Littérature scientifique sur le sujet « Oligogene »

Was ist neu? Hereditäre Pankreatitis In den letzten Jahren konnten mehrere Genmutationen nachgewiesen werden, die ursächlich für die Ausbildung einer hereditären Pankreatitis sind. Sie spielen auch bei der Entstehung einer chronischen Pankreatitis anderer Ätiologie eine wichtige Rolle, wobei Lebensstilfaktoren hierbei in den Vordergrund treten. Chronisch entzündliche Darmerkrankungen Das Wissen um die komplexe und multifaktorielle Ätiologie des Morbus Crohn und der Colitis ulcerosa wurde in den letzten Jahren durch die Identifikation von bislang über 200 Risikogenvarianten erweitert. Diese tragen zur Krankheitsentstehung bei, wobei Umweltfaktoren weiterhin eine entscheidende Rolle zukommt. Darüber hinaus wurden seltene mono- bzw. oligogene CED-Formen nachgewiesen, die sich durch ein frühes Erkrankungsalter auszeichnen und die die Möglichkeit spezifischer Therapieansätze bieten. Fettlebererkrankungen und hepatozelluläres Karzinom Genetische Varianten u. a. in den Genen PNPLA3, TM6SF2 und MBOAT7 tragen zu Entstehung und Progression einer Fettlebererkrankung auf dem Boden eines metabolischen Syndroms bzw. von Alkoholkonsum bei. Darüber hinaus erhöhen sie das Risiko für die Entwicklung eines hepatozellulären Karzinoms. Eine genetische Testung aller Patienten mit Fettleber wird derzeit (noch) nicht empfohlen.

ZusammenfassungDas Bardet-Biedl-Syndrom (BBS) ist eine seltene, erblich bedingte Ziliopathie, bei der neben einer Netzhautdystrophie, meist in Form einer Stäbchen-Zapfen-Dystrophie (Retinitis pigmentosa, RP), zahlreiche weitere Symptome bestehen, vor allem Stammfettsucht, Polydaktylie, Nierenveränderungen und Lernbehinderung bzw. Intelligenzminderung. Mindestens 25 ursächliche Gene, die für Proteine mit wichtiger Rolle bei Entwicklung und Funktion primärer Zilien kodieren, sind bisher bekannt. Die Störung der mit zahlreichen Entwicklungssignalwegen assoziierten Zilien erklärt die in unterschiedlichen Organen auftretenden Symptome. Aufgrund der ursächlichen Beteiligung so vieler Gene ist das BBS eine Erkrankung, bei der Ärzte in besonderem Maße von neuen Methoden der molekulargenetischen Diagnostik profitieren: Durch Next-Generation Sequencing (NGS) können alle krankheitsrelevanten Gene im Rahmen einer sogenannten „Panelanalyse“ parallel untersucht werden. Signifikante Genotyp-Phänotyp-Korrelationen hinsichtlich der Art der Netzhautbeteiligung bestehen nicht. Neben der klassischen autosomal-rezessiven Vererbung wurden oligogene oder triallelische Vererbungsformen, bei denen die Erkrankung aus einem kombinierten Effekt verschiedener Allele in mehreren Genen resultiert, beschrieben. Nach heutigem Kenntnisstand, der zunehmend aus großen NGS-Studien gespeist wird, spielen Letztere aber keine (wesentliche) Rolle. Mangels kausaler Therapieansätze beschränkt sich die augenärztliche Behandlung auf eine umfassende Rehabilitation mit vergrößernden Sehhilfen sowie die Versorgung mit Langstock und dem Training von lebenspraktischen Fähigkeiten.

