Polygenic Origin Research Articles

Modelling human diabetes ex vivo: a glance at maturity onset diabetes of the young.

Diabetes is a complex metabolic disease which most commonly has a polygenic origin; however, in rare cases, diabetes may be monogenic. This is indeed the case in both Maturity Onset Diabetes of the Young (MODY) and neonatal diabetes. These disease subtypes are believed to be simpler than Type 1 (T1D) and Type 2 Diabetes (T2D), which allows for more precise modelling. During the three last decades, many studies have focused on rodent models. These investigations provided a wealth of knowledge on both pancreas development and beta cell function. In particular, they allowed the establishment of a hierarchy of the transcription factors and highlighted the role of microenvironmental factors in the control of progenitor cell proliferation and differentiation. Transgenic mice also offered the possibility to decipher the mechanisms that define the functional identity of the pancreatic beta cells. Despite such interest in transgenic mice, recent data have also indicated that important differences exist between mice and human. To overcome these limitations, new human models are necessary. In the present review, we describe these ex vivo models, which are created using stem cells and organoids, and represent an important step toward islet cell therapy and drug discovery.

Place du traitement médicamenteux dans l’obésité de l’enfant et de l’adolescent

Child and adolescent obesity is definitely a pathology the understanding of which has faced dramatic changes in recent years thanks to the identification of the genetic background of some cases and an amazing increase in the knowledge of its biological background. The adipose tissue is an endocrine organ in permanent communication with other ones, including the appetite regulation centres of the brain and the neuroendocrine system of the digestive tract. A precise analysis of the trajectory of weight gain and its associated manifestations such as abnormal physical or developmental features and complications is mandatory while facing a child or adolescent with obesity. A close cooperation with reference centres for childhood obesity and nutrigenomics research units leading to the diagnosis of genetic forms, likely to be underdiagnosed, may allow the use of targeted and efficient drug treatment. A recent double-blind study has shown that a Glucagon like peptide 1 (GLP1) analogue, a key contributor of appetite regulation from intestinal origin, has a major beneficial impact on adolescents with obesity of polygenic origin. Further studies are still required to ensure the long-term effect and the lack of side effects of such a treatment. However, such results already challenge the indication of bariatric surgery. While prevention still must be a priority, many other molecules and therapeutic approaches are underway for the most frequent metabolic and chronic childhood disorder.

Brugada Syndrome: More than a Monogenic Channelopathy.

Brugada syndrome (BrS) is an inherited cardiac channelopathy first diagnosed in 1992 but still considered a challenging disease in terms of diagnosis, arrhythmia risk prediction, pathophysiology and management. Despite about 20% of individuals carrying pathogenic variants in the SCN5A gene, the identification of a polygenic origin for BrS and the potential role of common genetic variants provide the basis for applying polygenic risk scores for individual risk prediction. The pathophysiological mechanisms are still unclear, and the initial thinking of this syndrome as a primary electrical disease is evolving towards a partly structural disease. This review focuses on the main scientific advancements in the identification of biomarkers for diagnosis, risk stratification, pathophysiology and therapy of BrS. A comprehensive model that integrates clinical and genetic factors, comorbidities, age and gender, and perhaps environmental influences may provide the opportunity to enhance patients' quality of life and improve the therapeutic approach.

The use of assistance dogs in the detection of hypoglycemic episodes in type 1 diabetes: a descriptive and comprehensive review

