Tooth bleaching is one of the most frequently performed esthetic procedures in dentistry. Although peroxide-based bleaching agents effectively promote color change, their decomposition generates reactive oxygen species that may induce oxidative stress, cytotoxicity, genotoxicity, inflammation, and oral tissue alterations. This scoping review mapped and synthesized the available evidence regarding genotoxicity and oral tissue damage associated with tooth bleaching procedures, identified the biological models and analytical methods used to investigate these outcomes, and explored differences among bleaching protocols. The review followed the Joanna Briggs Institute methodology and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews guidelines. Searches were conducted in major electronic databases and supplementary searches. Ninety-four studies were included, comprising laboratory, animal, and human investigations. The most commonly used analytical methods included micronucleus assays, comet assays, oxidative stress biomarkers, molecular analyses, and histopathological evaluations. Peroxide-based bleaching agents were frequently associated with oxidative stress, cytotoxicity, genotoxicity, inflammatory responses, apoptosis, and tissue alterations, which appeared to occur in a concentration-dependent and time-dependent manner. Laboratory studies generally reported more pronounced biological effects, whereas animal and clinical investigations demonstrated the influence of physiological defense and repair mechanisms. Clinical studies frequently reported transient biological alterations. Oxidative stress emerged as the central mechanism linking peroxide exposure to cellular and tissue damage. Overall, peroxide concentration, exposure duration, and protocol design emerged as relevant factors modulating biological responses, whereas catalysts, antioxidants, and photobiomodulation therapies represented promising strategies to mitigate bleaching-induced damage. Further standardized and long-term clinical studies are required to clarify the biological significance and clinical relevance of these effects.
Prostate cancer (PCa) is one of the most heritable cancers, exhibiting significant familial aggregation, however, its underlying mechanisms remain incompletely understood. This review proposes a Genetics-Epigenetics-Environment (G-E-E) 3D framework, which not only integrates genetic factors frequently addressed in previous reviews but also incorporates overlooked intergenerational/transgenerational epigenetic inheritance (IEI/TEI) and family-shared environment (FSE). Regarding genetic factors, germline mutations (e.g. BRCA1/2, MLH1, HOXB13), single nucleotide polymorphisms (SNPs), germline copy number variations (GCNVs), and Y-chromosome haplotypes have been extensively documented in PCa familial aggregation research. Adverse parental environmental exposures can induce epigenomic abnormalities in germ cells (including DNA methylation, histone modifications, and non-coding RNAs), which can be transmitted intergenerationally or transgenerationally to drive the initiation and progression of PCa in offspring. Finally, we note that family-shared environments collectively influence all family members, thereby contributing to PCa familial aggregation. Together, these three classes of factors-genetic, epigenetic, and environmental-provide a more comprehensive perspective for explaining the familial aggregation of PCa, offering new insights into predicting its occurrence within families.
BACKGROUND:Somatic variant callers were originally developed to identify tumour-specific mutations in mixed tumour-normal samples. Increasingly, disciplines such as developmental biology, reproductive medicine, virology and mitochondrial genetics require detection of low-frequency variants from high-depth sequencing. Many laboratories therefore reuse cancer callers without clear guidance on their statistical assumptions or validation in non-cancer contexts. METHODS:We review widely used somatic callers and post-calling classifiers, summarising their underlying models and assumptions. We then synthesise peer-reviewed case studies (2020-2025) where these tools were applied to detect low-allele-fraction variants outside cancer. For each study, we extract sample type, sequencing depth, variant-allele-fraction thresholds, caller(s) used and validation approaches. We discuss technical challenges and propose practical adaptations. RESULTS:Cancer callers generally assume diploid genomes and moderate allele fractions, use Beta-binomial or Poisson-based models and apply filters for tumour/normal comparisons. In non-cancer applications, allele fractions frequently fall below 5%, confounded by ploidy differences and sequencing artefacts. Published studies demonstrate that somatic callers can be repurposed for detecting post-zygotic variants at 1-3% allele fraction, sperm mosaicism, mitochondrial heteroplasmy as low as 0.4-0.5%, minority viral variants around 5% and cfDNA variants at ≥ 1-5% allele fraction. Unique molecular identifiers, panel-of-normal filtering and machine-learning post-processing markedly improve specificity. Emerging long-read and deep-learning callers (e.g. DeepSomatic) promise enhanced sensitivity. CONCLUSIONS:Somatic callers offer versatile frameworks to interrogate low-allele-fraction variants across genomics; however, careful parameter tuning and validation are essential. Future work could integrate pangenome references and federated benchmarking datasets to make somatic variant detection more robust in diverse biological settings.