Embryo implantation requires the closely harmonized processes of apposition, attachment, and adhesion of the conceptus to the maternal endometrial epithelium. IL-11 and leukemia inhibitory factor (LIF), two IL-6 family cytokines, are produced by the endometrium and are absolutely required for implantation in mice. We examined the effect of IL-11 and LIF on human endometrial epithelial cell adhesion. Both cytokines increased adhesion of primary human endometrial epithelial cells to fibronectin and collagen IV. IL-11 stimulated, whereas LIF had no effect on the adhesion of trophoblast to endometrial epithelial cells. Focused oligogene arrays were used to identify extracellular matrix and adhesion molecules mRNAs regulated by endometrial epithelial cells. We demonstrated by real-time RT-PCR and antibody arrays that both cytokines increased integrin-α2 mRNA and protein by endometrial epithelial cells. Signal transducers and activators of transcription (STAT)-3 inhibition reduced IL-11- and LIF-mediated epithelial cell adhesion to fibronectin, suggesting both cytokines regulated adhesion via phosphorylation of STAT3. Addition of either IL-11 neutralizing antibody and IL-11 or LIF and LIF antagonist to endometrial epithelial cells abolished cytokine induced phosphorylated STAT3. LIF but not IL-11 induced adhesion to collagen IV was reduced by an integrin-α2β1 neutralizing antibody. This study demonstrated that IL-11 and LIF regulated endometrial epithelial cell adhesion, suggesting that targeting IL-11 and LIF may be useful in regulating fertility by either enhancing or blocking implantation.

BackgroundSeveral studies suggest that multiple rare genetic variants in genes causing monogenic forms of neurodegenerative disorders interact synergistically to increase disease risk or reduce the age of onset, but these studies have not been validated in large sporadic case series.MethodsWe analysed 980 neuropathologically characterised human brains with Alzheimer’s disease (AD), Parkinson’s disease-dementia with Lewy bodies (PD-DLB), frontotemporal dementia-amyotrophic lateral sclerosis (FTD-ALS) and age-matched controls. Genetic variants were assessed using the American College of Medical Genetics criteria for pathogenicity. Individuals with two or more variants within a relevant disease gene panel were defined as ‘oligogenic’.ResultsThe majority of oligogenic variant combinations consisted of a highly penetrant allele or known risk factor in combination with another rare but likely benign allele. The presence of oligogenic variants did not influence the age of onset or disease severity. After controlling for the single known major risk allele, the frequency of oligogenic variants was no different between cases and controls.ConclusionsA priori, individuals with AD, PD-DLB and FTD-ALS are more likely to harbour a known genetic risk factor, and it is the burden of these variants in combination with rare benign alleles that is likely to be responsible for some oligogenic associations. Controlling for this bias is essential in studies investigating a potential role for oligogenic variation in neurodegenerative diseases.

ObjectiveTo characterize the clinical and neuropathologic features of patients with amyotrophic lateral sclerosis (ALS) with the superoxide dismutase 1 (SOD1) p.Ala90Val mutation, as well as the mutation frequency and the role of oligogenic mechanisms in disease penetrance.MethodsAn index patient with autopsy-proven ALS was discovered to have the SOD1 p.Ala90Val mutation, which was screened in 2 Finnish ALS cohorts (n = 453). Additional contributing variants were analyzed from whole-genome or whole-exome sequencing data.ResultsSeven screened patients (1.5%) were found to carry the SOD1 heterozygous mutation. Allele-sharing analysis suggested a common founder haplotype. Common clinical features included limb-onset, long disease course, and sensory symptoms. No TDP43 pathology was observed. All cases were apparently sporadic, and pedigree analysis demonstrated that the mutation has reduced penetrance. Analysis of other contributing genes revealed a unique set of additional variants in each patient. These included previously described rare ANG and SPG11 mutations. One patient was compound heterozygous for SOD1 p.Ala90Val and p.Asp91Ala.ConclusionsOur data suggest that the penetrance of SOD1 p.Ala90Val is modulated by other genes and indicates highly individual oligogenic basis of apparently sporadic ALS. Additional genetic variants likely contributing to disease penetrance were very heterogeneous, even among Finnish patients carrying the SOD1 founder mutation.

