoide/anormalidades , Feminino , Humanos , Hipotireoidismo/genética , Masculino , Distribuição por SexoRESUMO
CYP1A1 is a cytochrome P450 which is inducible by polycyclic aromatic hydrocarbons (PAH). This induction is mediated via the Ahr locus which encodes the cytosolic Aryl hydrocarbon receptor. The induced activity of CYP1A1 can be measured in vitro by the ethoxyresorufin-O-deethylase (EROD) activity in lymphocytes after induction by benz(a)anthracene (B(a)A). Our purpose was to determine, using this assay, the genetic polymorphism of CYP1A1 induction. With this aim, a population and family study was undertaken. Using the statistical SKUMIX method, a bimodal distribution (two peaks) of the induced EROD activity among 102 unrelated individuals was obtained. We were unable to discriminate three classes of CYP1A1 induction phenotype since a trimodal distribution did not significantly improve the fit to the data (chi 2(1) = 0.37, p > 0.9). Segregation analysis performed on 57 nuclear families gave evidence of a major gene effect together with a polygenic component. The frequency of the high induction allele is equal to 0.11 with dominance on the low induction allele. This is an accordance with two distributions, with individuals showing low and high CYP1A1 induction phenotypes in proportions of 89% and 21% respectively. However, some degree of overlap between the two distributions prevented a clear genotype classification on the basis of the phenotype measured with the EROD assay. Further analyses should not be made with a dichotomized phenotype (low and high inducers) but should use quantitative measurements.
Assuntos
Benzo(a)Antracenos/farmacologia , Sistema Enzimático do Citocromo P-450/biossíntese , Sistema Enzimático do Citocromo P-450/genética , Linfócitos/enzimologia , Modelos Genéticos , Oxirredutases/biossíntese , Oxirredutases/genética , Polimorfismo Genético , Adolescente , Adulto , Idoso , Células Cultivadas , Citocromo P-450 CYP1A1 , Indução Enzimática , Feminino , Frequência do Gene , Humanos , Linfócitos/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Núcleo Familiar , Fenótipo , Probabilidade , FumarRESUMO
Data from 511 cases of Wilms' tumor in France (including 12 familial cases) and 8 pedigrees from the literature were analyzed to test three modifications of Knudson's classical bimutational theory, based on genomic imprinting in Wilms' tumor carcinogenesis. Analysis of data of age at diagnosis and segregation analysis were performed to determine the number of independent events for Wilms' tumor development and to search for a differential role of paternal and maternal alleles. Unexpectedly, we show that only one rare event is required for tumor development in isolated unilateral cases which are considered to be mainly nonhereditary. In familial cases, we observe no effect of the sex of the transmitting parent on either hge at diagnosis or segregation ratio. We show that this could be explained by models of genomic imprinting which assume two nonindependent events, or only one rare genetic event. In bilateral cases we show a bimodality for age at diagnosis which could be due to a mixture of hereditary and nonhereditary cases. This result completely questions the classical assumption according to which all bilateral cases would be hereditary. These findings support the hypothesis that this childhood cancer arises from a variety of etiological pathways and might be useful to find strategies for further molecular investigations.
Assuntos
Regulação Neoplásica da Expressão Gênica/fisiologia , Genes do Tumor de Wilms , Tumor de Wilms/genética , Adolescente , Idade de Início , Distribuição de Qui-Quadrado , Criança , Pré-Escolar , Cromossomos Humanos Par 11 , Pai , Feminino , Expressão Gênica , Humanos , Lactente , Modelos Lineares , Masculino , Modelos Genéticos , Mães , Linhagem , Fatores SexuaisRESUMO
Autosomal dominant type IIa hypercholesterolaemia (ADH) is characterised by an elevation of total plasma cholesterol associated with increased LDL particles. Numerous different molecular defects have been identified in the LDL receptor (LDLR) and few specific mutations in the apolipoprotein B (APOB) gene resulting in familial hypercholesterolaemia and familial defective apoB-100 respectively. To estimate the respective contribution of LDLR, APOB and other gene defects in this disease, we studied 33 well characterised French families diagnosed over at least three generations with ADH through the candidate gene approach. An estimation of the proportions performed with the HOMOG3R program showed that an LDLR gene defect was involved in approximately 50% of the families (P = 0.001). On the other hand, the estimated contribution of an APOB gene defect was only 15%. This low estimation of ADH due to an APOB gene defect is further strengthened by the existence of only two probands carrying the APOB (R3500Q) mutation in the sample. More importantly and surprisingly, 35% of the families in the sample were estimated to be linked to neither LDLR nor APOB genes. These data were confirmed by the exclusion of both genes through direct haplotyping in three families. Our results demonstrate that the relative contributions of LDLR and APOB gene defects to the disease are very different. Furthermore, our results also show that genetic heterogeneity is, generally, underestimated in ADH, and that at least three major groups of defects are involved. At this point, the contribution of the recently mapped FH3 gene to ADH cannot be assessed nor its importance in the group of 'non LDLR/non APOB' families.
