-
Obesity (Silver Spring, Md.) Jul 2022Obesity has emerged as a prominent risk factor for multiple serious disease states, including a variety of cancers, and is increasingly recognized as a primary...
OBJECTIVE
Obesity has emerged as a prominent risk factor for multiple serious disease states, including a variety of cancers, and is increasingly recognized as a primary contributor to preventable cancer risk. However, few studies of leukemia have been conducted in animal models of obesity. This study sought to characterize the impact of obesity, diet, and sex in a murine model of acute promyelocytic leukemia (APL).
METHODS
Male and female C57BL/6J.mCG mice, genetically predisposed to sporadic APL development, and C57BL/6J (wild type) mice were placed on either a high-fat diet (HFD) or a low-fat diet (LFD) for up to 500 days.
RESULTS
Relative to LFD-fed mice, HFD-fed animals displayed increased disease penetrance and shortened disease latency as indicated by accelerated disease onset. In addition, a diet-responsive sex difference in APL penetrance and incidence was identified, with LFD-fed male animals displaying increased penetrance and shortened latency relative to female counterparts. In contrast, both HFD-fed male and female mice displayed 100% disease penetrance and insignificant differences in disease latency, indicating that the sexual dimorphism was reduced through HFD feeding.
CONCLUSIONS
Obesity and obesogenic diet promote the development of APL in vivo, reducing sexual dimorphisms in disease latency and penetrance.
Topics: Animals; Diet, High-Fat; Female; Leukemia, Promyelocytic, Acute; Male; Mice; Mice, Inbred C57BL; Obesity; Penetrance; Sex Characteristics
PubMed: 35610936
DOI: 10.1002/oby.23435 -
Scientific Reports May 2017A pathogenic hexanucleotide repeat expansion within the C9orf72 gene has been identified as the major cause of two neurodegenerative syndromes, amyotrophic lateral...
A pathogenic hexanucleotide repeat expansion within the C9orf72 gene has been identified as the major cause of two neurodegenerative syndromes, amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). This mutation is known to have incomplete penetrance, with some patients developing disease in their twenties and a small portion of carriers surviving to their ninth decade without developing symptoms. Describing penetrance by age among C9orf72 carriers and identifying parameters that alter onset age are essential to better understanding this locus and to enhance predictive counseling. To do so, data from 1,170 individuals were used to model penetrance. Our analysis showed that the penetrance was incomplete and age-dependent. Additionally, familial and sporadic penetrance did not significantly differ from one another; ALS cases exhibited earlier age of onset than FTD cases; and individuals with spinal-onset exhibited earlier age of onset than those with bulbar-onset. The older age of onset among female cases in general, and among female bulbar-onset cases in particular, was the most striking finding, and there may be an environmental, lifestyle, or hormonal factor that is influencing these penetrance patterns. These results will have important applications for future clinical research, the identification of disease modifiers, and genetic counseling.
Topics: Adolescent; Adult; Age of Onset; Aged; Aging; Amyotrophic Lateral Sclerosis; C9orf72 Protein; Child; Child, Preschool; DNA Repeat Expansion; Female; Frontotemporal Dementia; Humans; Infant; Male; Middle Aged; Penetrance
PubMed: 28522837
DOI: 10.1038/s41598-017-02364-1 -
JAMA Ophthalmology Oct 2018The apparent genetic penetrance of macular telangiectasia type 2 (MacTel) is important for gene discovery studies and for clinical risk assessment of affected...
IMPORTANCE
The apparent genetic penetrance of macular telangiectasia type 2 (MacTel) is important for gene discovery studies and for clinical risk assessment of affected individuals' family members.
OBJECTIVE
To determine the genetic penetrance of MacTel.
DESIGN, SETTING, AND PARTICIPANTS
Descriptive cross-sectional study of patients with MacTel at a tertiary referral eye center. From 2008 to 2016, consecutive patients with MacTel were independently identified, and all of their available siblings and parents were recruited. Seventeen probands with MacTel were included in the study who satisfied the requirement of having at least 1 parent or sibling willing and able to participate. Data from these 17 families were included for the analysis of apparent genetic penetrance.
MAIN OUTCOMES AND MEASURES
Determination of MacTel genetic penetrance in probands' parents and siblings.
