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PubMed1993

Inheritance of plasma apolipoprotein B levels in families of patients undergoing coronary arteriography at an early age.

An elevated plasma level of apolipoprotein B (apoB), the major protein of low density lipoproteins, is a risk factor for coronary artery disease. This study tested the hypothesis, suggested by previous studies, that the apoB level is strongly influenced by a major gene. The study population included 832 family members of 116 subjects who had undergone elective coronary arteriography at an early age. The apoB level was adjusted for age, gender, body mass index, alcohol consumption, and cigarette smoking (R2 = 20%). ApoB levels revealed strong familial aggregation with correlations among spouses of 0.23, parent-offspring of 0.16, and siblings of 0.21. Regressive models were used to examine inter-individual variation in adjusted apoB levels. In the total sample, familial aggregation of the apoB level was consistent with two models: (1) a major gene model and (2) a polygenic model with a mixture of non-transmitted "types". Comparison of these two models in each family showed that 57 families supported the first model over the second. Segregation analysis in these 57 families conclusively favored a major gene model with codominant transmission. Genotypic means were 124, 164, and 208 mg/dl with relative frequencies of 45%, 44%, and 11%. Linkage studies in these families can be used to clarify the molecular basis of apoB regulation. However, in the whole population the genetic control of apoB levels may be quite complex.

Apolipoproteins B↗
PubMed1993

Exploring the HDL likelihood surface.

Using random initial parameter estimates, three segregation analysis models of the inheritance of HDL2 in the Berkeley GAW8 data set were maximized 5000 times each. Initial parameter estimates were assumed to be uniformly distributed on intervals formed by parameter boundaries. The three models were unrestricted, environmental, and Mendelian regressive type A models. Likelihood ratio tests of the global maxima rejected the Mendelian model and accepted the environmental model. However, tests using local maxima accepted the Mendelian model and both rejected and accepted the environmental model. Patterns among the initial parameter estimates of convergent runs were examined to develop empirical rules to increase the frequency of convergence. These rules were tested using data on apoAI in the Berkeley GAW8 data set.

Genetic Predisposition to Disease↗
PubMed1994

Linkage between the APOB gene and serum ApoB levels in a large pedigree from the Bogalusa Heart Study.

Maximum likelihood linkage analyses were performed to test for linkage between serum apoB levels and several candidate gene markers including apolipoprotein B, lipoprotein lipase, hepatic lipase, cholesterol ester transfer protein, and apolipoprotein AI in a large pedigree. Parameters of general Mendelian inheritance derived from maximum likelihood segregation analysis of the serum apoB levels were used in the linkage analysis. The highest two-point lod score between the quantitative trait and a marker defined by a single restriction digest was 1.86 at recombination fraction (theta) = 0. This was observed for linkage between serum apoB levels and the presence or absence of a PvuII digestion site in the apoB gene. Linkage between serum apoB levels and polymorphisms of the apoB gene defined by the two restriction digests EcoR1 and PvuII was supported by a lod score of 3.30, while inclusion of VNTR typings led to a lod score of 2.33. None of the other candidate genes gave positive evidence of linkage.

Adolescent↗
PubMed1995

Epidemiologic and genetic follow-up study of 544 Minnesota breast cancer families: design and methods.

In 1944, a case-control family study was initiated at the Dight Institute for Human Genetics at the University of Minnesota to study the influences of childbearing breastfeeding, and hereditary susceptibility on the occurrence and age-of-onset of breast cancer. Index cases (probands) were women ascertained at the Tumor Clinic of the University of Minnesota Hospital. Medical history and life style information were obtained on probands and relatives, and all cancers were histologically verified. A total of 544 families were studied, with probands diagnosed between 1931 and 1952. All of the records and pathology slides have been maintained from the original study; for most probands this includes the original tissue blocks. We are conducting a historical cohort study of selected of selected first- and second-degree female relatives (sisters, daughters, nieces, granddaughters) of the probands and a group of control women identified as the spouses of all male first- and second-degree relatives (brothers, sons, grandsons, and nephews). The subsequent development of breast cancer is being determined to quantify the absolute risk associated with a positive family history. Current disease status is ascertained with mammography, and stromal density is measured using digital imaging. Segregation analysis will be applied to examine how non-genetic factors such as diet, exogenous hormone use, and body fat distribution influence risk in women at high risk because of family history. A subset of families are being selected for molecular analysis of the BRCA1 gene or for linkage analyses to identify putative susceptibility loci other than BRCA1. Documented cancer histories were known for at least three generations, and the current study extends the pedigrees up to four or five generations for every family, allowing a detailed description of familial risk. This cohort study of breast cancer families is likely to be important in both quantity and quality of data and will serve as a major genetic epidemiologic resource, being free of selection bias and having relevant non-genetic exposure determined in at least four generations.

