Analisi spaziale e modellizzazione spaziotemporale di processi a scala di ecosistema, paesaggio e bioregione

The ecological systems are complex and multifold: many variables cooperate in the definition of the measured values and countless disturbances affect the sampling. Furthermore, often ecolog- ical systems show patterns of change both in time and space. Complexity calls for compromise: choosing a single driver of change, be it space or time, is always somewhat arbitrary owing to pre-packaged statistical analysis tools. Geographical Information Systems (GIS) are now widespread and offer many spatial modeling tools, but they lack the ability to capture the time variability. The statistical analysis of time series, on the other hand, is blind to spatial patterns. This work proposes an interpolation tool, which is able to include spatial as well as tem- poral variability: the Timescape Algorithm. This algorithm derives form the fusion of the consolidated spacetime interpolation techniques of Statistical Physics with the typical needs of ecological systems modeling. Two software versions have been derived from the general algo- rithm: a local (projected coordinates) and a global (longitude/latitude) version. The software is published according to an open license (GNU-GPL v3.0) and is distributed with a detailed manual, the source code and a sample dataset of isotopic abundances in precipitations. The software has been designed to be the slightest possible detour from a consolidated GIS work ow, since more and more researchers use a GIS environment for both data storage and modeling. The Timescape idea is the mathematical translation of a few quite general statements: -observations at different places and times can be mixed freely -the area of possible in uence grows with time -closer sites can in uence each other more than far ones -the value at a given time can in uence the future values The Timescape Algorithm has been presented at the 2016 European Geoscience Union Conference [Geophysical Research Abstracts Vol. 18, EGU2016-15864, 2016]. Spatial and spatiotemporal modeling is illustrated through three case studies, re ecting the author's activities within his grant at the Institute of Agro-Environmental and Forest Biology of the National Research Council of Italy. The first case study, Mycorrhiza Survival Strategy, is centered on the use of carbon and nitrogen stable isotopes relative abundances to investigate the symbiotic relationships among 1 fungi (Tuber aestivum) and host trees. According to the current literature, the interaction has been modeled according to a simple isotope fractionation scheme: carbon owing from host to fungus shows negligible fractionation whilst nitrogen owing from mycorrhiza to trees displays fractionation. This research was the main driver for the development of the Timescape idea, since the temporal variability could not be neglected for the truffles, which can continuously change the isotopic compositions of the fruit bodies during the collection season. The experiment was conducted on a protected area in Umbria region, within the STINA interregional park. Here, old Pinus spp. stands were partially replaced with broadleaved species. Several detailed Isoscapes (thematic maps that show the spatial distribution of stable isotopes, thus tracing an isotopic landscape) were produced in order to map the spatial patterns of soil 15N and leaves 15N and 13C. Soil and leaves did not need any special statistical treatment because their isotopic content is accumulated over time (one season for the leaves and longer times for the soil). Stumps were also sampled. The modeling shows a remarkable probability of symbiosis among tru es and pines. No signi cant statistical matching has been found with other species in the pine-cleared areas, suggesting a saprophytic behaviuor of the mycorrhiza, feeding on the remnant stumps. This relation seems to be con rmed by the isotopic signatures of the examined stumps. The results of this study have been presented at the First Isotope Ratio Mass Spectrometry Day - Constitution of the Italian IRMS Group [F. Camin (ed) - Proc 1st IRMS Day, ISBN-978-88-7843-046-4]. The second case is an Extra Virgin Olive Oil (EVOO) provenance assessment study for the geographic origin through carbon (13C) and oxygen (18O) stable isotopes. The aim is the protection of consumers from geofrauds i.e. the false declaration of origin which raise the product price pretending to use olives only from highly-reputed geographic areas. This kind of fraud is not related to the adulteration of EVOOs, for which consolidated chemical analysis methods exist, but to the subtler eld of falsely claimed geographical provenance. This study takes into account the isotopic compositions of 387 EVOO samples originated from di erent regions in the years of the 2009, 2010 and 2011 seasons. The autenticity of each harvesting was certi ed by UNAPROL, the consortium of EVOO producers. Ancillary meteorological and geomorphological data have been imported in a GIS framework for spatial isotopic modeling. In this case, contrary to the previous case study, there was no need to analyse time and space variability in a single model, since every year was treated independently from the others. This 2 is sensible since, statistically, both 13C and 18O fatty acids content integrates the carbon and water uptake from the atmosphere and available water, through the photosynthetic assimilation and the fractionation process occurring during the transpiration. It was assumed that the available water essentially re ects the integrated isotopic composition precipitations. The 13C and 18O values