Domenico Coviello
@gaslini.org
Laboratory of Human Genetics
IRCCS Istituto Giannina Gaslini,Genoa, Italy
Scopus Publications
Scopus Publications
Giuseppina Conteduca, Chiara Baldo, Alessia Arado, Joana Soraia Martinheira da Silva, Barbara Testa, Simona Baldassari, Federico Zara, Gilberto Filaci, Domenico Coviello, and Michela Malacarne
Elsevier BV
F. Fioredda, A. Beccaria, P. Casartelli, E. Turrini, C. Contratto, M. C. Giarratana, F. Bagnasco, F. Saettini, M. Pillon, A. Marzollo,et al.
Wiley
AbstractThis study identifies a new chronic form of immune neutropenia in the young with or without detectable indirect anti‐neutrophil antibodies, characterized by mild/moderate neutropenia low risk of severe infection (14%), tendency to develop autoimmune phenomena over the course of the disease (cumulative incidence of 58.6% after 20 years of disease duration), leukopenia, progressive reduction of absolute lymphocyte count and a T‐ and B‐cell profile similar to autoimmune disorders like Sjogren syndrome, rheumatoid arthritis, and systemic lupus erythematosus (increased HLADR+ and CD3 + TCRγδ cells, reduced T regulatory cells, increased double‐negative B and a tendency to reduced B memory cells). In a minority of patients, P/LP variants related to primary immuno‐regulatory disorders were found. This new form may fit the group of “Likely acquired neutropenia,” a provisional category included in the recent International Guidelines on Diagnosis and Management of Neutropenia of EHA and EUNET INNOCHRON ACTION 18233. The early recognition of this form of neutropenia would help clinicians to delineate better specific monitoring plans, genetic counseling, and potentially targeted therapies.
Giulio Calcagni, Federica Ferrigno, Alessio Franceschini, Maria Lisa Dentici, Rossella Capolino, Lorenzo Sinibaldi, Chiara Minotti, Alessia Micalizzi, Viola Alesi, Antonio Novelli,et al.
MDPI AG
Sotos syndrome is an autosomal dominant condition characterized by overgrowth with advanced bone age, macrodolicocephaly, motor developmental delays and learning difficulties, and characteristic facial features caused by heterozygous pathogenetic variants in the NSD1 gene located on chromosome 5q35. The prevalence of heart defects (HDs) in individuals with Sotos syndrome is estimated to be around 15–40%. Septal defects and patent ductus arteriosus are the most commonly diagnosed malformations, but complex defects have also been reported. The aim of our study was to analyze the prevalence of HD, the anatomic types, and the genetic characteristics of 45 patients with Sotos syndrome carrying pathogenetic variants of NSD1 or a 5q35 deletion encompassing NSD1, who were followed at Bambino Gesù Children’s Hospital in Rome. Thirty-nine of the forty-five patients (86.7%) had a mutation in NSD1, while six of the forty-five (13.3%) had a deletion. Most of the patients (62.2%, 28/45) were male, with a mean age of 14 ± 7 years (range 0.2–37 years). A total of 27/45 (60.0%) of the patients had heart defects, isolated or combined with other defects, including septal defects (12 patients), aortic anomalies (9 patients), mitral valve and/or tricuspid valve dysplasia/insufficiency (1 patient), patent ductus arteriosus (3 patients), left ventricular non-compaction/hypertrabeculated left ventricle (LV) (4 patients), aortic coarctation (1 patient), aortopulmonary window (1 patient), and pulmonary valve anomalies (3 patients). The prevalences of HD in the two subgroups (deletion versus intragenic mutation) were similar (66.7% (4/6) in the deletion group versus 58.91% (23/39) in the intragenic variant group). Our results showed a higher prevalence of HD in patients with Sotos syndrome in comparison to that described in the literature, with similar distributions of patients with mutated and deleted genes. An accurate and detailed echocardiogram should be performed in patients with Sotos syndrome at diagnosis, and a specific cardiological follow-up program is needed.