Introduction: Type 1 diabetes mellitus (T1DM) is a disease of autoimmune and polygenic origin, characterized by the destruction of the beta cells of the pancreatic islets and, consequently, the absence of insulin production. The treatment aims at imitating the physiological secretion of insulin in individuals without comorbidity, using insulin therapy. Hypoglycemia is defined as any event of abnormally low blood glucose, putting the person at potential risk. Tachycardia, tremors, pallor, cold sweating, lingual paresthesia, and blurred vision, possibly leading to coma, are its main signs and symptoms. The recognition of serious clinical conditions transmitted by both visual and olfactory signals can be understood and elaborated by the dog's cognitive system, allowing the rapid detection of a hypoglycemic episode and, thus, allowing adequate conduct before a serious episode. Objective: To analyze the advances, both in studies and in professional practices, in the use of assistance dogs to identify hypoglycemia in diabetics 1, as well as to seek to understand the consequences of unidentified and untreated hypoglycemia. Methods: The most relevant studies searched using the keywords "hypoglycemia AND diabetes", in addition to "diabetes alert dogs" in Google Scholar, were analyzed, with 4 corresponding to the objectives of the current research. Finally, pathology books and official documents from the Ministry of Health and the Brazilian Society of Diabetes were used to build a theoretical explanation. Results and Discussion: Dogs are conditioned to respond with specific alert behaviors, such as barking or licking, when levels of their owner's blood sugar levels are below the ideal range, as identified by the amount of isoprene released in the individual's breath. This attitude causes the patient to measure his plasma glucose level, helping him to carry out the appropriate measures to keep the levels back to normal. The hesitation of the occurrence of hypoglycemia causes some type 1 diabetic to contain their lifestyle to try to reduce the probability of the occurrence of a hypoglycemic episode, negatively affecting their quality of life and psychological well-being. In addition, they can intentionally maintain hyperglycemia to avoid a sudden drop in glucose, however, this practice results in late problems such as nephropathy, neuropathy, and cardiopathy. Conclusions: Hypoglycemia is one of the main threats for people with diabetes, as it results in severe symptoms that can lead to coma if not treated quickly. Possibly, dogs perceive plasma glycemic variations using, in addition to the olfactory apparatus, perceptions captured through other senses, mainly vision, but the scarcity of studies carried out with dogs trained to support people with diabetes problems, mainly in Brazil, makes the efficiency of these animals to detect alterations of glucose in the blood remains debatable.

Diamond Formation via Carbonate or CO2 Reduction under Pressures and Temperatures of the Lithospheric Mantle: Review of Experimental Data

Existing ideas about the polygenic origin of diamonds in nature involve various processes, mechanisms, and driving forces for diamond crystallization, including redox reactions, changes in P-T conditions, evolution of melt or fluid composition, and others. According to classical models, in the lithospheric mantle, diamond formation occurs at depths of 120–210 km and temperatures of 900–1500 °C as a result of metasomatic processes. The driving forces in these models are considered to be redox reactions leading to the reduction of carbonates, carbonate melts, or CO2 to elemental carbon. In this study, we provide a review and systematization, as well as experimental issues and possible future directions of experimental studies, on diamond crystallization from carbonate carbon through redox reactions at P,T (pressure, temperature) conditions relevant to the lithospheric mantle. These studies have demonstrated that silicon, metals (FeSi, Fe, Fe-Nialloys), carbides (SiC, Fe3C, Fe7C3), reduced components of C-O-H fluid, sulfides/sulfide melts, Fe-S-C melts, and the application of an electric field (potential difference) can act as reducing agents for carbonate/carbonate-bearing melts or CO2 fluid, leading to the formation of diamond and graphite. The experimental data reviewed in this paper not only indicate the fundamental possibility of diamond formation from carbonate carbon through the reduction of carbonate, carbonate-bearing phases, or CO2 in the mantle, but also reveal the characteristic features of the resulting diamonds. Furthermore, the significance of potential reducing agents (fluid, sulfide, silicon, metal, and carbide) in various geodynamic settings, including the lithospheric mantle at depths insufficient for stabilizing iron or carbides, has been identified.

Rapid degeneration of iPSC-derived motor neurons lacking Gdap1 engages a mitochondrial-sustained innate immune response

