Genetic epidemiology of early onset breast cancer.

Risks for breast cancer when there is a family history of the disease are usually calculated using data from segregation analyses which favour a single dominant gene with high penetrance. There are, however, at least three loci known to be associated with familial breast cancer (p53, BRCA1, and an as yet unpublished locus) and the frequencies and penetrances of these genes are not likely to be the same. We have attempted to address the problem of which genetic parameters should be used to calculate risks for different patterns of familial breast cancer. Data from 384 nuclear families ascertained through a proband selected for early onset breast cancer were subjected to complex segregation analysis, correcting for ascertainment bias resulting from selection for severe phenotype. Age of onset of breast cancer, incorporated as severity, provides additional information to the segregation model over and above that given by assigning liability classes on the basis of age at observation. The use of this additional parameter in the analysis is described. There is fair agreement between estimates from this sample and previous predictions from consecutive probands and consultands. The differences suggest more than one rare dominant gene for susceptibility to breast cancer, with different penetrances. Although refinements of segregation analysis will help to delineate these different genes, perfect resolution will require identification of the mutant alleles. Methods to estimate genetic parameters under genotype specific mortality need to be developed. Meanwhile, we suggest that high and low estimates of penetrance be used in risk estimation for genetic counselling, and as a guide to candidates for entry into clinical trials of screening and chemoprevention in breast cancer.     

病理性近视眼的遗传流行病学研究

目的 对上海市眼耳鼻喉科医院病理性近视眼患者６２个家系的遗传方式进行研究,探讨可能的遗传模式。方法 用ＳＥＧＲＡＮＢ软件进行简单分离分析,计算确认概率π,并在此基础上计算分离比ｐ和散发概率ｘ,用ＳＡＧＥ－ＲＥＧＤ软件进行复合分离分析,探讨可能的遗传模式和致病基因概率。结果 婚配类型为Ｎ＊Ｎ的家系表现为常染色体隐性遗传,Ａ＊Ｎ婚配类型则可能为隐性遗传模式（不能排除显性遗传模式）,两种婚配类型中均在一     

Segregation analysis of microcephaly

Microcephaly is a heterogeneous disorder with genetic and environmental causes. However, there is little information on what proportion of cases are caused by inherited susceptibility, or the mode of inheritance in familial cases. To address these questions, we have performed classical and complex segregation analyses for microcephaly on 2 sets of family data collected from genetic counseling clinics in Vancouver and Jerusalem. These samples consisted of 143 affected individuals in 127 families ascertained from Vancouver, and 101 affected individuals in 59 families ascertained from Jerusalem. The results of the segregation analyses for the Vancouver sample indicated that approximately half of all microcephaly cases were due to highly penetrant recessive mutant alleles, with the remainder being sporadic. Although a recessive model allowing for the occurrence of sporadic cases fit the data from Vancouver best, a dominant model could not be statistically rejected. The classical segregation analysis on the Jerusalem sample suggested that both a dominant model with 29% of the cases being sporadic and a purely recessive model provided adequate fit to the data. Although the complex segregation analysis of this sample indicated that a dominant model provided a more parsimonious explanation for the observed familial variation, a recessive model was only marginally rejected. It should be noted that in the Jerusalem sample, families tended to be ascertained in the genetic counseling clinic only after the birth of a second affected child. This could be a potential bias which could inflate the segregation ratio, thus giving the impression of dominant inheritance. Our analyses, while confirming the complex nature of the cause of microcephaly, indicate that it may be necessary to await the results of genetic linkage analysis before a definitive mode of inheritance can be determined. © 1996 Wiley-Liss, Inc.     

Complex segregation analysis of quantitative dermatoglyphic traits in five Indian populations

OBJECTIVE: Dermatoglyphics is widely used as a genetically determined trait in anthropogenetics although the genetic nature of its inheritance is still inconclusive, due to the lack of any established genetic model to resolve the existing inconsistencies in the literature. However, advanced statistical packages for complex segregation analyses are available and the aim of the present study is to determine the mode of dermatoglyphic trait inheritance in five different ethnic populations. METHODS: Five hundred families (2435 individuals) of two generations were used for principal component analysis, familial correlation and segregation analysis (package MAN-5). RESULTS: The similarity of three factors suggests a common internal structure. Significant familial correlation (except spouse) indicates the involvement of a familial component in the variation of dermatoglyphic traits. Segregation analyses suggest the transmission of a genetic effect in the families which follows the Mendelian model and confirms a major gene effect on factor 1 and factor 2 with two co-dominant alleles. There is no evidence of a major gene effect or environmental effect on factor 3 (a-b ridge counts). The nature of transmission and trait variance (H2) strongly supports the existence of a common nature of dermatoglyphic trait inheritance in populations, irrespective of ethnic and geographic area. CONCLUSION: Major gene involvement in finger dermatoglyphics according to Mendelian models is confirmed.     

