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Genome Medicine Dec 2022Genetic penetrance is the probability of a phenotype when harbouring a particular pathogenic variant. Accurate penetrance estimates are important across biomedical...
BACKGROUND
Genetic penetrance is the probability of a phenotype when harbouring a particular pathogenic variant. Accurate penetrance estimates are important across biomedical fields including genetic counselling, disease research, and gene therapy. However, existing approaches for penetrance estimation require, for instance, large family pedigrees or availability of large databases of people affected and not affected by a disease.
METHODS
We present a method for penetrance estimation in autosomal dominant phenotypes. It examines the distribution of a variant among people affected (cases) and unaffected (controls) by a phenotype within population-scale data and can be operated using cases only by considering family disease history. It is validated through simulation studies and candidate variant-disease case studies.
RESULTS
Our method yields penetrance estimates which align with those obtained via existing approaches in the Parkinson's disease LRRK2 gene and pulmonary arterial hypertension BMPR2 gene case studies. In the amyotrophic lateral sclerosis case studies, examining penetrance for variants in the SOD1 and C9orf72 genes, we make novel penetrance estimates which correspond closely to understanding of the disease.
CONCLUSIONS
The present approach broadens the spectrum of traits for which reliable penetrance estimates can be obtained. It has substantial utility for facilitating the characterisation of disease risks associated with rare variants with an autosomal dominant inheritance pattern. The yielded estimates avoid any kinship-specific effects and can circumvent ascertainment biases common when sampling rare variants among control populations.
Topics: Humans; Penetrance; Pedigree; Amyotrophic Lateral Sclerosis; Phenotype; Family Characteristics
PubMed: 36522764
DOI: 10.1186/s13073-022-01142-7 -
Genetics in Medicine : Official Journal... Mar 2023The congenital Long QT Syndrome (LQTS) and Brugada Syndrome (BrS) are Mendelian autosomal dominant diseases that frequently precipitate fatal cardiac arrhythmias....
PURPOSE
The congenital Long QT Syndrome (LQTS) and Brugada Syndrome (BrS) are Mendelian autosomal dominant diseases that frequently precipitate fatal cardiac arrhythmias. Incomplete penetrance is a barrier to clinical management of heterozygotes harboring variants in the major implicated disease genes KCNQ1, KCNH2, and SCN5A. We apply and evaluate a Bayesian penetrance estimation strategy that accounts for this phenomenon.
METHODS
We generated Bayesian penetrance models for KCNQ1-LQT1 and SCN5A-LQT3 using variant-specific features and clinical data from the literature, international arrhythmia genetic centers, and population controls. We analyzed the distribution of posterior penetrance estimates across 4 genotype-phenotype relationships and compared continuous estimates with ClinVar annotations. Posterior estimates were mapped onto protein structure.
RESULTS
Bayesian penetrance estimates of KCNQ1-LQT1 and SCN5A-LQT3 are empirically equivalent to 10 and 5 clinically phenotype heterozygotes, respectively. Posterior penetrance estimates were bimodal for KCNQ1-LQT1 and KCNH2-LQT2, with a higher fraction of missense variants with high penetrance among KCNQ1 variants. There was a wide distribution of variant penetrance estimates among identical ClinVar categories. Structural mapping revealed heterogeneity among "hot spot" regions and featured high penetrance estimates for KCNQ1 variants in contact with calmodulin and the S6 domain.
CONCLUSIONS
Bayesian penetrance estimates provide a continuous framework for variant interpretation.