RESULTS
Of 80 study participants, 50 (62.5%) were women. The mean (SD) age of study participants with MacTel was 61.2 (14.0) years (range, 23-81 years) and without MacTel was 60.7 (16.4) years (range, 24-92 years). There were 17 MacTel probands, and there was a high rate of enrollment of living siblings and parents: 52 of 71 living siblings (73%) and 11 of 12 parents (92%). Of 52 enrolled siblings, 9 (17%) were affected. Of 11 enrolled parents, 3 (27%) had MacTel. Apparent genetic penetrance was calculated to be 0.35 (95% CI, 0.14-0.6) by sibling analysis and 0.55 (95% CI, 0.02-1.00) by parent analysis. Combining the sibling and parent analyses, the apparent penetrance was calculated to be 0.38 (95% CI, 0.19-0.57).
CONCLUSIONS AND RELEVANCE
The genetic penetrance of MacTel in rigorously phenotyped multiple large families is described. Families such as these could be critical for successful identification of MacTel genes.
Topics: Adult; Aged; Aged, 80 and over; Cross-Sectional Studies; Female; Fluorescein Angiography; Genetic Markers; Genetic Predisposition to Disease; Humans; Male; Middle Aged; Optical Imaging; Parents; Pedigree; Penetrance; Phenotype; Retinal Telangiectasis; Risk Assessment; Siblings; Tomography, Optical Coherence; Visual Acuity; Young Adult
PubMed: 30098143
DOI: 10.1001/jamaophthalmol.2018.3283 -
Neurogastroenterology and Motility Nov 2019The objective of this mini-review is to provide insights on the advances in the understanding of the genetic variants associated with different manifestations of... (Review)
Review
The objective of this mini-review is to provide insights on the advances in the understanding of the genetic variants associated with different manifestations of Hirschsprung disease, which may present with a range of denervation from a short segment of colon to total colonic and small bowel or extensive aganglionosis. A recent article in this journal documented potential gene variants involved in long-segment Hirschsprung disease in 23 patients. Gene variants were identified using a 31-gene panel of genes related to Hirschsprung disease or enteric neural crest cell development, as previously reported in the literature. The study identified potentially harmful variants in eight genes across 13 patients, with a detection rate of 56.5% (13/23 patients). Five patients had pathologic variants in RET, NRG1, and L1CAM, and the remainder were considered variants of unknown significance. The authors attempted prenatal diagnosis of Hirschsprung disease utilizing an amniocentesis sample obtained for advanced maternal age in a family with a known deleterious RET mutation, manifested in the father (long-segment Hirschsprung disease) and older daughter (total colonic aganglionosis). The fetus had the same RET variant but, after several years of follow-up, has not developed any symptoms of Hirschsprung disease, supporting the conclusion that this RET mutation is an autosomal dominant gene with incomplete penetrance. This experience suggests that genetic counseling is appropriate to carefully assess the justification of prenatal testing, especially, when the phenotype of long-segment Hirschsprung disease is so variable and the disease is potentially curable with surgery.
Topics: Female; Genetic Predisposition to Disease; Genetic Variation; Hirschsprung Disease; Humans; Penetrance; Pregnancy; Prenatal Diagnosis
PubMed: 31609069
DOI: 10.1111/nmo.13732 -
JAMA Ophthalmology Jan 2019The p.Gln368Ter (rs74315329) risk allele in the myocilin gene (MYOC) was initially reported to have high penetrance in glaucoma registry-based studies, but much lower... (Comparative Study)
Comparative Study
IMPORTANCE
The p.Gln368Ter (rs74315329) risk allele in the myocilin gene (MYOC) was initially reported to have high penetrance in glaucoma registry-based studies, but much lower estimates were recently obtained from population-based studies. We investigated this disparity using data from Australia and the United Kingdom.
OBJECTIVES
To examine the penetrance and effect size of the MYOC p.Gln368Ter variant with glaucoma and ocular hypertension (OHT).
DESIGN, SETTING, AND PARTICIPANTS
This cross-sectional study within the UK Biobank (UKBB) included participants of white British ancestry. Glaucoma cases were defined by International Classification of Diseases, Ninth Revision (ICD-9) and Tenth Revision (ICD-10) diagnoses and self-reported questionnaires. Carriers of the MYOC p.Gln368Ter variant were identified using genotype imputation from arrays. In contrast, 2 Australian registry-based studies, the Australian and New Zealand Registry of Advanced Glaucoma and the Glaucoma Inheritance Study in Tasmania, ascertained glaucoma cases referred by eye care clinicians, with historic control participants recruited from other Australian studies. Samples were either directly sequenced or had genotypes determined by imputation (for the Australian registry and historic control participants). Recruitment to the UKBB occurred between 2006 and 2010, and data analysis occurred from September 2017 to July 2018.