Adult↗
PubMed1995

Major gene with sex-specific effects influences fat mass in Mexican Americans.

Increased adiposity has repeatedly been identified as a major risk factor for a variety of chronic diseases. However, the question still remains whether the amount of adipose tissue itself is genetically mediated. To address this question, a segregation analysis, using maximum likelihood techniques as implemented in the computer program Pedigree Analysis Package (PAP), was performed on fat mass (kilograms of body fat) in a large sample of extended Mexican American families residing in San Antonio, TX. The only model not rejected was a Mendelian mixed model for fat mass, incorporating genotype x sex interaction. In males the major gene accounted for 37% of the total variance compared with 43% in females. In both sexes homozygous recessive individuals have a fat mass more than double that of individuals of the other two genotypes. It was possible to reject linkage of the anonymous major gene for fat mass with several candidate loci for obesity. However, tentative evidence of linkage was detected with markers on both chromosomes 2 and 11, thereby providing hypotheses for future testing.

Adolescent↗
PubMed1995

Identification of susceptibility loci contributing to a complex disease using conventional segregation, linkage, and association methods.

We set out to apply conventional analytic methods to a GAW data set of nuclear families with an oligogenic disease that has a population prevalence of 0.023. We chose methods generally applied to disorders with at least one major gene. Our approaches included: 1) complex segregation analysis under two models of ascertainment, 2) linkage analysis assuming either a single-locus trait with possible genetic heterogeneity or a two-locus trait, and 3) allelic association studies using both a case/control approach and the haplotype relative risk (HRR) test. The association study was the only analysis of the three that provided evidence for genes playing a role in the etiology of this disorder.

Alleles↗
PubMed2001

Two-locus modeling of asthma in a Hutterite pedigree via Markov chain Monte Carlo.

Bayesian Markov chain Monte Carlo (MCMC) segregation analysis for asthma was performed on the whole 1,544-member Hutterite pedigree. Heterogeneous and epistatic two-locus models and complex one-locus models were investigated, with trait loci postulated to be linked to markers in regions previously found to be possibly linked to asthma or atopy. The epistatic two-locus dominant-dominant model provided the best estimates, among the models investigated, in terms of prediction of population prevalence and relative risk for sibs of the affected.

Asthma↗
PubMedDate not supplied

Immunogenetic studies of autoimmune chronic active hepatitis: HLA, immunoglobulin allotypes and autoantibodies.

The strategy of assigning a surrogate phenotype, defined as the presence of antinuclear and/or antismooth muscle antibodies to disease-free first degree relatives of index cases was used to search for a postulated disease susceptibility gene in autoimmune chronic active hepatitis. In addition to determining circulating autoantibody status, 10 patients, 51 first-degree relatives and 6 spouses of index chronic active hepatitis patients, each ascertained by the single patient, were genotyped for HLA (A, B and DR loci) and immunoglobulin allotype (G1m, G2m, G3m and A2m loci) haplotypes. Among the 10 chronic active hepatitis patients, 6 had HLA haplotypes B8 and DR3, and 3 of these patients had, in addition, the immunoglobulin allotype haplotype Gm a,x;g. Circulating autoantibodies defining the surrogate phenotype was found in 39% of the first-degree relatives. However, segregation analysis offered no support for either single autosomal dominant or recessive inheritance for the autoantibody-positive phenotype. Linkage between the postulated disease susceptibility locus and either the HLA (Chromosome 6) or immunoglobulin (Chromosome 14) locus was excluded by several analyses. Furthermore, logistic regression indicated that neither immunogenetic marker was statistically associated with autoantibody positively in these families. Therefore, despite the occurrence of autoantibody positivity in first-degree relatives of autoimmune chronic active hepatitis patients, we found no evidence that this trait has a simple genetic basis, or that it is an alternative manifestation of a postulated disease susceptibility gene for chronic active hepatitis.

Antibodies, Antinuclear↗
PubMed2002

Hereditary non-polyposis colorectal cancer (HNPCC): phenotype-genotype correlation between patients with and without identified mutation.