Topics: Humans; KCNQ1 Potassium Channel; Mutation; Penetrance; Bayes Theorem; Channelopathies; Arrhythmias, Cardiac
PubMed: 36496179
DOI: 10.1016/j.gim.2022.12.002 -
Philosophical Transactions of the Royal... Apr 2024Incomplete penetrance is the rule rather than the exception in Mendelian disease. In syndromic monogenic disorders, phenotypic variability can be viewed as the... (Review)
Review
Incomplete penetrance is the rule rather than the exception in Mendelian disease. In syndromic monogenic disorders, phenotypic variability can be viewed as the combination of incomplete penetrance for each of multiple independent clinical features. Within genetically identical individuals, such as isogenic model organisms, stochastic variation at molecular and cellular levels is the primary cause of incomplete penetrance according to a genetic threshold model. By defining specific probability distributions of causal biological readouts and genetic liability values, stochasticity and incomplete penetrance provide information about threshold values in biological systems. Ascertainment of threshold values has been achieved by simultaneous scoring of relatively simple phenotypes and quantitation of molecular readouts at the level of single cells. However, this is much more challenging for complex morphological phenotypes using experimental and reductionist approaches alone, where cause and effect are separated temporally and across multiple biological modes and scales. Here I consider how causal inference, which integrates observational data with high confidence causal models, might be used to quantify the relative contribution of different sources of stochastic variation to phenotypic diversity. Collectively, these approaches could inform disease mechanisms, improve predictions of clinical outcomes and prioritize gene therapy targets across modes and scales of gene function. This article is part of a discussion meeting issue 'Causes and consequences of stochastic processes in development and disease'.
Topics: Humans; Penetrance; Stochastic Processes; Causality; Phenotype; Biological Variation, Population
PubMed: 38432317
DOI: 10.1098/rstb.2023.0045 -
Haematologica Jul 2007Genetic susceptibility studies of lymphoma may serve to identify at risk populations and clarify important disease mechanisms. This review considered all studies... (Review)
Review
Genetic susceptibility studies of lymphoma may serve to identify at risk populations and clarify important disease mechanisms. This review considered all studies published through October 2006 on the contribution of genetic polymorphisms in the risk of lymphoma. Numerous studies implicate the role of genetic variants that promote B-cell survival and growth with increased risk of lymphoma. Several reports including a large pooled study by InterLymph, an international consortium of non-Hodgkin lymphoma (NHL) case-control studies, found positive associations between variant alleles in TNF -308G>A and IL10 -3575T>A genes and risk of diffuse large B-cell lymphoma. Four studies reported positive associations between a GSTT1 deletion and risk of Hodgkin and non-Hodgkin lymphoma. Genetic studies of folate-metabolizing genes implicate folate in NHL risk, but further studies that include folate and alcohol intakes are needed. Links between NHL and genes involved in energy regulation and hormone production and metabolism may provide insights into novel mechanisms implicating neuro- and endocrine-immune cross-talk with lymphomagenesis. However, this links will need replication in larger populations. Numerous studies suggest that common genetic variants with low penetrance influence lymphoma risk, though replication studies will be needed to eliminate false positive associations.