were compared to some geographical and meteorological param- eters. The best explanatory variables for isotope composition variations have been found to be the precipitation 18O and the xerothermic index, with various R2 gures according to the year; con dence intervals were calculated too. The result is a set of predicted isotopic maps (Isoscapes): predicted 13C for 2010 and 2011, and predicted 18O for 2009, 2010 and 2011. The study of the predicted Isoscapes highlighted four zones: North, Central Thyrrenean, Southern Adriatic and Islands, which of course include more than one actual DOP and IGP production area. Isoscape analysis is a promising technique for contrasting geofrauds, especially if supported by other chemical analyses (e.g., heavy elements content). This study is published on Food Chemistry [Chiocchini et al. - Food Chemistry 202 (2016) 291- 301. doi:10.1016/j.foodchem.2016.01.146]. The last case study concerns an ongoing project: Ecua ux. It is an international project about carbon ows and photosynthesis responses of Polylepis reticulata (locally called \paper tree" for the nely layered structure of the bark), an endemic high altitude tree of the Southern Ecuadorian Andes. The collection of samples, including soil, tree cores, leaves and other tissues, has started in January 2016 and is planned to cover three or four years. The collection is being conducted on six separate forest plots in three di erent catchments at about 4000m altitude, at the utmost altitudinal limit of the species. The sampling has been carefully designed for space and time modeling and will provide the ideal playground for testing the Timescape algorithm. The isotopic measurements (estimated number of about 2000 samples) will be centred on the reconstruction of the changes of the photosynthesis response in the area over the last years. Indeed, the study's site, the Cajas National Park in Ecuador, is an hot spot of climate change, being located at such high altitude on the equator and exposed to the climatic in uence of the Amazon Basin and the Paci c ocean as well. A few preliminary results can be seen on http://www.ub.edu/ecologia/ecua ux.I sistemi ecologici sono caratterizzati dalla variet a e complessit a delle relazioni tra grandezze misurabili e dalle innumerevoli fonti di disturbo sulle misure. Molto spesso i sistemi ecologici sono caratterizzati da una variabilit a sia spaziale che temporale. Il trattamento statistico della complessit a richiede importanti compromessi. Tuttavia, prediligere un unico fattore di cam- biamento, sia esso lo spazio o il tempo, e sempre arbitrario ed e legato essenzialmente all'uso di strumenti software preconfezionati per l'analisi geostatistica. I Sistemi Informativi Territo- riali (SIT o GIS: Geographical Information Systems) sono sempre pi u di usi e costituiscono validissimi strumenti di analisi geostatistica, ma non consentono di apprezzare la variabilit a temporale dei dati. D'altro canto, gli algoritmi di analisi statistica delle serie storiche ignorano completamente la variabilit a spaziale. Queso lavoro propone uno strumento di interpolazione in grado di cogliere contemporanea- mente gli aspetti di variabilit a spaziale e temporale: l'Algoritmo Timescape. Questo algo- ritmo deriva dalla fusione di tecniche consolidate delle sica statistica con le esigenze tipiche dei sistemi complessi in ecologia. Per coprire tutte le scale di possibile interesse, dall'algoritmo ge- nerale sono stati derivati due software: il primo utilizza coordinate locali proiettate; il secondo le coordinate geogra che (latitudine e longitudine). I programmi sono pubblicati con licenza open source GNU-GPL v.3.0; la distribuzione include un manuale dettagliato, il codice sorgente e un database di esempio di abbondanze isotopiche relative (idrogeno e ossigeno) nelle acque di precipitazione. Il software e congruo alle normali procedure di analisi GIS in ambito ecologico, tecnologia, quest'ultima, sempre pi u utilizzata per la memorizzazione e per il trattamento dei dati rilevati. L'idea alla base di un modello Timescape e la traduzione in termini matematici di alcune ri essioni di portata generale: deve essere possibile utilizzare osservazioni eseguite in tempi e luoghi di erenti l'area di in uenza di un fenomeno aumenta col tempo luoghi vicini tendono ad avere valori misurati pi u simili rispetto a luoghi lontani il valore in un dato istante tende ad in uenzare i valori futuri nello stesso luogo L'Algoritmo Timescape e stato presentato alla 2016 European Geoscience Union Conference [Geo- physical Research Abstracts Vol. 18, EGU2016-15864, 2016]. 4 La costruzione di modelli spaziali e spaziotemporali e qui illustrata con tre casi di studio. Questi fanno parte delle attivit a svolte dall'autore nell'ambito di un assegno di ricerca plu- riennale presso l'Istituto di Biologia Agroambientale e Forestale del Consiglio Nazionale delle Ricerche (CNR-IBAF). Il primo caso, Mycorrhiza Survival Strategy, illustra l'uso degli isotopi stabili di azoto e carbonio nello studio delle relazioni mutualistiche tra Tuber aestivum e piante ospite. Lo studio e stato condotto in un'area protetta nell'ambito umbro del parco interregionale dello STINA. L'area e parzialmente oggetto di conversione da impianti deperienti a Pinus spp. a bosco misto di latifoglie. In accordo con la letteratura corrente ed al ne di individuare l'ospite putativo, il modello di interazione adottato ricerca un alto frazionamento dei rapporti isotopici 15N/14N ma un basso frazionamento in termini di variazione di 13C/12C nei rapporti micorrizici. Questa ricerca ha rappresentato, in concreto, il movente per lo sviluppo dell'Algoritmo