Affected members of hereditary non-polyposis colorectal cancer (HNPCC) families develop colorectal cancer at an early age (mean 45 yr) and frequently get extracolonic cancers particularly in the uterus, urinary tract, and small intestine. They have a high risk of developing more than one primary colorectal cancer if not treated with subtotal colectomy at first operation and have more frequent right-sided colon cancers and less frequent rectum cancers, compared to patients with sporadic colorectal cancer. We have screened 31 families fulfilling the Amsterdam criteria and 54 families with a colorectal cancer clustering but not fulfilling the Amsterdam criteria for mutations in MLH1 and MSH2 by direct sequencing, and detected a mutation in 61% of the Amsterdam positive families but only in 15% of the Amsterdam negative families. Genotype-phenotype correlation was compared between 141 affected individuals with an identified mutation and 78 affected individuals from Amsterdam positive families in which a mutation was not identifiable in MLH1 or MSH2. In the affected persons with identified mutations, all expected phenotypic traits were represented, whereas affected persons in whom no mutation was detected fell into two clearly distinguishable subgroups. The minor subgroup, in which no mutation was identified, generally had the same characteristics as found in affected persons with identified mutations. The major subgroup differed significantly in clinical features and exhibited phenotypic traits similar to those found in late-onset families, including abundance of rectal cancer, few HNPCC-related cancers, lower frequency of multiple colorectal cancers, and later age at onset. Finally, for six missense mutations and one single codon deletion, the pathogenic potential was evaluated by domain localization, lod score calculation or segregation analysis when possible, and mutation-induced biochemical change. The results indicate that the majority of missense mutations are pathogenic, although further characterization by functional assays is necessary before implementation in predictive testing programs.

Adaptor Proteins, Signal Transducing↗
PubMed2004

The pedigree tool: web-based visualization of a family tree.

We describe the development of a novel tool that facilitates the design and visualization of pedigrees using a special Internet application. The tool is programmed in Java, using a PHP script as an interface. This web-based tool is used to generate, edit, and/or view pedigrees. The advantage of our novel tool is that it is based on a notation that allows the representation of any given number of generations, family members per generation, and multiple clinical or genetic features of an individual family member. In addition, the notation allows us to minimize the storage space by 100% to 500% and to standardize the presentation of family trees and segregation analysis for inheritance of mendelian disorders or even complex traits. This pedigree tool has been implemented with a database of thyroid-stimulating hormone receptor (TSHR) mutations (http://www.uni-leipzig.de/innere/tshr/).

Computer Graphics↗
PubMed2001

Novel frameshift mutations in CRX associated with Leber congenital amaurosis.

Mutations in CRX, a photoreceptor-specific transcription factor, can cause Leber congenital amaurosis (LCA), cone-rod dystrophy (CORD), and retinitis pigmentosa (RP), all of which feature severe visual impairment. Upon screening 55 patients with Leber congenital amaurosis, 75 patients with cone-rod dystrophy, 13 with cone dystrophy, and 36 with recessive or isolate RP for changes in the CRX sequence, we found two patients with Leber congenital amaurosis who carried heterozygously one of two novel frameshift mutations. The first mutation, Tyr191(1-bp del), was a de novo change and the second change, Pro263(1-bp del) was inherited from the proband's affected father. Both mutations are predicted to encode mutant versions of CRX with altered carboxy termini. We also found a previously reported missense mutation, Arg41Gln, heterozygously in a 47-year-old patient with a form of RP. The missense change Val242Met was found in an isolate case of CORD and no controls; however, its pathogenicity remains uncertain because only limited segregation analysis was possible. A nonpathogenic missense change, Ala158Thr, was found to be a variant present at relatively high frequency among African-Americans.

DNA↗
PubMed2006

Identification and in silico analyses of novel TGFBR1 and TGFBR2 mutations in Marfan syndrome-related disorders.

