Author: "Floriana Valentino" - Searchworks@Jio Institute Digital Library Search Results

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29 results on '"Floriana Valentino"'

1. Heterozygosity for neuronal ceroid lipofuscinosis predisposes to bipolar disorder

Author: Flavia Privitera, Maria A. Trusso, Floriana Valentino, Gabriella Doddato, Chiara Fallerini, Giulia Brunelli, Romina D’Aurizio, Simone Furini, Arianna Goracci, Andrea Fagiolini, Francesca Mari, Alessandra Renieri, and Francesca Ariani
Subjects: Bipolar disorder, WES, ZNF92, CLN6, Psychiatry, RC435-571
Abstract: Objective: Bipolar disorder is a heritable chronic mental disorder that causes psychosocial impairment through depressive/manic episodes. Familial transmission of bipolar disorder does not follow simple Mendelian patterns of inheritance. The aim of this study was to describe a large family with 12 members affected by bipolar disorder. Whole-exome sequencing was performed for eight members, three of whom were diagnosed with bipolar disorder, and another reported as “borderline.” Methods: Whole-exome sequencing data allowed us to select variants that the affected members had in common, including and excluding the “borderline” individual with moderate anxiety and obsessive-compulsive traits. Results: The results favored designating certain genes as predispositional to bipolar disorder: a heterozygous missense variant in CLN6 resulted in a “borderline” phenotype that, if combined with a heterozygous missense variant in ZNF92, is responsible for the more severe bipolar disorder phenotype. Both rare missense changes are predicted to disrupt protein function. Conclusions: Loss of both alleles in CLN6 causes neuronal ceroid lipofuscinosis, a severe progressive childhood neurological disorder. Our results indicate that heterozygous CLN6 carriers, previously reported as healthy, may be susceptible to bipolar disorder later in life if associated with additional variants in ZNF92.
Published: 2023
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2. Corrigendum: Exome Sequencing in BRCA1-2 Candidate Familias: The Contribution of Other Cancer Susceptibility Genes

Author: Gabriella Doddato, Floriana Valentino, Annarita Giliberti, Filomena Tiziana Papa, Rossella Tita, Lucia Pia Bruno, Sara Resciniti, Chiara Fallerini, Elisa Benetti, Maria Palmieri, Maria Antonietta Mencarelli, Alessandra Fabbiani, Mirella Bruttini, Alfredo Orrico, Margherita Baldassarri, Francesca Fava, Diego Lopergolo, Caterina Lo Rizzo, Vittoria Lamacchia, Sara Mannucci, Anna Maria Pinto, Aurora Currò, Virginia Mancini, Oncologic Multidisciplinary Team, Azienda Ospedaliera Universitaria Senese, Azienda Usl Toscana Sud Est, Francesca Mari, Alessandra Renieri, and Francesca Ariani
Subjects: BRCA1, BRCA2, cancer susceptibility genes, HBOC, ES (Exome Sequencing), Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Published: 2021
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3. Exome Sequencing in BRCA1-2 Candidate Familias: The Contribution of Other Cancer Susceptibility Genes

Author: Gabriella Doddato, Floriana Valentino, Annarita Giliberti, Filomena Tiziana Papa, Rossella Tita, Lucia Pia Bruno, Sara Resciniti, Chiara Fallerini, Elisa Benetti, Maria Palmieri, Maria Antonietta Mencarelli, Alessandra Fabbiani, Mirella Bruttini, Alfredo Orrico, Margherita Baldassarri, Francesca Fava, Diego Lopergolo, Caterina Lo Rizzo, Vittoria Lamacchia, Sara Mannucci, Anna Maria Pinto, Aurora Currò, Virginia Mancini, Oncologic Multidisciplinary Team, Azienda Ospedaliera Universitaria Senese, Oncologic Multidisciplinary Team, Azienda Usl Toscana Sud Est, Francesca Mari, Alessandra Renieri, Francesca Ariani, Alessandro Neri, Donato Casella, Andrea Bernini, Stefania Marsili, Roberto Petrioli, Salvatora Tindara Miano, Alessandra Pascucci, Ignazio Martellucci, Monica Crociani, Marta Vannini, Federica Fantozzi, Andrea Stella, Alessia Carmela Tripodi, Angelamaria Giusti, Alfonso Fausto, Lucia Mantovani, and Francesca Belardi
Subjects: BRCA1, BRCA2, cancer susceptibility genes, HBOC, ES (Exome Sequencing), Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Hereditary Breast and Ovarian Cancer (HBOC) syndrome is a condition in which the risk of breast and ovarian cancer is higher than in the general population. The prevalent pathogenesis is attributable to inactivating variants of the BRCA1-2 highly penetrant genes, however, other cancer susceptibility genes may also be involved. By Exome Sequencing (ES) we analyzed a series of 200 individuals selected for genetic testing in BRCA1-2 genes according to the updated National Comprehensive Cancer Network (NCCN) guidelines. Analysis by MLPA was performed to detect large BRCA1-2 deletions/duplications. Focusing on BRCA1-2 genes, data analysis identified 11 cases with pathogenic variants (4 in BRCA1 and 7 in BRCA1-2) and 12 with uncertain variants (7 in BRCA1 and 5 in BRCA2). Only one case was found with a large BRCA1 deletion. Exome analysis allowed to characterize pathogenic variants in 21 additional genes: 10 genes more traditionally associated to breast and ovarian cancer (ATM, BRIP1, CDH1, PALB2, PTEN, RAD51C, and TP53) (5% diagnostic yield) and 11 in candidate cancer susceptibility genes (DPYD, ERBB3, ERCC2, MUTYH, NQO2, NTHL1, PARK2, RAD54L, and RNASEL). In conclusion, this study allowed a personalized risk assessment and clinical surveillance in an increased number of HBOC families and to broaden the spectrum of causative variants also to candidate “non-canonical” genes.
Published: 2021
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4. Shorter androgen receptor polyQ alleles protect against life-threatening COVID-19 disease in European males

Author: Margherita Baldassarri, Nicola Picchiotti, Francesca Fava, Chiara Fallerini, Elisa Benetti, Sergio Daga, Floriana Valentino, Gabriella Doddato, Simone Furini, Annarita Giliberti, Rossella Tita, Sara Amitrano, Mirella Bruttini, Susanna Croci, Ilaria Meloni, Anna Maria Pinto, Nicola Iuso, Chiara Gabbi, Francesca Sciarra, Mary Anna Venneri, Marco Gori, Maurizio Sanarico, Francis P. Crawley, Uberto Pagotto, Flaminia Fanelli, Marco Mezzullo, Elena Dominguez-Garrido, Laura Planas-Serra, Agatha Schlüter, Roger Colobran, Pere Soler-Palacin, Pablo Lapunzina, Jair Tenorio, Aurora Pujol, Maria Grazia Castagna, Marco Marcelli, Andrea M. Isidori, Alessandra Renieri, Elisa Frullanti, and Francesca Mari
Subjects: Androgen receptor gene, Testosterone, COVID-19, LASSO logistic regression, WES, Viral infection and host genome, Medicine, Medicine (General), R5-920
Abstract: Background: While SARS-CoV-2 similarly infects men and women, COVID-19 outcome is less favorable in men. Variability in COVID-19 severity may be explained by differences in the host genome. Methods: We compared poly-amino acids variability from WES data in severely affected COVID-19 patients versus SARS-CoV-2 PCR-positive oligo-asymptomatic subjects. Findings: Shorter polyQ alleles (≤22) in the androgen receptor (AR) conferred protection against severe outcome in COVID-19 in the first tested cohort (both males and females) of 638 Italian subjects. The association between long polyQ alleles (≥23) and severe clinical outcome (p = 0.024) was also validated in an independent cohort of Spanish men
Published: 2021
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5. RB1 Germline Variant Predisposing to a Rare Ovarian Germ Cell Tumor: A Case Report

Author: Elisa Gelli, Chiara Fallerini, Floriana Valentino, Annarita Giliberti, Francesca Castiglione, Lucrezia Laschi, Maria Palmieri, Alessandra Fabbiani, Rossella Tita, Maria Antonietta Mencarelli, Alessandra Renieri, and Francesca Ariani
Subjects: RB1, hypomorphic variant, yolk sac tumor, ovarian cancer, tumor predisposition, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Malignant ovarian germ cell tumors (MOGCTs) are neoplasms of the ovary, of which, due to their rarity and heterogeneity, few is reported about genetic background and development. Here, we report a 18-years old patient diagnosed with an ovarian mixed germ cell tumor, without any previous history of malignancies, who has been treated with surgery and chemotherapy and died 4 years later due to peritoneal metastasis complications. Patient's blood DNA was screened for a panel of 52 cancer-related genes in order to identify predisposing aberrations to this rare cancer. The analysis discovered the uncharacterized c.2393G>A variant in RB1, the retinoblastoma gene, leading both to a missense change and a splicing perturbation of the RB1 transcript. The variant was found to be hypomorphic, damaging the C-terminal domain with a partially impaired protein function. The variant is inherited from the unaffected mother. Due to an imprinting mechanism, the maternal allele is ~3-fold more expressed than the paternal one. The parent-of-origin effect combined with the hypomorphic impact of the variant determines a rescue of sufficient tumor-suppressor activity to prevent retinoblastoma development but can predispose to other cancers in the adult age. In order to understand the somatic events acting on the germline predisposition we used the NGS-liquid biopsy covering 77 cancer driver genes. Using this approach, we detected deleterious mutations in TP53, SMAD4, FGFR3, and MSH2, indicative of a dis-regulation of cell cycle and DNA repair mechanisms pathways. In conclusion, we have pinpointed for the first time that an RB1 leaky variant, not leading to retinoblastoma because of its maternal origin, can predispose in adults to a very rare form of ovarian cancer and that the somatic disruption of few genes contributes to the tumor progression and aggressiveness.
Published: 2020
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6. Clinical and molecular characterization of COVID-19 hospitalized patients.

Author: Elisa Benetti, Annarita Giliberti, Arianna Emiliozzi, Floriana Valentino, Laura Bergantini, Chiara Fallerini, Federico Anedda, Sara Amitrano, Edoardo Conticini, Rossella Tita, Miriana d'Alessandro, Francesca Fava, Simona Marcantonio, Margherita Baldassarri, Mirella Bruttini, Maria Antonietta Mazzei, Francesca Montagnani, Marco Mandalà, Elena Bargagli, Simone Furini, GEN-COVID Multicenter Study, Alessandra Renieri, and Francesca Mari
Subjects: Medicine, Science
Abstract: Clinical and molecular characterization by Whole Exome Sequencing (WES) is reported in 35 COVID-19 patients attending the University Hospital in Siena, Italy, from April 7 to May 7, 2020. Eighty percent of patients required respiratory assistance, half of them being on mechanical ventilation. Fiftyone percent had hepatic involvement and hyposmia was ascertained in 3 patients. Searching for common genes by collapsing methods against 150 WES of controls of the Italian population failed to give straightforward statistically significant results with the exception of two genes. This result is not unexpected since we are facing the most challenging common disorder triggered by environmental factors with a strong underlying heritability (50%). The lesson learned from Autism-Spectrum-Disorders prompted us to re-analyse the cohort treating each patient as an independent case, following a Mendelian-like model. We identified for each patient an average of 2.5 pathogenic mutations involved in virus infection susceptibility and pinpointing to one or more rare disorder(s). To our knowledge, this is the first report on WES and COVID-19. Our results suggest a combined model for COVID-19 susceptibility with a number of common susceptibility genes which represent the favorite background in which additional host private mutations may determine disease progression.
Published: 2020
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7. New Candidates for Autism/Intellectual Disability Identified by Whole-Exome Sequencing

Author: Lucia Pia Bruno, Gabriella Doddato, Floriana Valentino, Margherita Baldassarri, Rossella Tita, Chiara Fallerini, Mirella Bruttini, Caterina Lo Rizzo, Maria Antonietta Mencarelli, Francesca Mari, Anna Maria Pinto, Francesca Fava, Alessandra Fabbiani, Vittoria Lamacchia, Anna Carrer, Valentina Caputo, Stefania Granata, Elisa Benetti, Kristina Zguro, Simone Furini, Alessandra Renieri, and Francesca Ariani
Subjects: autism, intellectual disability, whole-exome sequencing, Biology (General), QH301-705.5, Chemistry, QD1-999
Abstract: Intellectual disability (ID) is characterized by impairments in the cognitive processes and in the tasks of daily life. It encompasses a clinically and genetically heterogeneous group of neurodevelopmental disorders often associated with autism spectrum disorder (ASD). Social and communication abilities are strongly compromised in ASD. The prevalence of ID/ASD is 1–3%, and approximately 30% of the patients remain without a molecular diagnosis. Considering the extreme genetic locus heterogeneity, next-generation sequencing approaches have provided powerful tools for candidate gene identification. Molecular diagnosis is crucial to improve outcome, prevent complications, and hopefully start a therapeutic approach. Here, we performed parent–offspring trio whole-exome sequencing (WES) in a cohort of 60 mostly syndromic ID/ASD patients and we detected 8 pathogenic variants in genes already known to be associated with ID/ASD (SYNGAP1, SMAD6, PACS1, SHANK3, KMT2A, KCNQ2, ACTB, and POGZ). We found four de novo disruptive variants of four novel candidate ASD/ID genes: MBP, PCDHA1, PCDH15, PDPR. We additionally selected via bioinformatic tools many variants in unknown genes that alone or in combination can contribute to the phenotype. In conclusion, our data confirm the efficacy of WES in detecting pathogenic variants of known and novel ID/ASD genes.
Published: 2021
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8. Exome Sequencing in 200 Intellectual Disability/Autistic Patients: New Candidates and Atypical Presentations

Author: Floriana Valentino, Lucia Pia Bruno, Gabriella Doddato, Annarita Giliberti, Rossella Tita, Sara Resciniti, Chiara Fallerini, Mirella Bruttini, Caterina Lo Rizzo, Maria Antonietta Mencarelli, Francesca Mari, Anna Maria Pinto, Francesca Fava, Margherita Baldassarri, Alessandra Fabbiani, Vittoria Lamacchia, Elisa Benetti, Kristina Zguro, Simone Furini, Alessandra Renieri, and Francesca Ariani
Subjects: exome sequencing, intellectual disability, autism spectrum disorder, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract: Intellectual disability (ID) and autism spectrum disorder (ASD) belong to neurodevelopmental disorders and occur in ~1% of the general population. Due to disease heterogeneity, identifying the etiology of ID and ASD remains challenging. Exome sequencing (ES) offers the opportunity to rapidly identify variants associated with these two entities that often co-exist. Here, we performed ES in a cohort of 200 patients: 84 with isolated ID and 116 with ID and ASD. We identified 41 pathogenic variants with a detection rate of 22% (43/200): 39% in ID patients (33/84) and 9% in ID/ASD patients (10/116). Most of the causative genes are genes responsible for well-established genetic syndromes that have not been recognized for atypical phenotypic presentations. Two genes emerged as new candidates: CACNA2D1 and GPR14. In conclusion, this study reinforces the importance of ES in the diagnosis of ID/ASD and underlines that “reverse phenotyping” is fundamental to enlarge the phenotypic spectra associated with specific genes.
Published: 2021
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9. Analysis of the Zn-Binding Domains of TRIM32, the E3 Ubiquitin Ligase Mutated in Limb Girdle Muscular Dystrophy 2H