Ilaria Frattale, Rachele Sarnataro, Martina Siracusano, Assia Riccioni, Cinzia Galasso, Massimiliano Valeriani, Giuseppina Conteduca, Domenico Coviello, Luigi Mazzone, and Romina Moavero
Frontiers Media SA
BackgroundSotos syndrome (SoS) is a rare overgrowth genetic disease caused by intragenic mutations or microdeletions of the NSD1 gene located on chromosome 5q35. SoS population might present cognitive impairment and a spectrum of behavioral characteristics, with a worse profile in patients with microdeletion. Although patients with SoS are known to have impaired sleep habits, very little data are available. The present study aimed to assess the prevalence of sleep disorders (SDs) in a pediatric cohort of patients with SoS and their correlation with neuropsychiatric profiles.MethodsWe included patients with a SoS diagnosis and age < 18 years; all patients underwent a comprehensive neuropsychological assessment, including evaluation of cognition, adaptive functions through the Adaptive Behavior Assessment System-Second Edition (ABAS-II), and behavioral problems using the Achenbach Child Behavior Checklist (CBCL) and Conners’ Parent Rating Scale-Revised (CPRS-R:L) questionnaire. To investigate the presence of SD parents, the Sleep Disturbance Scale for Children (SDSC) was completed.ResultsThirty-eight patients (M 61%, F 39%, mean age 11.1 ± 4.65 years) were included in the study. Although only two had a prior SD diagnosis, 71.1% (N = 27) exhibited pathological scores on SDSC. No statistically significant associations were found between positive SDSC results and genetic microdeletion, intellectual disability (ID), or other medical conditions/treatments. However, a positive correlation emerged between SDSC scores and Conners’ Global Index (p = 0.048) and Restless/Impulsive (p = 0.01) scores, CBCL externalizing (p = 0.02), internalizing (p = 0.01), and total scores (p = 0.05). Conversely, a negative linear relationship was observed between the SDSC score and the ABAS GAC and ABAS CAD scores (p = 0.025).ConclusionWe detected an SD in 71.1% of our sample, with a positive relation between SD and internalizing and externalizing symptom levels, especially hyperactivity and impulsivity. Our study demonstrated a high prevalence of SD in pediatric patients with SoS, highlighting that all patients should be screened for this problem, which has a great impact on the quality of life of patients and their families.
Martina Siracusano, Caterina Dante, Rachele Sarnataro, Lucrezia Arturi, Assia Riccioni, Elisa Carloni, Mariagrazia Cicala, Leonardo Emberti Gialloreti, Cinzia Galasso, Giuseppina Conteduca,et al.
Wiley
AbstractDelineation of a developmental and behavioral trajectory is a key‐topic in the context of a genetic syndrome. Short‐ and long‐term implications concerning school outcome, independent living, and working opportunities are strictly linked to the cognitive and behavioral profile of an individual. For the first time, we present a longitudinal characterization of the adaptive and behavioral profile of a pediatric sample of 32 individuals with Sotos Syndrome (SoS) (18 males, 14 females; mean age 9.7 ± 4 years, eight carrying the NSD1 5q35 microdeletion and 24 with an intragenic mutation). We performed two clinical assessments: at baseline (T0) and at distance evaluation (T1) of adaptive and behavioral skills with a mean distance of 1.56 ± 0.95 years among timepoints. Our study reports a stability over the years—meant as lack of statistically significant clinical worsening or improvement—of both adaptive and behavioral skills investigated, regardless the level of Intellectual Quotient and chronological age at baseline. However, participants who did not discontinue intervention among T0 and T1, were characterized by a better clinical profile in terms of adaptive skills and behavioral profile at distance, emphasizing that uninterrupted intervention positively contributes to the developmental trajectory.
Cesare Danesino, Monica Gualtierotti, Matteo Origi, Angelina Cistaro, Michela Malacarne, Matteo Massidda, Katia Bencardino, Domenico Coviello, Giovanni Albani, Irene Giovanna Schiera,et al.