Charcot-Marie-Tooth disease is a chronic hereditary motor and sensory polyneuropathy targeting Schwann cells and/or motor neurons. Its multifactorial and polygenic origin portrays a complex clinical phenotype of the disease with a wide range of genetic inheritance patterns. The disease-associated gene GDAP1 encodes for a mitochondrial outer membrane protein. Mouse and insect models with mutations in Gdap1 have reproduced several traits of the human disease. However, the precise function in the cell types affected by the disease remains unknown. Here, we use induced-pluripotent stem cells derived from a Gdap1 knockout mouse model to better understand the molecular and cellular phenotypes of the disease caused by the loss-of-function of this gene. Gdap1-null motor neurons display a fragile cell phenotype prone to early degeneration showing (1) altered mitochondrial morphology, with an increase in the fragmentation of these organelles, (2) activation of autophagy and mitophagy, (3) abnormal metabolism, characterized by a downregulation of Hexokinase 2 and ATP5b proteins, (4) increased reactive oxygen species and elevated mitochondrial membrane potential, and (5) increased innate immune response and p38 MAP kinase activation. Our data reveals the existence of an underlying Redox-inflammatory axis fueled by altered mitochondrial metabolism in the absence of Gdap1. As this biochemical axis encompasses a wide variety of druggable targets, our results may have implications for developing therapies using combinatorial pharmacological approaches and improving therefore human welfare.A Redox-immune axis underlying motor neuron degeneration caused by the absence ofGdap1. Our results show that Gdap1–/– motor neurons have a fragile cellular phenotype that is prone to degeneration. Gdap1–/– iPSCs differentiated into motor neurons showed an altered metabolic state: decreased glycolysis and increased OXPHOS. These alterations may lead to hyperpolarization of mitochondria and increased ROS levels. Excessive amounts of ROS might be the cause of increased mitophagy, p38 activation and inflammation as a cellular response to oxidative stress. The p38 MAPK pathway and the immune response may, in turn, have feedback mechanisms, leading to the induction of apoptosis and senescence, respectively. CAC, citric acid cycle; ETC, electronic transport chain; Glc, glucose; Lac, lactate; Pyr, pyruvate.

Bone Microarchitecture and Strength Changes During Teriparatide and Zoledronic Acid Treatment in a Patient with Pregnancy and Lactation-Associated Osteoporosis with Multiple Vertebral Fractures

Pregnancy- and lactation-associated osteoporosis (PLO) is a rare form of osteoporosis, of which the pathogenesis and best treatment options are unclear. In this report, we describe the case of a 34-year old woman diagnosed with severe osteoporosis and multiple vertebral fractures after her first pregnancy, who was subsequently treated with teriparatide (TPTD) and zoledronic acid (ZA). We describe the clinical features, imaging examination, and genetic analysis. Substantial improvements were observed in areal and volumetric bone mineral density (BMD), microarchitecture, and strength between 7 and 40 months postpartum as assessed by dual-energy X-ray absorptiometry at the total hip and spine and by high-resolution peripheral quantitative CT at the distal radius and tibiae. At the hip, spine, and distal radius, these improvements were mainly enabled by treatment with TPTD and ZA, while at the distal tibiae, physiological recovery and postpartum physiotherapy due to leg pain after stumbling may have played a major role. Additionally, the findings show that, despite the improvements, BMD, microarchitecture, and strength remained severely impaired in comparison with healthy age- and gender-matched controls at 40 months postpartum. Genetic analysis showed no monogenic cause for osteoporosis, and it is suggested that PLO in this woman could have a polygenic origin with possible susceptibility based on familiar occurrence of osteoporosis.

Nature of Hydrocarbon Fluids at the Fields in the North of Western Siberia: the Geochemical Aspect

The paper presents original results of comprehensive geochemical studies of samples of oils, condensates, gases, core, and cuttings from wells drilled in the north of Western Siberia. The studies involved chromatographic and mass spectrometric determinations of the molecular and isotopic composition of the oils, gases, condensates, and rock extracts. Analysis of the results, considered together with literature data, made it possible to draw conclusions regarding the source of the hydrocarbons and the mechanism of formation of their accumulations. Information on the molecular and isotopic composition of the fluids and the distribution of their accumulations and fields in the sedimentary cover shows that most of them are of polychronic and polygenic origin. Features of the molecular and isotopic composition of the fluids make it possible to evaluate the contribution of various sources to the formation of hydrocarbon accumulations. The composition of their liquid component was formed as a result of the generation of hydrocarbons by the organic matter of Jurassic source rocks. The Lower and Middle Jurassic rocks with non-marine organic matter also made a significant contribution to the formation of the gas component of deposits in the north of Western Siberia, whereas the Cretaceous rocks generated only dry gas and were likely the main source of gas for the giant fields, whose methane has a light carbon isotope composition. The use of the isotopic composition of carbon in combination with molecular parameters makes it possible to clarify the conditions under which a particular field was formed and to elucidate the migration pathways and distances of hydrocarbon fluids to their accumulation sites

Neurog2 regulates Isl1 to modulate horizontal cell number.

