Penetrance rate estimation in autosomal dominant conditions

Accurate estimates of the penetrance rate of autosomal dominant conditions are important, among other issues, for optimizing recurrence risks in genetic counseling. The present work on penetrance rate estimation from pedigree data considers the following situations: 1) estimation of the penetrance rate K (brief review of the method); 2) construction of exact credible intervals for K estimates; 3) specificity and heterogeneity issues; 4) penetrance rate estimates obtained through molecular testing of families; 5) lack of information about the phenotype of the pedigree generator; 6) genealogies containing grouped parent-offspring information; 7) ascertainment issues responsible for the inflation of K estimates.     

Assessment of the risk of recurrence isolated cases of dominantly inherited diseases with incomplete penetrance and age-related dependence

A modification of the method for risk estimation in isolated cases of autosomal dominant disorders with reduced penetrance is presented. It is based on the Bayesian theorem and considers such parameters as fitness, age-specific expressivity of the gene and the effect of parental age on mutation rate. The definite expression of the risk estimation is proposed. Using hereditary polyposis as an example, possible risks are proposed. The table of risks, depending on the parental age, is given.     

A method for estimating penetrance of pathogenic mutations in a mitochondrial genome

Variation in the manifestation age is typical of many mitochondrial diseases. The estimation of penetrance of pathogenic mutations causing such diseases is usually conducted on samples of individuals whose age exceeds the maximum age of the disease manifestation. In the case of rare diseases, samples of sufficient size sometimes cannot be formed. In this study, we propose a method for estimating penetrance involving individuals of any age. The efficiency of the method is demonstrated using Leber hereditary optic neuropathy as an example. It is shown that the method provides an unbiased estimate of penetrance and considerably reduces the error of this estimate in comparison with a sample including individuals whose age exceeds the maximum age of disease manifestation.     

PENCALC: A program for penetrance estimation in autosomal dominant diseases

We present a computer program developed for estimating penetrance rates in autosomal dominant diseases by means of family kinship and phenotype information contained within the pedigrees. The program also determines the exact 95% credibility interval for the penetrance estimate. Both executable (PenCalc for Windows) and web versions (PenCalcWeb) of the software are available. The web version enables further calculations, such as heterozygosity probabilities and assessment of offspring risks for all individuals in the pedigrees. Both programs can be accessed and down-loaded freely at the home-page address http://www.ib.usp.br/~otto/software.htm.     

A Method for Estimating Penetrance of Pathogenic Mutations in a Mitochondrial Genome

Variation in the age of onset is typical of many mitochondrial diseases. The estimation of penetrance of deleterious mtDNA mutations causing such diseases is usually conducted on samples of individuals whose age exceeds the maximum age of the disease manifestation. In the case of rare diseases, samples of sufficient size sometimes cannot be formed. In this study, we propose a method for estimating penetrance involving individuals of any age. The efficiency of the method is demonstrated using Leber hereditary optic neuropathy as an example. It is shown that the method provides an unbiased estimate of penetrance and considerably reduces the error of this estimate in comparison with a sample including individuals whose age exceeds the maximum age of disease manifestation.     

Detection and localization of a single binary trait locus in experimental populations

The advancements made in molecular technology coupled with statistical methodology have led to the successful detection and location of genomic regions (quantitative trait loci; QTL) associated with quantitative traits. Binary traits (e.g. susceptibility/resistance), while not quantitative in nature, are equally important for the purpose of detecting and locating significant associations with genomic regions. Existing interval regression methods used in binary trait analysis are adapted from quantitative trait analysis and the tests for regression coefficients are tests of effect, not detection. Additionally, estimates of recombination that fail to take into account varying penetrance perform poorly when penetrance is incomplete. In this work a complete probability model for binary trait data is developed allowing for unbiased estimation of both penetrance and recombination between a genetic marker locus and a binary trait locus for backcross and F2 experimental designs. The regression model is reparameterized allowing for tests of detection. Extensive simulations were conducted to assess the performance of estimation and testing in the proposed parameterization. The proposed parameterization was compared with interval regression via simulation. The results indicate that our parameterization shows equivalent estimation capabilities, requires less computational effort and works well with only a single marker.     

The relative efficiency of penetrance estimators for sib pairs

Here we present analytical studies to evaluate the relative efficiency of commonly used penetrance estimators using linkage designs. We investigated three different methods of estimating penetrance using sib pairs: Maximum likehood estimation (MLE) with trait information alone, MLE with both trait and marker information and the MOD score approach. Modeling sib pairs with unknown phase, we evaluated the asymptotic relative efficiency between estimators under either random sampling or single ascertainment for an autosomal dominant or recessive disease. We then provide plots of the asymptotic relative efficiency, enabling researchers to easily determine regions where the MOD score or segregation alone performs with comparable efficiency relative to joint segregation and linkage.     