The emergence of statistical and predictive methods able to analyse genomic data has revolutionised the field of medical genetics, allowing the identification of disease-causing gene variants (i.e. mutations) for several human genetic diseases. Although these approaches have greatly improved our understanding of Mendelian «one gene – one phenotype» genetic models, studying diseases related to more intricate models that involve causative variants in several genes (i.e. oligogenic diseases) still remains a challenge, either due to the lack of sufficient methodologies and disease-specific cohorts to study or the phenotypic complexity associated with such diseases. This situation makes it difficult to not only understand the genetic mechanisms of the disease, but to also offer proper counseling and support to the patient. Until recently, no specialized predictive methods existed to directly predict causative variant combinations for oligogenic diseases. However, with the advent of data on variant combinations in gene pairs (i.e. bilocus variant combinations) leading to disease, collected at the Digenic Diseases Database (DIDA), we hypothesized that the transition from single to variant combination pathogenicity predictors is now possible.To investigate this hypothesis, we organised our research on two main routes. At first, we developed an interpretable variant combination pathogenicity predictor, called VarCoPP, for gene pairs. For this goal, we trained multiple Random Forest algorithms on pathogenic bilocus variant combinations from DIDA against neutral data from the 1000 Genomes Project and investigated the contribution of the incorporated variant, gene and gene pair features to the prediction outcome. In the second part, we explored the usefulness of different gene pair burden scores based on this novel predictive method, in discovering oligogenic signatures in neurodevelopmental diseases, which involve a spectrum of monogenic to polygenic cases. We performed a preliminary analysis on the Deciphering Developmental Diseases (DDD) project containing exome data of 4195 families and assessed the capability of our scores in supporting already diagnosed monogenic cases, discovering significant pairs compared to control cases and linking patients in communities based on the genetic burden they share, using the Leiden community detection algorithm.The performance of VarCoPP shows that it is possible to predict disease-causing bilocus variant combinations with good accuracy both during cross-validation and when testing on new cases. We also show its relevance for disease-related gene panels, and enhanced its clinical applicability by defining confidence zones that guarantee with 95\% or 99\% probability that a prediction is indeed a true positive, guiding clinical researchers towards the most relevant results. This method and additional biological annotations are incorporated in an online platform called ORVAL that allows the prediction and exploration of candidate disease-causing oligogenic variant combinations with predicted gene networks, based on patient variant data. Our preliminary analysis on the DDD cohort shows that - although all bi-locus burden scores show advantages, disadvantages and certain types of biases - taking the maximum pathogenicity score present inside a gene pair seems to provide, at the moment, the most unbiased results. We also show that our predictive methods enable us to detect patient communities inside DDD, based exclusively on the shared pathogenic bi-locus burden between patients, with more than half of these communities containing enriched phenotypic and molecular pathway information. Our predictive method is also able to bring to the surface genes not officially known to be involved in disease, but nevertheless, with a biological relevance, as well as a few examples of potential oligogenicity inside the network, paving the way for further exploration of oligogenic signatures for neurodevelopmental diseases.
Doctorat en Sciences
info:eu-repo/semantics/nonPublished

In the next generation sequencing era many bioinformatics tools have been developed for assisting scientists in their studies on the molecular basis of genetic diseases, often with the aim of identifying the pathogenic variants. As a consequence, in the last decades more than one hundred new disease-gene associations have been discovered. Nevertheless, the genetic basis of many genetic diseases yet remains undisclosed. It has been shown that many diseases considered as monogenic with an imperfect genotype-phenotype correlation or incomplete penetrance are, on the contrary, caused or modulated by more than one mutated gene, meaning that they are in fact oligogenic. Current bioinformatics methods used for identifying pathogenic variants are trained and fine-tuned for identifying a single variant responsible of a disease. This monogenic-oriented approach cannot be used to explore the impact of combinations of variants in different genes on the complexity and genetic heterogeneity of rare diseases. Digenic diseases are the simplest form of oligogenic disease and thus they can provide a conceptual bridge between monogenic and the poorly understood polygenic diseases.The ambition of this thesis is to collect and analyse digenic data, introducing this topic in the bioinformatics field where digenic diseases are still an unexplored branch. This can be divided in two steps: the first consists in the creation of a central repository containing detailed information on digenic diseases; the second is an analysis of their peculiarities, using machine learning methods for studying subclasses of digenic effects.In the first step we developed DIDA (DIgenic diseases DAtabase), a novel database that provides for the first time a curated collection of genes and associated variants involved in digenic diseases. Detailed information related to the digenic mechanism have been manually mined from the medical literature. All instances in DIDA were also assigned to two sub classes of digenic effects, annotated as true digenic (both genes are required for developing the disease) and composite classes (one gene is sufficient to produce the disease phenotype, the second one alters it or change significantly the age of onset).In the second step, we hypothesized that the digenic effect may be related to some biological properties characterizing digenic combinations. Using machine learning methods, we show that a set of variant, gene and higher-level features can differentiate between the true digenic and composite classes with high accuracy. Moreover, we show that a digenic effect decision profile, extracted from the predictive model, motivates why an instance is assigned to either of the two classes.Together, our results show that digenic disease data generates novel insights, providing a glimpse into the oligogenic realm.
Doctorat en Sciences
info:eu-repo/semantics/nonPublished