ACMG technical standards and guidelines for genetic testing for inherited colorectal cancer (Lynch syndrome,familial adenomatous polyposis,and MYH-associated polyposis)

Lynch syndrome, familial adenomatous polyposis, and Mut Y homolog (MYH)-associated polyposis are three major known types of inherited colorectal cancer, which accounts for up to 5% of all colon cancer cases. Lynch syndrome is most frequently caused by mutations in the mismatch repair genes MLH1, MSH2, MSH6, and PMS2 and is inherited in an autosomal dominant manner. Familial adenomatous polyposis is manifested as colonic polyposis caused by mutations in the APC gene and is also inherited in an autosomal dominant manner. Finally, MYH-associated polyposis is caused by mutations in the MUTYH gene and is inherited in an autosomal recessive manner but may or may not be associated with polyps. There are variants of both familial adenomatous polyposis (Gardner syndrome—with extracolonic features—and Turcot syndrome, which features medulloblastoma) and Lynch syndrome (Muir–Torre syndrome features sebaceous skin carcinomas, and Turcot syndrome features glioblastomas). Although a clinical diagnosis of familial adenomatous polyposis can be made using colonoscopy, genetic testing is needed to inform at-risk relatives. Because of the overlapping phenotypes between attenuated familial adenomatous polyposis, MYH-associated polyposis, and Lynch syndrome, genetic testing is needed to distinguish among these conditions. This distinction is important, especially for women with Lynch syndrome, who are at increased risk for gynecological cancers. Clinical testing for these genes has progressed rapidly in the past few years with advances in technologies and the lower cost of reagents, especially for sequencing. To assist clinical laboratories in developing and validating testing for this group of inherited colorectal cancers, the American College of Medical Genetics and Genomics has developed the following technical standards and guidelines. An algorithm for testing is also proposed.Genet Med16 1, 101–116.     

Unravelling the genetics of prostate cancer

This review describes what is currently known about the genetics of prostate cancer. Traditionally, the genetics of a suspected inherited cancer predisposition have generally been thought of in terms of a single, high-risk gene with a dominant mode of inheritance. Such a gene might be observed in families, as has been documented in familial breast cancer (BRCA1/2), familial colorectal cancer (HNPCC), retinoblastoma (RB1), and Wilms tumor (WT1). This review investigates the evidence for the existence, first of familial prostate cancer, and second, for the presence of such a high-risk gene in those families by epidemiological and experimental approaches. Another current area of interest in prostate cancer is the investigation of the contribution of common lower penetrance genes to the disease. This alternative approach has become popular, as it raises the issue of frequently seen genetic variations such as single nucleotide polymorphisms (SNPs) having relevance to the risk of developing the disease. Finally, this article will explore the way forward, with emphasis on worldwide collaboration from teams attempting to find the genes responsible for the disease and investment in new technologies that will aid in their discovery.     

Possible autosomal-recessive ocular coloboma

Ocular coloboma as an isolated anomaly often is inherited as an autosomal dominant trait. Possible autosomal recessive inheritance is suggested by the presence of colobomatous malformations in a brother and sister whose parents have apparently normal eyes. Possible genetic heterogeneity of isolated ocular coloboma makes genetic counseling in sporadic cases difficult since cases may be due to autosomal dominant and autosomal recessive mutations and non-genetic causes.     

Inheritance pattern of Beckwith-Wiedemann syndrome is heterogeneous in 291 families with an affected proband

Beckwith-Wiedemann syndrome (BWS) is congenital disorder whose molecular etiology is related to genetic and epigenetic mutations on 11p15. The majority of cases of BWS are sporadic, but a substantial proportion are familial, with an unknown inheritance pattern, although autosomal dominant and sex-dependent inheritance have been proposed. We tested the hypothesis that in familial BWS, autosomal dominant inheritance is the primary mode of transmission underlying familial instances. Segregation analysis was performed in 291 families ascertained with an affected child. Individuals were considered to have BWS if they had two of five major features: macroglossia, macrosomia, hypoglycemia at birth, abdominal wall defect, and ear pits or creases. Models of inheritance were tested using pedigree analysis package (PAP) parameterized for a discrete trait. A total of 291 families of an affected proband were included in the study. The analysis was based on a revised general model that included a boundary solution. Sporadic and environmental models were rejected. Overall, the results suggested Mendelian inheritance but under recessive or additive mode of inheritance, which fit the data equally well rather than dominant inheritance. However, the presence of families in the cohort consistent with dominant and sex-dependent inheritance suggest familial BWS may be a heterogeneous group comprised of different inheritance patterns. Familial BWS does not appear to be consistent with autosomal dominant transmission, and is likely a complex mixture of different inheritance patterns.     