Effects of misspecifying genetic parameters in lod score analysis

The lod score method is widely used to test linkage and to estimate the recombination fraction between a disease locus and a marker locus. The parameters (gene frequency, penetrance, and degree of dominance) are assumed to be known at each locus. This condition may not be fulfilled at the disease locus. In this paper, we evaluate the errors due to the use of wrong parameters. The power of the linkage test is sensitive to the degree of dominance, and slightly to the penetrance, but not to the gene frequency. In contrast, the estimation of the recombination fraction may be strongly affected by an error on any genetic parameter.     

Empirical, free of genetic model, estimation of recurrence risks in multifactorial diseases: conditional probability approach]

Conditional probability approach in estimation of recurrence risks in sibships of different parental phenotypic matings with the different set of affected and normal siblings is considered. The formulae are presented for calculation of recurrence risks in cases of equal and different susceptibility of two sexes under different ways of sampling of family data: direct selection of offsprings through the parents; indirect selection of offsprings through affected siblings--the probands, under different ascertainment probability--from pi = 1.0 ("exhaustive selection") up to pi----0 ("single selection"); for the case of different susceptibility of the two sexes a possibility of the differences in the ascertainment probabilities of men (pi m) and of women (pi w) is allowed, unlike "independent ascertainment model", which requires the constancy of pi. The case of multiple incompatible subforms is considered for estimation of the recurrence risks of the specified subforms. The methods of the risks estimation proposed are free of genetic models being universal both for classical mendelian traits (with the constant risks) and for multifactorial ones (with variable risks).     

Linkage between quantitative and marker loci. V. Joint analysis of various marker and quantitative traits

New versions are suggested to analyse marker and quantitative characters combinations. Possible modes of application of the algorithms developed for recombination analysis are discussed, including: 1) the estimation of crossing-over frequency between markers with incomplete penetrance, 2) the quantitative character variability account to analyse genetic interference, 3) search for genetic factors affecting a set of quantitative characters, 4) the evaluation of differences between male and female meiosis at the crossingover level etc.     

Evaluation of the risk in autosomal dominant diseases

A lot of traps and difficulties complicate the estimation of a genetic risk in the autosomal dominant diseases. The authors recapitulate the notions of mutation, penetrance and variability and illustrate by some examples the part of each of them, isolated or associated together. The increasing of molecular biology allows to resolve some of these problems, but generate new dangers which are analysed and illustrated.     

Mental retardation linked to fragility of chromosome X: current knowledge

The association of the fragile X chromosome with X-linked mental retardation is now well established. The main clinical features are mental retardation, typical facial dysmorphism and macroorchidism. Cytogenetically there is a fragile site in band Xq27-28 which can be demonstrated using specific techniques. The genetic studies are compatible with a X-linked dominant inheritance with an incomplete penetrance. A preliminary estimation of an overall frequency of 1: 2000 males for the fra(X)(q) condition is suggested.     

The 'common disease-common variant' hypothesis and familial risks

The recent large genotyping studies have identified a new repertoire of disease susceptibility loci of unknown function, characterized by high allele frequencies and low relative risks, lending support to the common disease-common variant (CDCV) hypothesis. The variants explain a much larger proportion of the disease etiology, measured by the population attributable fraction, than of the familial risk. We show here that if the identified polymorphisms were markers of rarer functional alleles they would explain a much larger proportion of the familial risk. For example, in a plausible scenario where the marker is 10 times more common than the causative allele, the excess familial risk of the causative allele is over 10 times higher than that of the marker allele. However, the population attributable fractions of the two alleles are equal. The penetrance mode of the causative locus may be very difficult to deduce from the apparent penetrance mode of the marker locus.     

The clinical and screening age-at-onset distribution for the MEN-2 syndrome.

The decision to screen for multiple endocrine neoplasia type 2 (MEN-2) is generally based on family history, the rationale for this approach being the presumed 100% penetrance of the disease. To determine the validity of this presumption we have estimated--by applying modifications of the life-table method--the clinical and screening age-at-diagnosis distributions for MEN-2, using families from the Cancer Research Campaign Medullary Thyroid Cancer Register and one large American family. The clinical penetrance of MEN-2 is shown to be incomplete, an estimated 41% of gene carriers not presenting with symptoms by age 70 on the basis of clinical history. Screening by the standard tests for detecting the earliest manifestations of the syndrome increases the penetrance to an estimated 93% by age 31. There is no evidence of a difference in the age-at-diagnosis distributions between maternal and paternal transmission, or among different families, but there is some suggestion of an earlier onset of medullary thyroid cancer in female gene carriers, and of a tendency of pheochromocytoma to cluster in families. These results can be used to calculate risks to relatives of affected individuals, which in turn can be used to guide decisions on which individuals to screen.     

