-
Second hit hypothesis in dystonia: Dysfunctional cross talk between neuroplasticity and environment?Neurobiology of Disease Nov 2021One of the great mysteries in dystonia pathophysiology is the role of environmental factors in disease onset and development. Progress has been made in defining the... (Review)
Review
One of the great mysteries in dystonia pathophysiology is the role of environmental factors in disease onset and development. Progress has been made in defining the genetic components of dystonic syndromes, still the mechanisms behind the discrepant relationship between dystonic genotype and phenotype remain largely unclear. Within this review, the preclinical and clinical evidence for environmental stressors as disease modifiers in dystonia pathogenesis are summarized and critically evaluated. The potential role of extragenetic factors is discussed in monogenic as well as adult-onset isolated dystonia. The available clinical evidence for a "second hit" is analyzed in light of the reduced penetrance of monogenic dystonic syndromes and put into context with evidence from animal and cellular models. The contradictory studies on adult-onset dystonia are discussed in detail and backed up by evidence from animal models. Taken together, there is clear evidence of a gene-environment interaction in dystonia, which should be considered in the continued quest to unravel dystonia pathophysiology.
Topics: Animals; Disease Models, Animal; Dystonic Disorders; Environmental Exposure; Gene-Environment Interaction; Humans; In Vitro Techniques; Neuronal Plasticity; Penetrance
PubMed: 34537328
DOI: 10.1016/j.nbd.2021.105511 -
Journal of Cystic Fibrosis : Official... Nov 2020Major issues of newborn screening (NBS) for CF are the assessment of disease liability of variants and of the penetrance of clinical CF, notably in inconclusive...
BACKGROUND
Major issues of newborn screening (NBS) for CF are the assessment of disease liability of variants and of the penetrance of clinical CF, notably in inconclusive diagnosis. The penetrance of CF is defined as the risk of a particular genotype to lead to a CF phenotype.
METHODS
We aimed to get insight into the penetrance of CF for fifteen CFTR variants: 5 frequent CF-causing and 10 classified as of varying clinical consequence (VCC) or associated with a CFTR-related disorder (CFTR-RD) in CFTR2 or CFTR-France databases. The penetrance was approached by: (1) comparison of variant allelic frequencies in CF patients (CFTR2) and in the general population; (2) estimation of the likelihood of a positive NBS test for the 14 compound heterozygous with F508del and the F508del homozygous genotypes, defined as the ratio of detected/expected number of neonates with a given genotype in the 2002-2017 period.
RESULTS
A full penetrance was observed for severe CF-causing variants. Five variants were more frequently found in the general population than in CF patients: TG11T5, TG12T5, TG13T5, L997F and R117H;T7. The likelihood of a positive NBS test was 0.03% for TG11T5, 0.3% for TG12T5, 1.9% for TG13T5, 0.6% for L997F, 11.7% for D1152H, and 17.8% for R117H;T7. Penetrance varied greatly for variants with discrepant classification between CFTR2 and CFTR-France: 5.1% for R117C, 12.3% for T338I, 43.5% for D110H and 52.6% for L206W.
CONCLUSION
These results illustrate the contribution of genetics population data to assess the disease liability of variants for diagnosis and genetic counselling purposes.
Topics: Alleles; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Female; Genetic Variation; Genotype; Humans; Infant, Newborn; Male; Neonatal Screening; Penetrance; Phenotype
PubMed: 32327388
DOI: 10.1016/j.jcf.2020.03.019 -
Breast Cancer Research : BCR 2000Numerous founder mutations have been reported in BRCA1 and BRCA2. For genetic screening of a population with a founder mutation, testing can be targeted to the mutation,... (Review)
Review
Numerous founder mutations have been reported in BRCA1 and BRCA2. For genetic screening of a population with a founder mutation, testing can be targeted to the mutation, allowing for a more rapid and less expensive test. In addition, more precise estimates of the prior probability of carrying a mutation and of the likelihood of a mutation carrier developing cancer should be possible. For a given founder mutation a large number of carriers are available, so that focused scientific studies of penetrance, expression, and genetic and environmental modifiers of risk can be performed. Finally, founder populations may be a powerful resource to localize additional breast cancer susceptibility loci, because of the reduction in locus heterogeneity.