Timescape. Infatti, non sarebbe stato corretto trascurare il fattore temporale nell'integrazione dei comp- lessi frazionamenti isotopici che hanno caratterizzato spazialmente la raccolta dati in ambiente reale. A tal proposito, si e partiti dalla elaborazione di diversi modelli Isoscape (da isotopic landscape: mappe tematiche della distribuzione delle abbondanze relative degli isotopi sta- bili). Questo ha permesso di analizzare la variabilit a spaziale dei rapporti isotopici 15N/14N nel suolo e sia 15N/14N che 13C/12C nei carpofori di tartufo e nelle foglie dei candidati ospiti. Sono stati misurati, inoltre, i valori isotopici di ceppaie in decomposizione, residuali nell'area di conversione a bosco misto di latifoglie. Il modello prodotto ha evidenziato una notevole probabilit a di simbiosi tra tartu e pini. Il modello isotopico non ha rilevato a nit a signi cativa con altre specie nelle aree in conver- sione. L'assenza in loco di individui vivi di pino, suggerisce in questo caso la capacot a di Tuber aestivum di cambiare in habitus sapro tico una precedente relazione micorrizica. Di fatto, a fronte del disturbo ecologico di una conversione o di un diradamento, questo comporterebbe per T. aestivum l'estensione della propria tness per un periodo pluriennale, grazie alle risorse nutritive fornite dalle ceppaie in decomposizione. Le analisi isotopiche eseguite sulle ceppaie validano l'applicazione del modello statistico spaziotemporale. I risultati di questo studio dono stati presentati al 1st Isotope Ratio Mass Spectrometry Day - Constitution of Italian IRMS Group [F. Camin (ed) - Proc. 1st IRMS Day, ISBN-978-88-7843-046-4]. 5 Il secondo caso di studio (Extra Virgin Olive Oil (EVOO) provenance assessment) e dedicato al controllo della zona di produzione di oli extra vergine di oliva italiani mediante gli isotopi stabili di carbonio (13C/12C) e ossigeno (18O/16O). Lo scopo e la protezione dei consumatori non tanto dall'adulterazione delprodotto, quanto dalla geofrode circa la supposta provenienza degli oli da zone ad alto valore aggiunto (DOP, IGP). Questo studio prende in considerazione la composizione isotopica di 387 EVOO delle annate 2009, 2010 e 2011 provenienti da diverse regioni italiane, certi cati dal consorzio UNAPROL. Sono stati utilizzati anche dati meteorologici ancillari; tutti i layer informativi sono stati inte- grati in un sistema GIS. Rispetto allo studio precedente, in questo caso non e stato necessario considerare contem- poraneamente la variabilit a spaziale e temporale, ma sono stati elaborati modelli di erenti per ogni anno. Ci o e statisticamente lecito in quanto i rapporti isotopici 13C/12C e 18O/16O dei trigliceridi dell'olio integrano tutta la biosintesi nel corso dell'annata di produzione. In ter- mini isotopici, la biosintesi e rmata dai processi fotosintetici (al riguardo della discriminazione verso 13C) e dal processo traspirativo rispetto alla captazione idrica radicale, per quanto attiene l'arricchimento in 18O della cosiddetta acqua metabolica nelle cellule del meso llo. Da notarsi come la source idrica per i processi di frazionamento dell'ossigeno, processi che si ri ettono sui prodotti del metabolismo della pianta, rispecchia in buona approssimazione la composizione isotopica delle precipitazioni locali. Le composizioni isotopiche 13C e 18O negli oli sono state incrociate con diverse variabili indipendenti geogra che e meteorologiche. le variabili con maggior potere esplicativo sono risultate essere il 18O delle acque di precipitazione e l'indice xerotermico, con diversi valori di R2 a seconda dell'annata. Sono stati anche calcolati gli intervalli di con denza dei modelli di regressione multilineare. Come risultato sono sono state elaborate mappe di previsione (Isoscape) di 13C per il 2010 e 2011, e di 18O per 2009, 2010 e 1011. L'analisi Isoscape ha evidenziato quattro macro aree di produzione EVOO: Nord, Tirreno centrale, Adriatico meridionale e Isole; queste zone includono diverse DOP e IGP. Si tratta, in ogni caso, di una tecnica promettente e sinergica ad alte analisi chimiche tradizionali (elementi pesanti) per il contrasto alle frodi sull'origine geogra ca degli EVOO. Lo studio e stato pubblicato su Food Chemistry [Chiocchini et al. - Food Chemistry 202 (2016) 291-301. doi:10.1016/j.foodchem.2016.01.146]. 6 L'ultimo caso di studio riguarda un progetto in corso: Ecua ux. Si tratta di una colla- borazione internazionale per lo studio dei ussi di carbonio organico e dell'adattamento della fotosintesi in Polylepis reticulata, un albero di alta montagna delle Ande australi ecuadoriane. La raccolta di campioni e iniziata nel gennaio 2016 e dovrebbe proseguire per ulteriori tre o quattro anni. Il campionamento e stato eseguito su sei plot forestali in tre diversi bacini a circa 4000m di quota, all'estremo limite altitudinale della specie. Essendo stata piani cata appositamente per lo studio delle variazioni spaziali e temporali questa ricerca costituisce il banco di prova ideale per la messa a punto dell'Algoritmo Timescape. Le misure isotopiche (si stimano circa duemila campioni a ne campagna) serviranno alla ricostruzione delle variazioni nella performance fotosintetica in un'area particolarmente inte- ressante, quale il Parco Nazionale Cajas in Ecuador. L'area rappresenta un hot spot per i fenomeni di cambiamento climatico: si trova all'equatore, e altimontana ed e esposta contem- poraneamente all'in uenza climatica del bacino amazzonico e dell'Oceano Pacifico centrale e meridionale. Alcuni risultati preliminari sono visibili su http://www.ub.edu/ecologia/ecua ux.Dottorato di ricerca in Scienze e tecnologie per la gestione forestale e ambiental

