Genetic Interpretation Research Articles

Deep learning of genomic variation and regulatory network data.

The human genome is now investigated through high-throughput functional assays, and through the generation of population genomic data. These advances support the identification of functional genetic variants and the prediction of traits (e.g. deleterious variants and disease). This review summarizes lessons learned from the large-scale analyses of genome and exome data sets, modeling of population data and machine-learning strategies to solve complex genomic sequence regions. The review also portrays the rapid adoption of artificial intelligence/deep neural networks in genomics; in particular, deep learning approaches are well suited to model the complex dependencies in the regulatory landscape of the genome, and to provide predictors for genetic variant calling and interpretation.

Childhood trauma, unconscious conflict and developmental transformation

Trauma is the subject of increasing attention in contemporary psychoanalysis. Its complexities will be explored in a clinical case, emphasizing traumatic experience and unconscious conflict across developmental phases. The patient, a young adult white man began analysis complaining of anxiety and depression. Born to adolescent parents, he had experienced infantile stress and childhood traumatic illness. Needy, greedy, and dependent, he was gratified by the frequency and intimacy of psychoanalysis. Genetic interpretation and reconstruction were particularly important in the analytic process. Analytic progress with attenuation of unconscious conflict and developmental transformation proved enduring after termination.

Genetic Evaluation of Cardiomyopathy—A Heart Failure Society of America Practice Guideline

This guideline describes the approach and expertise needed for the genetic evaluation of cardiomyopathy. First published in 2009 by the Heart Failure Society of America (HFSA), the guideline has now been updated in collaboration with the American College of Medical Genetics and Genomics (ACMG). The writing group, composed of cardiologists and genetics professionals with expertise in adult and pediatric cardiomyopathy, reflects the emergence and increased clinical activity devoted to cardiovascular genetic medicine. The genetic evaluation of cardiomyopathy is a rapidly emerging key clinical priority, because high-throughput sequencing is now feasible for clinical testing and conventional interventions can improve survival, reduce morbidity, and enhance quality of life. Moreover, specific interventions may be guided by genetic analysis. A systematic approach is recommended: always a comprehensive family history; an expert phenotypic evaluation of the proband and at-risk family members to confirm a diagnosis and guide genetic test selection and interpretation; referral to expert centers as needed; genetic testing, with pre- and post-test genetic counseling; and specific guidance as indicated for drug and device therapies. The evaluation of infants and children demands special expertise. The approach to managing secondary and incidental sequence findings as recommended by the ACMG is provided.

Sedimentary processes and facies on a high-latitude passive continental margin, Wilkes Land, East Antarctica

Abstract The impact of high-latitude physical processes on the sedimentary geology of a passive continental margin is addressed using a sediment record from the Wilkes Land margin of Antarctica. We present sequence stratigraphic models based on analytical data and genetic interpretations of sedimentary facies assemblages observed in drill cores collected by the Integrated Ocean Drilling Program. The examination of drill cores within a previously published seismostratigraphic context enhances the resolution of the sequence stratigraphic interpretations. Weaker tidal forcing, a stronger Coriolis effect and more pronounced seasonality are some of the physical processes that affect erosion and sedimentation at high latitudes, even if ice sheets are absent. In addition, the presence of an ice sheet affects erosion rates, crustal motion, and atmospheric and ocean circulation, with major implications for the development of depositional systems. As a result, high-latitude, ice-covered, passive margins show distinct sedimentary facies associations and their interpretation requires the application of a different suite of sequence stratigraphic models from those applied to low-latitude continental margins.

A population genetic interpretation of GWAS findings for human quantitative traits.

Human genome-wide association studies (GWASs) are revealing the genetic architecture of anthropomorphic and biomedical traits, i.e., the frequencies and effect sizes of variants that contribute to heritable variation in a trait. To interpret these findings, we need to understand how genetic architecture is shaped by basic population genetics processes—notably, by mutation, natural selection, and genetic drift. Because many quantitative traits are subject to stabilizing selection and because genetic variation that affects one trait often affects many others, we model the genetic architecture of a focal trait that arises under stabilizing selection in a multidimensional trait space. We solve the model for the phenotypic distribution and allelic dynamics at steady state and derive robust, closed-form solutions for summary statistics of the genetic architecture. Our results provide a simple interpretation for missing heritability and why it varies among traits. They predict that the distribution of variances contributed by loci identified in GWASs is well approximated by a simple functional form that depends on a single parameter: the expected contribution to genetic variance of a strongly selected site affecting the trait. We test this prediction against the results of GWASs for height and body mass index (BMI) and find that it fits the data well, allowing us to make inferences about the degree of pleiotropy and mutational target size for these traits. Our findings help to explain why the GWAS for height explains more of the heritable variance than the similarly sized GWAS for BMI and to predict the increase in explained heritability with study sample size. Considering the demographic history of European populations, in which these GWASs were performed, we further find that most of the associations they identified likely involve mutations that arose shortly before or during the Out-of-Africa bottleneck at sites with selection coefficients around s = 10−3.