The population sizes of different retinal cell types vary between different strains of mice, and that variation can be mapped to genomic loci in order to identify its polygenic origin. In some cases, controlling genes act independently, whereas in other instances, they exhibit epistasis. Here, we identify an epistatic interaction revealed through the mapping of quantitative trait loci from a panel of recombinant inbred strains of mice. The population of retinal horizontal cells exhibits a twofold variation in number, mapping to quantitative trait loci on chromosomes 3 and 13, where these loci are shown to interact epistatically. We identify a prospective genetic interaction underlying this, mediated by the bHLH transcription factor Neurog2, at the chromosome 3 locus, functioning to repress the LIM homeodomain transcription factor Isl1, at the chromosome 13 locus. Using single and double conditional knockout mice, we confirm the countervailing actions of each gene, and validate in vitro a crucial role for two single nucleotide polymorphisms in the 5'UTR of Isl1, one of which yields a novel E-box, mediating the repressive action of Neurog2.

Mitochondrial Genetic Background May Impact Statins Side Effects and Atherosclerosis Development in Familial Hypercholesterolemia

Heredity of familial hypercholesterolemia (FH) can present as a dominant monogenic disorder of polygenic origin or with no known genetic cause. In addition, the variability of the symptoms among individuals or within the same families evidence the potential contribution of additional factors than monogenic mutations that could modulate the development and severity of the disease. In addition, statins, the lipid-lowering drugs which constitute the first-line therapy for the disease, cause associated muscular symptoms in a certain number of individuals. Here, we analyze the evidence of the mitochondrial genetic variation with a special emphasis on the role of CoQ10 to explain this variability found in both disease symptoms and statins side effects. We propose to use mtDNA variants and copy numbers as markers for the cardiovascular disease development of FH patients and to predict potential statin secondary effects and explore new mechanisms to identify new markers of disease or implement personalized medicine strategies for FH therapy.

REE and Trace Elements Distribution in the Deep-sea Sediments from the Interoceanmetal (IOM) Polymetallic Nodule Exploration Area in the Clarion-Clipperton Fractures Zone, NE Pacific

Geochemical features of the deep-sea sediments from a high polymetallic nodule area in the eastern part of the Clarion-Clipperton Fractures Zone (CCZ), NE Pacific were studied. Box-corer samples from six stations in individual depth layers 0–3, 3–5, 5–10, 10–20 cm were collected from 4300–4500 m depth. The deep-sea sediments were classified as clayey-siliceous oozes according to the mineral and grain-size analyses. The chemical composition of the studied samples is compatible with that of pelagic sediments. Manganese content varies from 0.16% to 0.70% being the highest in the geochemically active layer (top 7–12 cm) and decreases with depth. The Mn/Fe ratio, Ba, Co, Ni and Cu have the highest values in the first (0–3) and second (3–5) layers and decrease with depth. REE range is 195.84–357.79 ppm showing low variation between the layers. PAAS-normalized REE patterns show significant enrichment of MREE and HREE with strong negative Ce anomaly and weak positive Eu and Y anomalies. The geochemical characteristics of the studied sediments infer polygenic origin. The redox sensitive oxides and barite presense, Eh values and negative Ce anomaly, indicate oxidizing environment of sediment formation.

Periodic Fever in Children: Etiology and Diagnostic Challenges.