Topics: Adult; Aged; BRCA2 Protein; Breast Neoplasms; Female; Genes, BRCA1; Genetic Testing; Heterozygote; Humans; Male; Mutation; Neoplasm Proteins; Penetrance; Probability; Risk Factors; Transcription Factors
PubMed: 11250694
DOI: 10.1186/bcr36 -
Journal of Clinical Oncology : Official... Oct 2018Lynch syndrome due to pathogenic variants in the DNA mismatch repair genes MLH1, MSH2, and MSH6 is predominantly associated with colorectal and endometrial cancer,...
PURPOSE
Lynch syndrome due to pathogenic variants in the DNA mismatch repair genes MLH1, MSH2, and MSH6 is predominantly associated with colorectal and endometrial cancer, although extracolonic cancers have been described within the Lynch tumor spectrum. However, the age-specific cumulative risk (penetrance) of these cancers is still poorly defined for PMS2-associated Lynch syndrome. Using a large data set from a worldwide collaboration, our aim was to determine accurate penetrance measures of cancers for carriers of heterozygous pathogenic PMS2 variants.
METHODS
A modified segregation analysis was conducted that incorporated both genotyped and nongenotyped relatives, with conditioning for ascertainment to estimates corrected for bias. Hazard ratios (HRs) and corresponding 95% CIs were estimated for each cancer site for mutation carriers compared with the general population, followed by estimation of penetrance.
RESULTS
In total, 284 families consisting of 4,878 first- and second-degree family members were included in the analysis. PMS2 mutation carriers were at increased risk for colorectal cancer (cumulative risk to age 80 years of 13% [95% CI, 7.9% to 22%] for males and 12% [95% CI, 6.7% to 21%] for females) and endometrial cancer (13% [95% CI, 7.0%-24%]), compared with the general population (6.6%, 4.7%, and 2.4%, respectively). There was no clear evidence of an increased risk of ovarian, gastric, hepatobiliary, bladder, renal, brain, breast, prostate, or small bowel cancer.
CONCLUSION
Heterozygous PMS2 mutation carriers were at small increased risk for colorectal and endometrial cancer but not for any other Lynch syndrome-associated cancer. This finding justifies that PMS2-specific screening protocols could be restricted to colonoscopies. The role of risk-reducing hysterectomy and bilateral salpingo-oophorectomy for PMS2 mutation carriers needs further discussion.
Topics: Adult; Aged; Colorectal Neoplasms, Hereditary Nonpolyposis; Female; Heterozygote; Humans; Male; Middle Aged; Mismatch Repair Endonuclease PMS2; Mutation; Neoplasms; Penetrance
PubMed: 30161022
DOI: 10.1200/JCO.2018.78.4777 -
Molecular Genetics & Genomic Medicine Jan 2019Isolated cardiac arrhythmia due to a variant in CACNA1C is of recent knowledge. Most reports have been of singleton cases or of quite small families, and estimates of...
BACKGROUND
Isolated cardiac arrhythmia due to a variant in CACNA1C is of recent knowledge. Most reports have been of singleton cases or of quite small families, and estimates of penetrance and expressivity have been difficult to obtain. We here describe a large pedigree, from which such estimates have been calculated.
METHODS
We studied a five-generation family, in which a CACNA1C variant c.2573G>A p.Arg858His co-segregates with syncope and cardiac arrest, documenting electrocardiographic data and cardiac symptomatology. The reported patients/families from the literature with CACNA1C gene variants were reviewed, and genotype-phenotype correlations are drawn.
RESULTS
The range of phenotype in the studied family is wide, from no apparent effect, through an asymptomatic QT interval prolongation on electrocardiography, to episodes of presyncope and syncope, ventricular fibrillation, and sudden death. QT prolongation showed inconsistent correlation with functional cardiology. Based upon analysis of 28 heterozygous family members, estimates of penetrance and expressivity are derived.
CONCLUSIONS
These estimates of penetrance and expressivity, for this specific variant, may be useful in clinical practice. Review of the literature indicates that individual CACNA1C variants have their own particular genotype-phenotype correlations. We suggest that, at least in respect of the particular variant reported here, "arrhythmogenic channelopathy" may be a more fitting nomenclature than long QT syndrome.
Topics: Adult; Aged; Arrhythmias, Cardiac; Calcium Channels, L-Type; Channelopathies; Child; Electrocardiography; Female; Genotype; Heterozygote; Humans; Infant; Male; Middle Aged; Mutation, Missense; Pedigree; Penetrance; Phenotype
PubMed: 30345660
DOI: 10.1002/mgg3.476 -
Congenital Anomalies Jan 2018Holoprosencephaly (HPE) is failure of the forebrain to divide completely during embryogenesis. Incomplete penetrance has not been reported previously in SIX3 whole gene...