Assuntos
Apolipoproteínas B/genética , Hiperlipoproteinemia Tipo II/genética , Receptores de LDL/genética , LDL-Colesterol/análise , Mapeamento Cromossômico , Cromossomos Humanos Par 1 , Feminino , Heterogeneidade Genética , Ligação Genética , Haplótipos , Humanos , Escore Lod , Masculino , Computação Matemática , Repetições de Microssatélites , Linhagem , Análise de Sequência de DNA , Triglicerídeos/análiseRESUMO
Population and family studies were undertaken to validate caffeine as a probe drug to establish the genetic status of rapid acetylators and slow acetylators. The acetylator status was established from the urinary metabolic ratio of 5-acetylamino-6-formylamino-3-methyluracil to 1-methylxanthine (AFMU/1X) after oral administration of caffeine. We confirmed a bimodal distribution (chi 2(1) = 229.48; p << 10(-9)) of the AFMU/1X ratio in 245 unrelated subjects. A third distribution did not significantly improve the fit to the data (chi 2(1) = 0.04; p = 0.84). Complex segregation analysis of 76 nuclear families confirmed the monogenic inheritance of N-acetyltransferase, with incomplete dominance of the rapid allele over the slow one. We observed a slight shift between the mean activities of heterozygous and homozygous rapid acetylators (t = 2.89; p < 0.01). However, the 30 obligate heterozygotes belonging to the 76 families were evenly distributed among the rapid acetylators and never located in a hypothetic intermediary group between slow acetylators and rapid acetylators.
Assuntos
Arilamina N-Acetiltransferase/metabolismo , Cafeína/farmacocinética , Uracila/análogos & derivados , Xantinas/urina , Acetilação , Arilamina N-Acetiltransferase/genética , Cafeína/urina , Família , Heterozigoto , Humanos , Modelos Estatísticos , Fatores de Tempo , Uracila/urinaRESUMO
BACKGROUND AND PURPOSE: Before 1974 about 5000 children were treated by radiotherapy at the Institut Gustave-Roussy (IGR) for a skin haemangioma. A human model whose characteristics are as close as possible to those of the patient at the time of the treatment is necessary to effectuate an accurate retrospective estimation of the radiation doses received at distant organs. METHODS: We have developed a software package which constructs an individualized phantom based on CT slices and auxological data (ICTA) for this purpose. A set of real CT slices is used to produce a 3-D representation of the human body which is then adjusted to fit the dimensions supplied by published auxological data relative to sex and age for each patient. One hundred sixty-one anatomical landmarks of epidemiological interest have been defined inside the phantom for dose estimation. RESULTS: The transverse, frontal and sagittal views of the phantom displayed permit accurate positioning of radioactive applicators. The software calculates the relevant parameters required for dose estimation based on the patient's probable anatomy.