Topics: Genetic Predisposition to Disease; Humans; Lymphoma; Penetrance; Polymorphism, Genetic
PubMed: 17606447
DOI: 10.3324/haematol.11011 -
Danish Medical Journal Mar 2018von Hippel-Lindau disease (vHL) is a hereditary tumor predisposition caused by mutations in the VHL tumor suppressor gene. VHL mutation-carriers are at life-long risk of... (Review)
Review
von Hippel-Lindau disease (vHL) is a hereditary tumor predisposition caused by mutations in the VHL tumor suppressor gene. VHL mutation-carriers are at life-long risk of multi-organ tumor development. The mainstay of vHL management is close surveillance and surgical tumor removal. The disease has been reported to be fully penetrant at 60 years of age, and has a highly variable phenotype, which complicates vHL management and causes distress and uncertainty for affected families. vHL survival has historically been poorer than the survival of the general population, with a median life expectancy for vHL patients of only 49 years. vHL life expectancy is expected to be improved by better surveillance, tumor diagnosis, and treatment approaches, although this has not yet been directly demonstrated. The prevalence of vHL is between 1 in 39,000 and 1 in 91,000 individuals, and the birth incidence is between 1 in 36,000 and 1 in 45,500 live births in different populations. Based on these estimates, vHL is underdiagnosed in Denmark, and many undiagnosed families are not offered genetic counseling or prophylactic surveillance. We aimed to assess 1) how the rate of new manifestation development is influenced by age, sex, genotype, tumor location, and pregnancy, 2) how vHL survival has developed over time, and is affected by sex, genotype, and surveillance attendance, 3) to determine the prevalence and incidence of vHL, and 4) to calculate vHL penetrance based on an unselected national cohort. We included almost all diagnosed vHL patients in Denmark in a retrospective cohort study. We further used the national health registers to find individuals who had a missed vHL diagnosis despite fulfilling the clinical diagnostic criteria. We found that the risk of new vHL manifestations varies with age, genotype, and tumor location. The risk of new retinal tumors is highest in the patients' teenage years, while cerebellar tumors developed at the highest rates in patients' thirties. Patients with truncating mutations had higher rates of new manifestation diagnosis than patients with missense mutations. Men tend to have higher manifestation rates in adulthood compared to women, and pregnancy was associated with a lower frequency of new manifestations. vHL survival has improved over time, and is getting closer to that of their siblings without vHL and the general population. Survival is significantly influenced by a patient's birth year, sex, and genotype. We estimate the mean life expectancy of VHL mutation-carriers born in 2000 to be 67 years for men and 60 years for women. We estimate the vHL prevalence to be about 1 in 46,900 individuals and the birth incidence to be about 1 in 27,300 live births. We found a penetrance at age 60 of 87%, and only 80% among pa-tients who have not attended surveillance prior to diagnosis, which is considerably lower than previous estimates. Our findings form the basis of a more targeted vHL surveillance and counseling. The lower age-related penetrance greatly influences risk assessment in a clinical genetic setting. Even though the prevalence has increased over recent years, vHL is still underdiagnosed, and there is a need for increased awareness about the disease.
Topics: Age Factors; Denmark; Female; Genetic Counseling; Genetic Predisposition to Disease; Heterozygote; Humans; Incidence; Male; Penetrance; Population Surveillance; Sex Factors; von Hippel-Lindau Disease
PubMed: 29510814
DOI: No ID Found -
The Israel Medical Association Journal... Dec 2014Breast cancer, specifically mammary carcinoma, is the most common cause of death from cancer in women worldwide, with a lifetime risk of one in nine, and its prevalence... (Review)
Review
Breast cancer, specifically mammary carcinoma, is the most common cause of death from cancer in women worldwide, with a lifetime risk of one in nine, and its prevalence is increasing. It represents around 30% of all cancer in females and approximately 40,000 deaths in the United States per year. Important advances have been made in detection and treatment, but a significant number of breast cancers are still detected late. This summary of its epidemiology and history, the molecular aspects of detection and the main implicated genes emphasizes the etiology and heterogeneity of the disease. It is still not clear whether the remaining cases of breast cancer negative to BRCA are due to mutations in another high penetrance gene or to unknown factors yet to be discovered.
Topics: Breast Neoplasms; Female; Genes, BRCA1; Genes, BRCA2; Genes, p53; Genetic Heterogeneity; Germ-Line Mutation; Humans; Male; Penetrance; Prevalence; Risk Assessment
PubMed: 25630211
DOI: No ID Found -
International Journal of Molecular... Oct 2022Leber’s hereditary optic neuropathy (LHON) is a maternally transmitted disease caused by mitochondria DNA (mtDNA) mutation. It is characterized by acute and subacute...