Testing patterns for genetically triggered aortic and arterial aneurysms and dissections at an academic center

ObjectiveThe contemporary practice of testing for genetically triggered aortic and arterial aneurysms and dissections is not well described. This study aimed to describe this practice at a tertiary care academic center and to ascertain the yield of testing in establishing the diagnosis in patients referred on the basis of clinical suspicion. MethodsThis is a retrospective cohort study of patients referred for vascular genetic testing at an academic medical center between 2010 and 2015. Patients were identified by Current Procedural Terminology diagnostic codes 81405, 81408, and 81479 for genetic testing (Marfan syndrome, Loeys-Dietz syndrome, aneurysms-osteoarthritis syndrome, COL3A1, and familial thoracic aortic aneurysm panel [ACTA2, COL3A1, TGFBR1, TGFBR2, SMAD3, TGFB2, MYLK, MYH11, and PRKG1 genes]) and by review of the collagen vascular laboratory database for genetic testing results. Data abstracted included demographics, clinical history, reason for referral, family history, referring provider type, and outcomes of genetic testing. ResultsNinety-six patients (44.3% male; median age, 40.8 years) were referred for suspected genetic vascular disease. Genetic testing was performed in 75 cases thought to have heritable mutations related to aortic or arterial aneurysms and dissections. The most common reason for genetic testing was a personal history of aortic or arterial aneurysms and dissections (62.3%; mean age, 45.8 ± 11.1 years), followed by a family history of aortic or arterial aneurysms and dissections without a personal history (26.6%; age, 28.8 ± 17.9 years). The most common genetic testing performed was a familial thoracic aortic aneurysm gene panel (44%), followed by single gene testing for vascular Ehlers-Danlos syndrome (33.3%). Genetic testing identified a pathogenic mutation in 36% of the cases. The highest likelihood of identifying a pathogenic mutation was in those who had a family history with an already diagnosed mutation (57.1%), followed by patients with aortic root and ascending aortic aneurysm or dissection (42.3%). ConclusionsIn patients with suspected genetically triggered vascular disease, the yield of clinical vascular genetic testing is reasonable when selective genetic testing is performed on the basis of personal or family history. These tests should be obtained with appropriate expertise in genetic counseling and interpretation of genetic testing results. Negative genetic test results in the setting of a positive family history demonstrate the limits of testing and known mutations leading to genetically triggered aortic and arterial aneurysms and dissections and support the need for novel gene discovery.

Models of out-of-line deformation in structural analysis of folding of the Ukrainian Carpathians

Structural analysis and reconstruction of folding of the Ukrainian (flysh) Carpathians have been executed according to materials (cross-sections) of medium-scale geological survey. Methodic development has been used within the limits of bending and out-of-flow theories. It has been shown with the help of asymmetric folding simulation that the recapture of folds into intermediate deformed state by removal of out-of-line flow and the statistic search of the most probable orientation of compression axis is the effective method of diagnostics. Conditions of appearance of Carparhians structures have been identified which can be a result of both longitudinal-transverse bending and horizontal out-of-line flow superimposed upon initially symmetric or asymmetrical bending folds. Within the limits of models of out-of-line deformation inclinations of compression axis and intensity of deformation are being determined which finally resulted in observed folding forms, specification of folds from different structural-facial zones of Carpathians according to the grade of their compactness and asymmetry has been shown, their genetic interpretation has been given.

"Bridge to the Literature"? Third-Party Genetic Interpretation Tools and the Views of Tool Developers.