Author: Elisa Lazzari, Medhat S. El-Halawany, Matteo De March, Floriana Valentino, Francesco Cantatore, Chiara Migliore, Silvia Onesti, and Germana Meroni
Subjects: TRIM family, E3 ubiquitin ligases, RING domain, B-box domain, Limb–Girdle Muscular Dystrophy type 2H, Cytology, QH573-671
Abstract: Members of the tripartite motif family of E3 ubiquitin ligases are characterized by the presence of a conserved N-terminal module composed of a RING domain followed by one or two B-box domains, a coiled-coil and a variable C-terminal region. The RING and B-box are both Zn-binding domains but, while the RING is found in a large number of proteins, the B-box is exclusive to the tripartite motif (TRIM) family members in metazoans. Whereas the RING has been extensively characterized and shown to possess intrinsic E3 ligase catalytic activity, much less is known about the role of the B-box domains. In this study, we adopted an in vitro approach using recombinant point- and deletion-mutants to characterize the contribution of the TRIM32 Zn-binding domains to the activity of this E3 ligase that is altered in a genetic form of muscular dystrophy. We found that the RING domain is crucial for E3 ligase activity and E2 specificity, whereas a complete B-box domain is involved in chain assembly rate modulation. Further, in vitro, the RING domain is necessary to modulate TRIM32 oligomerization, whereas, in cells, both the RING and B-box cooperate to specify TRIM32 subcellular localization, which if altered may impact the pathogenesis of diseases.
Published: 2019
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10. Correction to: High rate of HDR in gene editing of p.(Thr158Met) MECP2 mutational hotspot

Author: Susanna Croci, Miriam Lucia Carriero, Katia Capitani, Sergio Daga, Francesco Donati, Elisa Frullanti, Vittoria Lamacchia, Rossella Tita, Annarita Giliberti, Floriana Valentino, Elisa Benetti, Annalisa Ciabattini, Simone Furini, Caterina Lo Rizzo, Anna Maria Pinto, Silvestro Giovanni Conticello, Alessandra Renieri, and Ilaria Meloni
Subjects: Genetics, Genetics (clinical)
Published: 2023

11. Correction: New frontiers to cure Alport syndrome: COL4A3 and COL4A5 gene editing in podocyte-lineage cells

Author: Sergio Daga, Francesco Donati, Katia Capitani, Susanna Croci, Rossella Tita, Annarita Giliberti, Floriana Valentino, Elisa Benetti, Chiara Fallerini, Francesca Niccheri, Margherita Baldassarri, Maria Antonietta Mencarelli, Elisa Frullanti, Simone Furini, Silvestro Giovanni Conticello, Alessandra Renieri, and Anna Maria Pinto
Subjects: Genetics, Genetics (clinical)
Published: 2023

12. Identification of a Novel Pathogenic Variant in the NAGLU Gene in a Child with Neurodevelopmental Delay

Author: Bruno, L, Fava, F, Baldassarri, M, M Salvati, V, Scandurra, V, Canitano, R, Valentino, F, Doddato, G, Tita, R, Giliberti, A, Renieri, A, Ariani., F, Lucia Pia Bruno, Francesca Fava, Margherita Baldassarri, Virginia M Salvati, Valeria Scandurra, Roberto Canitano, Floriana Valentino, Gabriella Doddato, Rossella Tita, Annarita Giliberti, Alessandra Renieri, Francesca Ariani., Bruno, L, Fava, F, Baldassarri, M, M Salvati, V, Scandurra, V, Canitano, R, Valentino, F, Doddato, G, Tita, R, Giliberti, A, Renieri, A, Ariani., F, Lucia Pia Bruno, Francesca Fava, Margherita Baldassarri, Virginia M Salvati, Valeria Scandurra, Roberto Canitano, Floriana Valentino, Gabriella Doddato, Rossella Tita, Annarita Giliberti, Alessandra Renieri, and Francesca Ariani.
Published: 2022

13. An explainable model of host genetic interactions linked to COVID-19 severity

Author: Anthony, O, Nicola, P, Chiara, F, Margherita, B, Francesca, F, Francesca, C, Alessandra, R, Simone, F, Francesco, R, Mari, F, Daga, S, Benetti, E, Bruttini, M, Palmieri, M, Croci, S, Amitrano, S, Meloni, I, Frullanti, E, Doddato, G, Lista, M, Beligni, G, Valentino, F, Zguro, K, Tita, R, Giliberti, A, Antonietta Mencarelli, M, Lo Rizzo, C, Maria Pinto, A, Ariani, F, Di Sarno, L, Montagnani, F, Tumbarello, M, Rancan, I, Fabbiani, M, Rossetti, B, Bergantini, L, D’Alessandro, M, Cameli, P, Bennett, D, Anedda, F, Marcantonio, S, Scolletta, S, Franchi, F, Antonietta Mazzei, M, Guerrini, S, Conticini, E, Cantarini, L, Frediani, B, Tacconi, D, Spertilli Raffaelli, C, Feri, M, Donati, A, Scala, R, Guidelli, L, Spargi, G, Corridi, M, Nencioni, C, Croci, L, Piero Caldarelli, G, Romani, D, Piacentini, P, Bandini, M, Desanctis, E, Cappelli, S, Canaccini, A, Verzuri, A, Anemoli, V, Pisani, M, Ognibene, A, Pancrazzi, A, Lorubbio, M, Vaghi, M, D’Arminio Monforte, A, Gaia Miraglia, F, Bruno, R, Vecchia, M, Girardis, M, Venturelli, S, Busani, S, Cossarizza, A, Antinori, A, Vergori, A, Emiliozzi, A, Rusconi, S, Siano, M, Gabrieli, A, Riva, A, Francisci, D, Schiaroli, E, Paciosi, F, Tommasi, A, Zuccon, U, Vietri, L, Giorgio Scotton, P, Andretta, F, Panese, S, Baratti, S, Scaggiante, R, Gatti, F, Giuseppe Parisi, S, Castelli, F, Quiros-Roldan, E, Degli Antoni, M, Zanella, I, Della Monica, M, Piscopo, C, Capasso, M, Russo, R, Andolfo, I, Iolascon, A, Fiorentino, G, Carella, M, Castori, M, Aucella, F, Raggi, P, Perna, R, Bassetti, M, Di Biagio, A, Sanguinetti, M, Masucci, L, Guarnaccia, A, Valente, S, De Vivo, O, Bargagli, E, Mandalà, M, Giorli, A, Salerni, L, Zucchi, P, Parravicini, P, Menatti, E, Trotta, T, Giannattasio, F, Coiro, G, Lena, F, Lacerenza, G, Coviello, D, Mussini, C, Martinelli, E, Tavecchia, L, Ann Belli, M, Crotti, L, Parati, G, Sanarico, M, Biscarini, F, Stella, A, Rizzi, M, Maggiolo, F, Ripamonti, D, Suardi, C, Bachetti, T, Teresa La Rovere, M, Sarzi-Braga, S, Bussotti, M, Capitani, K, Dei, S, Ravaglia, S, Artuso, R, Andreucci, E, Gori, G, Pagliazzi, A, Fiorentini, E, Perrella, A, Bianchi, F, Bergomi, P, Catena, E, Colombo, R, Luchi, S, Morelli, G, Petrocelli, P, Iacopini, S, Modica, S, Baroni, S, Vladimiro Segala, F, Menichetti, F, Falcone, M, Tiseo, G, Barbieri, C, Matucci, T, Grassi, D, Ferri, C, Marinangeli, F, Brancati, F, Vincenti, A, Borgo, V, Lombardi, S, Lenzi, M, Antonio Di Pietro, M, Vichi, F, Romanin, B, Attala, L, Costa, C, Gabbuti, A, Menè, R, Colaneri, M, Casprini, P, Merla, G, Maria Squeo, G, Maffezzoni, M, Mantovani, S, Mondelli &amp, M, Ludovisi, S, Onoja, Anthony, Picchiotti, Nicola, Fallerini, Chiara, Baldassarri, Margherita, Fava, Francesca, Colombo, Francesca, Chiaromonte, Francesca, Renieri, Alessandra, Furini, Simone, Raimondi Francesco, Francesca Mari, Sergio Daga, Elisa Benetti, Mirella Bruttini, Maria Palmieri, Susanna Croci, Sara Amitrano, Ilaria Meloni, Elisa Frullanti, Gabriella Doddato, Mirjam Lista, Giada Beligni, Floriana Valentino, Kristina Zguro, Rossella Tita, Annarita Giliberti, Maria Antonietta Mencarelli, Caterina Lo Rizzo, Anna Maria Pinto, Francesca Ariani, Laura Di Sarno, Francesca Montagnani, Mario Tumbarello, Ilaria Rancan, Massimiliano Fabbiani, Barbara Rossetti, Laura Bergantini, Miriana D’Alessandro, Paolo Cameli, David Bennett, Federico Anedda, Simona Marcantonio, Sabino Scolletta, Federico Franchi, Maria Antonietta Mazzei, Susanna Guerrini, Edoardo Conticini, Luca Cantarini, Bruno Frediani, Danilo Tacconi, Chiara Spertilli Raffaelli, Marco Feri, Alice Donati, Raffaele Scala, Luca Guidelli, Genni Spargi, Marta Corridi, Cesira Nencioni, Leonardo Croci, Gian Piero Caldarelli, Davide Romani, Paolo Piacentini, Maria Bandini, Elena Desanctis, Silvia Cappelli, Anna Canaccini, Agnese Verzuri, Valentina Anemoli, Manola Pisani, Agostino Ognibene, Alessandro Pancrazzi, Maria Lorubbio, Massimo Vaghi, Antonella D’Arminio Monforte, Federica Gaia Miraglia, Raffaele Bruno, Marco Vecchia, Massimo Girardis, Sophie Venturelli, Stefano Busani, Andrea Cossarizza, Andrea Antinori, Alessandra Vergori, Arianna Emiliozzi, Stefano Rusconi, Matteo Siano, Arianna Gabrieli, Agostino Riva, Daniela Francisci, Elisabetta Schiaroli, Francesco Paciosi, Andrea Tommasi, Umberto Zuccon, Lucia Vietri, Pier Giorgio Scotton, Francesca Andretta, Sandro Panese, Stefano Baratti, Renzo Scaggiante, Francesca Gatti, Saverio Giuseppe Parisi, Francesco Castelli, Eugenia Quiros-Roldan, Melania Degli Antoni, Isabella Zanella, Matteo Della Monica, Carmelo Piscopo, Mario Capasso, Roberta Russo, Immacolata Andolfo, Achille Iolascon, Giuseppe Fiorentino, Massimo Carella, Marco Castori, Filippo Aucella, Pamela Raggi, Rita Perna, Matteo Bassetti, Antonio Di Biagio, Maurizio Sanguinetti, Luca Masucci, Alessandra Guarnaccia, Serafina Valente, Oreste De Vivo, Elena Bargagli, Marco Mandalà, Alessia Giorli, Lorenzo Salerni, Patrizia Zucchi, Pierpaolo Parravicini, Elisabetta Menatti, Tullio Trotta, Ferdinando Giannattasio, Gabriella Coiro, Fabio Lena, Gianluca Lacerenza, Domenico A. Coviello, Cristina Mussini, Enrico Martinelli, Luisa Tavecchia, Mary Ann Belli, Lia Crotti, Gianfranco Parati, Maurizio Sanarico, Filippo Biscarini, Alessandra Stella, Marco Rizzi, Franco Maggiolo, Diego Ripamonti, Claudia Suardi, Tiziana Bachetti, Maria Teresa La Rovere, Simona Sarzi-Braga, Maurizio Bussotti, Katia Capitani, Simona Dei, Sabrina Ravaglia, Rosangela Artuso, Elena Andreucci, Giulia Gori, Angelica Pagliazzi, Erika Fiorentini, Antonio Perrella, Francesco Bianchi, Paola Bergomi, Emanuele Catena, Riccardo Colombo, Sauro Luchi, Giovanna Morelli, Paola Petrocelli, Sarah Iacopini, Sara Modica, Silvia Baroni, Francesco Vladimiro Segala, Francesco Menichetti, Marco Falcone, Giusy Tiseo, Chiara Barbieri, Tommaso Matucci, Davide Grassi, Claudio Ferri, Franco Marinangeli, Francesco Brancati, Antonella Vincenti, Valentina Borgo, Stefania Lombardi, Mirco Lenzi, Massimo Antonio Di Pietro, Francesca Vichi, Benedetta Romanin, Letizia Attala, Cecilia Costa, Andrea Gabbuti, Roberto Menè, Marta Colaneri, Patrizia Casprini, Giuseppe Merla, Gabriella Maria Squeo, Marcello Maffezzoni, Stefania Mantovani, Mario U. Mondelli &, Serena Ludovisi, Anthony, O, Nicola, P, Chiara, F, Margherita, B, Francesca, F, Francesca, C, Alessandra, R, Simone, F, Francesco, R, Mari, F, Daga, S, Benetti, E, Bruttini, M, Palmieri, M, Croci, S, Amitrano, S, Meloni, I, Frullanti, E, Doddato, G, Lista, M, Beligni, G, Valentino, F, Zguro, K, Tita, R, Giliberti, A, Antonietta Mencarelli, M, Lo Rizzo, C, Maria Pinto, A, Ariani, F, Di Sarno, L, Montagnani, F, Tumbarello, M, Rancan, I, Fabbiani, M, Rossetti, B, Bergantini, L, D’Alessandro, M, Cameli, P, Bennett, D, Anedda, F, Marcantonio, S, Scolletta, S, Franchi, F, Antonietta Mazzei, M, Guerrini, S, Conticini, E, Cantarini, L, Frediani, B, Tacconi, D, Spertilli Raffaelli, C, Feri, M, Donati, A, Scala, R, Guidelli, L, Spargi, G, Corridi, M, Nencioni, C, Croci, L, Piero Caldarelli, G, Romani, D, Piacentini, P, Bandini, M, Desanctis, E, Cappelli, S, Canaccini, A, Verzuri, A, Anemoli, V, Pisani, M, Ognibene, A, Pancrazzi, A, Lorubbio, M, Vaghi, M, D’Arminio Monforte, A, Gaia Miraglia, F, Bruno, R, Vecchia, M, Girardis, M, Venturelli, S, Busani, S, Cossarizza, A, Antinori, A, Vergori, A, Emiliozzi, A, Rusconi, S, Siano, M, Gabrieli, A, Riva, A, Francisci, D, Schiaroli, E, Paciosi, F, Tommasi, A, Zuccon, U, Vietri, L, Giorgio Scotton, P, Andretta, F, Panese, S, Baratti, S, Scaggiante, R, Gatti, F, Giuseppe Parisi, S, Castelli, F, Quiros-Roldan, E, Degli Antoni, M, Zanella, I, Della Monica, M, Piscopo, C, Capasso, M, Russo, R, Andolfo, I, Iolascon, A, Fiorentino, G, Carella, M, Castori, M, Aucella, F, Raggi, P, Perna, R, Bassetti, M, Di Biagio, A, Sanguinetti, M, Masucci, L, Guarnaccia, A, Valente, S, De Vivo, O, Bargagli, E, Mandalà, M, Giorli, A, Salerni, L, Zucchi, P, Parravicini, P, Menatti, E, Trotta, T, Giannattasio, F, Coiro, G, Lena, F, Lacerenza, G, Coviello, D, Mussini, C, Martinelli, E, Tavecchia, L, Ann Belli, M, Crotti, L, Parati, G, Sanarico, M, Biscarini, F, Stella, A, Rizzi, M, Maggiolo, F, Ripamonti, D, Suardi, C, Bachetti, T, Teresa La Rovere, M, Sarzi-Braga, S, Bussotti, M, Capitani, K, Dei, S, Ravaglia, S, Artuso, R, Andreucci, E, Gori, G, Pagliazzi, A, Fiorentini, E, Perrella, A, Bianchi, F, Bergomi, P, Catena, E, Colombo, R, Luchi, S, Morelli, G, Petrocelli, P, Iacopini, S, Modica, S, Baroni, S, Vladimiro Segala, F, Menichetti, F, Falcone, M, Tiseo, G, Barbieri, C, Matucci, T, Grassi, D, Ferri, C, Marinangeli, F, Brancati, F, Vincenti, A, Borgo, V, Lombardi, S, Lenzi, M, Antonio Di Pietro, M, Vichi, F, Romanin, B, Attala, L, Costa, C, Gabbuti, A, Menè, R, Colaneri, M, Casprini, P, Merla, G, Maria Squeo, G, Maffezzoni, M, Mantovani, S, Mondelli &amp, M, Ludovisi, S, Onoja, Anthony, Picchiotti, Nicola, Fallerini, Chiara, Baldassarri, Margherita, Fava, Francesca, Colombo, Francesca, Chiaromonte, Francesca, Renieri, Alessandra, Furini, Simone, Raimondi Francesco, Francesca Mari, Sergio Daga, Elisa Benetti, Mirella Bruttini, Maria Palmieri, Susanna Croci, Sara Amitrano, Ilaria Meloni, Elisa Frullanti, Gabriella Doddato, Mirjam Lista, Giada Beligni, Floriana Valentino, Kristina Zguro, Rossella Tita, Annarita Giliberti, Maria Antonietta Mencarelli, Caterina Lo Rizzo, Anna Maria Pinto, Francesca Ariani, Laura Di Sarno, Francesca Montagnani, Mario Tumbarello, Ilaria Rancan, Massimiliano Fabbiani, Barbara Rossetti, Laura Bergantini, Miriana D’Alessandro, Paolo Cameli, David Bennett, Federico Anedda, Simona Marcantonio, Sabino Scolletta, Federico Franchi, Maria Antonietta Mazzei, Susanna Guerrini, Edoardo Conticini, Luca Cantarini, Bruno Frediani, Danilo Tacconi, Chiara Spertilli Raffaelli, Marco Feri, Alice Donati, Raffaele Scala, Luca Guidelli, Genni Spargi, Marta Corridi, Cesira Nencioni, Leonardo Croci, Gian Piero Caldarelli, Davide Romani, Paolo Piacentini, Maria Bandini, Elena Desanctis, Silvia Cappelli, Anna Canaccini, Agnese Verzuri, Valentina Anemoli, Manola Pisani, Agostino Ognibene, Alessandro Pancrazzi, Maria Lorubbio, Massimo Vaghi, Antonella D’Arminio Monforte, Federica Gaia Miraglia, Raffaele Bruno, Marco Vecchia, Massimo Girardis, Sophie Venturelli, Stefano Busani, Andrea Cossarizza, Andrea Antinori, Alessandra Vergori, Arianna Emiliozzi, Stefano Rusconi, Matteo Siano, Arianna Gabrieli, Agostino Riva, Daniela Francisci, Elisabetta Schiaroli, Francesco Paciosi, Andrea Tommasi, Umberto Zuccon, Lucia Vietri, Pier Giorgio Scotton, Francesca Andretta, Sandro Panese, Stefano Baratti, Renzo Scaggiante, Francesca Gatti, Saverio Giuseppe Parisi, Francesco Castelli, Eugenia Quiros-Roldan, Melania Degli Antoni, Isabella Zanella, Matteo Della Monica, Carmelo Piscopo, Mario Capasso, Roberta Russo, Immacolata Andolfo, Achille Iolascon, Giuseppe Fiorentino, Massimo Carella, Marco Castori, Filippo Aucella, Pamela Raggi, Rita Perna, Matteo Bassetti, Antonio Di Biagio, Maurizio Sanguinetti, Luca Masucci, Alessandra Guarnaccia, Serafina Valente, Oreste De Vivo, Elena Bargagli, Marco Mandalà, Alessia Giorli, Lorenzo Salerni, Patrizia Zucchi, Pierpaolo Parravicini, Elisabetta Menatti, Tullio Trotta, Ferdinando Giannattasio, Gabriella Coiro, Fabio Lena, Gianluca Lacerenza, Domenico A. Coviello, Cristina Mussini, Enrico Martinelli, Luisa Tavecchia, Mary Ann Belli, Lia Crotti, Gianfranco Parati, Maurizio Sanarico, Filippo Biscarini, Alessandra Stella, Marco Rizzi, Franco Maggiolo, Diego Ripamonti, Claudia Suardi, Tiziana Bachetti, Maria Teresa La Rovere, Simona Sarzi-Braga, Maurizio Bussotti, Katia Capitani, Simona Dei, Sabrina Ravaglia, Rosangela Artuso, Elena Andreucci, Giulia Gori, Angelica Pagliazzi, Erika Fiorentini, Antonio Perrella, Francesco Bianchi, Paola Bergomi, Emanuele Catena, Riccardo Colombo, Sauro Luchi, Giovanna Morelli, Paola Petrocelli, Sarah Iacopini, Sara Modica, Silvia Baroni, Francesco Vladimiro Segala, Francesco Menichetti, Marco Falcone, Giusy Tiseo, Chiara Barbieri, Tommaso Matucci, Davide Grassi, Claudio Ferri, Franco Marinangeli, Francesco Brancati, Antonella Vincenti, Valentina Borgo, Stefania Lombardi, Mirco Lenzi, Massimo Antonio Di Pietro, Francesca Vichi, Benedetta Romanin, Letizia Attala, Cecilia Costa, Andrea Gabbuti, Roberto Menè, Marta Colaneri, Patrizia Casprini, Giuseppe Merla, Gabriella Maria Squeo, Marcello Maffezzoni, Stefania Mantovani, Mario U. Mondelli &, and Serena Ludovisi
Abstract: We 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.
Published: 2022