Penalized estimation of frailty-based illness–death models for semi-competing risks

Semi-competing risks refer to the time-to-event analysis setting, where the occurrence of a non-terminal event is subject to whether a terminal event has occurred, but not vice versa. Semi-competing risks arise in a broad range of clinical contexts, including studies of preeclampsia, a condition that may arise during pregnancy and for which delivery is a terminal event. Models that acknowledge semi-competing risks enable investigation of relationships between covariates and the joint timing of the outcomes, but methods for model selection and prediction of semi-competing risks in high dimensions are lacking. Moreover, in such settings researchers commonly analyze only a single or composite outcome, losing valuable information and limiting clinical utility—in the obstetric setting, this means ignoring valuable insight into timing of delivery after preeclampsia has onset. To address this gap, we propose a novel penalized estimation framework for frailty-based illness–death multi-state modeling of semi-competing risks. Our approach combines non-convex and structured fusion penalization, inducing global sparsity as well as parsimony across submodels. We perform estimation and model selection via a pathwise routine for non-convex optimization, and prove statistical error rate results in this setting. We present a simulation study investigating estimation error and model selection performance, and a comprehensive application of the method to joint risk modeling of preeclampsia and timing of delivery using pregnancy data from an electronic health record.     

A Theoretical Model for Estimating Linkage in F2 Populations with Distorted Single Gene Segregation

A model is presented which allows estimation of linkage from dihybrid F₂ populations with distorted single gene segregation by applying the maximum-likelihood method. For different selection processes operating on one locus at either the gametic or the zygotic level, it can be demonstrated that, if the deficit is previously taken into account, testing for free recombination can be carried out without prior knowledge of the causes of this deficit. In the presence of linkage, the expected frequencies of two phenotypic classes depend on whether gametic or zygotic selection is operating. The remaining two classes can be utilized for the estimation of linkage as their frequency ratio is independent of these selection types. The application of this procedure to situations with coupling, incomplete penetrance, gametic and zygotic selection is discussed.     

On the mutation rate of neurofibromatosis.

A genetic study of 124 cases of neurofibromatosis was performed. The contingent of probands was mainly represented by a Russian population, most of the individuals being born in the European part of the RSFSR. Both parents of the probands were examined in only 58 cases, the proportion of sporadic cases in this group being 0.79, as compared to 0.77 for the whole group under study. The existing data evaluated by a direct method are not yet sufficient for a decisive estimation of the penetrance, which, however, cannot be under 80%. Segregation analysis of descendants from particular marriages showed a good correspondance to the hypothesis of Mendelian dominance (32 affected children out of 65). These results analyzed together with those obtained by other authors permit an inference on the full penetrance of neurofibromatosis. The genetic interpretation of sporadic cases as a result of new mutations is presented. The prevalence of neurofibromatosis among the 16-year-old youths was evaluated as 12.8 with 10-(5). This value is suggested to be an estimation of the incidence of the condition in the general population, the mutation rate evaluated by a direct method being equal to 4.4 with 10-(5) divided by 4.9 with 10-minus 5. The increased birth order of probands in sporadic cases (against the theoretical expectation) as well as increased paternal age (as compared with controls) were found to be statistically significant (P equals 0.004 and P equals 0.03, respectively) while the difference in maternal ages was statistically insignificant (P equals 0.008). No statistical relationship between sporadic cases and occupational exposure of parents to deleterious chemical and physical factors was found.     

Analysis of Survival Data with Two Dependent Competing Risks

Here we consider a competing risks model where the two risks of interest are not independent. The dependence is due to the additive effect of an independent contaminating risk on two initially independent risks. The problem is identifiable when the three risks fllow independent exponential distributions and also when the two initial risks follow proportional hazards model. Procedures are suggested for estimation and testing hypotheses regarding the parameters of the three exponentials in the first can and the constant of proportionality in the second case, when the information available consists of the times to death and the causes of death of the individuals.     

Clinical penetrance of C282Y homozygous HFE haemochromatosis

The prevalence of the C282Y homozygous HFE genotype is high, approximately 1 in 200 in populations of Anglo-Celtic descent, and most authorities assumed this mutation would have a high clinical penetrance. Recent studies report the clinical penetrance of C282Y homozygous hereditary haemochromatosis is much lower than its prevalence, with possibly less than 5% developing clinical disease, although there is lack of consensus on a precise estimate. This review discusses reasons for this paradigm shift, including controversy on various definitions of clinical penetrance.It is inescapable that there are pronounced variations in clinical penetrance, and that certain C282Y homozygous individuals will not develop the clinical phenotype. This has prompted a search for modifier gene mutations amongst iron-metabolism genes, especially the known non- HFE haemochromatosis genes, and for possible environmental factors which might explain the observed variation in clinical penetrance.     

History dependent effects on phenotypic expression of a newly emerged gene

In this study, we investigate the history dependence of the penetrance of a newly emerged gene. Penetrance is defined as the percentage of individuals with a given genotype who exhibit the phenotype associated with that particular genotype. Here, we used the glutamine synthetase gene and its mutants with lower fitness as model genes. They were introduced into host cells of Escherichia coli deprived of the gene, and their penetrance was measured using the host having a different history: either with or without glutamine starvation. Results show that for all genes tested, the value of penetrance was higher when they were introduced into the host cell without starvation than that when introduced into the starved cell, demonstrating the history dependence of the penetrance of a newly emerged gene. In addition, genes with lower fitness showed lower penetrance, and the effect of the difference in fitness on gene penetrance also depended on the history of the host cell.