Patients and health care consumers can obtain access to their "raw," or uninterpreted, genetic data from direct-to-consumer genetic testing companies, researchers, or providers and pursue self-directed analysis via third-party interpretation tools. Yet relatively little is known about the nature of currently available interpretation tools or the motivations of tool developers. We conducted a structured content analysis of 23 third-party interpretation tool websites and supporting information, tracking features such as types of information returned, modes of generating and presenting that information, and privacy and security measures. We additionally conducted qualitative interviews with a subset of 10 tool developers. A majority of tools (16 of 23, or 70%) offer some type of health or wellness-related information, often extracted from publicly available variant annotation databases. Half of those interviewed characterized their activities as "bridging" users to the scientific literature rather than interpretation, for which they gave a variety of scientific, ethical, and regulatory justifications. The scale, heterogeneity, and complexity of information available from third-party interpretation are unprecedented. While developers aim to enlighten and empower tool users, interpretation-free "bridging" to rapidly evolving databases may instead impose burdens on genetic counselors and other health care providers asked to provide further contextualization and explanation.

A Timanian island-arc fragment in North Greenland: The Midtkap igneous suite

The distribution of rocks with Timanian ages along the circum-arctic continental margins provides important information for the post-Rodinia palaeogeographic reconstruction of the Arctic. The Midtkap igneous suite in northern Peary Land, North Greenland, forms isolated outcrops (centres A–F) in early Palaeozoic deep-water sedimentary rocks of the Franklinian Basin. The suite is composed of intermediate and felsic intrusive rocks, serpentinite, and heterogeneous volcanic breccia. Timanian zircon ages of the intrusive rocks were previously reported from centres D, E, and F (628–570 Ma). Field observations, zircon U-Pb and biotite Ar–Ar dating, whole-rock geochemical and Sr–Nd isotope data allow greater insight into the composition of the suite and its genetic interpretation. A supra-subduction zone origin and a formation in an intra-oceanic volcanic arc is very likely for the whole suite. The intrusive rocks (monzonite, granitoids, gabbro, rodingite) were probably uplifted by serpentinite diapirism. The heterogeneous volcanic breccia (basalt/spilite mixed with arc-derived rocks) is interpreted as a mélange. Both serpentinite diapirs and mélanges indicate a forearc setting. A monzonite of centre B with a zircon 206Pb/238U age of 650 ± 3 Ma represents the oldest intrusion of the Timanian suite. 40Ar/39Ar biotite dating of a granite of centre A (∼535 Ma) points to a duration of the island-arc magmatism until the earliest Palaeozoic. Coeval volcaniclastic detritus derived from a Timanian island arc has also been found in the Pearya composite terrane at the north coast of the Canadian Ellesmere Island. The Timanian arc was possibly split and displaced during the Caledonian Orogeny.

Yield of the RYR2 Genetic Test in Suspected Catecholaminergic Polymorphic Ventricular Tachycardia and Implications for Test Interpretation.

Pathogenic RYR2 variants account for ≈60% of clinically definite cases of catecholaminergic polymorphic ventricular tachycardia. However, the rate of rare benign RYR2 variants identified in the general population remains a challenge for genetic test interpretation. Therefore, we examined the results of the RYR2 genetic test among patients referred for commercial genetic testing and examined factors impacting variant interpretability. Frequency and location comparisons were made for RYR2 variants identified among 1355 total patients of varying clinical certainty and 60 706 Exome Aggregation Consortium controls. The impact of the clinical phenotype on the yield of RYR2 variants was examined. Six in silico tools were assessed using patient- and control-derived variants. A total of 18.2% (218/1200) of patients referred for commercial testing hosted rare RYR2 variants, statistically less than the 59% (46/78) yield among clinically definite cases, resulting in a much higher potential genetic false discovery rate among referrals considering the 3.2% background rate of rare, benign RYR2 variants. Exclusion of clearly putative pathogenic variants further complicates the interpretation of the next novel RYR2 variant. Exonic/topologic analyses revealed overrepresentation of patient variants in exons covering only one third of the protein. In silico tools largely failed to show evidence toward enhancement of variant interpretation. Current expert recommendations have resulted in increased use of RYR2 genetic testing in patients with questionable clinical phenotypes. Using the largest to date catecholaminergic polymorphic ventricular tachycardia patient versus control comparison, this study highlights important variables in the interpretation of variants to overcome the 3.2% background rate that confounds RYR2 variant interpretation.