14. An explainable model of host genetic interactions linked to COVID-19 severity

Author: Onoja, Anthony, Picchiotti, Nicola, Fallerini, Chiara, Baldassarri, Margherita, Fava, Francesca, Colombo, Francesca, Chiaromonte, Francesca, Renieri, Alessandra, Furini, Simone, Raimondi, Francesco GEN-COVID Multicenter Study: Francesca Mari, Sergio, Daga, Elisa, Benetti, Mirella, Bruttini, Maria, Palmieri, Susanna, Croci, Sara, Amitrano, Ilaria, Meloni, Elisa, Frullanti, Gabriella, Doddato, Mirjam, Lista, Giada, Beligni, Floriana, Valentino, Kristina, Zguro, Rossella, Tita, Annarita, Giliberti, Maria Antonietta Mencarelli, Caterina Lo Rizzo, Anna Maria Pinto, Francesca, Ariani, Laura Di Sarno, Francesca, Montagnani, Mario, Tumbarello, Ilaria, Rancan, Massimiliano, Fabbiani, Barbara, Rossetti, Laura, Bergantini, Miriana, D'Alessandro, Paolo, Cameli, David, Bennett, Federico, Anedda, Simona, Marcantonio, Sabino, Scolletta, Federico, Franchi, Maria Antonietta Mazzei, Susanna, Guerrini, Edoardo, Conticini, Luca, Cantarini, Bruno, Frediani, Danilo, Tacconi, Chiara Spertilli Raffaelli, Marco, Feri, Alice, Donati, Raffaele, Scala, Luca, Guidelli, Genni, Spargi, Marta, Corridi, Cesira, Nencioni, Leonardo, Croci, Gian Piero Caldarelli, Davide, Romani, Paolo, Piacentini, Maria, Bandini, Elena, Desanctis, Silvia, Cappelli, Anna, Canaccini, Agnese, Verzuri, Valentina, Anemoli, Manola, Pisani, Agostino, Ognibene, Alessandro, Pancrazzi, Maria, Lorubbio, Massimo, Vaghi, Antonella D'Arminio Monforte, Federica Gaia Miraglia, Raffaele, Bruno, Marco, Vecchia, Massimo, Girardis, Sophie, Venturelli, Stefano, Busani, Andrea, Cossarizza, Andrea, Antinori, Alessandra, Vergori, Arianna, Emiliozzi, Stefano, Rusconi, Matteo, Siano, Arianna, Gabrieli, Agostino, Riva, Daniela, Francisci, Elisabetta, Schiaroli, Francesco, Paciosi, Andrea, Tommasi, Umberto, Zuccon, Lucia, Vietri, Pier Giorgio Scotton, Francesca, Andretta, Sandro, Panese, Stefano, Baratti, Renzo, Scaggiante, Francesca, Gatti, Saverio Giuseppe Parisi, Francesco, Castelli, Eugenia, Quiros-Roldan, Melania Degli Antoni, Isabella, Zanella, Matteo Della Monica, Carmelo, Piscopo, Mario, Capasso, Roberta, Russo, Immacolata, Andolfo, Achille, Iolascon, Giuseppe, Fiorentino, Massimo, Carella, Marco, Castori, Filippo, Aucella, Pamela, Raggi, Rita, Perna, Matteo, Bassetti, Antonio Di Biagio, Maurizio, Sanguinetti, Luca, Masucci, Alessandra, Guarnaccia, Serafina, Valente, Oreste De Vivo, Elena, Bargagli, Marco, Mandalà, Alessia, Giorli, Lorenzo, Salerni, Patrizia, Zucchi, Pierpaolo, Parravicini, Elisabetta, Menatti, Tullio, Trotta, Ferdinando, Giannattasio, Gabriella, Coiro, Fabio, Lena, Gianluca, Lacerenza, Domenico, A Coviello, Cristina, Mussini, Enrico, Martinelli, Luisa, Tavecchia, Mary Ann Belli, Lia, Crotti, Gianfranco, Parati, Maurizio, Sanarico, Filippo, Biscarini, Alessandra, Stella, Marco, Rizzi, Franco, Maggiolo, Diego, Ripamonti, Claudia, Suardi, Tiziana, Bachetti, Maria Teresa La Rovere, Simona, Sarzi-Braga, Maurizio, Bussotti, Katia, Capitani, Simona, Dei, Sabrina, Ravaglia, Rosangela, Artuso, Elena, Andreucci, Giulia, Gori, Angelica, Pagliazzi, Erika, Fiorentini, Antonio, Perrella, Francesco, Bianchi, Paola, Bergomi, Emanuele, Catena, Riccardo, Colombo, Sauro, Luchi, Giovanna, Morelli, Paola, Petrocelli, Sarah, Iacopini, Sara, Modica, Silvia, Baroni, Francesco Vladimiro Segala, Francesco, Menichetti, Marco, Falcone, Giusy, Tiseo, Chiara, Barbieri, Tommaso, Matucci, Grassi, Davide, Ferri, Claudio, Marinangeli, Franco, Brancati, Francesco, Antonella, Vincenti, Valentina, Borgo, Lombardi, Stefania, Mirco, Lenzi, Massimo Antonio Di Pietro, Francesca, Vichi, Benedetta, Romanin, Letizia, Attala, Cecilia, Costa, Andrea, Gabbuti, Roberto, Menè, Marta, Colaneri, Patrizia, Casprini, Giuseppe, Merla, Gabriella Maria Squeo, Marcello, Maffezzoni, Stefania, Mantovani, Mario, U Mondelli, Serena, Ludovisi, Onoja, Anthony, Picchiotti, Nicola, Fallerini, Chiara, Baldassarri, Margherita, Fava, Francesca, nbsp, Multicenter Study, GEN-COVID, Colombo, Francesca, Chiaromonte, Francesca, Renieri, Alessandra, Furini, Simone, Raimondi, Francesco, Anthony, O, Nicola, P, Chiara, F, Margherita, B, Francesca, F, Francesca, C, Alessandra, R, Simone, F, Francesco, R, Mari, F, Daga, S, Benetti, E, Bruttini, M, Palmieri, M, Croci, S, Amitrano, S, Meloni, I, Frullanti, E, Doddato, G, Lista, M, Beligni, G, Valentino, F, Zguro, K, Tita, R, Giliberti, A, Antonietta Mencarelli, M, Lo Rizzo, C, Maria Pinto, A, Ariani, F, Di Sarno, L, Montagnani, F, Tumbarello, M, Rancan, I, Fabbiani, M, Rossetti, B, Bergantini, L, D’Alessandro, M, Cameli, P, Bennett, D, Anedda, F, Marcantonio, S, Scolletta, S, Franchi, F, Antonietta Mazzei, M, Guerrini, S, Conticini, E, Cantarini, L, Frediani, B, Tacconi, D, Spertilli Raffaelli, C, Feri, M, Donati, A, Scala, R, Guidelli, L, Spargi, G, Corridi, M, Nencioni, C, Croci, L, Piero Caldarelli, G, Romani, D, Piacentini, P, Bandini, M, Desanctis, E, Cappelli, S, Canaccini, A, Verzuri, A, Anemoli, V, Pisani, M, Ognibene, A, Pancrazzi, A, Lorubbio, M, Vaghi, M, D’Arminio Monforte, A, Gaia Miraglia, F, Bruno, R, Vecchia, M, Girardis, M, Venturelli, S, Busani, S, Cossarizza, A, Antinori, A, Vergori, A, Emiliozzi, A, Rusconi, S, Siano, M, Gabrieli, A, Riva, A, Francisci, D, Schiaroli, E, Paciosi, F, Tommasi, A, Zuccon, U, Vietri, L, Giorgio Scotton, P, Andretta, F, Panese, S, Baratti, S, Scaggiante, R, Gatti, F, Giuseppe Parisi, S, Castelli, F, Quiros-Roldan, E, Degli Antoni, M, Zanella, I, Della Monica, M, Piscopo, C, Capasso, M, Russo, R, Andolfo, I, Iolascon, A, Fiorentino, G, Carella, M, Castori, M, Aucella, F, Raggi, P, Perna, R, Bassetti, M, Di Biagio, A, Sanguinetti, M, Masucci, L, Guarnaccia, A, Valente, S, De Vivo, O, Bargagli, E, Mandalà, M, Giorli, A, Salerni, L, Zucchi, P, Parravicini, P, Menatti, E, Trotta, T, Giannattasio, F, Coiro, G, Lena, F, Lacerenza, G, Coviello, D, Mussini, C, Martinelli, E, Tavecchia, L, Ann Belli, M, Crotti, L, Parati, G, Sanarico, M, Biscarini, F, Stella, A, Rizzi, M, Maggiolo, F, Ripamonti, D, Suardi, C, Bachetti, T, Teresa La Rovere, M, Sarzi-Braga, S, Bussotti, M, Capitani, K, Dei, S, Ravaglia, S, Artuso, R, Andreucci, E, Gori, G, Pagliazzi, A, Fiorentini, E, Perrella, A, Bianchi, F, Bergomi, P, Catena, E, Colombo, R, Luchi, S, Morelli, G, Petrocelli, P, Iacopini, S, Modica, S, Baroni, S, Vladimiro Segala, F, Menichetti, F, Falcone, M, Tiseo, G, Barbieri, C, Matucci, T, Grassi, D, Ferri, C, Marinangeli, F, Brancati, F, Vincenti, A, Borgo, V, Lombardi, S, Lenzi, M, Antonio Di Pietro, M, Vichi, F, Romanin, B, Attala, L, Costa, C, Gabbuti, A, Menè, R, Colaneri, M, Casprini, P, Merla, G, Maria Squeo, G, Maffezzoni, M, Mantovani, S, Mondelli &amp, M, and Ludovisi, S
Subjects: Genetics, Coronavirus disease 2019 (COVID-19), Host (biology), COVID-19, Medicine (miscellaneous), Settore BIO/11 - Biologia Molecolare, Biology, Settore MED/07 - MICROBIOLOGIA E MICROBIOLOGIA CLINICA, Whole Exome Sequencing, General Biochemistry, Genetics and Molecular Biology, machine learning, Phenotype, Exome Sequencing, Humans, Genetic Predisposition to Disease, Genome-Wide Association Study, General Agricultural and Biological Sciences, COVID, Human
Abstract: We 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 training of multiple supervised classifiers, to predict severity on the basis of screened features. Feature importance analysis from tree-based models allowed to identify a handful of 16 variants with 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 good accuracy (ACC=81.88%; ROC_AUC=96%; MCC=61.55%). Principal Component Analysis (PCA) and clustering of patients on important variants orthogonally identified two groups of individuals with a higher fraction of severe cases. 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, such as JAK-STAT, Cytokine, Interleukin, and C-type lectin receptor signaling. It also identified additional processes cross-talking with immune pathways, such as GPCR signalling, 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”, confirming their link with COVID-19 severity outcome. Taken together, our analysis suggests that curated genetic information can be effectively integrated along with other patient clinical covariates to forecast COVID-19 disease severity and dissect the underlying host genetic mechanisms for personalized medicine treatments.
Published: 2022