MDPI AG
Background: In Cri du Chat (CdC), cancer as comorbidity is extremely rare. In databases from Denmark, Spain, Australia, New Zealand, and Japan, no cancer was reported; in Italy and Germany, four cancers were identified out of 321 CdCs. Methods: In a 29-year-old CdC patient, clinical investigations following hematemesis led to the diagnosis of esophageal adenocarcinoma (EAC). A high pain threshold was also observed. Conventional and molecular cytogenetic defined the size of the deletion, and exome analysis on the trio completed the molecular work. Results: Cytogenetic analysis showed a de novo chromosomal alteration: 46,XY,ishdel(5)(p14.3)(D5S28-) and arr[GRCh37] 5p15.33p14.3(1498180_19955760)x1. A quantitative sensory test demonstrated a high heat threshold. A 18f-fluorodeoxyglucose PET/TC scan of the brain failed to detect reduction of metabolism in the somatosensory area or insular cortex. Exome analysis in the trio (patient and parents) failed to identify variants to be interpreted as a likely risk factor for EAC. Conclusion: We conclude that the presence of well-known risk factors (maleness, obesity, gastroesophageal reflux, and Barrett’s metaplasia) in a patient with very limited capability of expressing discomfort or referring clinical symptoms have been the main risk factors for developing EAC. At present, based on the available data, there is no evidence of any increased risk of developing cancer in CdC patients.
Costanza Ceni, Francesca Clemente, Francesca Mangiavacchi, Camilla Matassini, Rodolfo Tonin, Anna Caciotti, Federica Feo, Domenico Coviello, Amelia Morrone, Francesca Cardona,et al.
MDPI AG
Gaucher disease (GD) is a rare genetic metabolic disorder characterized by a dysfunction of the lysosomal glycoside hydrolase glucocerebrosidase (GCase) due to mutations in the gene GBA1, leading to the cellular accumulation of glucosylceramide (GlcCer). While most of the current research focuses on the primary accumulated material, lesser attention has been paid to secondary storage materials and their reciprocal intertwining. By using a novel approach based on flow cytometry and fluorescent labelling, we monitored changes in storage materials directly in fibroblasts derived from GD patients carrying N370S/RecNcil and homozygous L444P or R131C mutations with respect to wild type. In L444P and R131C fibroblasts, we detected not only the primary accumulation of GlcCer accumulation but also a considerable secondary increase in GM1 storage, comparable with the one observed in infantile patients affected by GM1 gangliosidosis. In addition, the ability of a trivalent trihydroxypiperidine iminosugar compound (CV82), which previously showed good pharmacological chaperone activity on GCase enzyme, to reduce the levels of storage materials in L444P and R131C fibroblasts was tested. Interestingly, treatment with different concentrations of CV82 led to a significant reduction in GM1 accumulation only in L444P fibroblasts, without significantly affecting GlcCer levels. The compound CV82 was selective against the GCase enzyme with respect to the β-Galactosidase enzyme, which was responsible for the catabolism of GM1 ganglioside. The reduction in GM1-ganglioside level cannot be therefore ascribed to a direct action of CV82 on β-Galactosidase enzyme, suggesting that GM1 decrease is rather related to other unknown mechanisms that follow the direct action of CV82 on GCase. In conclusion, this work indicates that the tracking of secondary storages can represent a key step for a better understanding of the pathways involved in the severity of GD, also underlying the importance of developing drugs able to reduce both primary and secondary storage-material accumulations in GD.
Jesse B. Hayesmoore, Zahurul A. Bhuiyan, Domenico A. Coviello, Desirée du Sart, Matthew Edwards, Maria Iascone, Deborah J. Morris-Rosendahl, Katie Sheils, Marjon van Slegtenhorst, and Kate L. Thomson
Springer Science and Business Media LLC
AbstractInherited cardiomyopathies and arrhythmias (ICAs) are a prevalent and clinically heterogeneous group of genetic disorders that are associated with increased risk of sudden cardiac death and heart failure. Making a genetic diagnosis can inform the management of patients and their at-risk relatives and, as such, molecular genetic testing is now considered an integral component of the clinical care pathway. However, ICAs are characterised by high genetic and allelic heterogeneity, incomplete / age-related penetrance, and variable expressivity. Therefore, despite our improved understanding of the genetic basis of these conditions, and significant technological advances over the past two decades, identifying and recognising the causative genotype remains challenging. As clinical genetic testing for ICAs becomes more widely available, it is increasingly important for clinical laboratories to consolidate existing knowledge and experience to inform and improve future practice. These recommendations have been compiled to help clinical laboratories navigate the challenges of ICAs and thereby facilitate best practice and consistency in genetic test provision for this group of disorders. General recommendations on internal and external quality control, referral, analysis, result interpretation, and reporting are described. Also included are appendices that provide specific information pertinent to genetic testing for hypertrophic, dilated, and arrhythmogenic right ventricular cardiomyopathies, long QT syndrome, Brugada syndrome, and catecholaminergic polymorphic ventricular tachycardia.
