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Genetic Testing and Molecular Biomarkers Nov 2017The variable penetrance of pathogenic variants (PVs) represents a major challenge to the field of human genetics, often complicating clinical decision-making and risk...
The variable penetrance of pathogenic variants (PVs) represents a major challenge to the field of human genetics, often complicating clinical decision-making and risk management. Nonpenetrance, the detection of PVs in the absence of disease manifestation, is a common phenomenon, yet, we know very little about the underlying factors, which may protect some individuals and not others. Placing a new focus on the genomic study of the healthy elderly may be pivotal for advancing our understanding of penetrance. Studying those who remain unaffected late into life, despite harboring known genetic risk variants, could provide important insights into disease mechanisms and ultimately inform clinical care, yet, it has received relatively little attention as a research strategy. The ever increasing use of sequencing technology is further driving the requirement to understand the penetrance of ascertained variants. The ASPREE Biobank of Healthy Ageing provides a unique opportunity to address this area of need. DNA has been collected from a cohort of over 14,000 healthy elderly individuals aged 70 years or older enrolled in an aspirin clinical trial. The ASPREE cohort represents a healthy reference population ascertained without the typical biases of a genetic study. The cohort is depleted of expressed monogenetic disease, yet will contain hundreds of elderly individuals with known PVs in clinically actionable genes. Investigating this population along with other cohorts of the healthy elderly will provide critical new knowledge into the penetrance of actionable variants as a foundation for informing clinical care.
Topics: Aged; Aged, 80 and over; Aspirin; Cohort Studies; Female; Genetic Predisposition to Disease; Genetic Testing; Genetic Variation; Healthy Volunteers; Humans; Male; Penetrance; Risk Factors
PubMed: 28876137
DOI: 10.1089/gtmb.2017.0126 -
Nature Communications Nov 2023Genetic and environmental variation are key contributors during organism development, but the influence of minor perturbations or noise is difficult to assess. This...
Genetic and environmental variation are key contributors during organism development, but the influence of minor perturbations or noise is difficult to assess. This study focuses on the stochastic variation in allele-specific expression that persists through cell divisions in the nine-banded armadillo (Dasypus novemcinctus). We investigated the blood transcriptome of five wild monozygotic quadruplets over time to explore the influence of developmental stochasticity on gene expression. We identify an enduring signal of autosomal allelic variability that distinguishes individuals within a quadruplet despite their genetic similarity. This stochastic allelic variation, akin to X-inactivation but broader, provides insight into non-genetic influences on phenotype. The presence of stochastically canalized allelic signatures represents a novel axis for characterizing organismal variability, complementing traditional approaches based on genetic and environmental factors. We also developed a model to explain the inconsistent penetrance associated with these stochastically canalized allelic expressions. By elucidating mechanisms underlying the persistence of allele-specific expression, we enhance understanding of development's role in shaping organismal diversity.
Topics: Humans; Animals; Armadillos; Phenotype; Alleles; Penetrance
PubMed: 37940702
DOI: 10.1038/s41467-023-43024-5 -
Nature Jan 2014Genes in which germline mutations confer highly or moderately increased risks of cancer are called cancer predisposition genes. More than 100 of these genes have been... (Review)
Review
Genes in which germline mutations confer highly or moderately increased risks of cancer are called cancer predisposition genes. More than 100 of these genes have been identified, providing important scientific insights in many areas, particularly the mechanisms of cancer causation. Moreover, clinical utilization of cancer predisposition genes has had a substantial impact on diagnosis, optimized management and prevention of cancer. The recent transformative advances in DNA sequencing hold the promise of many more cancer predisposition gene discoveries, and greater and broader clinical applications. However, there is also considerable potential for incorrect inferences and inappropriate clinical applications. Realizing the promise of cancer predisposition genes for science and medicine will thus require careful navigation.
Topics: Carcinogenesis; Genetic Association Studies; Genetic Predisposition to Disease; Humans; Molecular Targeted Therapy; Neoplasms; Penetrance; Physical Chromosome Mapping
PubMed: 24429628
DOI: 10.1038/nature12981 -
Translational Vision Science &... Oct 2021Animal models have demonstrated the role of dopamine in regulating axial elongation, the critical feature of myopia. Because frequent delivery of dopaminergic agents via...