15. Identification of a Novel Pathogenic Variant in the NAGLU Gene in a Child with Neurodevelopmental Delay

Author: Francesca Ariani, Francesca Fava, Gabriella Doddato, Virginia M. Salvati, Lucia Pia Bruno, Margherita Baldassarri, Valeria Scandurra, Roberto Canitano, Alessandra Renieri, Rossella Tita, Annarita Giliberti, and Floriana Valentino
Subjects: Genetics, Autism Spectrum Disorder, medicine.disease, Nervous System Malformations, Mucopolysaccharidosis III, Neurodevelopmental Disorders, NAGLU gene, Acetylglucosaminidase, Developmental and Educational Psychology, medicine, Autism, Neurodevelopmental delay, Humans, Identification (biology), Psychology, Child
Published: 2021

16. Exome Sequencing in 200 Intellectual Disability/Autistic Patients: New Candidates and Atypical Presentations

Author: Margherita Baldassarri, Maria Antonietta Mencarelli, Alessandra Fabbiani, Caterina Lo Rizzo, Vittoria Lamacchia, Anna Maria Pinto, Floriana Valentino, Gabriella Doddato, Francesca Ariani, Francesca Mari, Elisa Benetti, Alessandra Renieri, Simone Furini, Rossella Tita, Lucia Pia Bruno, Francesca Fava, Mirella Bruttini, Annarita Giliberti, Kristina Zguro, Sara Resciniti, and Chiara Fallerini
Subjects: 0301 basic medicine, Autism spectrum disorder al, Exome sequencing, Intellectual disability, Population, Neurosciences. Biological psychiatry. Neuropsychiatry, autism spectrum disorder, Disease, Article, 03 medical and health sciences, 0302 clinical medicine, mental disorders, medicine, education, Gene, Genetics, education.field_of_study, business.industry, General Neuroscience, medicine.disease, 030104 developmental biology, Autism spectrum disorder, intellectual disability, Cohort, Etiology, business, exome sequencing, 030217 neurology & neurosurgery, RC321-571
Abstract: Intellectual disability (ID) and autism spectrum disorder (ASD) belong to neurodevelopmental disorders and occur in ~1% of the general population. Due to disease heterogeneity, identifying the etiology of ID and ASD remains challenging. Exome sequencing (ES) offers the opportunity to rapidly identify variants associated with these two entities that often co-exist. Here, we performed ES in a cohort of 200 patients: 84 with isolated ID and 116 with ID and ASD. We identified 41 pathogenic variants with a detection rate of 22% (43/200): 39% in ID patients (33/84) and 9% in ID/ASD patients (10/116). Most of the causative genes are genes responsible for well-established genetic syndromes that have not been recognized for atypical phenotypic presentations. Two genes emerged as new candidates: CACNA2D1 and GPR14. In conclusion, this study reinforces the importance of ES in the diagnosis of ID/ASD and underlines that “reverse phenotyping” is fundamental to enlarge the phenotypic spectra associated with specific genes.
Published: 2021

17. Severe COVID-19 in Hospitalized Carriers of Single CFTR Pathogenic Variants

Author: Margherita Baldassarri, Francesca Fava, Chiara Fallerini, Sergio Daga, Elisa Benetti, Kristina Zguro, Sara Amitrano, Floriana Valentino, Gabriella Doddato, Annarita Giliberti, Laura Di Sarno, Maria Palmieri, Miriam Lucia Carriero, Diana Alaverdian, Giada Beligni, Nicola Iuso, Francesco Castelli, Eugenia Quiros-Roldan, Mario Umberto Mondelli, Rosalba Miceli, Elisa Frullanti, Simone Furini, Francesca Mari, Alessandra Renieri, Chiara Gabbi, and on behalf of the GEN-COVID Multicenter Study
Subjects: medicine.medical_specialty, Medicine (miscellaneous), Asymptomatic, Cystic fibrosis, Article, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, 030212 general & internal medicine, CFTR, CF carrier screening, Exome sequencing, 030304 developmental biology, 0303 health sciences, Respiratory tract infections, business.industry, Hazard ratio, COVID-19, medicine.disease, Host genetics, host genetics, Relative risk, Cohort, Medicine, medicine.symptom, business, Cohort study
Abstract: The clinical presentation of COVID-19 is extremely heterogeneous, ranging from asymptomatic to severely ill patients. Thus, host genetic factors may be involved in determining disease presentation and progression. Given that carriers of single cystic fibrosis (CF)-causing variants of the CFTR gene—CF-carriers—are more susceptible to respiratory tract infections, our aim was to determine their likelihood of undergoing severe COVID-19. We implemented a cohort study of 874 individuals diagnosed with COVID-19, during the first pandemic wave in Italy. Whole exome sequencing was performed and validated CF-causing variants were identified. Forty subjects (16 females and 24 males) were found to be CF-carriers. Among mechanically ventilated patients, CF-carriers were more represented (8.7%) and they were significantly (p &lt, 0.05) younger (mean age 51 years) compared to noncarriers (mean age 61.42 years). Furthermore, in the whole cohort, the age of male CF-carriers was lower, compared to noncarriers (p &lt, 0.05). CF-carriers had a relative risk of presenting an abnormal inflammatory response (CRP ≥ 20 mg/dL) of 1.69 (p &lt, 0.05) and their hazard ratio of death at day 14 was 3.10 (p &lt, 0.05) in a multivariate regression model, adjusted for age, sex and comorbidities. In conclusion, CF-carriers are more susceptible to the severe form of COVID-19, showing also higher risk of 14-day death.
Published: 2021

18. SARS-CoV-2 susceptibility and COVID-19 disease severity are associated with genetic variants affecting gene expression in a variety of tissues