Integrating Copernicus land cover data into the i-Tree Cool Air model to evaluate and map urban heat mitigation by tree cover

Cities host more than half of the world’s population and due to global warming and land use change their vulnerability to deadly heat waves has increased. A healthy vegetated landscape can abate heat wave severity and diminish the related urban heat island through the process of evapotranspiration. This research aimed to develop a methodology for cities to use publicly available Copernicus land cover maps within the i-Tree Cool Air water and energy balance model to map air temperature and humidity. The manuscript presents proof of concept using Naples, Italy with its Mediterranean climate characterized by limited soil water for cooling via evapotranspiration. The approach achieved strong correlations between predicted and observed air temperatures across the city (r ≥ 0.89). During the warm season of 2020, forested land cover was 5°C cooler than land cover dominated by impervious cover. Simulated land cover change, limited to a 10% increase or decrease in tree cover, generated an inverse change of 0.2°C in maximum hourly air temperature, with more trees obtaining cooler air. Soil water limited the cooling, with the generally wetter spring season enabling greater cooling of air temperatures, and summer droughts without irrigation had constrained cooling. Sustainable urban design will likely require an increase in plant cover along with a reduction of impervious surfaces that absorb and reradiate heat in order to improve community resilience to heat waves

Whole exome sequencing in an Italian family with isolated maxillary canine agenesis and canine eruption anomalies