MAIN OUTCOMES AND MEASURES
The penetrance and odds ratio (OR) were estimated for the MYOC p.Gln368Ter variants in participants with glaucoma and OHT.
RESULTS
A total of 411 337 UKBB participants of white British ancestry (mean [SD] age, 56.6 [8.0] years) were included, plus 3071 Australian registry and 6750 historic control participants. In the UKBB, the minor allele frequency of the MYOC p.Gln368Ter variant was 1 in 786 individuals (0.13%). The odds ratio of p.Gln368Ter in patients with primary open-angle glaucoma (POAG) was 6.76 (95% CI, 4.05-11.29); glaucoma (POAG, self-reported glaucoma, and unspecified glaucoma), 4.40 (95% CI, 3.38-5.71); OHT, 3.56 (95% CI, 2.53-4.92); and OHT and glaucoma combined, 4.18 (95% CI, 3.05-5.67). The penetrance of the MYOC p.Gln368Ter variant was 7.6% in patients with glaucoma, 24.3% in patients with OHT, and 30.8% in patients with OHT and glaucoma combined. In the Australian registry studies, the odds of MYOC p.Gln368Ter variant were 12.16 (95% CI, 6.34-24.97) in patients with advanced glaucoma and 3.97 (95% CI, 1.55-9.75) in those with nonadvanced glaucoma; the penetrance of glaucoma was 56.1%, and penetrance in those considered to have glaucoma or be glaucoma suspects was 69.5%.
CONCLUSIONS AND RELEVANCE
The MYOC p.Gln368Ter variant confers a very high-risk effect size for advanced glaucoma; the risk is lower in nonadvanced glaucoma and OHT. In the general population sample, approximately 50% of MYOC p.Gln368Ter carriers 65 years and older had glaucoma or OHT, with higher prevalence in the Australian registry studies.
Topics: Adult; Aged; Australia; Cross-Sectional Studies; Cytoskeletal Proteins; Eye Proteins; Female; Gene Frequency; Glaucoma, Open-Angle; Glycoproteins; Humans; Intraocular Pressure; Male; Middle Aged; Mutation; New Zealand; Ocular Hypertension; Odds Ratio; Penetrance; Polymorphism, Single Nucleotide; Registries; United Kingdom; White People
PubMed: 30267046
DOI: 10.1001/jamaophthalmol.2018.4477 -
Cancer Epidemiology, Biomarkers &... Apr 2018
Topics: Genetic Predisposition to Disease; Genome-Wide Association Study; Genomics; Humans; Mutation; Neoplasms; Penetrance
PubMed: 29615418
DOI: 10.1158/1055-9965.EPI-16-0914 -
Breast Cancer Research and Treatment Jan 2022Several male breast cancer (MBC) susceptibility genes have been identified, but the MBC risk for individuals with a pathogenic variant in each of these genes (i.e.,... (Review)
Review
PURPOSE
Several male breast cancer (MBC) susceptibility genes have been identified, but the MBC risk for individuals with a pathogenic variant in each of these genes (i.e., penetrance) remains unclear. We conducted a systematic review of studies reporting the penetrance of MBC susceptibility genes to better summarize current estimates of penetrance.
METHODS
A search query was developed to identify MBC-related papers indexed in PubMed/MEDLINE. A validated natural language processing method was applied to identify papers reporting penetrance estimates. These penetrance studies' bibliographies were reviewed to ensure comprehensiveness. We accessed the potential ascertainment bias for each enrolled study.
RESULTS
Fifteen penetrance studies were identified from 12,182 abstracts, covering five purported MBC susceptibility genes: ATM, BRCA1, BRCA2, CHEK2, and PALB2. Cohort (n = 6, 40%) and case-control (n = 5, 33%) studies were the two most common study designs, followed by family-based (n = 3, 20%), and a kin-cohort study (n = 1, 7%). Seven of the 15 studies (47%) adjusted for ascertainment adequately and therefore the MBC risks reported by these seven studies can be considered applicable to the general population. Based on these seven studies, we found pathogenic variants in ATM, BRCA2, CHEK2 c.1100delC, and PALB2 show an increased risk for MBC. The association between BRCA1 and MBC was not statistically significant.