Author: Matteo D’Antonio, Jennifer P. Nguyen, Timothy D. Arthur, Hiroko Matsui, Agnieszka D’Antonio-Chronowska, Kelly A. Frazer, Benjamin M. Neale, Mark Daly, Andrea Ganna, Christine Stevens, Gita A. Pathak, Shea J. Andrews, Masahiro Kanai, Mattia Cordioli, Juha Karjalainen, Renato Polimanti, Matti Pirinen, Nadia Harerimana, Kumar Veerapen, Brooke Wolford, Huy Nguyen, Matthew Solomonson, Rachel G. Liao, Karolina Chwialkowska, Amy Trankiem, Mary K. Balaconis, Caroline Hayward, Anne Richmond, Archie Campbell, Marcela Morris, Chloe Fawns-Ritchie, Joseph T. Glessner, Douglas M. Shaw, Xiao Chang, Hannah Polikowski, Petty E. Lauren, Hung-Hsin Chen, Zhu Wanying, Hakon Hakonarson, David J. Porteous, Jennifer Below, Kari North, Joseph B. McCormick, Paul R.H.J. Timmers, James F. Wilson, Albert Tenesa, Kenton D’Mellow, Shona M. Kerr, Mari E.K. Niemi, Lindokuhle Nkambul, Kathrin Aprile von Hohenstaufen, Ali Sobh, Madonna M. Eltoukhy, Amr M. Yassen, Mohamed A.F. Hegazy, Kamal Okasha, Mohammed A. Eid, Hanteera S. Moahmed, Doaa Shahin, Yasser M. El-Sherbiny, Tamer A. Elhadidy, Mohamed S. Abd Elghafar, Jehan J. El-Jawhari, Attia A.S. Mohamed, Marwa H. Elnagdy, Amr Samir, Mahmoud Abdel-Aziz, Walid T. Khafaga, Walaa M. El-Lawaty, Mohamed S. Torky, Mohamed R. El-shanshory, Chiara Batini, Paul H. Lee, Nick Shrine, Alexander T. Williams, Martin D. Tobin, Anna L. Guyatt, Catherine John, Richard J. Packer, Altaf Ali, Robert C. Free, Xueyang Wang, Louise V. Wain, Edward J. Hollox, Laura D. Venn, Catherine E. Bee, Emma L. Adams, Ahmadreza Niavarani, Bahareh Sharififard, Rasoul Aliannejad, Ali Amirsavadkouhi, Zeinab Naderpour, Hengameh Ansari Tadi, Afshar Etemadi Aleagha, Saeideh Ahmadi, Seyed Behrooz Mohseni Moghaddam, Alireza Adamsara, Morteza Saeedi, Hamed Abdollahi, Abdolmajid Hosseini, Pajaree Chariyavilaskul, Monpat Chamnanphon, Thitima B. Suttichet, Vorasuk Shotelersuk, Monnat Pongpanich, Chureerat Phokaew, Wanna Chetruengchai, Watsamon Jantarabenjakul, Opass Putchareon, Pattama Torvorapanit, Thanyawee Puthanakit, Pintip Suchartlikitwong, Nattiya Hirankarn, Voraphoj Nilaratanakul, Pimpayao Sodsai, Ben M. Brumpton, Kristian Hveem, Cristen Willer, Wei Zhou, Tormod Rogne, Erik Solligard, Bjørn Olav Åsvold, Malak Abedalthagafi, Manal Alaamery, Saleh Alqahtani, Dona Baraka, Fawz Al Harthi, Ebtehal Alsolm, Leen Abu Safieh, Albandary M. Alowayn, Fatimah Alqubaishi, Amal Al Mutairi, Serghei Mangul, Abdulraheem Alshareef, Mona Sawaji, Mansour Almutairi, Nora Aljawini, Nour Albesher, Yaseen M. Arabi, Ebrahim S. Mahmoud, Amin K. Khattab, Roaa T. Halawani, Ziab Z. Alahmadey, Jehad K. Albakri, Walaa A. Felemban, Bandar A. Suliman, Rana Hasanato, Laila Al-Awdah, Jahad Alghamdi, Deema AlZahrani, Sameera AlJohani, Hani Al-Afghani, May Alrashed, Nouf AlDhawi, Hadeel AlBardis, Sarah Alkwai, Moneera Alswailm, Faisal Almalki, Maha Albeladi, Iman Almohammed, Eman Barhoush, Anoud Albader, Salam Massadeh, Abdulaziz AlMalik, Sara Alotaibi, Bader Alghamdi, Junghyun Jung, Mohammad S. Fawzy, Yunsung Lee, Per Magnus, Lill-Iren S. Trogstad, Øyvind Helgeland, Jennifer R. Harris, Massimo Mangino, Tim D. Spector, Duncan Emma, Sandra P. Smieszek, Bartlomiej P. Przychodzen, Christos Polymeropoulos, Vasilios Polymeropoulos, Mihael H. Polymeropoulos, Israel Fernandez-Cadenas, Jordi Perez-Tur, Laia Llucià-Carol, Natalia Cullell, Elena Muiño, Jara Cárcel-Márquez, Marta L. DeDiego, Lara Lloret Iglesias, Anna M. Planas, Alex Soriano, Veronica Rico, Daiana Agüero, Josep L. Bedini, Francisco Lozano, Carlos Domingo, Veronica Robles, Francisca Ruiz-Jaén, Leonardo Márquez, Juan Gomez, Eliecer Coto, Guillermo M. Albaiceta, Marta García-Clemente, David Dalmau, Maria J. Arranz, Beatriz Dietl, Alex Serra-Llovich, Pere Soler, Roger Colobrán, Andrea Martín-Nalda, Alba Parra Martínez, David Bernardo, Silvia Rojo, Aida Fiz-López, Elisa Arribas, Paloma de la Cal-Sabater, Tomás Segura, Esther González-Villa, Gemma Serrano-Heras, Joan Martí-Fàbregas, Elena Jiménez-Xarrié, Alicia de Felipe Mimbrera, Jaime Masjuan, Sebastian García-Madrona, Anna Domínguez-Mayoral, Joan Montaner Villalonga, Paloma Menéndez-Valladares, Daniel I. Chasman, Julie E. Buring, Paul M. Ridker, Giulianini Franco, Howard D. Sesso, JoAnn E. Manson, Joseph R. Glessner, Carolina Medina-Gomez, Andre G. Uitterlinden, M. Arfan Ikram, Kati Kristiansson, Sami Koskelainen, Markus Perola, Kati Donner, Katja Kivinen, Aarno Palotie, Samuli Ripatti, Sanni Ruotsalainen, Mari Kaunisto, null FinnGen, Tomoko Nakanishi, Guillaume Butler-Laporte, Vincenzo Forgetta, David R. Morrison, Biswarup Ghosh, Laetitia Laurent, Alexandre Belisle, Danielle Henry, Tala Abdullah, Olumide Adeleye, Noor Mamlouk, Nofar Kimchi, Zaman Afrasiabi, Nardin Rezk Branka Vulesevic, Meriem Bouab, Charlotte Guzman, Louis Petitjean, Chris Tselios, Xiaoqing Xue, Erwin Schurr, Jonathan Afilalo, Marc Afilalo, Maureen Oliveira, Bluma Brenner, Pierre Lepage, Jiannis Ragoussis, Daniel Auld, Nathalie Brassard, Madeleine Durand, Michaël Chassé, Daniel E. Kaufmann, G. Mark Lathrop, Vincent Mooser, J. Brent Richards, Rui Li, Darin Adra, Souad Rahmouni, Michel Georges, Michel Moutschen, Benoit Misset, Gilles Darcis, Julien Guiot, Julien Guntz, Samira Azarzar, Stéphanie Gofflot, Yves Beguin, Sabine Claassen, Olivier Malaise, Pascale Huynen, Christelle Meuris, Marie Thys, Jessica Jacques, Philippe Léonard, Frederic Frippiat, Jean-Baptiste Giot, Anne-Sophie Sauvage, Christian Von Frenckell, Yasmine Belhaj, Bernard Lambermont, Sara Pigazzini, Lindokuhle Nkambule, Michelle Daya, Jonathan Shortt, Nicholas Rafaels, Stephen J. Wicks, Kristy Crooks, Kathleen C. Barnes, Christopher R. Gignoux, Sameer Chavan, Triin Laisk, Kristi Läll, Maarja Lepamets, Reedik Mägi, Tõnu Esko, Ene Reimann, Lili Milani, Helene Alavere, Kristjan Metsalu, Mairo Puusepp, Andres Metspalu, Paul Naaber, Edward Laane, Jaana Pesukova, Pärt Peterson, Kai Kisand, Jekaterina Tabri, Raili Allos, Kati Hensen, Joel Starkopf, Inge Ringmets, Anu Tamm, Anne Kallaste, Pierre-Yves Bochud, Carlo Rivolta, Stéphanie Bibert, Mathieu Quinodoz, Dhryata Kamdar, Noémie Boillat, Semira Gonseth Nussle, Werner Albrich, Noémie Suh, Dionysios Neofytos, Véronique Erard, Cathy Voide, null FHoGID, null RegCOVID, null P-PredictUs, null SeroCOVID, null CRiPSI, Rafael de Cid, Iván Galván-Femenía, Natalia Blay, Anna Carreras, Beatriz Cortés, Xavier Farré, Lauro Sumoy, Victor Moreno, Josep Maria Mercader, Marta Guindo-Martinez, David Torrents, Manolis Kogevinas, Judith Garcia-Aymerich, Gemma Castaño-Vinyals, Carlota Dobaño, Alessandra Renieri, Francesca Mari, Chiara Fallerini, Sergio Daga, Elisa Benetti, Margherita Baldassarri, Francesca Fava, Elisa Frullanti, Floriana Valentino, Gabriella Doddato, Annarita Giliberti, Rossella Tita, Sara Amitrano, Mirella Bruttini, Susanna Croci, Ilaria Meloni, Maria Antonietta Mencarelli, Caterina Lo Rizzo, Anna Maria Pinto, Giada Beligni, Andrea Tommasi, Laura Di Sarno, Maria Palmieri, Miriam Lucia Carriero, Diana Alaverdian, Stefano Busani, Raffaele Bruno, Marco Vecchia, Mary Ann Belli, Nicola Picchiotti, Maurizio Sanarico, Marco Gori, Simone Furini, Stefania Mantovani, Serena Ludovisi, Mario Umberto Mondelli, Francesco Castelli, Eugenia Quiros-Roldan, Melania Degli Antoni, Isabella Zanella, Massimo Vaghi, Stefano Rusconi, Matteo Siano, Francesca Montagnani, Arianna Emiliozzi, Massimiliano Fabbiani, Barbara Rossetti, Elena Bargagli, Laura Bergantini, Miriana D’Alessandro, Paolo Cameli, David Bennett, Federico Anedda, Simona Marcantonio, Sabino Scolletta, Federico Franchi, Maria Antonietta Mazzei, Susanna Guerrini, Edoardo Conticini, Luca Cantarini, Bruno Frediani, Danilo Tacconi, Chiara Spertilli, Marco Feri, Alice Donati, Raffaele Scala, Luca Guidelli, Genni Spargi, Marta Corridi, Cesira Nencioni, Leonardo Croci, Maria Bandini, Gian Piero Caldarelli, Paolo Piacentini, Elena Desanctis, Silvia Cappelli, Anna Canaccini, Agnese Verzuri, Valentina Anemoli, Agostino Ognibene, Alessandro Pancrazzi, Maria Lorubbio, Antonella D’Arminio Monforte, Federica Gaia Miraglia, Massimo Girardis, Sophie Venturelli, Andrea Cossarizza, Andrea Antinori, Alessandra Vergori, Arianna Gabrieli, Agostino Riva, Daniela Francisci, Elisabetta Schiaroli, Francesco Paciosi, Pier Giorgio Scotton, Francesca Andretta, Sandro Panese, Renzo Scaggiante, Francesca Gatti, Saverio Giuseppe Parisi, Stefano Baratti, Matteo Della Monica, Carmelo Piscopo, Mario Capasso, Roberta Russo, Immacolata Andolfo, Achille Iolascon, Giuseppe Fiorentino, Massimo Carella, Marco Castori, Giuseppe Merla, Gabriella Maria Squeo, Filippo Aucella, Pamela Raggi, Carmen Marciano, Rita Perna, Matteo Bassetti, Antonio Di Biagio, Maurizio Sanguinetti, Luca Masucci, Serafina Valente, Marco Mandalà, Alessia Giorli, Lorenzo Salerni, Patrizia Zucchi, Pierpaolo Parravicini, Elisabetta Menatti, Tullio Trotta, Ferdinando Giannattasio, Gabriella Coiro, Fabio Lena, Domenico A. Coviello, Cristina Mussini, Enrico Martinelli, Sandro Mancarella, Luisa Tavecchia, Lia Crotti, Chiara Gabbi, Marco Rizzi, Franco Maggiolo, Diego Ripamonti, Tiziana Bachetti, Maria Teresa La Rovere, Simona Sarzi-Braga, Maurizio Bussotti, Stefano Ceri, Pietro Pinoli, Francesco Raimondi, Filippo Biscarini, Alessandra Stella, Kristina Zguro, Katia Capitani, Claudia Suardi, Simona Dei, Gianfranco Parati, Sabrina Ravaglia, Rosangela Artuso, Giordano Bottà, Paolo Di Domenico, Ilaria Rancan, Antonio Perrella Francesco Bianchi, Davide Romani, Paola Bergomi, Emanuele Catena, Riccardo Colombo, Marco Tanfoni, Antonella Vincenti, Claudio Ferri, Davide Grassi, Gloria Pessina, Mario Tumbarello, Massimo Di Pietro, Ravaglia Sabrina, Sauro Luchi, Chiara Barbieri, Donatella Acquilini, Elena Andreucci, Francesco Vladimiro Segala, Giusy Tiseo, Marco Falcone, Mirjam Lista, Monica Poscente, Oreste De Vivo, Paola Petrocelli, Alessandra Guarnaccia, Silvia Baroni, Albert V. Smith, Andrew P. Boughton, Kevin W. Li, Jonathon LeFaive, Aubrey Annis, Anne E. Justice, Tooraj Mirshahi, Geetha Chittoor, Navya Shilpa Josyula, Jack A. Kosmicki, Manuel A.R. Ferreira, Joseph B. Leader, Dave J. Carey, Matthew C. Gass, Julie E. Horowitz, Michael N. Cantor, Ashish Yadav, Aris Baras, Goncalo R. Abecasis, David A. van Heel, Karen A. Hunt, Dan Mason, Qin Qin Huang, Sarah Finer, null Genes & Health Research Team, Bhavi Trivedi, Christopher J. Griffiths, Hilary C. Martin, John Wright, Richard C. Trembath, Nicole Soranzo, Jing Hua Zhao, Adam S. Butterworth, John Danesh, Emanuele Di Angelantonio, Lude Franke Marike Boezen, Patrick Deelen, Annique Claringbould, Esteban Lopera, Robert Warmerdam, Judith.M. Vonk, Irene van Blokland, Pauline Lanting, Anil P.S. Ori, Brooke Wolford Sebastian Zöllner, Jiongming Wang, Andrew Beck, Gina Peloso, Yuk-Lam Ho, Yan V. Sun, Jennifer E. Huffman, Christopher J. O’Donnell, Kelly Cho, Phil Tsao, J. Michael Gaziano, Michel (M.G.) Nivard, Eco (E.J.C.) de geus, Meike Bartels, Jouke Jan Hottenga, Scott T. Weiss, Elizabeth W. Karlson, Jordan W. Smoller, Robert C. Green, Yen-Chen Anne Feng, Josep Mercader, Shawn N. Murphy, James B. Meigs, Ann E. Woolley, Emma F. Perez, Daniel Rader, Anurag Verma, Marylyn D. Ritchie, Binglan Li, Shefali S. Verma, Anastasia Lucas, Yuki Bradford, Hugo Zeberg, Robert Frithiof, Michael Hultström, Miklos Lipcsey, Lindo Nkambul, Nicolas Tardif, Olav Rooyackers, Jonathan Grip, Tomislav Maricic, Konrad J. Karczewski, Elizabeth G. Atkinson, Kristin Tsuo, Nikolas Baya, Patrick Turley, Rahul Gupta, Shawneequa Callier, Raymond K. Walters, Duncan S. Palmer, Gopal Sarma, Nathan Cheng, Wenhan Lu, Sam Bryant, Claire Churchhouse, Caroline Cusick, Jacqueline I. Goldstein, Daniel King, Cotton Seed, Hilary Finucane, Alicia R. Martin, F. Kyle Satterstrom, Daniel J. Wilson, Jacob Armstrong, Justine K. Rudkin, Gavin Band, Sarah G. Earle, Shang-Kuan Lin, Nicolas Arning, Derrick W. Crook, David H. Wyllie, Anne Marie O’Connell, Chris C.A. Spencer, Nils Koelling, Mark J. Caulfield, Richard H. Scott, Tom Fowler, Loukas Moutsianas, Athanasios Kousathanas, Dorota Pasko, Susan Walker, Augusto Rendon, Alex Stuckey, Christopher A. Odhams, Daniel Rhodes, Georgia Chan, Prabhu Arumugam, Catherine A. Ball, Eurie L. Hong, Kristin Rand, Ahna Girshick, Harendra Guturu, Asher Haug Baltzell, Genevieve Roberts, Danny Park, Marie Coignet, Shannon McCurdy, Spencer Knight, Raghavendran Partha, Brooke Rhead, Miao Zhang, Nathan Berkowitz, Michael Gaddis, Keith Noto, Luong Ruiz, Milos Pavlovic, Laura G. Sloofman, Alexander W. Charney, Noam D. Beckmann, Eric E. Schadt, Daniel M. Jordan, Ryan C. Thompson, Kyle Gettler, Noura S. Abul-Husn, Steven Ascolillo, Joseph D. Buxbaum, Kumardeep Chaudhary, Judy H. Cho, Yuval Itan, Eimear E. Kenny, Gillian M. Belbin, Stuart C. Sealfon, Robert P. Sebra, Irene Salib, Brett L. Collins, Tess Levy, Bari Britvan, Katherine Keller, Lara Tang, Michael Peruggia, Liam L. Hiester, Kristi Niblo, Alexandra Aksentijevich, Alexander Labkowsky, Avromie Karp, Menachem Zlatopolsky, Michael Preuss, Ruth J.F. Loos, Girish N. Nadkarni, Ron Do, Clive Hoggart, Sam Choi, Slayton J. Underwood, Paul O’Reilly, Laura M. Huckins, Marissa Zyndorf, AII - Infectious diseases, Amsterdam Neuroscience - Neuroinfection & -inflammation, and Neurology
Subjects: Medical Physiology, Gene Expression, Genome-wide association study, Genome, Severity of Illness Index, colocalization, Gene expression, Databases, Genetic, Ethnicity, 2.1 Biological and endogenous factors, GWAS, Aetiology, Biology (General), Lung, Genetics, Chromosome Mapping, Single Nucleotide, Organ Specificity, Biotechnology, Cell type, QH301-705.5, Quantitative Trait Loci, Single-nucleotide polymorphism, Biology, eQTL, Polymorphism, Single Nucleotide, Article, General Biochemistry, Genetics and Molecular Biology, Databases, Genetic, SNP, Humans, Genetic Predisposition to Disease, COVID-19 Host Genetics Initiative, Polymorphism, Gene, COVID-19, SARS-CoV-2, Gene Expression Profiling, Prevention, Human Genome, Computational Biology, Genetic Variation, Good Health and Well Being, Expression quantitative trait loci, Biochemistry and Cell Biology, Transcriptome, Genome-Wide Association Study
Abstract: Variability in SARS-CoV-2 susceptibility and COVID-19 disease severity between individuals is partly due to genetic factors. Here, we identify 4 genomic loci with suggestive associations for SARS-CoV-2 susceptibility and 19 for COVID-19 disease severity. Four of these 23 loci likely have an ethnicity-specific component. Genome-wide association study (GWAS) signals in 11 loci colocalize with expression quantitative trait loci (eQTLs) associated with the expression of 20 genes in 62 tissues/cell types (range: 1:43 tissues/gene), including lung, brain, heart, muscle, and skin as well as the digestive system and immune system. We perform genetic fine mapping to compute 99% credible SNP sets, which identify 10 GWAS loci that have eight or fewer SNPs in the credible set, including three loci with one single likely causal SNP. Our study suggests that the diverse symptoms and disease severity of COVID-19 observed between individuals is associated with variants across the genome, affecting gene expression levels in a wide variety of tissue types., Graphical abstract, D’Antonio et al. characterize associations between GWAS signals for COVID-19 disease and eQTLs in 69 human tissues to identify causal variants and their underlying molecular mechanisms. They show that diverse symptoms and disease severity of COVID-19 are associated with variants affecting gene expression in a wide variety of tissues.
Published: 2022

19. Author response: Association of Toll-like receptor 7 variants with life-threatening COVID-19 disease in males: findings from a nested case-control study