Holoprosencephaly (HPE) is failure of the forebrain to divide completely during embryogenesis. Incomplete penetrance has not been reported previously in SIX3 whole gene deletions, which are known to cause HPE. Both chromosomal microarray and whole exome sequencing (WES) were used to evaluate families with inherited HPE. Two families showed inherited deletions that contain SIX3 and were incompletely penetrant for HPE. Using WES, we ruled out parental mosaicism, a SIX3 hypomorph, and clinically significant variants in genes that are known to interact with SIX3 as causes of incomplete penetrance. We demonstrate the importance of molecular cascade testing in families with HPE and we answer important questions about incomplete penetrance.
Topics: Adult; Child, Preschool; Eye Proteins; Gene Deletion; Gene Expression; Holoprosencephaly; Homeodomain Proteins; Humans; Infant; Infant, Newborn; Microarray Analysis; Nerve Tissue Proteins; Penetrance; Prosencephalon; Exome Sequencing; Homeobox Protein SIX3
PubMed: 28670735
DOI: 10.1111/cga.12234 -
PloS One 2020Mutations conferring susceptibility to complex disorders also occur in healthy individuals but at significantly lower frequencies than in patients, indicating that these...
Mutations conferring susceptibility to complex disorders also occur in healthy individuals but at significantly lower frequencies than in patients, indicating that these mutations are not completely penetrant. Therefore, it is important to estimate the penetrance or the likelihood of developing a disease in presence of a mutation. Recently, a method to calculate penetrance and its credible intervals was developed on the basis of the Bayesian method and since been used in literature. However, in the present form, this approach demands programming skills for its utility. Here, we developed 'CalPen', a web-based tool for straightforward calculation of penetrance and its credible intervals by entering the number of mutations identified in controls and patients, and the number of patients and controls studied. For validation purposes, we show that CalPen-derived penetrance values are in good agreement with the published values. As further demonstration of its utility, we used schizophrenia as an example of complex disorder and estimated penetrance values for 15 different copy number variants (CNVs) reported in 39,059 patients and 55,084 controls, and 145 SNPs reported in 45,405 patients and 122,761 controls. CNVs showed an average penetrance of 7% with 22q11.21 CNVs having highest value (~20%) and 15q11.2 deletions with lowest value (~1.4%). Most SNPs, on the other hand showed a penetrance of 0.7% with rs1801028 having the highest penetrance (1.6%). In summary, CalPen is an accurate and user-friendly web-based tool useful in human genetic research to ascertain the ability of the mutation/ variant to cause a complex genetic disorder.
Topics: Bayes Theorem; DNA Copy Number Variations; Genetic Diseases, Inborn; Genetic Predisposition to Disease; Humans; Internet; Models, Statistical; Penetrance; Polymorphism, Single Nucleotide; Schizophrenia; Software
PubMed: 31995602
DOI: 10.1371/journal.pone.0228156 -
Human Molecular Genetics Jul 2022Non-syndromic cleft lip with or without cleft palate (NSCL/P) is a common, severe craniofacial malformation that imposes significant medical, psychosocial and financial...
Non-syndromic cleft lip with or without cleft palate (NSCL/P) is a common, severe craniofacial malformation that imposes significant medical, psychosocial and financial burdens. NSCL/P is a multifactorial disorder with genetic and environmental factors playing etiologic roles. Currently, only 25% of the genetic variation underlying NSCL/P has been identified by linkage, candidate gene and genome-wide association studies. In this study, whole-genome sequencing and genome-wide genotyping followed by polygenic risk score (PRS) and linkage analyses were used to identify the genetic etiology of NSCL/P in a large three-generation family. We identified a rare missense variant in PDGFRA (c.C2740T; p.R914W) as potentially etiologic in a gene-based association test using pVAAST (P = 1.78 × 10-4) and showed decreased penetrance. PRS analysis suggested that variant penetrance was likely modified by common NSCL/P risk variants, with lower scores found among unaffected carriers. Linkage analysis provided additional support for PRS-modified penetrance, with a 7.4-fold increase in likelihood after conditioning on PRS. Functional characterization experiments showed that the putatively causal variant was null for signaling activity in vitro; further, perturbation of pdgfra in zebrafish embryos resulted in unilateral orofacial clefting. Our findings show that a rare PDGFRA variant, modified by additional common NSCL/P risk variants, have a profound effect on NSCL/P risk. These data provide compelling evidence for multifactorial inheritance long postulated to underlie NSCL/P and may explain some unusual familial patterns.