River channel planforms and floodplains: a study in the Wessex landscape

ABSTRACTFor south ‘Wessex’, despite complexity evident on the ground, there is little research that directly links river channel form with historic economic development; that is, channel genesis and planforms are seldom discussed in relation to landscape development within valleys. Of specific interest are relationships linking channel topography, artificial cuts and floodplains with development associated with mills, water-meadows, artificial watercourses and gravel extraction. These are an outcome of a strong regional culture of economic development including water management. It is demonstrated that river planforms within the valleys determine the location of fixed assets and there is a strong relationship between soils and floodplain development. It is concluded that there is an intricate continuum between perceived ‘natural’ fluvial process and human-influenced environmental change, and that genetic interpretation of river channel forms presents a challenge for landscape historians.

Pachydermoperiostosis: a case report

Pachydermoperiostosis (PHO) or primary hypertrophic osteoarthropathy is a rare genetic disease that typically begins during childhood or adolescence. It is characterized by digital clubbing, pachydermia and periosteal reaction and progresses gradually over the years prior to disease stabilization. Two genes are reported to be associated with PHO – HPGD and SLCO2A1. These genes are involved in prostaglandin E2 metabolism.
 We present a description of a 19-year-old patient with PHO. We found two mutations in the SLCO2A1 gene: p.Gly183Ar (chr3:133673888, NM_005630.2:c.547G>A) and p.Cys444Gly (chr3:133664070, NM_005630.2:c.1330T>G) through molecular genetic analysis. The mutation (p.Cys444Gly) has never been recorded in previous studies.
 This work expands our knowledge of the mutation spectrum of PHO, which will facilitate faster genetic diagnosis and interpretation of genetic information in prenatal diagnosis and genetic counseling.

Clinical Cardiovascular Genetic Counselors Take a Leading Role in Team-based Variant Classification.

We sought to delineate the genetic test review and interpretation practices of clinical cardiovascular genetic counselors. A one-time anonymous online survey was taken by 46 clinical cardiovascular genetic counselors recruited through the National Society of Genetic Counselors Cardiovascular Special Interest Group. Nearly all (95.7%) gather additional information on variants reported on clinical genetic test reports and most (81.4%) assess the classification of such variants. Clinical cardiovascular genetic counselors typically (81.0%) classify variants in collaboration with cardiologist and/or geneticist colleagues, with the genetic counselor as the team member who is primarily responsible. Variant classification is a relatively recent (mean 3.2years) addition to practice. Most genetic counselors learned classification skills on the job from clinical and laboratory colleagues. Recent graduates were more likely to have learned this in graduate school (p < 0.001). Genetic counselors are motivated to take responsibility for the classification of variants because of prior experiences with variant reclassification, inconsistencies between laboratories, and incomplete laboratory reports. They are also driven by a sense of professional duty and their proximity to the clinical context. This practice represents a broadening of the skill set of clinical cardiovascular genetic counselors and a unique expertise that they contribute to the interdisciplinary teams in which they work.

Applying High-Resolution Variant Classification to Cardiac Arrhythmogenic Gene Testing in a Demographically Diverse Cohort of Sudden Unexplained Deaths.

Genetic variant interpretation contributes to testing yield differences reported for sudden unexplained death. Adapting a high-resolution variant interpretation framework, which considers disease prevalence, reduced penetrance, genetic heterogeneity, and allelic contribution to determine the maximum tolerated allele count in gnomAD, we report an evaluation of cardiac channelopathy and cardiomyopathy genes in a large, demographically diverse sudden unexplained death cohort that underwent thorough investigation in the United States' largest medical examiner's office. The cohort has 296 decedents: 147 Blacks, 64 Hispanics, 49 Whites, 22 Asians, and 14 mixed ethnicities; 142 infants (1 to 11 months), 39 children (1 to 17 years), 74 young adults (18 to 34 years), and 41 adults (35 to 55 years). Eighty-nine cardiac disease genes were evaluated. Using a high-resolution variant interpretation workflow, we classified 17 variants as pathogenic or likely pathogenic (2 of which were incidental findings and excluded in testing yield analysis), 46 novel variants of uncertain significance, and 130 variants of uncertain significance. Nine pathogenic or likely pathogenic variants in ClinVar were reclassified to likely benign and excluded in testing yield analysis. The yields of positive cases by ethnicity and age were 21.4% in mixed ethnicities, 10.2% Whites, 4.5% Asians, 3.1% Hispanics, and 2% Blacks; 7.7% children, 7.3% in adults, 5.4% young adults, and 2.8% infants. The percentages of uncertain cases with variants of uncertain significance by ethnicity were 45.5% in Asians, 45.3% Hispanics, 44.20% Blacks, 36.7% Whites, and 14.3% in mixed ethnicities. High-resolution variant interpretation provides diagnostic accuracy and healthcare efficiency. Under-represented populations warrant greater inclusion in future studies.