Objective: The aim of this study was the clinical and molecular characterization of a family segregating a trait consisting of a phenotype specifically involving the maxillary canines, including agenesis, impaction and ectopic eruption, characterized by incomplete penetrance and variable expressivity. Design: Clinical standardized assessment of 14 family members and a whole-exome sequencing (WES) of three affected subjects were performed. WES data analyses (sequence alignment, variant calling, annotation and prioritization) were carried out using an in-house implemented pipeline. Variant filtering retained coding and splice-site high quality private and rare variants. Variant prioritization was performed taking into account both the disruptive impact and the biological relevance of individual variants and genes. Sanger sequencing was performed to validate the variants of interest and to carry out segregation analysis. Results: Prioritization of variants “by function” allowed the identification of multiple variants contributing to the trait, including two concomitant heterozygous variants in EDARADD (c.308C>T, p.Ser103Phe) and COL5A1 (c.1588G>A, p.Gly530Ser), specifically associated with a more severe phenotype (i.e. canine agenesis). Differently, heterozygous variants in genes encoding proteins with a role in the WNT pathway were shared by subjects showing a phenotype of impacted/ectopic erupted canines. Conclusions: This study characterized the genetic contribution underlying a complex trait consisting of isolated canine anomalies in a medium-sized family, highlighting the role of WNT and EDA cell signaling pathways in tooth development

Head and neck osteosarcoma—the ongoing challenge about reconstruction and dental rehabilitation

Head and Neck osteosarcoma is an uncommon disease. Hitherto, the treatment is surgical resection and survival is influenced by the presence of free margins. However, the dimension of the resection may represent a hurdle for an adequate Quality of Life (QOL). Maxillofacial district is a narrow space where the function, esthetics and patient’s relational skills fit together like the gears of a clock. The functional results depend on the type of reconstruction and prosthetic rehabilitation that are both important to guarantee a good aesthetic result and finally increase the patient’s self-esteem. This study aims to report our experience about head and neck (HN) osteosarcoma focusing the attention on reconstructive and dental-rehabilitative problems. It is a retrospective study all patients were surgically treated in our department. Subjects with histological diagnosis of HN osteosarcoma, treated between 2005 and 2017 were included. The demographic characteristics, surgical treatment, eventually secondary reconstruction and prosthetic rehabilitation, performed in the same department, have been collected. The QOL was assessed through the EORTC QLQ-H&N35 (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Head and Neck 35) questionnaire. Fifteen patients were enrolled, eight received a free flap microsurgical reconstruction. Dental rehabilitation was performed in five cases and a mobile prosthesis was always delivered. Eighteen implants were inserted in fibula bones for three patients; highly porous implants were use

Rethinking the history of common walnut (Juglans regia L.) in Europe: Its origins and human interactions

Common walnut (Juglans regia L) is an economically important species cultivated worldwide for its high-quality wood and nuts. It is generally accepted that after the last glaciation J. regia survived and grew in almost completely isolated stands in Asia, and that ancient humans dispersed walnuts across Asia and into new habitats via trade and cultural expansion. The history of walnut in Europe is a matter of debate, however. In this study, we estimated the genetic diversity and structure of 91 Eurasian walnut populations using 14 neutral microsatellites. By integrating fossil pollen, cultural, and historical data with population genetics, and approximate Bayesian analysis, we reconstructed the demographic history of walnut and its routes of dispersal across Europe. The genetic data confirmed the presence of walnut in glacial refugia in the Balkans and western Europe. We conclude that human-mediated admixture between Anatolian and Balkan walnut germplasm started in the Early Bronze Age, and between western Europe and the Balkans in eastern Europe during the Roman Empire. A population size expansion and subsequent decline in northeastern and western Europe was detected in the last five centuries. The actual distribution of walnut in Europe resulted from the combined effects of expansion/contraction from multiple refugia after the Last Glacial Maximum and its human exploitation over the last 5,000 years

Mutations in KCNK4 that Affect Gating Cause a Recognizable Neurodevelopmental Syndrome

Aberrant activation or inhibition of potassium (K+) currents across the plasma membrane of cells has been causally linked to altered neurotransmission, cardiac arrhythmias, endocrine dysfunction, and (more rarely) perturbed developmental processes. The K+ channel subfamily K member 4 (KCNK4), also known as TRAAK (TWIK-related arachidonic acid-stimulated K+ channel), belongs to the mechano-gated ion channels of the TRAAK/TREK subfamily of two-pore-domain (K2P) K+ channels. While K2P channels are well known to contribute to the resting membrane potential and cellular excitability, their involvement in pathophysiological processes remains largely uncharacterized. We report that de novo missense mutations in KCNK4 cause a recognizable syndrome with a distinctive facial gestalt, for which we propose the acronym FHEIG (facial dysmorphism, hypertrichosis, epilepsy, intellectual disability/developmental delay, and gingival overgrowth). Patch-clamp analyses documented a significant gain of function of the identified KCNK4 channel mutants basally and impaired sensitivity to mechanical stimulation and arachidonic acid. Co-expression experiments indicated a dominant behavior of the disease-causing mutations. Molecular dynamics simulations consistently indicated that mutations favor sealing of the lateral intramembrane fenestration that has been proposed to negatively control K+ flow by allowing lipid access to the central cavity of the channel. Overall, our findings illustrate the pleiotropic effect of dysregulated KCNK4 function and provide support to the hypothesis of a gating mechanism based on the lateral fenestrations of K2P channels