Periodic fever in children is an autoinflammatory illness with an unknown cause. Symptoms include frequent episodes of fever that are followed by an increase in inflammatory markers. A genetic background for periodic fever of unknown origin has been hypothesized, based on its family clustering and parallels to other autoinflammatory illnesses such as familial Mediterranean fever. Genome analysis has been used in studies to look for related gene variations in periodic fever of unknown origin in the pediatric population. Children with periodic fevers might be a diagnostic challenge. After ruling out the most prevalent causes, a wide variety of other possibilities are investigated. Infectious and noninfectious causes of periodic fever in children are discussed in this article.Inflammasomes (intracellular proteins that activate interleukin (IL)-1b and IL-18) and genetic/hereditary variations are thought to be implicated in the pathogenesis of periodic fever. Evaluation and ruling out possible infective or noninfective causes is vital in the diagnosis of periodic fever in children. Investigations demonstrate that there isn't a single gene linked to it, suggesting that it may have a multifactorial or polygenic origin, with an environmental trigger causing inflammasome activation and fever flares. Treatment is usually symptomatic, with drugs such as colchicine and cimetidine having shown promising results in trials.We explored the literature on periodic fever in children for its epidemiology, pathophysiology, the role of various genes and how they influence the disease and associated complications, and its various treatment modalities.

Congenital diaphragmatic hernia.

Congenital diaphragmatic hernia (CDH) is a rare birth defect characterized by incomplete closure of the diaphragm and herniation of fetal abdominal organs into the chest that results in pulmonary hypoplasia, postnatal pulmonary hypertension owing to vascular remodelling and cardiac dysfunction. The high mortality and morbidity rates associated with CDH are directly related to the severity of cardiopulmonary pathophysiology. Although the aetiology remains unknown, CDH has a polygenic origin in approximately one-third of cases. CDH is typically diagnosed with antenatal ultrasonography, which also aids in risk stratification, alongside fetal MRI and echocardiography. At specialized centres, prenatal management includes fetal endoscopic tracheal occlusion, which is a surgical intervention aimed at promoting lung growth in utero. Postnatal management focuses on cardiopulmonary stabilization and, in severe cases, can involve extracorporeal life support. Clinical practice guidelines continue to evolve owing to the rapidly changing landscape of therapeutic options, which include pulmonary hypertension management, ventilation strategies and surgical approaches. Survivors often have long-term, multisystem morbidities, including pulmonary dysfunction, gastroesophageal reflux, musculoskeletal deformities and neurodevelopmental impairment. Emerging research focuses on small RNA species as biomarkers of severity and regenerative medicine approaches to improve fetal lung development.

Role of Glucokinase Enzyme in the Treatment of Type 2 Diabetes

Diabetes mellitus is a condition that affects people all over the world, and the rate at which the number of diabetes patients grows puts medical professionals under a lot of pressure to manage it efficiently. Because of its polygenic origin and various genes' participation in its pathophysiology, understanding this disease is more difficult. Current therapies, including as dietary adjustments, lifestyle changes, and pharmacological therapy such as insulin, appear to be ineffective in reversing the trend. There are a number of targets that the researchers are focusing on in order to properly tackle this disease. One of the novel and growing targets is glucokinase (GK). Because it's found in pancreatic and liver cells, it's a more appealing target. The presence of GK in pancreatic and hepatic cells plays an important role in glucose homoeostasis regulation. In the cells of the pancreas and the liver, it serves as a “glucose sensor” and a “glucose gate keeper.” In T2DM patients, small compounds that activate GK give an alternate option for restoring/improving glycemic homeostasis. This review explains the various aspects of the glucokinase enzyme that are helpful for maintaining this disastrous disease in a well and efficient manner as comparison to other targets.

Targeting human Glucokinase for the treatment of type 2 diabetes: an overview of allosteric Glucokinase activators.