I disturbi del neurosviluppo (NDD) sono un gruppo eterogeneo di disordini che coinvolgono il sistema nervoso, tra cui i disordini dello spettro autistico (ASD), che colpiscono circa l'1-3% dei bambini. Sono state rilevate differenti varianti causative a carico di molti geni, a evidenziare una eterogeneità genetica, ma per molti pazienti l’origine genetica rimane ancora sconosciuta. Emergono sempre più evidenze a sostegno di un’origine più complessa, caratterizzata da meccanismi oligogenici che vedono coinvolti due o più geni, con diverso impatto (major gene o modifier). La presenza in uno stesso individuo di varianti deleterie in geni differenti potrebbe avere determinato con effetto additivo il quadro clinico diversificato osservato nei singoli pazienti. La Sindrome di Poland (PS. OMIM 173800), rara patologia congenita (prevalenza 1-9/100.000), è caratterizzata da agenesia/ipoplasia del muscolo pettorale, generalmente unilaterale, talvolta associata ad anomalie toraciche e/o dell’arto superiore. Di solito presente in forma sporadica, un 4% di casi può mostrare famigliarità con eterogeneità fenotipica anche all’interno della stessa famiglia. Per la maggior parte dei casi è stata ipotizzata un’origine poligenica/multifattoriale anche se sono stati riportati casi con ereditarietà autosomica dominante e autosomica recessiva. Al momento non sono noti geni associati a PS. i) È stata eseguita un’analisi retrospettiva dei risultati di Array-CGH su 526 casi NDD. È stata valutata la patogenicità dei CNV identificati attraverso lo studio della letteratura e la ricerca in database che riportano geni associati a NDD, in particolare a disabilità intellettiva (ID) e ASD. (ii) È stata effettuata l’analisi dell’intero esoma (WES) di 53 famiglie con ASD ed identificato alcuni geni/varianti candidati. Per indagare il meccanismo oligogenico sono stati utilizzati vari approcci. I dati WES sono stati analizzati utilizzando una nuova piattaforma open source di analisi: ORVAL. È stata eseguita analisi di Gene Enrichment in pathways e processi biologici associati a NDD per i geni candidati ottenuti sia dall’analisi CNV che da WES utilizzando gli strumenti bionformatici GeneCodis4 e Cytoscape. (iii) Sono stati analizzati mediante WES 30 pazienti con PS che avevano caratteristiche fenotipiche simili a un caso indice in cui erano stati identificati 2 geni candidati per lo sviluppo della patologia. Sono stati effettuati studi funzionali delle varianti identificate per verificarne l’effetto su localizzazione cellulare e livelli di espressione delle proteine codificate dai geni mutati. Per questo obbiettivo, sono stati effettuati mutagenesi in vitro ed analisi di localizzazione cellulare (western blot di lisati cellulari frazionati, ImageStream e Opera Phenix), e test della luciferasi. Sono state trovate CNVs patogenetiche in circa il 42% dei casi NDD, mentre il 58% delle CNVs identificate rimangono di significato incerto. Lo studio dei dati array ha portato all’identificazione di nuovi geni e nuovi meccanismi (“double-hit” mechanisms) che potrebbero essere alla base di NDD. Meccanismi oligogenici sono stati anche riscontrati in alcuni casi della coorte di pazienti ASD analizzati con WES. Dallo studio effettuato è inoltre emerso il coinvolgimento di geni diversi in pathway e processi biologici comuni a più pazienti con NDD. Nei pazienti con PS sono state riscontrate varianti deleterie in due geni implicati nella formazione di muscolo pettorale e cartilagine e in meccanismi di polarità cellulare e divisioni cellulari asimmetriche che potrebbero contribuire sinergicamente al fenotipo PS facendo ipotizzare un meccanismo digenico.
