-
Translational Research : the Journal of... Jan 2013Mutations in genes encoding ion channel pore-forming α-subunits and accessory β-subunits as well as intracellular calcium-handling proteins that collectively maintain... (Review)
Review
Mutations in genes encoding ion channel pore-forming α-subunits and accessory β-subunits as well as intracellular calcium-handling proteins that collectively maintain the electromechanical function of the human heart serve as the underlying pathogenic substrate for a spectrum of sudden cardiac death (SCD)-predisposing heritable cardiac arrhythmia syndromes, including long QT syndrome (LQTS), short QT syndrome (SQTS), Brugada syndrome (BrS), and catecholaminergic polymorphic ventricular tachycardia (CPVT). Similar to many Mendelian disorders, the cardiac "channelopathies" exhibit incomplete penetrance, variable expressivity, and phenotypic overlap, whereby genotype-positive individuals within the same genetic lineage assume vastly different clinical courses as objectively assessed by phenotypic features such electrocardiographic abnormalities and number/type of cardiac events. In this Review, we summarize the current understanding of the global architecture of complex electrocardiographic traits such as the QT interval, focusing on the role of common genetic variants in the modulation of ECG parameters in health and the environmental and genetic determinants of incomplete penetrance and variable expressivity in the heritable cardiac arrhythmia syndromes most likely to be encountered in clinical practice.
Topics: Arrhythmias, Cardiac; Genetic Variation; Humans; Penetrance; Polymorphism, Genetic; Syndrome
PubMed: 22995932
DOI: 10.1016/j.trsl.2012.08.005 -
Annals of Neurology Aug 2022The aim of the current study is to understand why some individuals avoid developing Parkinson disease (PD) despite being at relatively high genetic risk, using the... (Meta-Analysis)
Meta-Analysis
OBJECTIVE
The aim of the current study is to understand why some individuals avoid developing Parkinson disease (PD) despite being at relatively high genetic risk, using the largest datasets of individual-level genetic data available.
METHODS
We calculated polygenic risk score to identify controls and matched PD cases with the highest burden of genetic risk for PD in the discovery cohort (International Parkinson's Disease Genomics Consortium, 7,204 PD cases and 9,412 controls) and validation cohorts (Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinson's Disease, 8,968 cases and 7,598 controls; UK Biobank, 2,639 PD cases and 14,301 controls; Accelerating Medicines Partnership-Parkinson's Disease Initiative, 2,248 cases and 2,817 controls). A genome-wide association study meta-analysis was performed on these individuals to understand genetic variation associated with resistance to disease. We further constructed a polygenic resilience score, and performed multimarker analysis of genomic annotation (MAGMA) gene-based analyses and functional enrichment analyses.
RESULTS
A higher polygenic resilience score was associated with a lower risk for PD (β = -0.054, standard error [SE] = 0.022, p = 0.013). Although no single locus reached genome-wide significance, MAGMA gene-based analyses nominated TBCA as a putative gene. Furthermore, we estimated the narrow-sense heritability associated with resilience to PD (h = 0.081, SE = 0.035, p = 0.0003). Subsequent functional enrichment analysis highlighted histone methylation as a potential pathway harboring resilience alleles that could mitigate the effects of PD risk loci.
INTERPRETATION
The present study represents a novel and comprehensive assessment of heritable genetic variation contributing to PD resistance. We show that a genetic resilience score can modify the penetrance of PD genetic risk factors and therefore protect individuals carrying a high-risk genetic burden from developing PD. ANN NEUROL 2022;92:270-278.
Topics: Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Parkinson Disease; Penetrance; Polymorphism, Single Nucleotide; Risk Factors
PubMed: 35599344
DOI: 10.1002/ana.26416 -
European Heart Journal Apr 2020We aimed to assess structural progression in arrhythmogenic cardiomyopathy (AC) patients and mutation-positive family members and its impact on arrhythmic outcome in a...
AIMS
We aimed to assess structural progression in arrhythmogenic cardiomyopathy (AC) patients and mutation-positive family members and its impact on arrhythmic outcome in a longitudinal cohort study.
METHODS AND RESULTS
Structural progression was defined as the development of new Task Force imaging criteria from inclusion to follow-up and progression rates as annual changes in imaging parameters. We included 144 AC patients and family members (48% female, 47% probands, 40 ± 16 years old). At genetic diagnosis and inclusion, 58% of family members had penetrant AC disease. During 7.0 [inter-quartile range (IQR) 4.5-9.4] years of follow-up, 47% of family members without AC at inclusion developed AC criteria, resulting in a yearly new AC penetrance of 8%. Probands and family members had a similar progression rate of right ventricular outflow tract diameter (0.5 mm/year vs. 0.6 mm/year, P = 0.28) by mixed model analysis of 598 echocardiographic examinations. Right ventricular fractional area change progression rate was even higher in family members (-0.6%/year vs. -0.8%/year, P < 0.01). Among 86 patients without overt structural disease or arrhythmic history at inclusion, a first severe ventricular arrhythmic event occurred in 8 (9%), of which 7 (88%) had concomitant structural progression. Structural progression was associated with higher incidence of severe ventricular arrhythmic events adjusted for age, sex, and proband status (HR 21.24, 95% CI 2.47-182.81, P < 0.01).