This paper compiles results from six systematic reviews and meta-analyses on associations between environmental and occupational exposure to chemicals and levels of DNA strand breaks in human leukocytes, measured by the comet assay. There are no differences in effect sizes when using different comet descriptors. However, lower central tendencies are obtained by using a non-parametric test as compared to the standard parametric analysis, indicating that the standard meta-analyses tend to overestimate the effect size. The compiled results indicate that exposures can be sorted into three groups with decreasing effect size: high (pesticides), moderate (volatile organic compounds, heavy metals and antineoplastic drugs), and low (anaesthetic gases and air pollution). Interestingly, studies from middle-income countries have higher effect sizes than those seen in studies from high-income countries. This may be related to higher exposures or lower socioeconomic status in middle-income countries. However, there is also some co-variability between studies from middle-income countries and the risk of comet assay measurement bias, assessed as information provided in published papers. Lack of information on assay controls and blinded/coded sample analysis appears to be a general issue in studies on comet assay results. Risk of exposure misclassification is mainly related to the type of exposure; there are good biomarkers for some exposures (e.g. heavy metals), whereas other exposures are more challenging to assess with biomarkers (e.g. pesticides). In conclusion, all examined exposures result in significant increases in DNA strand breaks at the population level, though to varying degrees.
Canine mammary tumors (CMTs) are the most prevalent neoplasms in intact female dogs, accounting for up to 50% of all neoplasms, with malignancy rates ranging from 50% to 89%. Human breast cancer (HBC) remains a leading cause of cancer morbidity and mortality worldwide. Both diseases exhibit remarkable biological and molecular similarity, making the domestic dog an excellent spontaneous model for studying HBC. CMTs and HBC share histopathological features. They also have comparable classification systems, including hormone receptor-based subtypes (luminal A, luminal B, HER2-positive) and the triple-negative subtype, as well as dysregulation of pathways such as PI3K/AKT and Wnt/β-catenin. Furthermore, they share several risk factors and environmental determinants. In contrast to rodent models, dogs offer natural genetic variation and comparable environmental exposures, enabling more physiological studies of cancer development. This review focuses on genomic instability, specifically microsatellite instability (MSI) and loss of heterozygosity (LOH), as an important driver of neoplastic growth in both species. MSI results from DNA mismatch repair defects, whereas LOH indicates tumor suppressor gene inactivation. Emerging evidence shows that these alterations occur in CMTs just as they do in HBC. Investigating MSI and LOH in dogs can uncover common molecular mechanisms, identify reliable biomarkers, and reveal novel therapeutic targets. Ultimately, this comparative approach reinforces the "One Health" concept, bridging veterinary and human medicine to improve cancer outcomes for both species.
Inherited long QT syndrome (LQTS) is a life-threatening cardiac channelopathy characterized by impaired ventricular repolarization and heightened susceptibility to ventricular arrhythmias and sudden cardiac death. While mutations in ion channel genes (e.g., KCNQ1, KCNH2) are well-known causes of LQTS, emerging evidence highlights the critical role of regulatory proteins, including a-kinase anchoring protein 9 (AKAP9), in modulating channel function. AKAP9 scaffolds protein kinase A (PKA), protein phosphatase 1 (PP1), and phosphodiesterase PDE4D3 into a macromolecular complex with KCNQ1, enabling dynamic phosphorylation of the potassium channels in response to β-adrenergic stimulation. Mutations in AKAP9 gene (e.g., S1570L) or its binding partner KCNQ1 (e.g., G589D) destabilize this complex, impairing PKA-mediated phosphorylation of KCNQ1 at serine-27. This defect blunts the sympathetic enhancement of slow delayed rectifier potassium channel (IKs), a critical mechanism for augmenting repolarization reserve during stress. Consequently, action potential duration prolongation, QT interval elongation, and early afterdepolarizations even polymorphic ventricular tachycardia were induced, particularly under conditions of heightened sympathetic tone. This review focuses on how AKAP9 mutations disrupt the sympathetic regulation of the IKs, mediated by the KCNQ1-KCNE1 channel complex, and contribute to the pathogenesis of LQTS type 11.