Topics: Animals; Cleft Lip; Cleft Palate; Genetic Predisposition to Disease; Genome-Wide Association Study; Genotype; Multifactorial Inheritance; Mutation; Penetrance; Polymorphism, Single Nucleotide; Zebrafish
PubMed: 35147171
DOI: 10.1093/hmg/ddac037 -
Human Heredity 2011Many complex diseases show a diversity of inheritance patterns ranging from familial disease, manifesting with autosomal dominant inheritance, through to simplex...
BACKGROUND/AIMS
Many complex diseases show a diversity of inheritance patterns ranging from familial disease, manifesting with autosomal dominant inheritance, through to simplex families in which only one person is affected, manifesting as apparently sporadic disease. The role of ascertainment bias in generating apparent patterns of inheritance is often overlooked. We therefore explored the role of two key parameters that influence ascertainment, penetrance and family size, in rates of observed familiality.
METHODS
We develop a mathematical model of familiality of disease, with parameters for penetrance, mutation frequency and family size, and test this in a complex disease: amyotrophic lateral sclerosis.
RESULTS
Monogenic, high-penetrance variants can explain patterns of inheritance in complex diseases and account for a large proportion of those with no apparent family history. With current demographic trends, rates of familiality will drop further. For example, a variant with penetrance 0.5 will cause apparently sporadic disease in 12% of families of size 10, but 80% of families of size 1. A variant with penetrance 0.9 has only an 11% chance of appearing sporadic in families of a size similar to those of Ireland in the past, compared with 57% in one-child families like many in China.
CONCLUSIONS
These findings have implications for genetic counselling, disease classification and the design of gene-hunting studies. The distinction between familial and apparently sporadic disease should be considered artificial.
Topics: Amyotrophic Lateral Sclerosis; Family Characteristics; Genetic Diseases, Inborn; Humans; Models, Genetic; Mutation; Penetrance; Probability; Superoxide Dismutase; Superoxide Dismutase-1
PubMed: 21846995
DOI: 10.1159/000330167 -
PloS One 2022Significant advances have been made to understand the genetic basis of breast cancer. High, moderate and low penetrance variants have been identified with inter-ethnic...
Significant advances have been made to understand the genetic basis of breast cancer. High, moderate and low penetrance variants have been identified with inter-ethnic variability in mutation frequency and spectrum. Genome wide association studies (GWAS) are widely used to identify disease-associated SNPs. Understanding the functional impact of these risk-SNPs will help the translation of GWAS findings into clinical interventions. Here we aim to characterize the genetic patterns of high and moderate penetrance breast cancer susceptibility genes and to assess the functional impact of non-coding SNPs. We analyzed BRCA1/2, PTEN, STK11, TP53, ATM, BRIP1, CHEK2 and PALB2 genotype data obtained from 135 healthy participants genotyped using Affymetrix Genome-Wide Human SNP-Array 6.0. Haplotype analysis was performed using Haploview.V4.2 and PHASE.V2.1. Population structure and genetic differentiation were assessed using principal component analysis (PCA) and fixation index (FST). Functional annotation was performed using In Silico web-based tools including RegulomeDB and VARAdb. Haplotype analysis showed distinct LD patterns with high levels of recombination and haplotype blocks of moderate to small size. Our findings revealed also that the Tunisian population tends to have a mixed origin with European, South Asian and Mexican footprints. Functional annotation allowed the selection of 28 putative regulatory variants. Of special interest were BRCA1_ rs8176318 predicted to alter the binding sites of a tumor suppressor miRNA hsa-miR-149 and PALB2_ rs120963 located in tumorigenesis-associated enhancer and predicted to strongly affect the binding of P53. Significant differences in allele frequencies were observed with populations of African and European ancestries for rs8176318 and rs120963 respectively. Our findings will help to better understand the genetic basis of breast cancer by guiding upcoming genome wide studies in the Tunisian population. Putative functional SNPs may be used to develop an efficient polygenic risk score to predict breast cancer risk leading to better disease prevention and management.
Topics: Breast Neoplasms; Female; Gene Frequency; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; MicroRNAs; Penetrance; Polymorphism, Single Nucleotide
PubMed: 35333900
DOI: 10.1371/journal.pone.0265638