Assuntos
Hemangioma/radioterapia , Imagens de Fantasmas , Planejamento da Radioterapia Assistida por Computador , Neoplasias Cutâneas/radioterapia , Tomografia Computadorizada por Raios X , Adulto , Pré-Escolar , Simulação por Computador , Feminino , Seguimentos , Hemangioma/diagnóstico por imagem , Humanos , Lactente , Recém-Nascido , Masculino , Doses de Radiação , Reprodutibilidade dos Testes , Estudos Retrospectivos , Neoplasias Cutâneas/diagnóstico por imagemRESUMO
We undertook a family study of children treated at the Institute Gustave-Roussy in France to investigate a familial aggregation of cancer in the families of children with non-Hodgkin's lymphoma (NHL). We obtained family dat for 284 children with NHL. Using the Standardized Incidence Ratio, we compared the observed and expected number of families with at least one proband relative affected by cancer at a young age (before 46 years). We found a small but non-significant excess of all tumors in first-degree relatives (SIR = 1.3, 95% CI = 0.7-2.3) explained by a small but non-significant excess of hematological malignancies (SIR = 1.5, 95% CI = 0.2-5.5), particularly Hodgkin's disease and leukemia, and of osteosarcoma (SIR = 7.5, 95% CI = 0.1-41.4). This is probably a lower bound of the SIR, because the expected number of families was estimated from cancer incidence in France between 1978 and 1982, whereas most cancers occurred before this period. Other tumors were not in excess in first-degree relatives.
Assuntos
Saúde da Família , Linfoma não Hodgkin/genética , Neoplasias/genética , Adolescente , Neoplasias Ósseas/genética , Criança , Pré-Escolar , Feminino , Doença de Hodgkin/genética , Humanos , Incidência , Leucemia/genética , Masculino , Pessoa de Meia-Idade , Neoplasias/epidemiologia , Osteossarcoma/genéticaRESUMO
Red cell porphobilinogen deaminase is known to be an indicator of the carrier state for acute intermittent porphyria (AIP). This enzyme was assayed in three groups of individuals at least 15 years old: 105 affected individuals or obligate carriers, 234 unaffected first-degree relatives of patients, and 217 unrelated control persons. Analysis of the distribution of the control enzyme activities suggested presence of three commingled distributions. Also, the overlap between carrier-group and control-group values must be taken into account for genetic counseling of relatives whose enzyme activity lies within the overlap. A Bayesian approach is proposed to derive risks for these individuals, using the observed carrier and control distributions. The method is illustrated by deriving risks for a family from our sample.
Assuntos
Amônia-Liases/sangue , Hidroximetilbilano Sintase/sangue , Porfirias/genética , Adolescente , Adulto , Idoso , Teorema de Bayes , Eritrócitos/enzimologia , Feminino , Genes Dominantes , Triagem de Portadores Genéticos , Humanos , Masculino , Pessoa de Meia-Idade , Porfiria Aguda Intermitente , Porfirias/enzimologia , RiscoRESUMO
From a series of 1,408 patients with craniosynostosis hospitalized between 1976 and 1994, 561 probands with non-syndromal isolated sagittal synostosis were analyzed. The prevalence of sagittal synostosis was estimated in the order of 1 in 5,000 children. Family information was obtained from 373 probands distributed among 366 families. The male:female ratio was 3.5:1. There was no maternal or paternal age effect. In 22 of the 366 pedigrees, a high degree of familial aggregation was observed, giving a 6% figure of familial cases. Segregation analysis of 253 families indicates that sagittal synostosis is transmitted as a dominant disorder with 38% penetrance and 72% of sporadic cases. The frequency of twinning was 4.8% with only 1 concordance for sagittal synostosis in a monozygotic twin pair. The possibility of a mechanical pathogenesis in sporadic cases is discussed.
Assuntos
Craniossinostoses/genética , Adolescente , Adulto , Peso ao Nascer , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , LinhagemRESUMO
From a series of 1265 individuals with different craniosynostoses hospitalized between 1976 and 1993, 260 probands with nonsyndromic unilateral (181) or bilateral (79) coronal synostosis were analysed. The prevalence of craniosynostoses was estimated as 1 in 2100 children. In the group of coronal synostosis, family history was obtained on 192 probands in 180 pedigrees. The male:female ratio was 1:2. The average paternal age was 32.7 +/- 6.4 years, which is significantly higher than normal. In 26 of the 180 pedigrees, a high degree of familial aggregation was observed, giving a 14.4% figure of familial cases. The bicoronal synostoses were significantly more often familial than the unicoronal synostoses. Segregation analysis of these families leads to the conclusion that coronal synostosis is transmitted as a dominant disorder with 0.60 penetrance and 61% of sporadic cases.