Mutations impairing GSK3-mediated MAF phosphorylation cause cataract, deafness, intellectual disability, seizures, and a down syndrome-like facies

Transcription factors operate in developmental processes to mediate inductive events and cell competence, and perturbation of their function or regulation can dramatically affect morphogenesis, organogenesis, and growth. We report that a narrow spectrum of amino-acid substitutions within the transactivation domain of the v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog (MAF), a leucine zipper-containing transcription factor of the AP1 superfamily, profoundly affect development. Seven different de novo missense mutations involving conserved residues of the four GSK3 phosphorylation motifs were identified in eight unrelated individuals. The distinctive clinical phenotype, for which we propose the eponym Aymé-Gripp syndrome, is not limited to lens and eye defects as previously reported for MAF/Maf loss of function but includes sensorineural deafness, intellectual disability, seizures, brachycephaly, distinctive flat facial appearance, skeletal anomalies, mammary gland hypoplasia, and reduced growth. Disease-causing mutations were demonstrated to impair proper MAF phosphorylation, ubiquitination and proteasomal degradation, perturbed gene expression in primary skin fibroblasts, and induced neurodevelopmental defects in an in vivo model. Our findings nosologically and clinically delineate a previously poorly understood recognizable multisystem disorder, provide evidence for MAF governing a wider range of developmental programs than previously appreciated, and describe a novel instance of protein dosage effect severely perturbing developmen

Role of DNA Methylation Profile in Diagnosing Astroblastoma: A Case Report and Literature Review

Astroblastoma is a rare tumor of the central nervous system (CNS) with uncertain clinical behavior. Recently, DNA methylation profiling has been shown to provide a highly robust and reproducible approach for the classification of all CNS tumors across different age groups. By using DNA methylation profiling, a subset of CNS high-grade tumors with astroblastoma-like morphology characterized by the meningioma 1 gene (MN1) rearrangements, has been identified; they were termed “CNS high-grade neuroepithelial tumors with MN1 alteration” (CNS-HGNET-MN1). Here, we describe a case of CNS-HGNET-MN1 diagnosed by DNA methylation profiling, using Illumina Infinium HumanMethylationEPIC BeadChip (EPIC), that offers the opportunity to conduct a brief literature review. The patient presented with an episode of partial seizures involving the right hemisoma. A gross total resection was performed. No other treatment was proposed in light of the histological and molecular findings. After 21 months, the patient is disease-free in good clinical conditions. Also in view of this case, we recommend DNA-methylation profiling as an important tool for diagnosis and more effective patient stratification and management

Childhood-onset dystonia-causing KMT2B variants result in a distinctive genomic hypermethylation profile

Background: Dystonia is a clinically and genetically heterogeneous movement disorder characterized by sustained or intermittent muscle contractions causing abnormal, often repetitive, movements and/or postures. Heterozygous variants in lysine methyltransferase 2B (KMT2B), encoding a histone H3 methyltransferase, have been associated with a childhood-onset, progressive and complex form of dystonia (dystonia 28, DYT28). Since 2016, more than one hundred rare KMT2B variants have been reported, including frameshift, nonsense, splice site, missense and other in-frame changes, many having an uncertain clinical impact. Results: We characterize the genome-wide peripheral blood DNA methylation profiles of a cohort of 18 patients with pathogenic and unclassified KMT2B variants. We resolve the “episignature” associated with KMT2B haploinsufficiency, proving that this approach is robust in diagnosing clinically unsolved cases, properly classifying them with respect to other partially overlapping dystonic phenotypes, other rare neurodevelopmental disorders and healthy controls. Notably, defective KMT2B function in DYT28 causes a non-random DNA hypermethylation across the genome, selectively involving promoters and other regulatory regions positively controlling gene expression. Conclusions: We demonstrate a distinctive DNA hypermethylation pattern associated with DYT28, provide an epigenetic signature for this disorder enabling accurate diagnosis and reclassification of ambiguous genetic findings and suggest potential therapeutic approaches