Neurodevelopmental disorders (NDDs) are a group of heterogeneous disease affecting the nervous system, including autism spectrum disorders (ASD), and present in about 1-3% of children. ASD is characterized by communicative impairments, difficulties in social interaction, behavior abnormalities and complex pathogenetic mechanisms. Increasing findings support an oligogenic model of inheritance with a combination of inherited and/or de novo variants, involved in different pathways and biological processes. The presence in the same individual of multiple deleterious variants in different genes could contribute, according to an additive model, to heterogeneity of clinical features observed in NDD patients. The genetic etiology of NDDs has not yet been fully clarified. Poland Syndrome (PS, OMIM 173800) is a rare congenital condition (incidence of 1-9/100.000) with variable phenotype characterized by pectoral muscle agenesis/hypoplasia that may include ipsilateral thoracic and upper limb anomalies. Most cases of PS are sporadic, familial recurrence has been observed (4%) with phenotypic heterogeneity. Different inheritance patterns have been reported and polygenic/multifactorial mechanisms have been hypothesized in some cases. The genetic etiology of PS remains unknown. Recent studies proved that the use of Whole Exome Sequencing (WES) together with the copy number variations (CNVs) analysis can help to the identification of the molecular bases of heterogeneous genetic disorders. In this study we aimed at investigating the genetic mechanisms underlying NDDs and PS. i) A retrospective Array-CGH analysis was performed on 526 NDD cases. The pathogenicity of CNVs was investigated through mining of literature and searching through databases reporting genes associated with NDD, particularly intellectual disability (ID) and ASD. (ii) Fifty-three ASD families were investigated by Whole exome sequencing, and potentially deleterious variants prioritized by custom filtering strategies including the use of Oligogenic Resource for Variant Analysis Platform (ORVAL) and enrichment analysis of candidate genes with GeneCodis4. (iii) A cohort of 30 PS patients were analysed by WES, and potentially deleterious variants prioritized by custom filtering strategies including oligogenic variant analysis. Functional analyses of identified variants included in vitro mutagenesis followed by cell imaging and gene reporter assays. Pathogenetic CNVs have been found in 42% of NDD cases, while 58% of the identified CNVs remain of uncertain significance. The study of arrays data led to the identification of new genes and "double-hit" mechanisms that could account for the NDDs. By using an oligogenic approach to the analysis of WES data, we identified inherited variants in different genes that globally could explain the complex phenotype in some cases. The study also revealed the involvement of different genes in pathways and biological processes common to several patients with NDD. In patients with PS, deleterious variants were found in two different genes, one involved in the pectoral muscle and cartilage development, and one involved in mechanisms of cell polarity and asymmetric cell divisions that could contribute synergistically to the PS phenotype, suggesting a digenic mechanism.