Physical forces modulate cell differentiation and proliferation processes.

Currently, the predominant hypothesis explains cellular differentiation and behaviour as an essentially genetically driven intracellular process, suggesting a gene‐centrism paradigm. However, although many living species genetic has now been described, there is still a large gap between the genetic information interpretation and cell behaviour prediction. Indeed, the physical mechanisms underlying the cell differentiation and proliferation, which are now known or suspected to guide such as the flow of energy through cells and tissues, have been often overlooked. We thus here propose a complementary conceptual framework towards the development of an energy‐oriented classification of cell properties, that is, a mitochondria‐centrism hypothesis based on physical forces‐driven principles. A literature review on the physical–biological interactions in a number of various biological processes is analysed from the point of view of the fluid and solid mechanics, electricity and thermodynamics. There is consistent evidence that physical forces control cell proliferation and differentiation. We propose that physical forces interfere with the cell metabolism mostly at the level of the mitochondria, which in turn control gene expression. The present perspective points towards a paradigm shift complement in biology.

ClinVar: improving access to variant interpretations and supporting evidence.

ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/) is a freely available, public archive of human genetic variants and interpretations of their significance to disease, maintained at the National Institutes of Health. Interpretations of the clinical significance of variants are submitted by clinical testing laboratories, research laboratories, expert panels and other groups. ClinVar aggregates data by variant-disease pairs, and by variant (or set of variants). Data aggregated by variant are accessible on the website, in an improved set of variant call format files and as a new comprehensive XML report. ClinVar recently started accepting submissions that are focused primarily on providing phenotypic information for individuals who have had genetic testing. Submissions may come from clinical providers providing their own interpretation of the variant (‘provider interpretation’) or from groups such as patient registries that primarily provide phenotypic information from patients (‘phenotyping only’). ClinVar continues to make improvements to its search and retrieval functions. Several new fields are now indexed for more precise searching, and filters allow the user to narrow down a large set of search results.

ACOG

With the increased emphasis on patient-driven health care and readily available access to patients through the internet and media, many genetic testing companies have begun to market directly to consumers. Direct-to-consumer genetic testing raises unique concerns and considerations, including limited knowledge among patients and health care providers of available genetic tests, difficulty in interpretation of genetic test results, lack of oversight of companies that offer genetic testing, and issues of privacy and confidentiality. When undergoing any direct-to-consumer genetic testing, the consumer should be apprised of risk from screening or susceptibility test results that can neither prove nor eliminate disease potential. Because ordering an appropriate genetic test and interpretation of genetic test results are complex, an obstetrician-gynecologist or other health care provider with knowledge of genetics should be involved in ordering and interpreting the results of any genetic test with medical implications. When an individual presents test results to a health care provider from a direct-to-consumer genomic test that putatively assesses the risk of specific diseases, the patient should be referred to an obstetrician-gynecologist or other health care provider who is skilled in risk assessment for the diseases of interest and interpretation of genetic testing results in the context of the individual's relevant medical and family history. Because of these considerations and in view of the fact that the interpretation of the results requires specific training and medical knowledge, direct-to-consumer genetic testing should be discouraged because of the potential harm of a misinterpreted or inaccurate result.

Committee Opinion No. 724 Summary: Consumer Testing for Disease Risk.