Genetic transmission of Alzheimer''s disease among families in a Dutch population based study.

We evaluated age at onset and transmission patterns of Alzheimer's disease (AD) in families of 198 patients who had onset of symptoms before the age of 65 years and were diagnosed before the age of 70 years. Patients were ascertained in a population based study in The Netherlands. The results suggest that the risk of AD by the age of 90 in first degree relatives is 39% (95% confidence interval 27 to 51). By the age of 90, this risk is 2.8 (95% confidence interval 1.5-5.2) times greater than the corresponding risk of 14% among relatives of age and sex matched control subjects. Segregation analysis indicated that patterns of familial clustering are best explained by transmission of a major autosomal dominant gene with reduced penetrance and a multifactorial component. However, the single major locus model could be rejected in favour of the mixed model only when a cohort effect for heritability was allowed for. The frequency of the AD susceptibility allele was estimated to be 0.48% in the single major locus model and 0.31% in the mixed model. Although our study confirms that a dominant major gene is implicated in early onset AD, the results suggest that other genetic or perhaps non-genetic factors may account for the disease in a considerable number of patients.     

Complex segregation analysis of quantitative dermatoglyphic traits in five Indian populations

Objective: Dermatoglyphics is widely used as a genetically determined trait in anthropogenetics although the genetic nature of its inheritance is still inconclusive, due to the lack of any established genetic model to resolve the existing inconsistencies in the literature. However, advanced statistical packages for complex segregation analyses are available and the aim of the present study is to determine the mode of dermatoglyphic trait inheritance in five different ethnic populations. Methods: Five hundred families (2435 individuals) of two generations were used for principal component analysis, familial correlation and segregation analysis (package MAN-5). Results: The similarity of three factors suggests a common internal structure. Significant familial correlation (except spouse) indicates the involvement of a familial component in the variation of dermatoglyphic traits. Segregation analyses suggest the transmission of a genetic effect in the families which follows the Mendelian model and confirms a major gene effect on factor 1 and factor 2 with two co-dominant alleles. There is no evidence of a major gene effect or environmental effect on factor 3 (a–b ridge counts). The nature of transmission and trait variance (H²) strongly supports the existence of a common nature of dermatoglyphic trait inheritance in populations, irrespective of ethnic and geographic area. Conclusion: Major gene involvement in finger dermatoglyphics according to Mendelian models is confirmed.     

Segregation analyses and a genome-wide linkage search confirm genetic heterogeneity and suggest oligogenic inheritance in some Milroy congenital primary lymphedema families

We previously described six families with Milroy congenital lymphedema, only one of which showed possible linkage to a candidate locus on chromosome 5 [Witte et al., 1998]. We have now performed a complex segregation analysis of these families, and performed linkage analyses with the other 387 markers used in our genome-wide search. Our results confirm that Milroy lymphedema is generally inherited as a dominant condition. However, this mode of inheritance, as elucidated from the segregation analyses, did not account for all observed familial correlations. The segregation analysis also suggested that shared environmental or additional genetic factors are important in explaining the observed familial aggregation. The finding of linkage to multiple locations in the largest family studied by multipoint parametric mapping (one of which was confirmed by sib-pair non-parametric mapping), suggests that Milroy congenital lymphedema may be oligogenic in this family.     