This study combines different approaches in order to evaluate the vertical component of tectonic movements of the upper crust in regions of active mountain building. The study area covers a NE oriented, 40 km wide, and 220 km long strip of land which crosses the Central Apennines, from the Tyrrhenian to the Adriatic shorelines, and is aligned between the cities of Rome and S. Benedetto del Tronto. The Central Apennine is an East-verging fold-and-thrust mountain belt overriding and accreting on the subducting Adria plate. Compressional tectonics originated in Late Oligocene (25-30 Ma) and progressively migrated northeastward affecting Meso-Cenozoic marine carbonate sequences and Neogene fore-deep siliciclastic units. Since Late Miocene (ca. 6 Ma) the emerged portion of the mountain belt also experienced contemporaneous compression at the thrust leading edge and back-arc extension, all combined with crustal uplift. In this study observations were aimed at identifying geomorphic, geological, and structural features which could have better characterised either crustal blocks or faults and fault-systems. As such, a wide range of methodologies have been applied, and on the whole, deformations have been detected at different spatial scales (103-10-2 m) and over a wide time-window (106-103 years). An outline of the topography at regional scale was done by using a Digital Elevation Model, which allowed to calculate several geomorphic parameters. Geomorphologic features providing information about crustal uplift have also been identified and detected with the aid of aerial-photo analysis and field surveys. On the basis of these analyses the mountain belt shows to be remarkably asymmetric and to be characterised by five crustal blocks. The five blocks not only show different geomorphic parameters but also express the signature of different geological evolutions. They have in common a step-like topography but with different spacing which probably reflects the different vertical displacement they have undergone over the last few million years. Uplift rates relative to sea-level variations have been determined in coastal areas by analysing marine terraces. Whereas the analysis of remnant land-surfaces, in the interiors, helped evaluate the maximum expected rate of uplift, relative to the adjacent blocks, and the style of crustal deformation in correspondence of the main faults. From the study of remnant land-surfaces it is also evident that the intermontane basins, which are typical half-grabens controlled by normal faults on the eastern side, represent independent minor down-thrown areas with respect to the uplifting surrounding ranges. Crustal uplift rates, averaged over ca. 1 Ma, seems to be very slow (<1 mm a-1) in comparison to other mountain ranges. Net uplift rate in the Adriatic side is faster then that in the Tyrrhenian side, in accordance with the asymmetric shape of the range. Major fault-systems separate the five crustal blocks, over-thrusting affects the NE side of the mountain range whereas 3 main normal fault-systems displace the SW side. The normal faults commonly strike NW-SE, plunge SW, and have a dip-slip kinematics which clearly evidences a deformation field with NE-SW trending principal extension axis. Their age spans over the Plio- Quaternary and are progressively younger from SW toward NE. A detailed geo-structural study was carried on in the narrow belt affected by the easternmost normal fault-system by analysing meso- and micro-scale structural features, displaced land-surfaces, and displaced continental deposits at several outcrops and in trenches dug across the fault-traces. 14C dating confirmed that the fault belonging to this system have been active in Late Pleistocene - Holocene time with an average slip-rate of about 0.2-0.5 mm a-1. On the whole, the above observations could be summarised in a model which point at defining a complex geo-dynamic framework that includes an active W plunging subduction driving an East oriented orogenic wave with a consequent crustal extension in the rear that dominates the tectonic style of the back-arc. If this process is still active and carries on the model predicts that the next generation of normal faults will eventually be located to the East of the present ones. The zone affected by the 1997 Umbria-Marche earthquakes, located about 60 km NW of the above mentioned study area, has also been investigated to contribute at understanding the relationships between moderate earthquakes, the faults which are recognisable in the geological record, and the vertical deformation they are able to produce at the surface. By analysing geological and seismological data related to the earthquake swarm, it was found that the mainshocks occurred on September 26, 1997 (ML=5.6 and ML=5.9) originated on the same structure reactivating at depth a listric normal fault and did not break the surface. The largest event produced surface warping similar to those occurring in extensional forced-folds. This deformation was measured by repeated levelling surveys which allowed to detect a maximum of a few decimetre coseismic warping at 2 km distance from the fault-trace in the hanging-wall and a 20% post-seismic rebound. The earthquake occurred on October 14, 1997 (ML=5.5) originated on another fault-branch and produced surface ruptures, with an offset of a few centimetre, in an area where no faults were previously mapped. The analysis of the geological structures suggests a possible correlation between the long-term (Middle Pleistocene) cumulative effects of the Colfiorito Fault System (CFFS) and the short-term behaviour of the fault planes observed during this earthquake swarm, favouring the idea of a seismogenic source producing clustered moderate-size earthquakes rather than large events scattered in time. These results also suggest that the integration of geological and seismological observations can constrain the seismotectonic interpretation in regions of low level seismicity and that this integration can pose a reliable basis in the seismic hazard assessment.
Università di Roma La Sapienza Consiglio Nazionale delle Ricerche
Unpublished
open