Antineoplastic agents are toxic compounds, generally used in the treatment of cancers, which are recognized as carrying a cancer development risk. In this systematic review and meta-analysis of human biomonitoring studies, we have assessed the effects of exposure to antineoplastic drugs on levels of DNA strand breaks in leukocytes, measured by the comet assay.Focusing on the application of the comet assay in human biomonitoring of occupational exposure to antineoplastic agents, we have analyzed 458 original research studies which used this assay, following the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA-ScR). The systematic review led to 23 studies, of which 20 studies met the criteria for inclusion in the meta-analysis. Using standardized mean difference and 95% confidence interval (CI), the meta-analyses show increased levels of DNA strand breaks in subjects exposed to antineoplastic drugs (1.26, 95% CI: 0.78, 1.73). Results originate mainly from studies on healthcare workers, with only one study in an industrial setting. Subgroup analysis indicates that all studies combined from middle-income countries have a higher effect size (1.77, 95% CI: 1.00, 2.55) than studies from high-income countries (0.49, 95% CI: 0.09, 0.90). This difference between middle- and high-income countries may be attributable in part to differences in exposure levels or exposure assessment. Additionally, sensitivity analysis indicates that studies with moderate/high risk of comet assay measurement bias have higher effect size (2.07, 95% CI: 0.82, 3.31) than studies with low risk of bias (0.73, 95% CI: 0.34, 1.13); and that studies with high risk of exposure misclassification have higher effect size (1.47, 95% CI: 0.89, 2.06) than studies with low/moderate risk (0.13, 955 CI: -0.08, 0.33). Most studies have low/moderate risk of bias related to the comet assay procedure (15 out of 20 studies), absence of reporting the use of assay controls (1 out of 20 studies), blinded analysis of samples (7 out 20 studies); exposure assessment (16 out of 20 studies).In conclusion, this systematic review and meta-analysis shows that exposure to antineoplastic drugs is associated with increased levels of DNA strand breaks in human leukocytes.
Aging is a progressive and irreversible physiological process driven by a complex network of interrelated molecular and cellular mechanisms. Among these, cellular senescence and chronic inflammation, as two core hallmarks of aging, are interlinked and jointly promote the development and progression of aging. However, the precise molecular crosstalk between these two processes remains unclarified. Mitochondrial DNA (mtDNA), as the only cytoplasmic DNA, has recently emerged as a pivotal "bridge" linking cellular senescence and chronic inflammation through various mechanisms. Anchored on the unique characteristics of mtDNA, this review systematically elucidates its central roles in mitochondrial dysfunction and oxidative stress, with a particular emphasis on the dynamic changes of mtDNA within the cytosol and extracellular space that construct and amplify the cellular "inflammation-senescence" coupling network. Furthermore, we propose a conceptual framework linking mtDNA mutation/damage to the cellular senescence and the propagation of chronic inflammation. Finally, we discuss the therapeutic potential of targeting mtDNA dynamics and highlight key challenges and future directions in this emerging field, offering novel insights for mitigating aging and age-related diseases.
Anaesthetic gases are agents used to induce and maintain general anaesthesia during surgical procedures. Common examples include sevoflurane, isoflurane, and desflurane, which act by depressing the central nervous system to produce unconsciousness and analgesia. These gases are administered through a vaporiser and inhaled via a mask or endotracheal tube. While effective, they can contribute to environmental pollution and increase the risk of occupational exposure. Medical personnel working in operating or post-operating facilities are unavoidably exposed to anaesthetic gases. Several adverse health effects have been associated with anaesthetic gas exposure; therefore, this review aims to summarise findings on DNA strand breaks, assessed by the comet assay in leucocytes of exposed medical workers. Standardised mean differences (SMDs) have been calculated by random effects models. The meta-analysis included 16 studies. Of these, 11 showed statistically significant increased levels of DNA strand breaks, whereas another five studies showed no significant effect. Overall, there is an increased level of DNA strand breaks in exposed subjects in unadjusted analysis (SMD = 1.17, 95 % confidence interval: 0.71, 1.62) as well as analysis adjusted for missing studies by the trim-and-fill method (SMD = 0.53, 95 % confidence interval: -0.14, 1.21). In conclusion, this systematic review and meta-analysis demonstrate that exposure to anaesthetic gases in an occupational setting induces primary DNA damage in human leucocytes, warranting further research to minimise any adverse effects on exposed medical personnel. Besides, the relevance of the use of the comet assay in assessing DNA damage in human biomonitoring studies is proven.