With the increased emphasis on patient-driven health care and readily available access to patients through the internet and media, many genetic testing companies have begun to market directly to consumers. Direct-to-consumer genetic testing raises unique concerns and considerations, including limited knowledge among patients and health care providers of available genetic tests, difficulty in interpretation of genetic test results, lack of oversight of companies that offer genetic testing, and issues of privacy and confidentiality. When undergoing any direct-to-consumer genetic testing, the consumer should be apprised of risk from screening or susceptibility test results that can neither prove nor eliminate disease potential. Because ordering an appropriate genetic test and interpretation of genetic test results are complex, an obstetrician-gynecologist or other health care provider with knowledge of genetics should be involved in ordering and interpreting the results of any genetic test with medical implications. When an individual presents test results to a health care provider from a direct-to-consumer genomic test that putatively assesses the risk of specific diseases, the patient should be referred to an obstetrician-gynecologist or other health care provider who is skilled in risk assessment for the diseases of interest and interpretation of genetic testing results in the context of the individual's relevant medical and family history. Because of these considerations and in view of the fact that the interpretation of the results requires specific training and medical knowledge, direct-to-consumer genetic testing should be discouraged because of the potential harm of a misinterpreted or inaccurate result.

Distinguishing pathogenic mutations from background genetic noise in cardiology: The use of large genome databases for genetic interpretation.

Advances in clinical genetic testing have led to increased insight into the human genome, including how challenging it is to interpret rare genetic variation. In some cases, the ability to detect genetic mutations exceeds the ability to understand their clinical impact, limiting the advantage of these technologies. Obstacles in genomic medicine are many and include: understanding the level of certainty/uncertainty behind pathogenicity determination, the numerous different variant interpretation-guidelines used by clinical laboratories, delivering the certain or uncertain result to the patient, helping patients evaluate medical decisions in light of uncertainty regarding the consequence of the findings. Through publication of large publicly available exome/genome databases, researchers and physicians are now able to highlight dubious variants previously associated with different cardiac traits. Also, continuous efforts through data sharing, international collaborative efforts to develop disease-gene-specific guidelines, and computational analyses using large data, will indubitably assist in better variant interpretation and classification. This article discusses the current, and quickly changing, state of variant interpretation resources within cardiovascular genetic research, e.g., publicly available databases and ways of how cardiovascular genetic counselors and geneticists can aid in improving variant interpretation in cardiology.

Hydrothermal reequilibration of igneous magnetite in altered granitic plutons and its implications for magnetite classification schemes: Insights from the Handan-Xingtai iron district, North China Craton

Magnetite is a common mineral in igneous rocks and has been used as an important petrogenetic indicator as its compositions and textures reflect changing physiochemical parameters such as temperature, oxygen fugacity and melt compositions. In upper crustal settings, igneous rocks are often altered by hydrothermal fluids such that the original textures and compositions of igneous magnetite may be partly or completely obliterated, posing interpretive problems in petrological and geochemical studies. In this paper, we present textural and compositional data of magnetite from variably albitized granitoid rocks in the Handan-Xingtai district, North China Craton to characterize the hydrothermal reequilibration of igneous magnetite.Four types of magnetite have been identified in the samples studied: pristine igneous magnetite (type 1), reequilibrated porous magnetite (type 2), reequilibrated nonporous magnetite (type 3), and hydrothermal magnetite (type 4). Pristine igneous magnetite contains abundant well-developed ilmenite exsolution lamellae that are largely replaced by titanite during subsequent hydrothermal alteration. The titanite has a larger molar volume than its precursor ilmenite and thus causes micro-fractures in the host magnetite grains, facilitating dissolution and reprecipitation of magnetite. During sodic alteration, the igneous magnetite is extensively replaced by type 2 and type 3 magnetite via fluid-induced dissolution and reprecipitation. Porous type 2 magnetite is the initial replacement product of igneous magnetite and is subsequently replaced by the nonoporous type 3 variety as its surface area is reduced and compositional equilibrium with the altering fluid is achieved. Hydrothermal type 4 magnetite is generally euhedral and lacks exsolution lamellae and porosity, and is interpreted to precipitate directly from the ore-forming fluids.Hydrothermal reequilibration of igneous magnetite has led to progressive chemical purification, during which trace elements such as Ti, Al, Mg, Zn, and Cr contents decrease dramatically (up to 2–3 orders of magnitude different), coupled with significant increase in iron concentrations from less than 64wt.% to higher than 70wt.%. Results presented here show that magnetite is much more susceptible to textural and compositional reequilibration than previously thought. The reequilibrated magnetite has geochemical patterns that may be distinctively different from its precursor, making existing discrimination plots questionable when applied to genetic interpretation. Based on textural characterization and high-resolution in situ compositional analyses, we propose that the Fe versus V/Ti diagram can be more confidently used to discriminate between pristine igneous magnetite, reequilibrated magnetite, and hydrothermal magnetite.