CONCLUSION
More than half of family members had AC criteria at genetic diagnosis and yearly AC penetrance was 8%. Structural progression was similar in probands and family members and was associated with higher incidence of severe ventricular arrhythmic events.
Topics: Adult; Arrhythmogenic Right Ventricular Dysplasia; Disease Progression; Family; Female; Humans; Longitudinal Studies; Male; Middle Aged; Penetrance; Young Adult
PubMed: 31504415
DOI: 10.1093/eurheartj/ehz570 -
Current Neurology and Neuroscience... Nov 2013The dystonias comprise a group of syndromes characterized by prolonged involuntary muscle contractions resulting in repetitive movements and abnormal postures. Primary... (Review)
Review
The dystonias comprise a group of syndromes characterized by prolonged involuntary muscle contractions resulting in repetitive movements and abnormal postures. Primary dystonia has been associated with over 14 different genotypes, most of which follow an autosomal dominant inheritance pattern with reduced penetrance. Independent of etiology, the disease is characterized by extensive variability in disease phenotype and clinical severity. Recent neuroimaging studies investigating this phenomenon in manifesting and non-manifesting genetic carriers of dystonia have discovered microstructural integrity differences in the cerebello-thalamo-cortical tract in both groups related to disease penetrance. Further study suggests these differences to be specific to subrolandic white matter regions somatotopically related to clinical phenotype. Clinical severity was correlated to the degree of microstructural change. These findings suggest a mechanism for the penetrance and clinical variability observed in dystonia and may represent a novel therapeutic target for patients with refractory limb symptoms.
Topics: Animals; Comprehension; Dystonia; Humans; Penetrance; Phenotype
PubMed: 24114145
DOI: 10.1007/s11910-013-0401-0 -
Genetics in Medicine : Official Journal... Jan 2016Germ-line mutations in MLH1, MSH2, MSH6, and PMS2 have been shown to cause Lynch syndrome. The penetrance of the cancer and tumor spectrum has been repeatedly studied,... (Review)
Review
Germ-line mutations in MLH1, MSH2, MSH6, and PMS2 have been shown to cause Lynch syndrome. The penetrance of the cancer and tumor spectrum has been repeatedly studied, and multiple professional societies have proposed clinical management guidelines for affected individuals. Several studies have demonstrated a reduced penetrance for monoallelic carriers of PMS2 mutations compared with the other mismatch repair (MMR) genes, but clinical management guidelines have largely proposed the same screening recommendations for all MMR gene carriers. The authors considered whether enough evidence existed to propose new screening guidelines specific to PMS2 mutation carriers with regard to age at onset and frequency of colonic screening. Published reports of PMS2 germ-line mutations were combined with unpublished cases from the authors' research registries and clinical practices, and a discussion of potential modification of cancer screening guidelines was pursued. A total of 234 monoallelic PMS2 mutation carriers from 170 families were included. Approximately 8% of those with colorectal cancer (CRC) were diagnosed before age 30, and each of these tumors presented on the left side of the colon. As it is currently unknown what causes the early onset of CRC in some families with monoallelic PMS2 germline mutations, the authors recommend against reducing cancer surveillance guidelines in families found having monoallelic PMS2 mutations in spite of the reduced penetrance.Genet Med 18 1, 13-19.
Topics: Adenosine Triphosphatases; Colorectal Neoplasms, Hereditary Nonpolyposis; DNA Repair Enzymes; DNA-Binding Proteins; Early Detection of Cancer; Germ-Line Mutation; Heterozygote; Humans; Mismatch Repair Endonuclease PMS2; Penetrance
PubMed: 25856668
DOI: 10.1038/gim.2015.27 -
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 -
Annals of Clinical and Translational... May 2023To compute penetrance and recurrence risk using a genome-wide PRS (including and excluding the APOE region) in families with Alzheimer's disease.
OBJECTIVE
To compute penetrance and recurrence risk using a genome-wide PRS (including and excluding the APOE region) in families with Alzheimer's disease.
METHODS
Genotypes from the National Institute on Aging Late-Onset Alzheimer's Disease Family-Based Study and a study of familial Alzheimer's disease in Caribbean Hispanics were used to compute PRS with and without variants in the 2 MB region flanking APOE. PRS was calculated in using clumping/thresholding and Bayesian methods and was assessed for association with Alzheimer's disease and age at onset. Penetrance and recurrence risk for carriers in highest and lowest PRS quintiles were compared separately within APOE-ε4 carriers and non-carriers.