Genetic data was obtained from a colony of Parachartergus colobopterus using DNA microsatellites. A colony cycle referred to as cyclical oligogyny is believed to account for the high relatedness in this polygynous species. The genetic data was analyzed to support the presence of cyclical oligogyny and determine some of the specific mechanisms behind it. Specifically, queen reduction, increasing reproductive dominance, sexual specialization by queens, and maternity of males (worker vs. queen) were examined. There was evidence for queen reduction occurring in this colony. To the contrary, no support was found for either increasing reproductive dominance or sexual specialization among the queens. It appears that the queens produced all of the males in this colony. This concurs with a worker preference for queen laying of the males that was seen in relatedness estimates.

Recent advances in Next Generation Sequencing (NGS) technologies have facilitated the generation of massive amounts of genomic data which in turn is bringing the promise that personalized medicine will soon become widely available. As a result, there is an increasing pressure to develop computational tools to analyze and interpret genomic data. In this dissertation, we present a systematic approach for interrogating patients’ genomes to identify candidate causal genomic variants of Mendelian and oligogenic diseases. To achieve that, we leverage the use of biomedical data available from extensive biological experiments along with machine learning techniques to build predictive models that rival the currently adopted approaches in the field. We integrate a collection of features representing molecular information about the genomic variants and information derived from biological networks. Furthermore, we incorporate genotype-phenotype relations by exploiting semantic technologies and automated reasoning inferred throughout a cross-species phenotypic ontology network obtained from human, mouse, and zebra fish studies. In our first developed method, named PhenomeNet Variant Predictor (PVP), we perform an extensive evaluation of a large set of synthetic exomes and genomes of diverse Mendelian diseases and phenotypes. Moreover, we evaluate PVP on a set of real patients’ exomes suffering from congenital hypothyroidism. We show that PVP successfully outperforms state-of-the-art methods, and provides a promising tool for accurate variant prioritization for Mendelian diseases. Next, we update the PVP method using a deep neural network architecture as a backbone for learning and illustrate the enhanced performance of the new method, DeepPVP on synthetic exomes and genomes. Furthermore, we propose OligoPVP, an extension of DeepPVP that prioritizes candidate oligogenic combinations in personal exomes and genomes by integrating knowledge from protein-protein interaction networks and we evaluate the performance of OligoPVP on synthetic genomes created by known disease-causing digenic combinations. Finally, we discuss some limitations and future steps for extending the applicability of our proposed methods to identify the genetic underpinning for Mendelian and oligogenic diseases.

Short QT syndrome (SQTS) is a very rare, sporadic or autosomal dominant inherited channelopathy characterized by abnormally short QT intervals on the electrocardiogram and increased propensity to atrial and ventricular tachyarrhythmias and/or sudden cardiac death. Since its recognition as a distinct clinical entity in 2000, significant progress has been made in defining the clinical, molecular, and genetic basis of SQTS. To date, several causative gain-of-function mutations in potassium channel genes and loss-of-function mutations in calcium channel genes have been identified. The physiological consequence of these mutations is an accelerated repolarization, thus abbreviated action potentials and shortened QT interval with an increased inhomogeneity and dispersion of repolarization. Regarding other rare monogenetic arrhythmias, a genetic basis of atrial fibrillation was considered very unlikely until very recently. However, in the last decade the heritability of atrial fibrillation in the general population has been well described in several epidemiological studies. So far, more than 30 genes have been implicated in atrial fibrillation through candidate gene approach studies, and 14 loci were found to be associated with atrial fibrillation through genome-wide association studies. This genetic heterogeneity and the low prevalence of mutations in any single gene restrict the clinical utility of genetic screening in atrial fibrillation.

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare inherited disorder associated with syncope and sudden death manifesting in the young during sympathetic activation. The electrocardiogram is normal and the heart is structurally normal. The diagnosis is usually made with an exercise stress test that shows a typical pattern of onset and offset of adrenergically induced ventricular arrhythmias. Molecular screening of RyR2, the major CPVT gene, is recommended whenever the suspicion of CPVT is high. If a disease-causing mutation is identified, cascade screening allows pre-symptomatic diagnosis among family members. All affected subjects should be treated with beta blockers (nadolol or propranolol). Preliminary data support the association of beta blockers with flecainide. After a cardiac arrest, an implantable cardioverter defibrillator (ICD) should be implanted, but it is accompanied by a disquietingly high incidence of adverse effects. After syncope on beta blocker therapy, left cardiac sympathetic denervation is most effective, preserves quality of life, and does not preclude a subsequent ICD implantation.

The heritable arrhythmogenic disorder Brugada syndrome (BrS), a cardiac ion channelopathy first described in 1992, is inherited as an autosomal dominant trait characterized by incomplete penetrance, variable expression, and phenotypic overlap. These characteristics all complicate the elucidation of the underlying molecular genetic pathway. Clearly, SCN5A, the gene encoding the pore-forming alpha subunit of the cardiac sodium channel, is the major susceptibility gene associated with BrS: 20–30% of BrS patients harbour pathogenic variants in this gene and BrS patients have a more than eight times higher burden of rare variants in this gene compared to controls. Rare pathogenic variants have also been reported in several sodium, potassium, and calcium channel genes, pacemaker genes, and sodium channel interacting genes. Given the minor collective contribution of these additional BrS-associated genes to the total genetic diagnostic yield, the hypothesis has been raised that other (genetic) determinants are involved. Indeed, the monogenic nature of BrS has been questioned and more support has recently been gained for the hypothesis of a complex inheritance based on genome-wide and gene panel studies. Probably, the BrS inheritance pattern is a continuum ranging from a monogenic, over an oligogenic towards even a polygenic spectrum. This, however, further impedes the interpretation of the contribution of (likely) pathogenic variants to the phenotype and urges for a cautious policy in a prenatal and preimplantation genetic diagnostic context: in many cases disease prevention will imply a risk reduction instead of an elimination of disease (development).