Author: Diego Ripamonti, Sandro Panese, Agnese Verzuri, Giancarlo Bosio, Francesco Castelli, Leonardo Croci, Maurizio Spagnesi, Sergio Daga, Massimiliano Fabbiani, Barbara Rossetti, Silvia Cappelli, Giada Beligni, Gabriella Coiro, Antonio Di Biagio, Domenico A Coviello, Massimo Girardis, Pamela Raggi, Roberta Russo, Federico Franchi, Matteo Bassetti, Stefano Baratti, Gianfranco Parati, Francesca Montagnani, Marco Rizzi, Eugenia Quiros-Roldan, Francesca Fava, Tiziana Bachetti, Agostino Riva, Filippo Aucella, Francesca Gatti, Anna Canaccini, Anna Maria Pinto, Sandro Mancarella, Alessandra Renieri, Arianna Gabrieli, Mario Chiariello, Rossella Tita, Luca Guidelli, Sophie Venturelli, Ilaria Meloni, Luisa Tavecchia, Marta Corridi, Susanna Croci, Francesca Mari, Pierpaolo Parravicini, Andrea Tommasi, Carmelo Piscopo, Tullio Trotta, Miriana d'Alessandro, Maria Antonietta Mencarelli, Cristina Mussini, Simone Furini, Alessandra Vergori, Gen-Covid Multicenter Study, Margherita Baldassarri, Daniela Francisci, Giuseppe Fiorentino, Simona Sarzi-Braga, Mirella Bruttini, Sabino Scolletta, Mario Capasso, Melania Degli Antoni, Serafina Valente, Alice Donati, Maria Antonietta Mazzei, Maurizio Bussotti, Chiara Fallerini, Laura Di Sarno, Federico Anedda, Davide Romani, Katia Capitani, Gian Piero Caldarelli, Elisa Frullanti, Caterina Lo Rizzo, Bruno Frediani, Marco Castori, Arianna Emiliozzi, Andrea Cossarizza, Elena Desanctis, Luca Cantarini, Cesira Nencioni, Ottavia Spiga, Fabio Lena, Isabella Zanella, Genni Spargi, Francesco Paciosi, Pier Giorgio Scotton, Simona Dei, Marco Mandalà, Giacomo Zanelli, Alessia Giorli, Elena Bargagli, Maria Palmieri, Stefano Rusconi, Laura Bergantini, Ferdinando Giannattasio, David Bennett, Carmen Marciano, Chiara Spertilli, Maria Bandini, Serena Ludovisi, Enrico Martinelli, Edoardo Conticini, Valentina Anemoli, Nicola Iuso, Elisa Benetti, Matteo Siano, Achille Iolascon, Danilo Tacconi, Mario U. Mondelli, Sara Amitrano, Raffaele Scala, Paolo Piacentini, Lia Crotti, Maria Teresa La Rovere, Nicola Picchiotti, Patrizia Zucchi, Elisabetta Schiaroli, Immacolata Andolfo, Francesca Andretta, Gabriella Doddato, Annarita Giliberti, Stefano Busani, Simona Marcantonio, Antonella d'Arminio Monforte, Mary Ann Belli, Luca Masucci, Rita Perna, Chiara Gabbi, Gabriella Maria Squeo, Franco Maggiolo, Marco Feri, Susanna Guerrini, Paolo Cameli, Elisabetta Menatti, Maurizio Sanguinetti, Andrea Antinori, Lorenzo Salerni, Saverio Giuseppe Parisi, Stefania Mantovani, Floriana Valentino, Federica Gaia Miraglia, Agostino Ognibene, Marco Gori, Renzo Scaggiante, Matteo Della Monica, Giuseppe Merla, Massimo Vaghi, and Massimo Carella
Subjects: Toll-like receptor, Coronavirus disease 2019 (COVID-19), business.industry, Association (object-oriented programming), Nested case-control study, Immunology, Medicine, Disease, business
Published: 2021

20. Post-Mendelian genetic model in COVID-19

Author: Mirella Bruttini, Sergio Daga, Pietro Pinoli, C. Gabbi, Sara Amitrano, Francis P. Crawley, Chiara Fallerini, Anna Maria Pinto, Francesca Fava, Laura Di Sarno, Margherita Baldassarri, Gen-Covid Multicenter Study, Susanna Croci, Stefano Ceri, Francesca Mari, Nicola Picchiotti, Elisa Frullanti, Annarita Giliberti, Kristina Zguro, Diana Alaverdian, Alessandra Renieri, Gabriella Doddato, Nicola Iuso, Floriana Valentino, Antonio Esposito, Simone Furini, Elisa Benetti, Marco Gori, Ilaria Meloni, Giada Beligni, and Rossella Tita
Subjects: Genetics, Candidate gene, symbols.namesake, Genetic model, Mutation (genetic algorithm), Mendelian inheritance, symbols, Oligogenic Inheritance, Genome-wide association study, General Medicine, Threshold model, Biology, Allele frequency
Abstract: Host genetics is an emerging theme in COVID-19 and few common polymorphisms and some rare variants have been identified, either by GWAS or candidate gene approach, respectively. However, an organic model is still missing. Here, we propose a new model that takes into account common and rare germline variants applied in a cohort of 1,300 Italian SARS-CoV-2 positive individuals. Ordered logistic regression of clinical WHO grading on sex and age was used to obtain a binary phenotypic classification. Genetic variability from WES was synthesized in several boolean representations differentiated according to allele frequencies and genotype effect. LASSO logistic regression was used for extracting relevant genes. We defined about 100 common driver polymorphisms corresponding to classical “threshold model”. Extracted genes were demonstrated to be gender specific. Stochastic rare more penetrant events on about additional 100 extracted genes, when occurred in a medium or severe background (common within the family), simulate Mendelian inheritance in 14% of subjects (having only 1 mutation) or oligogenic inheritance (in 10% having 2 mutations, in 11% having 3 mutations, etc).The combined effect of common and rare results can be described as an integrated polygenic score computed as: (nseverity − nmildness) + F (mseverity − mmildness)where n is the number of common driver genes, m is the number of driver rare variants and F is a factor for appropriately weighing the more powerful rare variants. We called the model “post-Mendelian”. The model well describes the cohort, and patients are clustered in severe or mild by the integrated polygenic scores, the F factor being calibrated around 2, with a prediction capacity of 65% in males and 70% in females. In conclusion, this is the first comprehensive model interpreting host genetics in a holistic post-Mendelian manner. Further validations are needed in order to consolidate and refine the model which however holds true in thousands of SARS-CoV-2 Italian subjects.
Published: 2021

21. Genetic mechanisms of critical illness in COVID-19

Author: Pairo-Castineira, Erola, Clohisey, Sara, Klaric, Lucija, Bretherick, Andrew D, Rawlik, Konrad, Pasko, Dorota, Walker, Susan, Parkinson, Nick, Fourman, Max Head, Russell, Clark D, Furniss, James, Richmond, Anne, Gountouna, Elvina, Wrobel, Nicola, Harrison, David, Wang, Bo, Yang, Wu, Meynert, Alison, Griffiths, Fiona, Oosthuyzen, Wilna, Kousathanas, Athanasios, Moutsianas, Loukas, Yang, Zhijian, Zhai, Ranran, Zheng, Chenqing, Grimes, Graeme, Beale, Rupert, Millar, Jonathan, Shih, Barbara, Keating, Sean, Zechner, Marie, Haley, Chris, Porteous, David J, Hayward, Caroline, Yang, Jian, Knight, Julian, Summers, Charlotte, Shankar-Hari, Manu, Klenerman, Paul, Turtle, Lance, Antonia, Ho, Moore, Shona C, Hinds, Charles, Horby, Peter, Nichol, Alistair, Maslove, David, Ling, Lowell, Mcauley, Danny, Montgomery, Hugh, Walsh, Timothy, Pereira, Alexandre C, Renieri, Johnny, Millar, Alistair, Nichol, Tim, Walsh, Manu, Shankar-Hari, Chris, Ponting, Jen, Meikle, Paul, Finernan, Ellie, Mcmaster, Andy, Law, J Kenneth Baillie, Trevor, Paterson, Tony, Wackett, Ruth, Armstrong, Richard, Clark, Audrey, Coutts, Lorna, Donnelly, Tammy, Gilchrist, Katarzyna, Hafezi, Louise, Macgillivray, Alan, Maclean, Sarah, Mccafferty, Kirstie, Morrice, Jane, Weaver, Ceilia, Boz, Ailsa, Golightly, Mari, Ward, Hanning, Mal, Helen, Szoor-McElhinney, Adam, Brown, Ross, Hendry, Andrew, Stenhouse, Louise, Cullum, Dawn, Law, Sarah, Law, Rachel, Law, Maaike, Swets, Nicky, Day, Filip, Taneski, Esther, Duncan, Nicholas, Parkinson, Collier, D, Wood, S, Zak, A, Borra, C, Matharu, M, May, P, Alldis, Z, Mitchelmore, O, Bowles, R, Easthope, A, Bibi, F, Lancoma-Malcolm, I, Gurasashvili, J, Pheby, J, Shiel, J, Bolton, M, Patel, M, Taylor, M, Zongo, O, Ebano, P, Harding, P, Astin-Chamberlain, R, Choudhury, Y, Cox, A, Kallon, D, Burton, M, Hall, R, Blowes, S, Prime, Z, Biddle, J, Prysyazhna, O, Newman, T, Tierney, C, Kassam, J, Shankar-Hari, M, Ostermann, M, Campos, S, Bociek, A, Lim, R, Grau, N, O Jones, T, Whitton, C, Marotti, M, Arbane, G, Bonner, S, Hugill, K, Reid, J, Welters, I, Waugh, V, Williams, K, Shaw, D, J Fernandez Roman, M Lopez Martinez, Johnson, E, Waite, A, Johnston, B, Hamilton, D, Mulla, S, Mcphail, M, Smith, J, K Baillie, J, Barclay, L, Hope, D, Mcculloch, C, Mcquillan, L, Clark, S, Singleton, J, Priestley, K, Rea, N, Callaghan, M, Campbell, R, Andrew, G, Marshall, L, Mckechnie, S, Hutton, P, Bashyal, A, Davidson, N, Summers, C, Polgarova, P, Stroud, K, Pathan, N, Elston, K, Agrawal, S, Battle, C, Newey, L, Rees, T, Harford, R, Brinkworth, E, Williams, M, Murphy, C, White, I, Croft, M, Bandla, N, Gellamucho, M, Tomlinson, J, Turner, H, Davies, M, Quinn, A, Hussain, I, Thompson, C, Parker, H, Bradley, R, Griffiths, R, Scriven, J, Nilsson, A, Bates, M, Dasgin, J, Gill, J, Puxty, A, Cathcart, S, Salutous, D, Turner, L, Duffy, K, Puxty, K, Joseph, A, Herdman-Grant, R, Simms, R, Swain, A, Naranjo, A, Crowe, R, Sollesta, K, Loveridge, A, Baptista, D, Morino, E, Davey, M, Golden, D, 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Konrad [0000-0002-0010-370X], Walker, Susan [0000-0002-5016-6426], Fourman, Max Head [0000-0001-7381-2278], Russell, Clark D [0000-0002-9873-8243], Gountouna, Elvina [0000-0001-7870-2780], Wang, Bo [0000-0002-1580-797X], Wu, Yang [0000-0002-0128-7280], Kousathanas, Athanasios [0000-0001-6265-6521], Moutsianas, Loukas [0000-0001-5453-345X], Zhai, Ranran [0000-0002-5834-9120], Beale, Rupert [0000-0002-6705-8560], Keating, Sean [0000-0001-8552-5604], Haley, Chris [0000-0002-9811-0210], Porteous, David J [0000-0003-1249-6106], Hayward, Caroline [0000-0002-9405-9550], Yang, Jian [0000-0003-2001-2474], Knight, Julian [0000-0002-0377-5536], Summers, Charlotte [0000-0002-7269-2873], Shankar-Hari, Manu [0000-0002-5338-2538], Turtle, Lance [0000-0002-0778-1693], Moore, Shona C [0000-0001-8610-2806], Hinds, Charles [0000-0001-5094-8324], McAuley, Danny [0000-0002-3283-1947], Montgomery, Hugh [0000-0001-8797-5019], Renieri, Alessandra [0000-0002-0846-9220], Shen, Xia [0000-0003-4390-1979], Ponting, Chris P [0000-0003-0202-7816], Tenesa, Albert [0000-0003-4884-4475], Caulfield, Mark [0000-0001-9295-3594], Rowan, Kathy [0000-0001-8217-5602], Murphy, Lee [0000-0001-6467-7449], Openshaw, Peter JM [0000-0002-7220-2555], Semple, Malcolm G [0000-0001-9700-0418], Law, Andrew [0000-0003-1868-2364], Vitart, Veronique [0000-0002-4991-3797], Wilson, James F [0000-0001-5751-9178], Baillie, J Kenneth [0000-0001-5258-793X], Apollo - University of Cambridge Repository, Pairo-Castineira, E., Clohisey, S., Klaric, L., Bretherick, A. 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T., Love, N., van Koutrik, L., Hunt, J., Kaye, D., Fisher, E., Brayne, A., Tuckey, V., Jackson, P., Parkin, J., Tariq, A., Houlden, H., Tucci, A., Hardy, J., Moncur, E., Highgate, J., Cowley, A., Mitra, A., Stead, R., Behan, T., Burnett, C., Newton, M., Heeney, E., Pollard, R., Hatton, J., Patel, A., Kasipandian, V., Allibone, S., Genetu, R. M., O'Brien, L., Omar, Z., Perkins, E., Davies, K., Tetla, D., Shelley, B., Irvine, V., Williams, S., Williams, P., Goodsell, J., Tutton, R., Bough, L., Winter-Goodwin, B., Kitson, R., Pinnell, J., Wilson, A., Nortcliffe, T., Wood, T., Home, M., Holdroyd, K., Robinson, M., Shaw, R., Greig, J., Brady, M., Haigh, A., Matupe, L., Usher, M., Mellor, S., Dale, S., Gledhill, L., Shaw, L., Turner, G., Kelly, D., Anwar, B., Riley, H., Sturgeon, H., Ali, A., Thomis, L., Melia, D., Dance, A., Humphreys, S., Frost, I., Gopal, V., Godden, J., Holden, A., Swann, S., Smith, T., Clapham, M., Poultney, U., Harper, R., Rice, P., Reece-Anthony, R., Gurung, B., Moultrie, S., Odam, M., Mayer, A., Bellini, A., Pickard, A., Bryant, J., Roe, N., Sowter, J., Lang, K., Taylor, J., Barry, P., Hobrok, M., Tench, H., Wolf-Roberts, R., Mcguinness, H., Loosley, R., Hawcutt, D., Rad, L., O'Malley, L., Saunderson, P., Seddon, G., Anderson, T., Rogers, N., Ruddy, J., Harkins, M., Beith, C., Mcalpine, A., Ferguson, L., Grant, P., Macfadyen, S., Mclaughlin, M., Baird, T., Rundell, S., Welsh, B., Hamill, R., Fisher, F., Gregory, J., Campbell, A., Smuts, S., Kenneth Baillie, J., Carson, G., Alex, B., Bach, B., Barclay, W. S., Bogaert, D., Chand, M., Cooke, G. S., Docherty, A. B., Dunning, J., da Silva Filipe, A., Fletcher, T., Green, C. A., Harrison, E. M., Hiscox, J. A., Ho, A. Y. W., Horby, P. W., Ijaz, S., Khoo, S., Lim, W. S., Mentzer, A. J., Merson, L., Meynert, A. M., Noursadeghi, M., Palmarini, M., Paxton, W. A., Pollakis, G., Price, N., Rambaut, A., Robertson, D. L., Sancho-Shimizu, V., Scott, J. T., de Silva, T., Sigfrid, L., Solomon, T., Sriskandan, S., Stuart, D., Tedder, R. S., Thomson, E. C., Thompson, A. A. R., Thwaites, R. S., Turtle, L. C. W., Zambon, M., Hardwick, H., Donohue, C., Lyons, R., Norman, L., Pius, R., Drake, T. M., Fairfield, C. J., Knight, S. R., Mclean, K. A., Murphy, D., Shaw, C. A., Dalton, J., Girvan, M., Saviciute, E., Roberts, S., Harrison, J., Marsh, L., Connor, M., Halpin, S., Gamble, C., Leeming, G., Wham, M., Greenhalf, W., Shaw, V., Mcdonald, S., Ganna, A., Sulem, P., van Heel, D. A., Cordioli, M., Sveinbjornsson, G., Niemi, M. E. K., Shelton, J. F., Shastri, A. J., Ye, C., Weldon, C. H., Filshtein-Sonmez, T., Coker, D., Symons, A., Esparza-Gordillo, J., Aslibekyan, S., Auton, A., Krieger, J. E., Marques, E., Jannes, C. E., Mari, F., Daga, S., Baldassarri, M., Benetti, E., Furini, S., Fallerini, C., Fava, F., Valentino, F., Doddato, G., Giliberti, A., Tita, R., Amitrano, S., Bruttini, M., Croci, S., Meloni, I., Pinto, A. M., Frullanti, E., Mencarelli, M. A., Rizzo, C. L., Montagnani, F., Di Sarno, L., Tommasi, A., Palmieri, M., Emiliozzi, A., Fabbiani, M., Rossetti, B., Zanelli, G., Bargagli, E., Bergantini, L., D'Alessandro, M., Cameli, P., Bennet, D., Anedda, F., Marcantonio, S., Scolletta, S., Franchi, F., Mazzei, M. A., Guerrini, S., Conticini, E., Cantarini, L., Frediani, B., Tacconi, D., Spertilli, C., Feri, M., Donati, A., Scala, R., Guidelli, L., Spargi, G., Corridi, M., Nencioni, C., Croci, L., Caldarelli, G. P., Spagnesi, M., Piacentini, P., Bandini, M., Desanctis, E., Cappelli, S., Canaccini, A., Verzuri, A., Anemoli, V., Ognibene, A., Vaghi, M., D'Arminio Monforte, A., Merlini, E., Mondelli, M. U., Mantovani, S., Ludovisi, S., Girardis, M., Venturelli, S., Sita, M., Cossarizza, A., Antinori, A., Vergori, A., Rusconi, S., Siano, M., Gabrieli, A., Riva, A., Francisci, D., Schiaroli, E., Scotton, P. G., Andretta, F., Panese, S., Scaggiante, R., Gatti, F., Parisi, S. G., Castelli, F., Quiros-Roldan, M. E., Magro, P., Zanella, I., Della Monica, M., Piscopo, C., Capasso, M., Russo, R., Andolfo, I., Iolascon, A., Fiorentino, G., Carella, M., Castori, M., Merla, G., Aucella, F., Raggi, P., Marciano, C., Perna, R., Bassetti, M., Di Biagio, A., Sanguinetti, M., Masucci, L., Valente, S., Mandala, M., Giorli, A., Salerni, L., Zucchi, P., Parravicini, P., Menatti, E., Baratti, S., Trotta, T., Giannattasio, F., Coiro, G., Lena, F., Coviello, D. A., Mussini, C., Bosio, G., Martinelli, E., Mancarella, S., Tavecchia, L., Crotti, L., Picchiotti, N., Gori, M., Gabbi, C., Sanarico, M., Ceri, S., Pinoli, P., Raimondi, F., Biscarini, F., Stella, A., Shen, X., Ponting, C. P., Fawkes, A., Tenesa, A., Caulfield, M., Scott, R., Rowan, K., Murphy, L., Openshaw, P. J. M., Semple, M. G., Vitart, V., and Wilson, J. F.
Subjects: 0301 basic medicine, Male, CCR2, Chromosomes, Human, Pair 21, Genome-wide association study, Receptor, Interferon alpha-beta, Disease, Bioinformatics, Genome-wide association studies, 23andMe Investigators, Interferon alpha-beta, 0302 clinical medicine, Receptors, 2',5'-Oligoadenylate Synthetase, Pair 12, genetics, Lung, BRACOVID Investigators, Multidisciplinary, GenOMICC Investigators, Tyrosine kinase 2, 030220 oncology & carcinogenesis, Multigene Family, Medical genetics, Female, Dipeptidyl-Peptidases and Tripeptidyl-Peptidase, 5'-Oligoadenylate Synthetase, Human, Receptor, medicine.medical_specialty, Critical Care, Receptors, CCR2, General Science & Technology, Critical Illness, Chromosomes, 03 medical and health sciences, Intensive care, Mendelian randomization, Immunogenetics, medicine, Humans, Dipeptidyl-Peptidases and Tripeptidyl-Peptidases, Gen-COVID Investigators, Inflammation, TYK2 Kinase, Chromosomes, Human, Pair 12, Pair 19, SARS-CoV-2, business.industry, Drug Repositioning, COVID-19, United Kingdom, COVID-19 Human Genetics Initiative, 030104 developmental biology, Viral infection, Chromosomes, Human, Pair 19, Genome-Wide Association Study, Pharmacogenomics, ISARICC Investigators, Pair 21, 2', business
Abstract: Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079,P=1.65×10−8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1,OAS2andOAS3); on chromosome 19p13.2 (rs74956615,P=2.3×10−8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069,P=3.98× 10−12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757,P=4.99×10−8) in the interferon receptor geneIFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression ofIFNAR2, or high expression ofTYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte–macrophage chemotactic receptorCCR2is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice.
Published: 2020
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22. Shorter androgen receptor polyQ alleles protect against life-threatening COVID-19 disease in males