Natural background radiation (NBR) delivers chronic low-dose-rate ionizing radiation worldwide, with a global average annual effective dose of ∼2.4 mSv. In certain high-background radiation areas (HBRAs), annual doses range from 10 to > 200 mSv. While the linear no-threshold (LNT) model assumes any radiation dose carries some cancer risk, epidemiological studies in HBRAs (Kerala-India, Ramsar-Iran, Yangjiang-China, Guarapari-Brazil) have consistently failed to detect the predicted cancer excess. Some cytogenetic and molecular investigations suggest enhanced DNA repair proficiency or lower-than-expected chromosomal damage in chronically exposed residents. This narrative review critically synthesizes epidemiological, cytogenetic, and limited molecular evidence from HBRAs, evaluates the ability of current dose-response models (LNT versus non-linear alternatives) to explain these observations, identifies major knowledge gaps, and discusses implications for low-dose radiation risk assessment and public health policy.
Humans are exposed to environmental or occupational air pollution from combustion emissions in outdoor and indoor environments. Irrespective of the sources, combustion emissions are characterized by being a complex mixture of particles, volatile compounds and gases. The present systematic review summarizes results on DNA strand breaks measured by the comet assay in leukocytes, from studies on human exposure to traffic-related vehicle exhaust, biomass combustion and coke oven work environments. These exposures have in common the combustion of fuel, which generates particles and polycyclic aromatic hydrocarbons. Standardized mean differences (SMDs) have been calculated by random effects models. Meta-analyses show increased levels of DNA strand breaks in studies on traffic-related exhausts (SMD = 0.62, 95% CI: 0.36, 0.89, n = 21), biomass combustion (1.73, 95% CI: 0.72, 2.74, n = 10) and coke oven emission (0.84, 95% CI: 0.30, 1.37, n = 10). Studies from high-income countries have reported much smaller differences in DNA strand break levels than have studies from middle-income countries. These differences may be attributed to higher exposures related to less strict emission control, and more susceptible populations in middle-income populations; unrecognized confounding despite efforts to match subjects on traditional confounders; or higher risk of comet assay measurement bias and exposure misclassification. In conclusion, this systematic review and meta-analysis show that exposure to combustion-derived air pollution, with clear exposure gradients in terms of particulate matter or polycyclic aromatic hydrocarbons, is associated with increased levels of DNA strand breaks in human leukocytes.
Exposure to volatile organic compounds (VOCs) such as benzene, styrene, toluene and formaldehyde is associated with genotoxicity and increased risk of cancer. In this systematic review and meta-analysis, we have assessed the effects of VOCs exposure on levels of DNA strand breaks in leukocytes, measured by the comet assay, in human biomonitoring studies. The literature search led to 57 studies included in the review. Of these, 50 studies met the criteria to be used in the meta-analysis. Using standardized mean difference and 95 % confidence interval (CI), the meta-analyses show increased levels of DNA strand breaks in subjects exposed to benzene (1.59, 95 % CI: 0.94, 2.24), styrene (0.87, 95 % CI: 0.23, 1.51), formaldehyde (0.39, 95 % CI: -0.15, 0.92) and other organic solvents (2.14, 95 % CI: 1.48, 2.81). Results originate mainly from studies on workers, with only a few studies on environmental benzene exposure. Subgroup analysis indicates that all studies combined from middle-income countries have a higher effect size (1.81, 95 % CI: 1.26, 2.36, n = 28) than studies from high-income countries (0.87, 95 % CI: 0.49, 1.24, n = 22). This difference between middle- and high-income countries may be due to differences in exposure levels or exposure assessment. However, this might not be the only reason, as sensitivity analysis indicates that effect sizes are at risk of comet assay measurement bias, as 78 % (39 out of 50 studies) and 60 % (30 studies) have not reported the use of assay controls and blinded analysis of samples, respectively. Relatively few studies have a high risk of bias due to an inadequate comet assay procedure description (14 %, 7 studies) and exposure misclassification (16 %, 8 studies). Limitations of the study were the differences in protocols, comet descriptors, exposure assessment and control for confounding factors among the studies. In conclusion, this systematic review and meta-analysis shows that exposure to VOCs - benzene, styrene, formaldehyde and others - is associated with increased levels of DNA strand breaks in human leukocytes.