Long QT syndrome (LQTS) is a collective term used for a group of inherited arrhythmogenic disorders characterized by a prolonged cardiac action potential duration that predisposes affected individuals to the development of life-threatening arrhythmias, especially during phases of adrenergic activation (exercise, emotions). From the genetic standpoint, LQTS is mainly transmitted as an autosomal dominant trait, caused by point mutations in genes coding for protein channels that regulate the duration of cardiac action potentials. To date, 17 genes have been associated with LQTS, but the first three genotypes discovered (LQT1, LQT2, and LQT3) account for the majority of genotype-positive cases. LQT1 and LQT2 (75% of LQTS cases) are caused by loss-of-function mutations in genes (KCNQ1 and KCNH2) coding for potassium channels (I_Ks and I_Kr) involved in the repolarization phase of cardiomyocytes, while LQT3 is caused by gain-of-function mutations affecting the gene SCN5A coding for the Na_v1.5 sodium channel, which is the major determinant of depolarization of cardiomyocytes. Genetic testing has a great potential for the management of patients with LQTS and may contribute to better define the diagnosis, the risk stratification, and the choice of therapy.

Long QT syndrome(s) (LQTS) includes a group of inherited arrhythmogenic disorders characterized by a prolonged cardiac repolarization that predisposes to the development of life-threatening arrhythmias, typically in conditions of adrenergic activation (exercise, emotions). LQTS can show both autosomal dominant and autosomal recessive transmission with variable penetrance. Several genes have been causally linked to the disease phenotype, all coding for ion channel proteins and their regulatory partners that control cardiac action potentials duration. To date, 17 genes have been identified. Still, the first three genotypes discovered in the early nineties (LQT1, LQT2, and LQT3) account for the large majority of mutation-positive cases (approximately 80–90%). Genotype-negative LQTS subjects still represent an area of investigation: large duplications and deletions, undetectable to standard screening methodologies and, more recently, polygenic inheritance and the role of modifiers are emerging as possible players for (apparently) genotype-negative LQTSx1. Knowing the genotype of a LQTS patient can provide a relevant contribution for the clinical management by supporting the diagnostic process, the risk stratification, and the choice of therapy.

Short QT syndrome (SQTS) is a very rare, sporadic or autosomal dominant inherited channelopathy characterized by abnormally short QT intervals on the electrocardiogram and increased propensity to atrial and ventricular tachyarrhythmias and/or sudden cardiac death. Since its recognition as a distinct clinical entity in 2000, significant progress has been made in defining the clinical, molecular, and genetic basis of SQTS. To date, several causative gain-of-function mutations in potassium channel genes and loss-of-function mutations in calcium channel genes have been identified. The physiological consequence of these mutations is an accelerated repolarization, thus abbreviated action potentials and shortened QT interval with an increased inhomogeneity and dispersion of repolarization. Regarding other rare monogenetic arrhythmias, a genetic basis of atrial fibrillation was considered very unlikely until very recently. However, in the last decade the heritability of atrial fibrillation in the general population has been well described in several epidemiological studies. So far, more than 30 genes have been implicated in atrial fibrillation through candidate gene approach studies, and more than 25 loci were found to be associated with atrial fibrillation through genome-wide association studies. This genetic heterogeneity and the low prevalence of mutations in any single gene restrict the clinical utility of genetic screening in atrial fibrillation.

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare inherited disorder associated with syncope and sudden death manifesting in the young during sympathetic activation. The electrocardiogram is normal and the heart is structurally normal. The diagnosis is usually made with an exercise stress test that shows a typical pattern of onset and offset of adrenergically induced ventricular arrhythmias. Molecular screening of RyR2, the major CPVT gene, is recommended whenever the suspicion of CPVT is high. If a disease-causing mutation is identified, cascade screening allows pre-symptomatic diagnosis among family members. All affected subjects should be treated with beta blockers (nadolol or propranolol). Preliminary data support the association of beta blockers with flecainide. After a cardiac arrest, an implantable cardioverter defibrillator (ICD) should be implanted, but it is accompanied by a disquietingly high incidence of adverse effects. After syncope on beta blocker therapy, left cardiac sympathetic denervation is most effective, preserves quality of life, and does not preclude a subsequent ICD implantation.