Leber’s hereditary optic neuropathy (LHON) is a maternally transmitted disease caused by mitochondria DNA (mtDNA) mutation. It is characterized by acute and subacute visual loss predominantly affecting young men. The mtDNA mutation is transmitted to all maternal lineages. However, only approximately 50% of men and 10% of women harboring a pathogenic mtDNA mutation develop optic neuropathy, reflecting both the incomplete penetrance and its unexplained male prevalence, where over 80% of patients are male. Nuclear modifier genes have been presumed to affect the penetrance of LHON. With conventional genetic methods, prior studies have failed to solve the underlying pathogenesis. Whole exome sequencing (WES) is a new molecular technique for sequencing the protein-coding region of all genes in a whole genome. We performed WES from five families with 17 members. These samples were divided into the proband group (probands with acute onset of LHON, n = 7) and control group (carriers including mother and relative carriers with mtDNSA 11778 mutation, without clinical manifestation of LHON, n = 10). Through whole exome analysis, we found that many mitochondria related (MT-related) nuclear genes have high percentage of variants in either the proband group or control group. The MT genes with a difference over 0.3 of mutation percentage between the proband and control groups include AK4, NSUN4, RDH13, COQ3, and FAHD1. In addition, the pathway analysis revealed that these genes were associated with cofactor metabolism pathways. Family-based analysis showed that several candidate MT genes including METAP1D (c.41G > T), ACACB (c.1029del), ME3 (c.972G > C), NIPSNAP3B (c.280G > C, c.476C > G), and NSUN4 (c.4A > G) were involved in the penetrance of LHON. A GWAS (genome wide association study) was performed, which found that ADGRG5 (Chr16:575620A:G), POLE4 (Chr2:7495872T:G), ERMAP (Chr1:4283044A:G), PIGR (Chr1:2069357C:T;2069358G:A), CDC42BPB (Chr14:102949A:G), PROK1 (Chr1:1104562A:G), BCAN (Chr 1:1566582C:T), and NES (Chr1:1566698A:G,1566705T:C, 1566707T:C) may be involved. The incomplete penetrance and male prevalence are still the major unexplained issues in LHON. Through whole exome analysis, we found several MT genes with a high percentage of variants were involved in a family-based analysis. Pathway analysis suggested a difference in the mutation burden of MT genes underlining the biosynthesis and metabolism pathways. In addition, the GWAS analysis also revealed several candidate nuclear modifier genes. The new technology of WES contributes to provide a highly efficient candidate gene screening function in molecular genetics.
Topics: DNA, Mitochondrial; Female; Gastrointestinal Hormones; Genes, Modifier; Genome-Wide Association Study; Humans; Hydrolases; Male; Methyltransferases; Mutation; Optic Atrophy, Hereditary, Leber; Pedigree; Penetrance; Vascular Endothelial Growth Factor, Endocrine-Gland-Derived
PubMed: 36233195
DOI: 10.3390/ijms231911891 -
Clinics in Laboratory Medicine Dec 2010Clinical screening is most effective in diseases in which the disease is in its earliest form and may not have symptoms or signs but can be readily diagnosed with an... (Review)
Review
Clinical screening is most effective in diseases in which the disease is in its earliest form and may not have symptoms or signs but can be readily diagnosed with an inexpensive, noninvasive test. This article discusses the general principles of genetic disease architecture that can guide screening and diagnostic approaches for all of the cardiomyopathies and inherited diseases. It addresses how the genetic architecture of the trait guides, and how clinical characteristics of the disease influence, a clinical screening approach.
Topics: Arrhythmogenic Right Ventricular Dysplasia; Cardiomyopathies; Genetic Testing; Humans; Mass Screening; Molecular Diagnostic Techniques; Penetrance
PubMed: 20832651
DOI: 10.1016/j.cll.2010.07.003 -
JAMA May 2022
Topics: Genetic Predisposition to Disease; Humans; Mutation; Penetrance; Phenotype
PubMed: 35579644
DOI: 10.1001/jama.2022.4634 -
JAMA May 2022
Topics: Genetic Predisposition to Disease; Humans; Mutation; Penetrance; Phenotype
PubMed: 35579648
DOI: 10.1001/jama.2022.4631