CONCLUSION
This work supports the conclusion that pathogenic variants in ATM, BRCA2, CHEK2 c.1100delC, and PALB2 increase the risk of MBC, whereas pathogenic variants in BRCA1 may not be associated with increased MBC risk.
Topics: Ataxia Telangiectasia Mutated Proteins; Breast Neoplasms, Male; Checkpoint Kinase 2; Cohort Studies; Fanconi Anemia Complementation Group N Protein; Genes, BRCA2; Genetic Predisposition to Disease; Humans; Male; Penetrance
PubMed: 34642874
DOI: 10.1007/s10549-021-06413-2 -
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 -
Journal of Medical Genetics Dec 2015Colorectal carcinoma (CRC) is the third most common cancer worldwide. Hereditary factors are important in 15%-35% of affected patients. This review provides an update on... (Review)
Review
Colorectal carcinoma (CRC) is the third most common cancer worldwide. Hereditary factors are important in 15%-35% of affected patients. This review provides an update on the genetic basis of inherited predisposition to CRC. Currently known genetic factors include a group of highly penetrant mutant genes associated with rare mendelian cancer syndromes and a group of common low-penetrance alleles that have been identified through genetic association studies. Additional mechanisms, which may underlie a predisposition to CRC, will be outlined, for example, variants in intermediate penetrance alleles. Recent findings, including mutations in POLE, POLD1 and NTHL1, will be highlighted, and we identify gaps in present knowledge and consider how these may be addressed through current and emerging genomic approaches. It is expected that identification of the missing heritable component of CRC will be resolved through evermore comprehensive cataloguing and phenotypic annotation of CRC-associated variants identified through sequencing approaches. This will have important clinical implications, particularly in areas such as risk stratification, public health and CRC prevention.
Topics: Alleles; Colon; Colorectal Neoplasms; Genetic Association Studies; Genetic Predisposition to Disease; Humans; Mutation; Penetrance; Risk Factors
PubMed: 26297796
DOI: 10.1136/jmedgenet-2015-103298 -
Clinical Endocrinology Jan 2019With the discovery that familial phaeochromocytoma and paraganglioma syndrome can be caused by mutations in each subunit of the succinate dehydrogenase enzyme (SDH), has... (Review)
Review
OBJECTIVE
With the discovery that familial phaeochromocytoma and paraganglioma syndrome can be caused by mutations in each subunit of the succinate dehydrogenase enzyme (SDH), has come the recognition that mutations in the individual subunits have their own distinct natural histories. Increased genetic screening is leading to the identification of increasing numbers of, mostly asymptomatic, gene mutation carriers and the implementation of screening strategies for these individuals. Yet there is, to date, no international consensus regarding screening strategies for asymptomatic carriers.
DESIGN
A comprehensive PubMed search from 1/1/2000 to 28/2/2018 was undertaken using multiple search terms and subsequently a manual review of references in identified papers to identify all clinically relevant cases and cohorts. In this review, the accumulated, published experience of phenotype and malignancy risks of individual SDH subunits is analysed. Where possible screening results for asymptomatic SDH mutation carriers have been analysed separately to define the penetrance in asymptomatic carriers (asymptomatic penetrance).
RESULTS
The combined data confirms that "asymptomatic penetrance" is highest for SDHD and when there is penetrance, the most likely site to develop a PGL is head and neck (SDHD) and extra-adrenal abdominal (SDHB). However, the risk in SDHB carriers of developing HNPGL is also high (35.5%) and a PCC is low (15.1%), and in SDHD carriers there is a high risk of developing a PCC (35.8%) or abdominal PGL (9.4%) and a small, but significant risk at other sympathetic sites. The data suggest that the risk of malignant transformation is the same for both PCC and extra-adrenal abdominal PGLs (30%-35%) in SDHB carriers. In SDHD carriers, the risk of malignant transformation was highest in HNPGLs (7.5%) and similar for sympathetic sites (3.8%-5.2%).
CONCLUSIONS
Using this data, we suggest surveillance screening of asymptomatic carriers can be tailored to the underlying SDH subunit and review possible surveillance programmes.
Topics: Genetic Predisposition to Disease; Genetic Testing; Head and Neck Neoplasms; Heterozygote; Humans; Mutation; Penetrance; Phenotype; Protein Subunits; Succinate Dehydrogenase
PubMed: 30303539
DOI: 10.1111/cen.13877