Common inheritance of susceptibility to colonic adenomatous polyps and associated colorectal cancers

We studied 670 persons in 34 kindreds by flexible proctosigmoidoscopic examination (60 cm) to determine how frequently colorectal adenomas and cancers result from an inherited susceptibility. Kindreds were selected through either a single person with an adenomatous polyp or a cluster of relatives with colonic cancer. The kindreds all had common colorectal cancers, not the rare inherited conditions familial polyposis coli and nonpolyposis inherited colorectal cancer. Likelihood analysis strongly supported the dominant inheritance of a susceptibility to colorectal adenomas and cancers, with a gene frequency of 19 percent. According to the most likely genetic model, adenomatous polyps and colorectal cancers occur only in genetically susceptible persons; however, the 95 percent confidence interval for this proportion was 53 to 100 percent. These results suggest that an inherited susceptibility to colonic adenomatous polyps and colorectal cancer is common and that it is responsible for the majority of colonic neoplasms observed clinically. The results also reinforce suggestions that first-degree relatives of patients with colorectal cancer should be screened for colonic tumors. This evidence of an inherited susceptibility to a cancer with well-recognized environmental risk factors supports the hypothesis that genetic and environmental factors interact in the formation and transformation of polyps.     

Inheritance of six anthropometric traits in Vaidyas of West Bengal, India

BACKGROUND: Anthropometric traits are important quantitative traits used by biological anthropologists. Surprisingly little is known about their pattern of inter-generational transmission, probably due to lack of use of developed statistical analysis in previous studies. AIM: The present study is an attempt to approach the problem of the inheritance of anthropometric traits through advanced statistical applications. SUBJECTS AND METHODS: Measurements of 824 individuals from 200 families including two generations were collected from Barasat, West Bengal. The study includes age correction by regression, familial correlation, heritability estimation and segregation analyses. RESULTS: Results showed that there is strong involvement of the familial component in variation of anthropometric traits. The magnitude of heritability (h2= 57-83%) also supports their strong genetic basis. The results indicated that additive genes are not the only contributing factor; the effect of environment is considerable and that of dominant genes not negligible. Due to genetic interaction with the local environment (specific for each trait), heritabilities vary from one trait to another. Length measurements have higher heritability than breadth measurements. Segregation analysis revealed that either the additive or dominant major gene (MG) is responsible for this effect, which follows simple Mendelian transmission. Beside this, the possibility of the existence of an additional minor gene cannot be discarded. CONCLUSION: Anthropometric traits have a genetic basis but their mode of inheritance is quite complex in nature. There is evidence of major gene effect (along with polygenes) with Mendelian transmission.     

The inheritance of juvenile onset primary open angle glaucoma

Juvenile onset open angle glaucoma (JOAG) affects patients before 40 years of age, who present with high intraocular pressure and deep steep cupping of the optic nerve head. While it was considered to be inherited in an autosomal dominant fashion, recent studies have shown an autosomal recessive pattern as well as sporadic occurrence of the disease in several families. In this review, we analyze the genetic basis of the disease along with common mutations and their association with JOAG. We also analyzed the inheritance patterns in a large group of unrelated JOAG patients (n = 336) from Northern India wherein the prevalence of familial occurrence was assessed and segregation analysis performed, to determine the mode of inheritance.     

Evidence of a major gene effect for angiotensinogen among Nigerians

To dissect the genetic pathway of hypertension, we measured angiotensinogen in 685 members of 186 families recruited from a rural community in southwest Nigeria. Commingling and segregation analyses were carried out. A mixture of two and/or three distributions fits the data significantly better than a single distribution in commingling analysis, suggesting a major gene effect. Segregation analysis confirmed that a recessive major gene model for low values of angiotensinogen provides the best fit to the data and about 13% of the variance was due to the recessive gene segregation.     

Autosomal dominant inheritance of a predisposition to thoracic aortic aneurysms and dissections and intracranial saccular aneurysms

A genetic predisposition for thoracic aortic aneurysms and dissections (TAAD) can be inherited in an autosomal dominant manner with decreased penetrance and variable expression. Four genes identified to date for familial TAAD account for approximately 20% of the heritable predisposition. In a cohort of 514 families with two or more members with presumed autosomal dominant TAAD, 48 (9.3%) families have one or more members who were at 50% risk to inherit the presumptive gene causing TAAD had an intracranial vascular event. In these families, gender is significantly associated with disease presentation (P < 0.001), with intracranial events being more common in women (65.4%) while TAAD events occurred more in men (64.2%,). Twenty‐nine of these families had intracranial aneurysms (ICA) that could not be designated as saccular or fusiform due to incomplete data. TGFBR1, TGFBR2, and ACTA2 mutations were found in 4 families with TAAD and predominantly fusiform ICAs. In 15 families, of which 14 tested negative for 3 known TAAD genes, 17 family members who were at risk for inheriting TAAD had saccular ICAs. In 2 families, women who harbored the genetic mutation causing TAAD had ICAs. In 2 additional families, intracranial, thoracic and abdominal aortic aneurysms were observed. This study documents the autosomal dominant inheritance of TAADs with saccular ICAs, a previously recognized association that has not been adequately characterized as heritable. In these families, routine cerebral and aortic imaging for at risk members could prevent cerebral hemorrhages and aortic dissections. © 2011 Wiley‐Liss, Inc.     