PURPOSE
Animal models have demonstrated the role of dopamine in regulating axial elongation, the critical feature of myopia. Because frequent delivery of dopaminergic agents via peribulbar, intravitreal, or intraperitoneal injections is not clinically viable, we sought to evaluate ocular penetration and safety of the topically applied dopaminergic prodrug etilevodopa.
METHODS
The ocular penetration of dopamine and dopaminergic prodrugs (levodopa and etilevodopa) were quantified using an enzyme-linked immunosorbent assay in enucleated porcine eyes after a single topical administration. The pharmacokinetic profile of the etilevodopa was then assessed in rats. A four-week once-daily application of etilevodopa as a topical eye drop was conducted to establish its safety profile.
RESULTS
At 24 hours, the studied prodrugs showed increased dopaminergic derivatives in the vitreous of porcine eyes. Dopamine 0.5% (P = 0.0123) and etilevodopa 10% (p = 0.370) achieved significant vitreous concentrations. Etilevodopa 10% was able to enter the posterior segment of the eye after topical administration in rats with an intravitreal half-life of eight hours after single topical administration. Monthly application of topical etilevodopa showed no alterations in retinal ocular coherence tomography, electroretinography, caspase staining, or TUNEL staining.
CONCLUSIONS
At similar concentrations, no difference in ocular penetration of levodopa and etilevodopa was observed. However, etilevodopa was highly soluble and able to be applied at higher topical concentrations. Dopamine exhibited both high solubility and enhanced penetration into the vitreous as compared to other dopaminergic prodrugs.
TRANSLATIONAL RELEVANCE
These findings indicate the potential of topical etilevodopa and dopamine for further study as a therapeutic treatment for myopia.
Topics: Animals; Dopamine; Levodopa; Penetrance; Prodrugs; Rats; Retina; Swine
PubMed: 34609478
DOI: 10.1167/tvst.10.12.5 -
Current Opinion in Genetics &... Jun 2017Myotonic dystrophy (DM) is an autosomal dominant neuromuscular disease primarily characterized by myotonia and progressive muscle weakness. The pathogenesis of DM... (Review)
Review
Myotonic dystrophy (DM) is an autosomal dominant neuromuscular disease primarily characterized by myotonia and progressive muscle weakness. The pathogenesis of DM involves microsatellite expansions in noncoding regions of transcripts that result in toxic RNA gain-of-function. Each successive generation of DM families carries larger repeat expansions, leading to an earlier age of onset with increasing disease severity. At present, diagnosis of DM is challenging and requires special genetic testing to account for somatic mosaicism and meiotic instability. While progress in genetic testing has been made, more rapid, accurate, and cost-effective approaches for measuring repeat lengths are needed to establish clear correlations between repeat size and disease phenotypes.
Topics: Age of Onset; Genetic Testing; Humans; Myotonic Dystrophy; Penetrance; Phenotype; Repetitive Sequences, Nucleic Acid
PubMed: 28213156
DOI: 10.1016/j.gde.2017.01.007 -
TTN truncation variants produce sarcomere-integrating proteins of uncertain functional significance.The Journal of Clinical Investigation Jan 2024Titin (TTN) is one of the largest and most complex proteins expressed in humans, and truncation variants are the most prevalent genetic lesion identified in individuals...
Titin (TTN) is one of the largest and most complex proteins expressed in humans, and truncation variants are the most prevalent genetic lesion identified in individuals with dilated cardiomyopathy (DCM) or other disorders of impaired cardiac contractility. Two reports in this issue of the JCI shed light on a potential mechanism involving truncated TTN sarcomere integration and the potential for disruption of sarcomere structural integrity. Kellermayer, Tordai, and colleagues confirmed the presence of truncated TTN protein in human DCM samples. McAfee and authors developed a patient-specific TTN antibody to study truncated TTN subcellular localization and to explore its functional consequences. A "poison peptide" mechanism emerges that inspires alternative therapeutic approaches while opening new lines for inquiry, such as the role of haploinsufficiency of full-length TTN protein, mechanisms explaining sarcomere dysfunction, and explanations for variable penetrance.