Author: Jair Tenorio, F. Sciarra, Floriana Valentino, Pere Soler-Palacín, Marco Gori, Aurora Pujol, Margherita Baldassarri, Laura Planas-Serra, Elisa Benetti, Sergio Daga, Francis P. Crawley, Francesca Mari, Maria Grazia Castagna, Francesca Fava, Mirella Bruttini, Sara Amitrano, Roger Colobran, Uberto Pagotto, Alessandra Renieri, C. Gabbi, Andrea M. Isidori, Ilaria Meloni, Simone Furini, Elena Dominguez-Garrido, Anna Maria Pinto, Rossella Tita, Pablo Lapunzina, Marco Mezzullo, Gabriella Doddato, Maurizio Sanarico, Susanna Croci, Spanish Covid Hge, Agatha Schlüter, Gen-Covid Multicenter Study, Annarita Giliberti, Nicola Picchiotti, Mary Anna Venneri, Chiara Fallerini, Elisa Frullanti, Flaminia Fanelli, and Marco Marcelli
Subjects: medicine.medical_specialty, business.industry, medicine.drug_class, Disease, Bioinformatics, Androgen, Asymptomatic, Androgen receptor, Epidemiology, Cohort, Medicine, Genetic variability, Allele, medicine.symptom, business
Abstract: BackgroundCOVID-19 presentation ranges from asymptomatic to fatal. The variability in severity may be due in part to impaired Interferon type I response due to specific mutations in the host genome or to autoantibodies, explaining about 15% of the cases when combined. Exploring the host genome is thus warranted to further elucidate disease variability.MethodsWe developed a synthetic approach to genetic data representation using machine learning methods to investigate complementary genetic variability in COVID-19 infected patients that may explain disease severity, due to poly-amino acids repeat polymorphisms. Using host whole-exome sequencing data, we compared extreme phenotypic presentations (338 severe versus 300 asymptomatic cases) of the entire (men and women) Italian GEN-COVID cohort of 1178 subjects infected with SARS-CoV-2. We then applied the LASSO Logistic Regression model on Boolean gene-based representation of the poly-amino acids variability.FindingsShorter polyQ alleles (≤22) in the androgen receptor (AR) conferred protection against a more severe outcome in COVID-19 infection. In the subgroup of males with age AR long-polyQ (≥23), possibly indicating receptor resistance (p=0.004 Mann-Whitney U test). Inappropriately low testosterone levels for the long-polyQ alleles predicted the need for intensive care in COVID-19 infected men. In agreement with the known anti-inflammatory action of testosterone, patients with long-polyQ (≥23) and age>60 years had increased levels of C Reactive Protein (p=0.018).InterpretationOur results may contribute to design reliable clinical and public health measures and provide a rationale to test testosterone treatment as adjuvant therapy in symptomatic COVID-19 men expressing AR polyQ longer than 23 repeats.FundingMIUR project “Dipartimenti di Eccellenza 2018-2020” to Department of Medical Biotechnologies University of Siena, Italy (Italian D.L. n.18 March 17, 2020). Private donors for COVID research and charity funds from Intesa San Paolo.BoxesEvidence before this studyWe searched on Medline, EMBASE, and Pubmed for articles published from January 2020 to August 2020 using various combinations of the search terms “sex-difference”, “gender” AND SARS-Cov-2, or COVID. Epidemiological studies indicate that men and women are similarly infected by COVID-19, but the outcome is less favorable in men, independently of age. Several studies also showed that patients with hypogonadism tend to be more severely affected. A prompt intervention directed toward the most fragile subjects with SARS-Cov2 infection is currently the only strategy to reduce mortality. glucocorticoid treatment has been found cost-effective in improving the outcome of severe cases. Clinical algorithms have been proposed, but little is known on the ability of genetic profiling to predict outcome and disclose novel therapeutic strategies.Added-value of this studyIn a cohort of 1178 men and women with COVID-19, we used a supervised machine learning approach on a synthetic representation of the uncovered variability of the human genome due to poly-amino acid repeats. Comparing the genotype of patients with extreme manifestations (severe vs. asymptomatic), we found that the poly-glutamine repeat of the androgen receptor (AR) gene is relevant for COVID-19 disease and defective AR signaling identifies an association between male sex, testosterone exposure, and COVID-19 outcome. Failure of the endocrine feedback to overcome AR signaling defect by increasing testosterone levels during the infection leads to the fact that polyQ becomes dominant to T levels for the clinical outcome.Implications of all the available evidenceWe identify the first genetic polymorphism predisposing some men to develop a more severe disease irrespectively of age. Based on this, we suggest that sizing the AR poly-glutamine repeat has important implications in the diagnostic pipeline of patients affected by life-threatening COVID-19 infection. Most importantly, our studies open to the potential of using testosterone as adjuvant therapy for severe COVID-19 patients having defective androgen signaling, defined by this study as ≥23 PolyQ repeats and inappropriate levels of circulating androgens.
Published: 2020

23. A new mutation in DNM2 gene in a large Italian family

Author: Anna Maria Pinto, Diego Lopergolo, Nila Volpi, Federica Ginanneschi, Gabriella Doddato, Alessandra Renieri, Fabio Giannini, Floriana Valentino, and Silvia Bocci
Subjects: congenital, hereditary, and neonatal diseases and abnormalities, Context (language use), Dermatology, Disease, Charcot-Marie-Tooth (CMT) disease, Gene mutation, Biology, 03 medical and health sciences, Dynamin II, 0302 clinical medicine, Charcot-Marie-Tooth Disease, medicine, Humans, 030212 general & internal medicine, Centronuclear myopathy, Gene, Genetics, Genetic heterogeneity, DNM2, General Medicine, medicine.disease, Modifier genes, Phenotype, nervous system diseases, Psychiatry and Mental health, Italy, Mutation, Neurology (clinical), 030217 neurology & neurosurgery, Myopathies, Structural, Congenital
Abstract: The Charcot-Marie-Tooth (CMT) disease is the most common inherited peripheral neuropathy with great clinical and genetic heterogeneity. Mutations in DNM2 have been associated with CMT dominant intermediate B (CMTDIB). However, mutations in the same gene are known to induce also axonal CMT (CMT2M) or centronuclear myopathy. Moreover, the ability of effectively and simultaneously sequencing different CMT-related genes by next-generation sequencing approach makes it possible to detect even the presence of modifier genes that sometimes give reason of clinical variability in the context of complex phenotypes. Here, we describe an Italian family with very variable severity of phenotype among members harboring a novel DNM2 gene mutation which caused a prevalent CMT2M phenotype. The contemporary presence of a de novo variant in PRX gene in the most severely affected family member suggests a possible modulator effect of the PRX variant thus highlighting the possible impact of modifier genes in CMT.
Published: 2020

24. ACE2gene variants may underlie interindividual variability and susceptibility to COVID-19 in the Italian population

Author: Mrgherita Baldassarri, Elisa Benetti, Vincenzo Nigro, Giovanni Birolo, Annarita Giliberti, Andrea Ciolfi, Alessandro Bruselles, Anna Maria Pinto, Francesca Mari, Alfonso Trezza, Marco Seri, Annalaura Torella, Marco Tartaglia, Giuseppe Matullo, Gabriella Doddato, Francesco Musacchia, Floriana Valentino, Rosanna Asselta, Cterina Marconi, Bruttini Mirella, Rossella Tita, Alessandra Renieri, Alfredo Brusco, Simone Furini, Ottavia Spiga, and Tommaso Pippucci
Subjects: Genetics, education.field_of_study, Proteases, media_common.quotation_subject, Population, Disease, Biology, Disease cluster, medicine.disease_cause, medicine, Missense mutation, Internalization, education, Exome sequencing, media_common, Coronavirus
Abstract: In December 2019, an initial cluster of interstitial bilateral pneumonia emerged in Wuhan, China. A human-to-human transmission was assumed and a previously unrecognized entity, termed coronavirus-disease-19 (COVID-19) due to a novel coronavirus (SARS-CoV-2) was described. The infection has rapidly spread out all over the world and Italy has been the first European country experiencing the endemic wave with unexpected clinical severity in comparison with Asian countries.It has been shown that SARS-CoV-2 utilizes angiotensin converting enzyme 2 (ACE2) as host receptor and host proteases for cell surface binding and internalization. Thus, a predisposing genetic background can give reason for inter-individual disease susceptibility and/or severity. Taking advantage of the Network of Italian Genomes (NIG), here we mined whole-exome-sequencing data of 6930 Italian control individuals from five different centers looking forACE2variants. A number of variants with a potential impact on protein stability were identified. Among these, three more common missense changes, p.(Asn720Asp), p.(Lys26Arg), p.(Gly211Arg) were predicted to interfere with protein structure and stabilization. Rare variants likely interfering with the internalization process, namely p.(Leu351Val) and p.(Pro389His), predicted to interfere with SARS-CoV-2 spike protein binding, were also observed. Comparison ofACE2WES data between a cohort of 131 patients and 258 controls allowed identifying a statistically significant (P value
Published: 2020