RESULTS
PRS excluding the APOE region was strongly associated with clinical and neuropathological diagnosis of AD. PRS association with AD was similar in participants who did not carry an APOE-ε4 allele (OR = 1.74 [1.53-1.91]) compared with APOE-ε4 carriers (1.53 [1.4-1.68]). Compared to the lowest quintile, the highest PRS quintile had a 10% higher penetrance at age 70 (p = 0.0006) and a 20% higher penetrance at age 80 (p < 10e-05). Stratifying by APOE-ε4 allele, PRS in the highest quintile was significantly more penetrant than the lowest quintile, both, within APOE-ε4 carriers (14.5% higher at age 80, p = 0.002) and non-carriers (26% higher at 80, p < 10e-05). Recurrence risk for siblings conferred by a co-sibling in the highest PRS quintile increased from 4% between the ages of 65-74 years to 39% at age 85 and older.
INTERPRETATION
PRS can be used to estimate penetrance and recurrence risk in familial Alzheimer's disease among carriers and non-carries of APOE-ε4.
Topics: Humans; Aged; Aged, 80 and over; Alzheimer Disease; Penetrance; Bayes Theorem; Risk Factors; Apolipoproteins E
PubMed: 36946865
DOI: 10.1002/acn3.51757 -
Genes Sep 2021Retinitis pigmentosa 11 (RP11) is caused by dominant mutations in , however a significant proportion of mutation carriers do not develop retinopathy. Here, we...
Retinitis pigmentosa 11 (RP11) is caused by dominant mutations in , however a significant proportion of mutation carriers do not develop retinopathy. Here, we investigated the relationship between polymorphism, repeat copy number and disease penetrance in RP11 patients and non-penetrant carriers (NPCs). We further characterized and expression in fibroblasts from eight RP11 patients and one NPC from a family carrying the c.1205C>T variant. Retinal organoids (ROs) and retinal pigment epithelium (RPE) were differentiated from induced pluripotent stem cells derived from RP11 patients, an NPC and a control subject. All RP11 patients were homozygous for the 3-copy repeat in the promoter, while 3/5 NPCs carried a 4-copy repeat. The rs4806718 genotype did not correlate with disease penetrance. expression declined with age in adult cadaveric retina. and expression was reduced in RP11 fibroblasts, RO and RPE compared with controls. Both RP11 and NPC RPE displayed shortened primary cilia compared with controls, however a subpopulation of cells with normal cilia lengths was present in NPC RPE monolayers. Our results indicate that RP11 non-penetrance is associated with the inheritance of a 4-copy repeat, but not with polymorphisms.
Topics: Adolescent; Adult; Aged; Cells, Cultured; Child; Eye Proteins; Female; Genes, Modifier; Humans; Male; Middle Aged; Penetrance; Polymorphism, Genetic; Retina; Retinitis Pigmentosa; Scavenger Receptors, Class A; Transcription Factors
PubMed: 34680937
DOI: 10.3390/genes12101542 -
American Journal of Human Genetics Jan 2023The risk of Leber hereditary optic neuropathy (LHON) has largely been extrapolated from disease cohorts, which underestimate the population prevalence of pathogenic...
The risk of Leber hereditary optic neuropathy (LHON) has largely been extrapolated from disease cohorts, which underestimate the population prevalence of pathogenic primary LHON variants as a result of incomplete disease penetrance. Understanding the true population prevalence of primary LHON variants, alongside the rate of clinical disease, provides a better understanding of disease risk and variant penetrance. We identified pathogenic primary LHON variants in whole-genome sequencing data of a well-characterized population-based control cohort and found that the prevalence is far greater than previously estimated, as it occurs in approximately 1 in 800 individuals. Accordingly, we were able to more accurately estimate population risk and disease penetrance in LHON variant carriers, validating our findings by using other large control datasets. These findings will inform accurate counseling in relation to the risk of vision loss in LHON variant carriers and disease manifestation in their family. This Matters Arising paper is in response to Lopez Sanchez et al. (2021), published in The American Journal of Human Genetics. See also the response by Mackey et al. (2022), published in this issue.
Topics: Humans; Optic Atrophy, Hereditary, Leber; Penetrance; Mutation; DNA, Mitochondrial; Risk Factors
PubMed: 36565700
DOI: 10.1016/j.ajhg.2022.11.013 -
Journal of Surgical Oncology Jun 2022Germline CDH1 defects are related with the development of multiple cancers due its pleiotropic nature. These several conditions are associated with various risks of... (Review)
Review
Germline CDH1 defects are related with the development of multiple cancers due its pleiotropic nature. These several conditions are associated with various risks of penetrance and with different clinical management strategies. In this clinical review, we described the penetrance risks of gastric, breast, prostate, and colorectal cancers, in CDH1 carriers, within as well as outside the familial setting, and the best approaches to manage each risk, using either prophylactic surgery or surveillance.
Topics: Antigens, CD; Cadherins; Genetic Predisposition to Disease; Germ Cells; Germ-Line Mutation; Heterozygote; Humans; Male; Penetrance; Stomach Neoplasms
PubMed: 35277969
DOI: 10.1002/jso.26847