Kati Koido, Charlotta Ingvoldstad Malmgren, Lejla Pojskic, Peter Z. Almos, Sarah E. Bergen, Isabella Borg, Nada Božina, Domenico A. Coviello, Franziska Degenhardt, Lana Ganoci,et al.
Elsevier BV
Edoardo Bertero, Giulia Fracasso, Virginia Eustachi, Domenico Coviello, Massimiliano Cecconi, Stefano Giovinazzo, Matteo Toma, Marco Merlo, Gianfranco Sinagra, Italo Porto,et al.
Wiley
AIMS
We assessed the diagnostic yield of genetic testing and the relationship of left ventricular (LV) reverse remodelling (LVRR) with the presence of DNA pathogenic (P) or likely pathogenic (LP) variants in patients with dilated cardiomyopathy (DCM).
METHODS AND RESULTS
From 680 outpatients followed at the Heart Failure Outpatient Clinic of our institution, we selected subjects with a diagnosis of DCM as defined by LV ejection fraction (LVEF) ≤40% and LV dilatation not explained by coronary artery disease or other causes. All patients were offered genetic investigation of 42 disease-associated DCM genes with next-generation sequencing. Seventy patients fulfilled the definition of DCM and 66 underwent genetic investigation. We identified 18 P/LP variants in 16 patients, with a diagnostic yield of 24%. The most common variants were truncating TTN variants (n = 7), followed by LMNA (n = 3), cytoskeleton Z-disc (n = 3), ion channel (n = 2), motor sarcomeric (n = 2), and desmosomal (n = 1) genes. After a median follow-up of 53 months (inter-quartile range 20-111), patients without P/LP variants exhibited higher systolic and diastolic blood pressure, lower plasma brain natriuretic peptide levels, and a larger extent of LVRR, as reflected by the increase in LVEF (+14% vs. +1%, P = 0.0008) and decrease in indexed LV end-diastolic diameter (-6.5 vs. -2 mm/m2 , P = 0.03) compared with patients with P/LP variants.
CONCLUSIONS
Our results confirm the high diagnostic yield of genetic testing in selected DCM patients and suggest that identification of P/LP variants in DCM portends poorer LVRR in response to guideline-directed medical therapy.
Martina Siracusano, Assia Riccioni, Ilaria Frattale, Lucrezia Arturi, Caterina Dante, Cinzia Galasso, Leonardo Emberti Gialloreti, Giuseppina Conteduca, Barbara Testa, Michela Malacarne,et al.
Wiley
Sotos syndrome (SoS) is a congenital overgrowth syndrome with variable degree of intellectual disability caused in the 90% of cases by pathogenetic variants of the Nuclear receptor binding SET Domain protein1 (NSD1) gene. NSD1 gene functions can be abrogated by different genetic alterations (i.e., small intragenic pathogenic variants like deletions/insertions, nonsense/missense pathogenic variants, partial gene deletions and whole deletions or microdeletion of 5q35 chromosomal region). Therefore, correlation of the genotype-phenotype with a possible contribution of more implicated genes to the medical, cognitive and behavioral profile is a topic of great interest. Although a more severe learning disability has been described in individuals with 5q35 microdeletion when compared to individuals with NSD1 intragenic pathogenic variants a fully delineated cognitive and behavioral phenotype has not been described yet. The importance of providing clinical characterization in relation to the genotype comes from the necessity to early identify children more at risk of developing psychopathological disorders. We characterize the cognitive, adaptive and behavioral phenotype of a pediatric sample of 64 individuals affected by SoS, performing a standardized neuropsychological evaluation. Secondly, we compare cognitive-behavioral profiles of SoS individuals carrying and not carrying the 5q35 microdeletion. SoS participants were characterized by a mild cognitive impairment of both Intellectual Quotient and adaptive skills in association to borderline symptoms of attention deficit. Our results suggest that the 5q35 microdeletion is associated with lower scores specifically concerning the cognitive, adaptive functioning and behavioral domains. However, longitudinal studies are necessary to confirm these findings and delineate a developmental trajectory of SoS.