Very recently, heterozygous mutations in the genes encoding transforming growth factor beta receptors I (TGFBR1) and II (TGFBR2) have been reported in Loeys-Dietz aortic aneurysm syndrome (LDS). In addition, dominant TGFBR2 mutations have been identified in Marfan syndrome type 2 (MFS2) and familial thoracic aortic aneurysms and dissections (TAAD). In the past, mutations of these genes were associated with atherosclerosis and several human cancers. Here, we report a total of nine novel and one known heterozygous sequence variants in the TGFBR1 and TGFBR2 genes in nine of 70 unrelated individuals with MFS-like phenotypes who previously tested negative for mutations in the gene encoding the extracellular matrix protein fibrillin-1 (FBN1). To assess the pathogenic impact of these sequence variants, in silico analyses were performed by the PolyPhen, SIFT, and Fold-X algorithms and by means of a 3D homology model of the TGFBR2 kinase domain. Our results showed that in all but one of the patients the pathogenic effect of at least one sequence variant is highly probable (c.722C > T, c.799A > C, and c.1460G > A in TGFBR1 and c.773T > G, c.1106G > T, c.1159G > A, c.1181G > A, and c.1561T > C in TGFBR2). These deleterious alleles occurred de novo or segregated with the disease in the families, indicating a causative association between the sequence variants and clinical phenotypes. Since TGFBR2 mutations found in patients with MFS-related disorders cannot be distinguished from heterozygous TGFBR2 mutations reported in tumor samples, we emphasize the importance of segregation analysis in affected families. In order to be able to find the mutation that is indeed responsible for a MFS-related phenotype, we also propose that genetic testing for sequence alterations in TGFBR1 and TGFBR2 should be complemented by mutation screening of the FBN1 gene.

Activin Receptors, Type I↗
PubMed2005

Molecular characterization and cancer risk associated with BRCA1 and BRCA2 splice site variants identified in multiple-case breast cancer families.

Genetic screening of women from multiple-case breast cancer families and other research-based endeavors have identified an extensive collection of germline variations of BRCA1 and BRCA2 that can be classified as deleterious and have clinical relevance. For some variants, such as those in the conserved intronic splice site regions which are highly likely to alter splicing, it is not possible to classify them based on the identified DNA sequence variation alone. We studied 11 multiple-case breast cancer families carrying seven distinct splice site region genetic alterations in BRCA1 or BRCA2 (BRCA1, c.IVS6-2delA, c.IVS9-2A>C, c.IVS4-1G>T, c.IVS20+1G>A and BRCA2, c.IVS17-1G>C, c.IVS20+1G>A, c.IVS7-1G>A) and applied SpliceSiteFinder to predict possible changes in efficiency of splice donor and acceptor sites, characterized the transcripts, and estimated the average age-specific cumulative risk (penetrance) using a modified segregation analysis. SpliceSiteFinder predicted and we identified transcipts that illustrated that all variants caused exon skipping, and all but two led to frameshifts. The risks of breast cancer to age 70 yrs, averaged over all variants, over BRCA1 variants alone, and over BRCA2 variants alone, were 73% (95% confidence interval 47-93), 64% (95%CI 28-96) and 79% (95%CI 48-98) respectively (all P<0.0001). Therefore five of these seven consensus splice site variants of BRCA1 and BRCA2 produce a transcript similar to that of other previously described deleterious exonic variants and are associated with similar high lifetime risks.

Alternative Splicing↗
PubMed2004

Inherited predisposition to early onset lung cancer according to histological type.

The role of hereditary factors in lung cancer is less well understood than in many other human neoplastic diseases. We used a nation-wide family dataset to search for evidence for a genetic predisposition in lung cancer. The Swedish Family-Cancer Database includes all Swedes born in 1932 and later (0- to 68-year-old offspring) with their parents, totaling over 10.2 million individuals. Cancer cases were retrieved from the Swedish Cancer Registry up to year 2000. Standardized incidence ratios (SIR) and 95% confidence limits (CI) were calculated for age-specific familial risks in offspring by parental or sibling proband, separately. A Kappa test was used to examine the association between familial risk and histology. Compared to the rate of lung cancers among persons without family history, a high risk by parental family history in adenocarcinoma (2.03) and large cell carcinoma (2.14) was found, and only a slightly lower risk was found among patients with squamous cell carcinoma (1.63) and small cell carcinoma (1.55). Among siblings, an increased risk was shown for concordant adenocarcinoma and small cell carcinoma at all ages and for all histological types when cancer was diagnosed before age 50. At young age, risks between siblings were higher than those between offspring and parents. The present data suggest that a large proportion of lung cancers before age 50 years appears to be heritable and probably due to a high-penetrant recessive gene or genes that predispose to tobacco carcinogens; however, this hypothesis needs to be tested in segregation analysis with a large number of pedigrees.

Adenocarcinoma↗
PubMed2004

Differences in age at onset and familial aggregation between clinical types of idiopathic Parkinson's disease.