There is a growing body of epidemiological evidence for elevated risks of a variety of multifactorial diseases such as cancer, neurodegenerative diseases (e.g., Parkinson’s disease and dementia) and cerebrovascular diseases (e.g., stroke) following radiation exposure of the brain. Implications of available scientific evidence for radiation protection need to be assessed, e.g., in terms of radiation effect classification (tissue reactions vs stochastic effects), dose and dose-rate effectiveness, target identification (at levels of cells, tissues and organs inside/outside the brain) for dose monitoring and risk management, radiation weighting approach for the mixed radiation field, and individual differences in radiation responses (e.g., with sex, age, populations, genetics, epigenetics, comorbidity, co-exposure). On the other hand, whole brain irradiation has clinically been tested to treat neurodegenerative diseases, particularly Alzheimer’s disease. Action of radiation seems to represent a double-edged sword (i.e., detrimental to the healthy brain vs therapeutic to the diseased brain) not only for cancer, but also for non-cancer diseases. Justification of radiation exposure and optimization of radiation protection would therefore be of critical importance. This paper gives a brief overview of emerging evidence for radiation effects in the brain, and considers its potential implications for radiation protection.
Oral cancer poses a significant health challenge in Southeast Asia, with a high incidence and mortality. Despite extensive genomic research, a molecular classification for this disease is lacking. This study aimed to address this gap by proposing a molecular classification of oral cancer based on genetic alterations. We conducted a comprehensive literature search on PubMed, identifying 8176 articles related to oral cancer genomics. From these, we selected studies focusing on genomics and compiled a list of 48 genes implicated in carcinogenesis, cross-referencing our findings with the TCGA database. Using cluster analysis and gene ontology, we grouped these genes by function and interactions, and then constructed protein-protein interaction networks to develop our proposed classification. Our results categorize the genes into five main groups: cell-cycle dysregulation (including growth activation and apoptotic dysregulation), immune-mediated, xenobiotic metabolism-associated, inflammatory pathway activation, and viral protein activation. Cell-cycle dysregulation was the most frequently studied, affecting over 60 % of cases, with TP53 being the most common alteration. While immune-mediated and inflammatory pathways are recognized for their therapeutic relevance, xenobiotic and viral mechanisms remain less explored. This review provides the first molecular classification of oral cancer, identifying five key carcinogenic pathways. This framework is expected to improve our understanding of the molecular diversity of oral cancer and guide the development of targeted therapies, especially for understudied pathways like xenobiotic metabolism and inflammation.
Non-thermal plasma (NTP), a partially ionized gas enriched with reactive oxygen and nitrogen species (RONS) and UV radiation, is increasingly used in medicine, agriculture, and food processing applications. While its oxidative and antimicrobial effects are well documented, the molecular mechanisms underlying its genotoxic and mutagenic effects in eukaryotic systems remain poorly understood. This review consolidates the current evidence on how NTP interacts with cellular and molecular targets to induce DNA damage. Key mechanisms are identified that link plasma-generated RONS and physical components to base oxidation (8-oxoG formation), single- and double-strand breaks (γ-H2AX foci), and chromosomal instability (micronuclei formation). The extent and nature of these effects are further influenced by plasma parameters—including source configuration, working gas composition, exposure duration, and delivered dose—as well as by intrinsic cellular factors such as DNA repair capacity, antioxidant defenses, and overall metabolic state. In addition to cataloguing genotoxic outcomes, this review synthesizes mechanistic insights across unicellular, plant, and animal models, emphasizing comparative sensitivity, methodological variability, and the influence of plasma dosimetry on biological responses. By integrating these findings, we highlight both the potential therapeutic selectivity of NTP—particularly against tumor cells—and the remaining challenges for safe biomedical translation.