Ariam Boaglio, Carlos Luis Parra-Calderón, Alicia Martinez-García, María José Escalona-Cuaresma, Norbert Maggi, Domenico Coviello, Paolo Uva, and Mauro Giacomini
IOS Press
Results of two major projects funded by the European Union are taken into consideration: Fair4Health regarding the possibility of sharing clinical data in various environments applying FAIR principles and 1+Million Genome for the in-depth study of the human genome in Europe. Specifically, the Gaslini hospital plans to move on both areas joining the Hospital on FHIR initiative matured within the fair4health project and also collaborate with other Italian healthcare facilities through the implementation of a Proof of Concept (PoC) in the 1+MG. The aim of this short paper is to evaluate the applicability of some of the tools of the fair4health project to the Gaslini infrastructure to facilitate its participation in the PoC. One of the aims is also to prove the possibility of reuse the results of well-performed European funded projects to boost routine research in qualified healthcare facilities.
Rute Luísa Cabrita Pinto, Silvia Viaggi, Edoardo Canale, Marina Martinez Popple, Valeria Capra, Giuseppina Conteduca, Barbara Testa, Domenico Coviello, and Angela Elvira Covone
MDPI AG
The CC2D2A gene is essential for primary cilia formation, and its disruption has been associated with Joubert Syndrome-9 (JBTS9), a ciliopathy with typical neurodevelopmental features. Here, we describe an Italian pediatric patient with typical features of Joubert Syndrome (JBTS): “Molar Tooth Sign”, global developmental delay, nystagmus, mild hypotonia, and oculomotor apraxia. Whole exome sequencing and segregation analysis identified in our infant patient a novel heterozygous germline missense variant c.3626C > T; p.(Pro1209Leu) inherited from the father and a novel 7.16 kb deletion inherited from the mother. To the best of our knowledge, this is the first report showing a novel missense and deletion variant involving exon 30 of the CC2D2A gene.
Lisa Pavinato, Andrea Delle Vedove, Diana Carli, Marta Ferrero, Silvia Carestiato, Jennifer L Howe, Emanuele Agolini, Domenico A Coviello, Ingrid van de Laar, Ping Yee Billie Au,et al.
Oxford University Press (OUP)
Abstract We describe an autosomal dominant disorder associated with loss-of-function variants in the Cell cycle associated protein 1 (CAPRIN1; MIM*601178). CAPRIN1 encodes a ubiquitous protein that regulates the transport and translation of neuronal mRNAs critical for synaptic plasticity, as well as mRNAs encoding proteins important for cell proliferation and migration in multiple cell types. We identified 12 cases with loss-of-function CAPRIN1 variants, and a neurodevelopmental phenotype characterized by language impairment/speech delay (100%), intellectual disability (83%), attention deficit hyperactivity disorder (82%) and autism spectrum disorder (67%). Affected individuals also had respiratory problems (50%), limb/skeletal anomalies (50%), developmental delay (42%) feeding difficulties (33%), seizures (33%) and ophthalmologic problems (33%). In patient-derived lymphoblasts and fibroblasts, we showed a monoallelic expression of the wild-type allele, and a reduction of the transcript and protein compatible with a half dose. To further study pathogenic mechanisms, we generated sCAPRIN1+/− human induced pluripotent stem cells via CRISPR–Cas9 mutagenesis and differentiated them into neuronal progenitor cells and cortical neurons. CAPRIN1 loss caused reduced neuronal processes, overall disruption of the neuronal organization and an increased neuronal degeneration. We also observed an alteration of mRNA translation in CAPRIN1+/− neurons, compatible with its suggested function as translational inhibitor. CAPRIN1+/− neurons also showed an impaired calcium signalling and increased oxidative stress, two mechanisms that may directly affect neuronal networks development, maintenance and function. According to what was previously observed in the mouse model, measurements of activity in CAPRIN1+/− neurons via micro-electrode arrays indicated lower spike rates and bursts, with an overall reduced activity. In conclusion, we demonstrate that CAPRIN1 haploinsufficiency causes a novel autosomal dominant neurodevelopmental disorder and identify morphological and functional alterations associated with this disorder in human neuronal models.