Diabetes mellitus is a worldwide impacting disorder and the ratio through which the number of diabetic patients had increased worldwide, puts medical professionals to serious stress for its effective management. Due to its polygenic origin and involvement of multiple genes to its pathophysiology, leads to understanding of this ailment more complex. It seems that current interventions, such as dietary changes, life style changes and drug therapy such as oral hypoglycaemics and insulin, are unable to halt the trend. There are various novel and emerging targets on which the researchers are paying attention to combat with this ailment successfully. Human glucokinase (GK) enzyme is one of these novel and emerging targets for management of diabetes. Its availability in the pancreas and liver cells makes this target more lucrative. GK's presence in the pancreatic and hepatic cells plays a very important function for the management of glucose homoeostasis. Small molecules that activateGK allosterically provide an alternative strategy for restoring/improving glycaemic regulation, especially in type 2 diabetic patients. Although after enduring many setbacks in the development of the GK activators, interest has been renewed especially due to introduction of novel dual acting GK activator dorzagliatin, and a novel hepato-selective GK activator, TTP399. This review article has been formulated to discuss importance of GK in glucose homeostasis, recent updates on small molecules of GK activators, clinical status of GK activators and challenges in development of GK activators.

Origin of the Coloured Karst Fills in the Neogene Extensional System of NE Iberia (Spain)

Karst fills from the onshore Penedès Basin and offshore València Trough display red, pink, orange and ochre colours. Their Mössbauer spectra indicate that Fe3+ contained in goethite is the dominant species in reddish-pink fills, whereas Fe2+ contained in dolomite and clays is more dominant in the orange and ochre ones. The lower δ13C values and higher 87Sr/86Sr ratios of the karst fills with respect to their host carbonates can reflect the input of soil-derived CO2 and an external radiogenic source into the karst system. This geochemical composition, together with the non-carbonate fraction of the fills, consists of authigenic and transported illite, illite-smectite interlayers, as well as kaolinite, chlorite, pyrite, quartz, ilmenite, magnetite, apatite and feldspar, account for a mixed residual-detrital origin of fills. This polygenic origin agrees with that of the terra rossa sediments described worldwide. The different colours of karst fills are attributed to fluctuations in the water table, which control the Eh/pH conditions in the karst system. Thus, reddish colours reflect low water table levels and oxidising episodes, and orange and ochre ones reflect high water table levels and more reducing episodes. The greenish colours of fills could be related to fluctuations in the Fe3+/Fe2+ ratio.

Genetic Determinants of Plasma Low-Density Lipoprotein Cholesterol Levels: Monogenicity, Polygenicity, and "Missing" Heritability.

Changes in plasma low-density lipoprotein cholesterol (LDL-c) levels relate to a high risk of developing some common and complex diseases. LDL-c, as a quantitative trait, is multifactorial and depends on both genetic and environmental factors. In the pregenomic age, targeted genes were used to detect genetic factors in both hyper- and hypolipidemias, but this approach only explained extreme cases in the population distribution. Subsequently, the genetic basis of the less severe and most common dyslipidemias remained unknown. In the genomic age, performing whole-exome sequencing in families with extreme plasma LDL-c values identified some new candidate genes, but it is unlikely that such genes can explain the majority of inexplicable cases. Genome-wide association studies (GWASs) have identified several single-nucleotide variants (SNVs) associated with plasma LDL-c, introducing the idea of a polygenic origin. Polygenic risk scores (PRSs), including LDL-c-raising alleles, were developed to measure the contribution of the accumulation of small-effect variants to plasma LDL-c. This paper discusses other possibilities for unexplained dyslipidemias associated with LDL-c, such as mosaicism, maternal effect, and induced epigenetic changes. Future studies should consider gene–gene and gene–environment interactions and the development of integrated information about disease-driving networks, including phenotypes, genotypes, transcription, proteins, metabolites, and epigenetics.

Polymorphisms and gene expression in the almond IGT family are not correlated to variability in growth habit in major commercial almond cultivars.