Peroxisomes are essential, highly conserved organelles in eukaryotic cells, with well-characterized roles in fatty acid β-oxidation, ether phospholipid (a key component of myelin lipid) synthesis, and maintaining redox homeostasis. Peroxisomal disorders primarily arise from abnormalities in peroxisome biogenesis or degradation, as well as enzyme deficiencies, often with genetic mutations serving as their underlying drivers. To date, effective therapeutic strategies for these disorders remain scarce. This review focuses on elucidating the pathogenesis of peroxisome biogenesis disorders (PBDs), while also clarifying the diagnostic and therapeutic approaches for PBDs specifically. It also includes a brief discussion on the role of artificial intelligence (AI) in the management of these disorders. This ultimately aims to provide a theoretical basis and practical reference for future clinical interventions.
Acute myeloid leukemia (AML) is the most common type of acute leukemia in adults, and its incidence increases with age and is more common in elderly population. The current treatment methods for AML mainly include chemotherapy, targeted therapy, immunotherapy and hematopoietic stem cell transplantation, among which chemotherapy and targeted therapy are the most common methods. Combined therapy further enhances the therapeutic effect of AML and reduces drug toxicity. At present, drug resistance is a common problem in the treatment of AML. Gene mutations and treatment-induced mutations are the main causes of drug resistance in AML, and drug resistance is also generated during the interaction between tumor microenvironment and AML. Real-time monitoring of tumor markers such as the most common gene mutations and the changes of novel biomarkers, provides certain reference value for the occurrence of AML and the prevention of drug resistance in the process of AML diagnosis and treatment. Finally, a new direction in the future diagnosis and treatment of AML is proposed based on the current diagnosis and treatment status.
The maintenance of the genome in eukaryotic cells is dependent on the proper maintenance of the structure and function of the nuclear envelope which encases the genome. The nuclear envelope in higher eukaryotic cells is composed of the outer nuclear membrane, the inner nuclear membrane, and the nuclear lamina which resides just inside of the inner nuclear membrane. The nuclear lamina provides mechanical support to the nuclear envelope, plays essential roles in transport of molecules between the cytoplasm and the nucleus, and is pivotal in regulating global chromatin structure and three-dimensional nuclear architecture. Proper functioning of the nuclear lamina plays roles in regulating the cell cycle, transcription, RNA splicing, chromatin organization, DNA replication, and DNA repair. The nuclear lamina is conserved in metazoans and is composed of a meshwork of interwoven proteins called lamins, as well as lamin associated proteins. The protein known as lamin A is a vital constituent of the nuclear lamina. Alterations in lamin A, particularly those associated with disruptions in posttranslational processing of lamin A by zinc metallopeptidase ste24, have been linked to a variety of genetic disorders that give rise to genome instability and accelerated aging. This review will concentrate primarily on what has been learned about the dependency of effective DNA repair and DNA replication on a functional nuclear lamina, with particular emphasis on how modifications in the protein lamin A may corrupt a cell’s ability to maintain genome stability.
Wilson's disease (WD) is an autosomal recessive disorder caused by mutations in the ATP7B gene, which impair cellular copper excretion and lead to toxic copper accumulation in the liver, brain, and other organs. Clinically, WD presents with a broad spectrum of hepatic and neurological manifestations. The pronounced phenotypic variability among patients harboring identical ATP7B mutations, including affected siblings, suggests the influence of additional genetic and/or epigenetic factors such as non-coding RNAs (ncRNAs), in modulating disease presentation. This review explores the potential involvement of ncRNAs in shaping the hepatic phenotype of WD. Although a few transcriptomic and network-based studies in mouse models have underscored the relevance of ncRNAs in WD pathogenesis, there remains a paucity of research investigating their role in the spectrum of hepatic severity observed in human patients. To address this gap, we collated existing evidence on ncRNAs implicated in WD and further sought to predict additional candidate ncRNAs by aligning hepatic severity categories in WD with general liver diseases that exhibit similar clinical features. Through a systematic literature review, we identified dysregulated ncRNAs in these liver diseases that may serve as surrogates for WD severity groups. Furthermore, our in silico analyses highlighted several microRNAs (miRNAs) that, if upregulated, could downregulate ATP7B or its putative modifier genes, raising the possibility that miRNA dysregulation may phenocopy certain pathogenic effects of ATP7B mutations, especially in WD cases exhibiting missing heritability.