Barbara Testa, Giuseppina Conteduca, Marina Grasso, Massimiliano Cecconi, Francesca Lantieri, Chiara Baldo, Alessia Arado, Laura Andraghetti, Michela Malacarne, Donatella Milani,et al.
MDPI AG
Sotos syndrome is a rare genetic disorder caused by haploinsufficiency of the NSD1 (nuclear receptor binding SET domain containing protein 1) gene. No clinical diagnostic consensus criteria are published yet, and molecular analysis reduces the clinical diagnostic uncertainty. We screened 1530 unrelated patients enrolled from 2003 to 2021 at Galliera Hospital and Gaslini Institute in Genoa. NSD1 variants were identified in 292 patients including nine partial gene deletions, 13 microdeletions of the entire NSD1 gene, and 115 novel intragenic variants never previously described. Thirty-two variants of uncertain significance (VUS) out of 115 identified were re-classified. Twenty-five missense NSD1 VUS (25/32, 78.1%) changed class to likely pathogenic or likely benign, showing a highly significant shift in class (p < 0.01). Apart from NSD1, we identified variants in additional genes (NFIX, PTEN, EZH2, TCF20, BRWD3, PPP2R5D) in nine patients analyzed by the NGS custom panel. We describe the evolution of diagnostic techniques in our laboratory to ascertain molecular diagnosis, the identification of 115 new variants, and the re-classification of 25 VUS in NSD1. We underline the utility of sharing variant classification and the need to improve communication between the laboratory staff and the referring physician.
Giuseppina Conteduca, Chiara Baldo, Alessia Arado, Monica Traverso, Barbara Testa, Michela Malacarne, Domenico Coviello, Federico Zara, and Simona Baldassari
Elsevier BV
Giuseppina Conteduca, Barbara Testa, Chiara Baldo, Alessia Arado, Michela Malacarne, Giovanni Candiano, Andrea Garbarino, Domenico A. Coviello, and Claudia Cantoni
Elsevier BV
P. Cavarzere, A. Pietrobelli, A. Gandini, S. Munari, A. M. Baffico, M. Maffei, R. Gaudino, A. Guzzo, M. Arrigoni, D. Coviello,et al.
Springer Science and Business Media LLC
Margherita Vinciguerra, Filippo Leto, Filippo Cassarà, Viviana Tartaglia, Michela Malacarne, Domenico Coviello, Valentina Cigna, Emanuela Orlandi, Francesco Picciotto, Gaspare Cucinella,et al.
MDPI AG
Background: Turner syndrome is a rare genetic condition in which a female is partly or completely missing an X chromosome. Signs and symptoms vary among those affected. In fetuses that survive at birth and without congenital malformations, the prognosis is usually positive, but it has high lethality in utero, especially in the first trimester of pregnancy. Methods: We report a case of monosomy X detected during a prenatal diagnosis for beta thalassemia on coelomic fluid (CF) at the VIII week of gestation. Beta globin gene analysis, whole genome amplification (WGA), quantitative fluorescent PCR and array comparative genomic hybridization (array-CGH) were performed on DNA extracted from CF. Results: A monoallelic pattern of all Short Tandem Repeats mapped on the X chromosome was found and array-CGH performed on WGA from a few fetal erythroblasts confirmed monosomy X. Conclusion: This report underlines the importance of an early prenatal diagnosis and the countless potentialities of array-CGH that could make definition of molecular karyotype possible from a few fetal cells, unlike conventional cytogenetic techniques that require a greater cellular content. This is the first report of a molecular karyotype obtained from two cells selected by micromanipulation of CF and defined at such an early gestational age.
Anthony Onoja, Nicola Picchiotti, Chiara Fallerini, Margherita Baldassarri, Francesca Fava, Francesca Mari, Sergio Daga, Elisa Benetti, Mirella Bruttini, Maria Palmieri,et al.