25. New frontiers to cure Alport syndrome: COL4A3 and COL4A5 gene editing in podocyte-lineage cells

Author: Margherita Baldassarri, Sergio Daga, Francesco Donati, Chiara Fallerini, Susanna Croci, Alessandra Renieri, Simone Furini, Maria Antonietta Mencarelli, Silvestro G. Conticello, Rossella Tita, Annarita Giliberti, Anna Maria Pinto, Katia Capitani, Elisa Frullanti, Francesca Niccheri, Floriana Valentino, and Elisa Benetti
Subjects: 0301 basic medicine, Adult, Collagen Type IV, Genetic enhancement, Nephritis, Hereditary, Biology, medicine.disease_cause, Autoantigens, Article, 03 medical and health sciences, 0302 clinical medicine, Plasmid, Genetics research, Genetics, medicine, CRISPR, Humans, Cell Lineage, Genomic engineering, Alport syndrome, Gene, Genetics (clinical), Cells, Cultured, Gene Editing, Mutation, Podocytes, Glomerular basement membrane, Genetic disorder, Genetic Therapy, medicine.disease, 030104 developmental biology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Next-generation sequencing, Female, CRISPR-Cas Systems
Abstract: Alport syndrome (AS) is an inherited genetic disorder characterized by range of alterations from glomerular basement membrane abnormalities up to end-stage renal disease. Pathogenic variants in the collagen α3, α4, and α5 encoding genes are causative both of the autosomal dominant and of the X-linked forms of AS. Podocytes are the only renal cells that are able to produce the COL(IV)a3-a4a5 heterotrimer. We have previously demonstrated how it is possible to isolate podocyte-lineage cells from urine of patients, providing an easily accessible cellular model closer to the podocytes’ physiological conditions. Taking advantage of disease-relevant cell lines, we employed a two-plasmid approach in order to achieve a beneficial and stable variant-specific correction using CRISPR/Cas9 genome editing. One plasmid carries a Donor DNA and a reporter system mCherry/GFP to track the activity of Cas9 in cells. The other plasmid carries a self-cleaving SpCas9 and the variant-specific sgRNA. We have analyzed two stable podocyte-lineage cell lines, harboring a variant in the X-linked COL4A5 (p.(Gly624Asp)) and in the autosomal COL4A3 gene (p.(Gly856Glu)). We have achieved reversion of variants greater than 40% with undesired insertions/deletions lower than 15%. Overall, we have demonstrated a new gene therapy approach directly on patients’ cells, key players of Alport pathogenesis, and we have reverted COL4 causative variants towards the wild type state. These results, in combination with preclinical models, could open new frontiers in the management and the treatment of the disorder.
Published: 2020

26. Shorter Androgen Receptor PolyQ Alleles Protect Against Life-Threatening COVID-19 Disease in Males

Author: Margherita Baldassarri, Mirella Bruttini, Sergio Daga, Annarita Giliberti, Francis P. Crawley, marco marcelli, Floriana Valentino, C. Gabbi, Alessandra Renieri, Maurizio Sanarico, Susanna Croci, Ilaria Meloni, Francesca Fava, Rossella Tita, Francesca Mari, Anna Maria Pinto, Elisa Frullanti, Maria Grazia Castagna, Andrea M. Isidori, Simone Furini, Gen-Covid Multicenter Study, Marco Gori, Chiara Fallerini, Gabriella Doddato, Sara Amitrano, Elisa Benetti, and Nicola Picchiotti
Subjects: Androgen receptor, business.industry, Cohort, Medicine, Testosterone (patch), Genome-wide association study, Disease, Genetic variability, Allele, business, Bioinformatics, Gene
Abstract: Background: COVID-19 presentation ranges from asymptomatic to fatal. The variability in severity is due in part to specific mutations in the host genome. GWAS effectively identifies genetic variability due to common biallelic polymorphisms. Efforts in genetic research are trying to identify significant associations in patients infected by SARS-CoV-2. Methods: We developed a synthetic approach to genetic data representation using machine learning methods to investigate complementary genetic variability in COVID-19 infected patients that might explain disease severity due to rare variants and poly-amino acids repeat polymorphisms. Using host whole-exome sequencing data, we compared extreme phenotypic presentations of an Italian cohort of 939 subjects infected with SARS-CoV-2. We then applied the LASSO Logistic Regression model on Boolean gene-based representation of the entire set of human genes. Findings: Polymorphisms/rare variants in certain genes, including short polyQ (≤22) of the androgen receptor ( AR ), conferred protection against severe forms of COVID-19. We then demonstrated that testosterone was higher in males with AR long-polyQ (≥23), confirming receptor resistance (p=0.004 Mann-Whitney U test). Finally, long-polyQ (≥23) correlates with increased inflammation markers (p=0.021) and fibrinogen consumption (p=0.039), confirming the anti-inflammatory role of testosterone. Interpretation: Our results contribute to designing reliable clinical and public health measures and provide a rationale to test testosterone supplementation as adjuvant treatment in symptomatic COVID-19 men expressing AR polyQ longer than 23. Funding: MIUR project “Dipartimenti di Eccellenza 2018-2020” to Department of Medical Biotechnologies University of Siena, Italy; Private donors for COVID research (Italian D.L. n.18 March 17, 2020). Declaration of Interests: The authors declare no competing interests. Ethics Approval Statement: The GEN-COVID study was approved by the University Hospital of Siena Ethics Review Board (Protocol n. 16917, dated March 16, 2020).
Published: 2020

27. ACE2gene variants may underlie interindividual variability and susceptibility to COVID-19 in the Italian population

Author: Elisa, Benetti, primary, Rossella, Tita, additional, Ottavia, Spiga, additional, Andrea, Ciolfi, additional, Giovanni, Birolo, additional, Alessandro, Bruselles, additional, Gabriella, Doddato, additional, Annarita, Giliberti, additional, Caterina, Marconi, additional, Francesco, Musacchia, additional, Tommaso, Pippucci, additional, Annalaura, Torella, additional, Alfonso, Trezza, additional, Floriana, Valentino, additional, Margherita, Baldassarri, additional, Alfredo, Brusco, additional, Rosanna, Asselta, additional, Mirella, Bruttini, additional, Simone, Furini, additional, Marco, Seri, additional, Vincenzo, Nigro, additional, Giuseppe, Matullo, additional, Marco, Tartaglia, additional, Francesca, Mari, additional, Alessandra, Renieri, additional, and Maria, Pinto Anna, additional
Published: 2020
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28. High rate of HDR in gene editing of p.(Thr158Met) MECP2 mutational hotspot

Author: Rossella Tita, Floriana Valentino, Susanna Croci, Vittoria Lamacchia, Annalisa Ciabattini, Ilaria Meloni, Miriam Lucia Carriero, Elisa Benetti, Alessandra Renieri, Simone Furini, Katia Capitani, Sergio Daga, Francesco Donati, Caterina Lo Rizzo, Elisa Frullanti, Silvestro G. Conticello, Annarita Giliberti, and Anna Maria Pinto
Subjects: Methyl-CpG-Binding Protein 2, Induced Pluripotent Stem Cells, Mutation, Missense, Rett syndrome, Computational biology, Biology, Article, MECP2, 03 medical and health sciences, Neurodevelopmental disorder, Genome editing, Genetics, medicine, Rett Syndrome, CRISPR, Humans, Induced pluripotent stem cell, Genetics (clinical), Cells, Cultured, Gene Editing, Neurons, 0303 health sciences, Cas9, 030305 genetics & heredity, Neurodevelopmental disorders, Recombinational DNA Repair, Genetic Therapy, Fibroblasts, medicine.disease, Cellular Reprogramming, Targeted gene repair, HEK293 Cells, CRISPR-Cas Systems, Reprogramming
Abstract: Rett syndrome is a progressive neurodevelopmental disorder which affects almost exclusively girls, caused by variants in MECP2 gene. Effective therapies for this devastating disorder are not yet available and the need for tight regulation of MECP2 expression for brain to properly function makes gene replacement therapy risky. For this reason, gene editing with CRISPR/Cas9 technology appears as a preferable option for the development of new therapies. To study the disease, we developed and characterized a human neuronal model obtained by genetic reprogramming of patient-derived primary fibroblasts into induced Pluripotent Stem Cells. This cellular model represents an important source for our studies, aiming to correct MECP2 variants in neurons which represent the primarily affected cell type. We engineered a gene editing toolkit composed by a two-plasmid system to correct a hotspot missense variant in MECP2, c.473 C > T (p.(Thr158Met)). The first construct expresses the variant-specific sgRNA and the Donor DNA along with a fluorescent reporter system. The second construct brings Cas9 and targets for auto-cleaving, to avoid long-term Cas9 expression. NGS analysis on sorted cells from four independent patients demonstrated an exceptionally high editing efficiency, with up to 80% of HDR and less than 1% of indels in all patients, outlining the relevant potentiality of the approach for Rett syndrome therapy.
Published: 2019

29. Analysis of the Zn-Binding Domains of TRIM32, the E3 Ubiquitin Ligase Mutated in Limb Girdle Muscular Dystrophy 2H

Author: Francesco Cantatore, Floriana Valentino, Matteo De March, Medhat S. El-Halawany, Germana Meroni, Chiara Migliore, Elisa Lazzari, Silvia Onesti, Lazzari, Elisa, El-Halawany, Medhat, De March, Matteo, Valentino, Floriana, Cantatore, Francesco, Migliore, Chiara, Onesti, Silvia, and Meroni, Germana
Subjects: 0301 basic medicine, Ubiquitin-Protein Ligases, B-box domain, E3 ubiquitin ligases, Ring (chemistry), Article, Cell Line, Tripartite Motif Proteins, 03 medical and health sciences, Mice, 0302 clinical medicine, TRIM family, RING domain, Limb–Girdle Muscular Dystrophy type 2H, Ubiquitin, Protein Domains, medicine, Animals, Humans, Muscular dystrophy, lcsh:QH301-705.5, biology, Chemistry, General Medicine, medicine.disease, Tripartite motif family, Cell biology, Ubiquitin ligase, Zinc, 030104 developmental biology, Muscular Dystrophies, Limb-Girdle, lcsh:Biology (General), E3 ubiquitin ligase, Domain (ring theory), Mutation, biology.protein, Biocatalysis, Mutant Proteins, Protein Multimerization, TRIM Family, 030217 neurology & neurosurgery, Limb-girdle muscular dystrophy, Transcription Factors
Abstract: Members of the tripartite motif family of E3 ubiquitin ligases are characterized by the presence of a conserved N-terminal module composed of a RING domain followed by one or two B-box domains, a coiled-coil and a variable C-terminal region. The RING and B-box are both Zn-binding domains but, while the RING is found in a large number of proteins, the B-box is exclusive to the tripartite motif (TRIM) family members in metazoans. Whereas the RING has been extensively characterized and shown to possess intrinsic E3 ligase catalytic activity, much less is known about the role of the B-box domains. In this study, we adopted an in vitro approach using recombinant point- and deletion-mutants to characterize the contribution of the TRIM32 Zn-binding domains to the activity of this E3 ligase that is altered in a genetic form of muscular dystrophy. We found that the RING domain is crucial for E3 ligase activity and E2 specificity, whereas a complete B-box domain is involved in chain assembly rate modulation. Further, in vitro, the RING domain is necessary to modulate TRIM32 oligomerization, whereas, in cells, both the RING and B-box cooperate to specify TRIM32 subcellular localization, which if altered may impact the pathogenesis of diseases.
Published: 2019

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29 results on '"Floriana Valentino"'

1. Heterozygosity for neuronal ceroid lipofuscinosis predisposes to bipolar disorder

2. Corrigendum: Exome Sequencing in BRCA1-2 Candidate Familias: The Contribution of Other Cancer Susceptibility Genes

3. Exome Sequencing in BRCA1-2 Candidate Familias: The Contribution of Other Cancer Susceptibility Genes

4. Shorter androgen receptor polyQ alleles protect against life-threatening COVID-19 disease in European males

5. RB1 Germline Variant Predisposing to a Rare Ovarian Germ Cell Tumor: A Case Report

6. Clinical and molecular characterization of COVID-19 hospitalized patients.

7. New Candidates for Autism/Intellectual Disability Identified by Whole-Exome Sequencing

8. Exome Sequencing in 200 Intellectual Disability/Autistic Patients: New Candidates and Atypical Presentations

9. Analysis of the Zn-Binding Domains of TRIM32, the E3 Ubiquitin Ligase Mutated in Limb Girdle Muscular Dystrophy 2H

10. Correction to: High rate of HDR in gene editing of p.(Thr158Met) MECP2 mutational hotspot

11. Correction: New frontiers to cure Alport syndrome: COL4A3 and COL4A5 gene editing in podocyte-lineage cells

12. Identification of a Novel Pathogenic Variant in the NAGLU Gene in a Child with Neurodevelopmental Delay

13. An explainable model of host genetic interactions linked to COVID-19 severity

14. An explainable model of host genetic interactions linked to COVID-19 severity

15. Identification of a Novel Pathogenic Variant in the NAGLU Gene in a Child with Neurodevelopmental Delay

16. Exome Sequencing in 200 Intellectual Disability/Autistic Patients: New Candidates and Atypical Presentations

17. Severe COVID-19 in Hospitalized Carriers of Single CFTR Pathogenic Variants

18. SARS-CoV-2 susceptibility and COVID-19 disease severity are associated with genetic variants affecting gene expression in a variety of tissues

19. Author response: Association of Toll-like receptor 7 variants with life-threatening COVID-19 disease in males: findings from a nested case-control study

20. Post-Mendelian genetic model in COVID-19

21. Genetic mechanisms of critical illness in COVID-19

22. Shorter androgen receptor polyQ alleles protect against life-threatening COVID-19 disease in males

23. A new mutation in DNM2 gene in a large Italian family

24. ACE2gene variants may underlie interindividual variability and susceptibility to COVID-19 in the Italian population

25. New frontiers to cure Alport syndrome: COL4A3 and COL4A5 gene editing in podocyte-lineage cells

26. Shorter Androgen Receptor PolyQ Alleles Protect Against Life-Threatening COVID-19 Disease in Males

27. ACE2gene variants may underlie interindividual variability and susceptibility to COVID-19 in the Italian population

28. High rate of HDR in gene editing of p.(Thr158Met) MECP2 mutational hotspot

29. Analysis of the Zn-Binding Domains of TRIM32, the E3 Ubiquitin Ligase Mutated in Limb Girdle Muscular Dystrophy 2H

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