Idiopathic Parkinson's disease (PD) can be subdivided by its patterns of motor symptoms into tremor-dominant (TDT), akinetic-rigid (ART), and mixed type (MT). Our objective was to determine whether age at onset and family history are different in these three types. In total, 366 patients with PD were assigned in a standardized approach to one of the three subtypes. Age at onset and family history were obtained in all patients and all presumably affected family members were examined. Mean ages at disease onset were similar in all three groups, but distribution of age at onset was markedly different: monophasic in TDT with a peak around 60 years, biphasic in ART with two peaks, one in the middle of the sixth decade (earlier onset, ART-EO), another during the first half of the seventh decade (later onset, ART-LO), and increasing with age only in MT patients A positive family history was significantly associated only with TDT (odds ratio = 5.7) and ART-EO (odds ratio = 7.8), but not with MT or ART-LO patients. Segregation analysis suggested an autosomal recessive mode of transmission in ART-EO and an autosomal dominant mode of transmission in TDT.

Age of Onset↗
PubMed2006

Familial essential tremor with apparent autosomal dominant inheritance: should we also consider other inheritance modes?

A positive family history is present in many patients with essential tremor (ET), but twin studies and segregation analysis have suggested that ET is not entirely a genetic disorder. Two genetic loci have been identified in autosomal dominant (AD) ET and polymorphisms in the DRD3 and HS1-BP3 genes have been proposed as the possible susceptibility factors for ET. There is also evidence for further genetic heterogeneity. We evaluated 4 unrelated large kindreds with ET with an apparent AD mode of transmission. Each kindred spanned at least 3 generations and contained at least 13 living affected subjects who met criteria for definitive ET. None of the pedigrees had evidence for inheritance of ET from both parents. Known genetic ET loci were excluded in these families. We detected a preferential transmission of ET in every kindred and the proportion of affected offspring varied from 75% to 90% (P < 0.05) in the generations with complete ascertainment. Our data indicate that non-Mendelian preferential transmission of an affected allele is a feature in many ET kindreds with multiple affected members and an apparent AD mode of inheritance. ET may have a complex etiology. Additional genetic models need to be considered, including an interaction of susceptibility genes and environmental risk factors.

Adolescent↗
PubMed1991

A clinical and genetic study of familial Parkinson's disease.

The clinical features of familial Parkinson's disease (PD) were investigated by examining the families of 20 British probands who were selected on the basis of having clinically typical PD and at least one affected relative. Forty-nine secondary cases were identified. These subjects were clinically indistinguishable from sporadic cases of idiopathic PD. If it is assumed that familial PD has a genetic basis, pedigree and segregation analysis suggested autosomal dominant inheritance of a gene or genes with reduced penetrance as the most likely explanation. The data did not support the possibilities of either mitochondrial or polygenic inheritance, although the latter cannot be excluded. The role of genetic factors in sporadic cases of PD remains unclear.

Adult↗
PubMed1996

Linkage studies in alcohol-responsive myoclonic dystonia.

A large German family with "myoclonic dystonia with lightning jerks responsive to alcohol" was identified. Eleven affected pedigree members and six obligate gene carriers from five generations were identified. A description of one branch of this pedigree was published in 1964. Our examination 30 years after the initial report confirms the clinical syndrome of a nonprogressive movement disorder characterized by myoclonic jerks affecting the proximal muscles and the muscles of the trunk, accompanied by mild dystonic features in some affected family members. Segregation analysis favors autosomal dominant inheritance with high, but incomplete, penetrance in males and much lower penetrance in females. Linkage analysis was performed using simple sequence repeat polymorphisms (CA repeats) closely associated with or spanning the chromosomal regions containing 15 candidate genes: the gene for early-onset generalized torsion dystonia, DYT1 (chromosome 9q34); the genes for subunits alpha 2, beta 1, and gamma 1 (chromosome 4p12-4q13); for alpha 1, alpha 6, beta 2, and gamma 2 (chromosome 5q31.1-5q31.3); for alpha 4, alpha 5, beta 3, and gamma 3 (chromosome 15q11-15q13); for rho 1 and rho 2 (chromosome 6q14-6q21) of the gamma-aminobutyric acid A receptor; and for the alpha subunit of the glycine receptor (chromosome 5q31). By a combination of pairwise and multipoint linkage analysis, it could be excluded that any of these candidate gene-bearing chromosomal regions contain the disease gene in this family. We also excluded major portions of three chromosomal regions syntenic with mouse chromosome 3, which carries the murine beta subunit of the glycine receptor.

Adolescent↗