Springer Science and Business Media LLC
AbstractWe employed a multifaceted computational strategy to identify the genetic factors contributing to increased risk of severe COVID-19 infection from a Whole Exome Sequencing (WES) dataset of a cohort of 2000 Italian patients. We coupled a stratified k-fold screening, to rank variants more associated with severity, with the training of multiple supervised classifiers, to predict severity based on screened features. Feature importance analysis from tree-based models allowed us to identify 16 variants with the highest support which, together with age and gender covariates, were found to be most predictive of COVID-19 severity. When tested on a follow-up cohort, our ensemble of models predicted severity with high accuracy (ACC = 81.88%; AUCROC = 96%; MCC = 61.55%). Our model recapitulated a vast literature of emerging molecular mechanisms and genetic factors linked to COVID-19 response and extends previous landmark Genome-Wide Association Studies (GWAS). It revealed a network of interplaying genetic signatures converging on established immune system and inflammatory processes linked to viral infection response. It also identified additional processes cross-talking with immune pathways, such as GPCR signaling, which might offer additional opportunities for therapeutic intervention and patient stratification. Publicly available PheWAS datasets revealed that several variants were significantly associated with phenotypic traits such as “Respiratory or thoracic disease”, supporting their link with COVID-19 severity outcome.
Alessandra Colombini, Francesca Libonati, Davide Cangelosi, Silvia Lopa, Paola De Luca, Domenico Antonio Coviello, Matteo Moretti, and Laura de Girolamo
Frontiers Media SA
Inflammatory processes contribute to osteoarthritis (OA) severity and progression. Mesenchymal stem cells, particularly those derived from adipose tissue (ASCs), are able to sense and control the inflammatory environment. This immunomodulatory potential can be boosted by different priming strategies based on inflammatory stimulation. The aim of the present study is to investigate the transcriptional modulation of a huge panel of genes and functionally verify the predicted immunomodulatory ability of ASCs after interleukin one beta (IL-1β) priming. ASCs were isolated from adipose tissue obtained from three donors and expanded. After stimulation with 1 ng/ml of IL-1β for 48 h, cells were collected for gene array and functional tests. Pooled cells from three donors were used for RNA extraction and gene array analysis. Gene Ontology (GO) enrichment analysis and Gene Set Enrichment Analysis (GSEA) were performed to assess the involvement of the modulated genes after priming in specific biological processes and pathways. Functional co-culture tests of ASCs with T cells and macrophages were performed to assess the ability of primed ASCs to modulate immune cell phenotype. Among the overall genes analyzed in the gene array, about the 18% were up- or down-regulated in ASCs after IL-1β priming. GO enrichment analysis of up- or down-regulated genes in ASCs after IL-1β priming allowed identifying specific pathways involved in the modulation of inflammation and extracellular matrix remodeling. The main processes enriched according to the GSEA are related to the inflammatory response and cell proliferative processes. Functional tests on immune cells showed that primed and non-primed ASCs induced a decrease in the CD3+ T lymphocytes survival rate and an anti-inflammatory macrophage polarization. In conclusion, IL-1β priming represents a tailored strategy to enhance the ability of ASCs to direct macrophages towards an anti-inflammatory phenotype and, consequently, improve the efficacy of ASCs in counteracting the OA inflammatory component.
Elisa Tassano, Sara Uccella, Patrizia Ronchetto, Joana Soraia Martinheira Da Silva, Silvia Viaggi, Margherita Mancardi, Luca Ramenghi, Alessandra Murri, Marina Biondi, Giorgio Gimelli,et al.
S. Karger AG
Interstitial 2q24.2q24.3 microdeletions are rare cytogenetic aberrations associated with heterogeneous clinical features depending on the size of the deletion. Here, we describe 2 patients with overlapping de novo 2q24.2q24.3 deletions, characterized by array-CGH. This is the smallest 2q24.2q24.3 region of overlap described in the literature encompassing only 9 genes (<i>SLC4A10</i>, <i>DPP4</i>, <i>GCG</i>, <i>FAP</i>, <i>IFIH1</i>, <i>GCA</i>, <i>KCNH7</i>, <i>FIGN</i>,<i> GRB14</i>). We focused our attention on <i>SLC4A10, DPP4,</i> and <i>KCNH7,</i> genes associated with neurological features. Our patients presented similar features: intellectual disability, developmental and language delay, hypotonia, joint laxity, and dysmorphic features. Only patient 2 showed profound deafness and also carried a heterozygous mutation of the <i>GJB2</i> gene responsible for autosomal recessive deafness 1A (DFNB1A: OMIM 220290). Could the disruption of a gene present in the 2q24.2q24.3 deleted region be responsible for her profound hearing loss?