Almond breeding programs aimed at selecting cultivars adapted to intensive orchards have recently focused on the optimization of tree architecture. This multifactorial trait is defined by numerous components controlled by processes such as hormonal responses, gravitropism and light perception. Gravitropism sensing is crucial to control the branch angle and therefore, the tree habit. A gene family, denominated IGT family after a shared conserved domain, has been described as involved in the regulation of branch angle in several species, including rice and Arabidopsis, and even in fruit trees like peach. Here we identified six members of this family in almond: LAZY1, LAZY2, TAC1, DRO1, DRO2, IGT-like. After analyzing their protein sequences in forty-one almond cultivars and wild species, little variability was found, pointing a high degree of conservation in this family. To our knowledge, this is the first effort to analyze the diversity of IGT family proteins in members of the same tree species. Gene expression was analyzed in fourteen cultivars of agronomical interest comprising diverse tree habit phenotypes. Only LAZY1, LAZY2 and TAC1 were expressed in almond shoot tips during the growing season. No relation could be established between the expression profile of these genes and the variability observed in the tree habit. However, some insight has been gained in how LAZY1 and LAZY2 are regulated, identifying the IPA1 almond homologues and other transcription factors involved in hormonal responses as regulators of their expression. Besides, we have found various polymorphisms that could not be discarded as involved in a potential polygenic origin of regulation of architectural phenotypes. Therefore, we have established that neither the expression nor the genetic polymorphism of IGT family genes are correlated to diversity of tree habit in currently commercialized almond cultivars, with other gene families contributing to the variability of these traits.

Unusual Case Report: Ectopic Canines, Resorption and Hypodontia in Monozygotic Twins

Ectopic maxillary canines are present in 1–3% of the population and may consequentially cause root resorption in 66.7% of lateral incisors. Ectopic canines are thought to be of polygenic and multifactorial origin, although Msx1 and Pax9 are suggested genetic candidates. Hypodontia is present in up to 11.3% of the population and is associated with mutations in Msx1, Pax9 and Axin2. Previous studies have separately demonstrated similarities in hypodontia and ectopic canines in monozygotic twins. This report discusses similarities clinically and using cone beam computed tomography in 14-year-old male genetically identical twins. While hypodontia and ectopic canines have both previously been linked with a genetic origin, this report suggests there is also a genetic predisposition to root resorption. The association between hypodontia and ectopic canines is usually associated with the guidance theory and hypodontia of upper lateral incisors; however, this report highlights the occurrence of ectopic canines and hypodontia of premolar teeth. It also presents the sequelae of severe root resorption associated with ectopic canines and idiopathically in areas of non-impacted canines CPD/Clinical Relevance: The role of the general dental practitioner in early recognition of hypodontia and ectopic canines and the importance of referral for an orthodontic opinion is emphasized.

Identifying new potential genetic biomarkers for HELLP syndrome using massive parallel sequencing.

Preeclampsia (PE) is a frequently occurring multisystemic disease affecting ~5% of pregnancies. PE patients may develop HELLP syndrome (haemolysis, elevated liver enzymes, and low platelet), a mother and foetus life-threatening condition. Research into HELLP's genetic origin has been relatively unsuccessful, mainly because normal placental function and blood pressure regulation involve the fine-regulation of hundreds of genes. To identify new genes and mutations constituting potential biomarkers for HELLP syndrome. The present case-control study involved whole-exome sequencing of 79 unrelated HELLP women. Candidate variants were screened in a control population constituted by 176 individuals. Stringent bioinformatics filters were used for selecting potentially etiological sequence variants in a subset of 487 genes. We used robust in silico mutation modelling for predicting the potential effect on protein structure. We identified numerous sequence variants in genes related to angiogenesis/coagulation/blood pressure regulation, cell differentiation/communication/adhesion, cell cycle and transcriptional gene regulation, extracellular matrix biology, lipid metabolism and immunological response. Five sequence variants generated premature stop codons in genes playing an essential role in placental physiology (STOX1, PDGFD, IGF2, MMP1 and DNAH11). Six variants (ERAP1- p.Ile915Thr, ERAP2- p.Leu837Ser, COMT-p.His192Gln, CSAD-p.Pro418Ser, CDH1- p.Ala298Thr and CCR2-p.Met249Lys) led to destabilisation of protein structure as they had significant energy and residue interaction-related changes. We identified at least two mutations in 57% of patients, arguing in favour of a polygenic origin for the HELLP syndrome. Our results provide novel evidence regarding PE/HELLP's genetic origin, leading to new biomarkers, having potential clinical usefulness, being proposed.