Topics: Humans; Connectin; Sarcomeres; Cardiomyopathy, Dilated; Penetrance; Mutation
PubMed: 38226618
DOI: 10.1172/JCI175206 -
Acta Obstetricia Et Gynecologica... Nov 2020
Topics: Female; Genetic Counseling; Genetic Diseases, Inborn; Humans; Penetrance; Pregnancy; Prenatal Care; Prenatal Diagnosis
PubMed: 33084292
DOI: 10.1111/aogs.13963 -
Neuron Oct 2022Male sex is a strong risk factor for autism spectrum disorder (ASD). The leading theory for a "female protective effect" (FPE) envisions males and females have... (Review)
Review
Male sex is a strong risk factor for autism spectrum disorder (ASD). The leading theory for a "female protective effect" (FPE) envisions males and females have "differing thresholds" under a "liability threshold model" (DT-LTM). Specifically, this model posits that females require either a greater number or larger magnitude of risk factors (i.e., greater liability) to manifest ASD, which is supported by the finding that a greater proportion of females with ASD have highly penetrant genetic mutations. Herein, we derive testable hypotheses from the DT-LTM for ASD, investigating heritability, familial recurrence, correlation between ASD penetrance and sex ratio, population traits, clinical features, the stability of the sex ratio across diagnostic changes, and highlight other key prerequisites. Our findings reveal that several key predictions of the DT-LTM are not supported by current data, requiring us to establish a different conceptual framework for evaluating alternate models that explain sex differences in ASD.
Topics: Female; Male; Humans; Autism Spectrum Disorder; Sex Characteristics; Phenotype; Penetrance
PubMed: 35868305
DOI: 10.1016/j.neuron.2022.06.020 -
Genetics in Medicine : Official Journal... Aug 2017Carnitine palmitoyltransferase 1 isoform A (CPT1A) is a crucial enzyme for the transport of long-chain fatty acids into the mitochondria. The CPT1A p.P479L variant is... (Review)
Review
Carnitine palmitoyltransferase 1 isoform A (CPT1A) is a crucial enzyme for the transport of long-chain fatty acids into the mitochondria. The CPT1A p.P479L variant is found in high frequencies among indigenous populations residing on the west and north coasts of Alaska and Canada and in northeast Siberia and Greenland. Epidemiological studies have reported a statistical association between P479L homozygosity and infant death in Alaska Native and Canadian Inuit populations. Here, we review the available evidence about the P479L variant and apply to these data the epidemiological criteria for assessing causal associations. We found insufficient evidence to support a causal association with infant death and, further, that if a causal association is present, then the genotype is likely to be only one of a complex set of factors contributing to an increased risk of infant death. We conclude that additional research is needed to clarify the observed association and to inform effective preventative measures for infant death. In light of these findings, we discuss the policy implications for public health efforts because policies based on the observed association between P479L homozygosity and infant death data are premature.Genet Med advance online publication 26 January 2017.
Topics: Alaska; Canada; Carnitine O-Palmitoyltransferase; Cause of Death; Fatty Acids; Genetic Variation; Health Policy; Humans; Infant; Infant Death; Inuit; Penetrance
PubMed: 28125087
DOI: 10.1038/gim.2016.202 -
Annals of the New York Academy of... Dec 2021Neurodevelopmental neuropsychiatric disorders, such as autism spectrum disorder and schizophrenia, have strong genetic risk components, but the underlying mechanisms... (Review)
Review
Neurodevelopmental neuropsychiatric disorders, such as autism spectrum disorder and schizophrenia, have strong genetic risk components, but the underlying mechanisms have proven difficult to decipher. Rare, high-risk variants may offer an opportunity to delineate the biological mechanisms responsible more clearly for more common idiopathic diseases. Indeed, different rare variants can cause the same behavioral phenotype, demonstrating genetic heterogeneity, while the same rare variant can cause different behavioral phenotypes, demonstrating variable expressivity. These observations suggest convergent underlying biological and neurological mechanisms; identification of these mechanisms may ultimately reveal new therapeutic targets. At the 2021 Keystone eSymposium "Neuropsychiatric and Neurodevelopmental Disorders: Harnessing Rare Variants" a panel of experts in the field described significant progress in genomic discovery and human phenotyping and raised several consistent issues, including the need for detailed natural history studies of rare disorders, the challenges in cohort recruitment, and the importance of viewing phenotypes as quantitative traits that are impacted by rare variants.
Topics: Congresses as Topic; Genetic Variation; Humans; Mental Disorders; Neurodevelopmental Disorders; Penetrance; Research Report
PubMed: 34342000
DOI: 10.1111/nyas.14658