Combined pedigree and twin family study to determine the sources of variation in serum biotinidase activity: The usefulness of multiple study designs

Biotinidase, the enzyme responsible for recycling the vitamin biotin, is deficient in most individuals with late-onset multiple carboxylase deficiency. Based on clinical criteria, biotinidase deficiency appears to be inherited as an autosomal recessive trait; however, the inheritance of biotinidase serum activity as a quantitative trait has not been studied previously. In this study, both segregation analysis of proband families and the analysis of twin family data were used to determine the relative contributions of a major gene, polygenes and environment to the variation in serum biotinidase activity. Segregation analysis of 24 families of biotinidase-deficient individuals indicated that serum biotinidase activity is determined by the segregation of a single codominant major gene with the variability about the mean of each major genotype attributable to environmental effects. Significant polygenic effects could not be detected by this analysis. Variance component analysis of 128 twin families, which included the twins, their spouses, and their offspring, indicated that 70% of total variance in biotinidase activity is attributable to additive genetic effects, 22% to individual environmental effects, and 8% to shared environmental effects. The model also included an age effect for females. A portion (27%) of the estimated additive variance may be attributed to the segregation of the major gene. This study emphasizes the usefulness of studying multiple data sets representing different types of family relationships. © 1993 Wiley-Liss, Inc.     

Genetics of dementia: Update and guidelines for the clinician

With increased frequency, clinical geneticists are asked for genetic advice on the heredity of dementia in families. Alzheimer's disease is in most cases a complex disease, but may be autosomal dominant inherited. Mutations in the PSEN1 gene are the most common genetic cause of early onset Alzheimer's disease, whereas APP and PSEN2 gene mutations are less frequent. Familial frontotemporal dementia may be associated with a mutation in the MAPT or GRN gene, or with a repeat expansion in the C9orf72 gene. All these genes show autosomal dominant inheritance with a high penetrance. Although Alzheimer's disease and frontotemporal dementia are clinically distinguishable entities, phenotypical overlap may occur. Rarely, dementia is caused by mutations in other autosomal dominant genes or by genetic defects with autosomal recessive, X-linked dominant or mitochondrial inheritance. The inherited forms of frontotemporal dementia and Alzheimer's disease show a large phenotypic variability also within families, resulting in many remaining uncertainties for mutation carriers. Therefore, genetic counseling before performing genetic testing is essential in both symptomatic individuals and healthy at risk relatives. This review provides an overview of the genetic causes of dementia and discusses all aspects relevant for genetic counseling and testing. Furthermore, based on current knowledge, we provide algorithms for genetic testing in patients with early onset Alzheimer's disease or frontotemporal dementia. ? 2012 Wiley Periodicals, Inc.     

Segregation analysis of hypospadias: A reanalysis of published pedigree data

Little is known about the cause of hypospadias, one of the most common urogenital anomalies in males. Familial clustering of hypospadias is well recognized, with heritability estimated to be about 70% under a simple multifactorial threshold model. Neither alternative genetic mechanisms nor shared environmental factors within families have been explored fully. To learn more about possible genetic mechanisms, we used 2 methods of segregation analysis to analyze a set of published family data. These analyses are based on the families of 103 probands with hypospadias, who were ascertained through surgery departments in Denmark [Sørensen, 1953]. Urogenital examinations were performed on 95% (n = 1,510) of available male relatives, and 2.2% were found to have hypospadias. Within the probands' nuclear families, 12% of nonproband sons of normal fathers were affected. Using the mixed model of inheritance, both the autosomal dominant (AD) and codominant models fit these data better than either autosomal recessive (AR) or multifactorial models. Using the regressive logistic models, both AD and AR models were equally likely, and a model of nonMendelian sibship clustering gave a better fit to these data. These inconsistent findings illustrate the difficulties commonly encountered in segregation analysis. Using 2 different statistical approaches, we found 2 different explanations, both of which differ from the autosomal recessive model originally suggested by Sørensen [1953]. Hypospadias in these families is almost certainly heterogeneous. Determining the cause of familial clustering of hypospadias will require careful delineation of persons with recognized syndromes from uncomplicated cases and detaied information on potential prenatal risk factors. © 1993 Wiley-Liss, Inc.