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1. Host genetics and COVID-19 severity: increasing the accuracy of latest severity scores by Boolean quantum features

Author

Gabriele Martelloni, Alessio Turchi, Chiara Fallerini, Andrea Degl’Innocenti, Margherita Baldassarri, Simona Olmi, Simone Furini, Alessandra Renieri, GEN-COVID Multicenter study, Francesca Mari, Sergio Daga, Ilaria Meloni, Mirella Bruttini, Susanna Croci, Mirjam Lista, Debora Maffeo, Elena Pasquinelli, Giulia Brunelli, Kristina Zguro, Viola Bianca Serio, Enrica Antolini, Simona Letizia Basso, Samantha Minetto, Giulia Rollo, Martina Rozza, Angela Rina, Rossella Tita, Maria Antonietta Mencarelli, Caterina Lo Rizzo, Anna Maria Pinto, Francesca Ariani, Francesca Montagnani, Mario Tumbarello, Ilaria Rancan, Massimiliano Fabbiani, 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 Raffaelli, Arianna Emiliozzi, 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, Maria Lorubbio, Alessandro Pancrazzi, Massimo Vaghi, Antonella D’Arminio Monforte, Federica Gaia Miraglia, Mario U. Mondelli, Stefania Mantovani, Raffaele Bruno, Marco Vecchia, Marcello Maffezzoni, Enrico Martinelli, Massimo Girardis, Stefano Busani, Sophie Venturelli, Andrea Cossarizza, Andrea Antinori, Alessandra Vergori, Stefano Rusconi, Matteo Siano, Arianna Gabrieli, Agostino Riva, Daniela Francisci, Elisabetta Schiaroli, Carlo Pallotto, Saverio Giuseppe Parisi, Monica Basso, Sandro Panese, Stefano Baratti, Pier Giorgio Scotton, Francesca Andretta, Mario Giobbia, Renzo Scaggiante, Francesca Gatti, 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, Giuseppe Merla, Gabriella Maria Squeo, Filippo Aucella, Pamela Raggi, Rita Perna, Matteo Bassetti, Antonio Di Biagio, Maurizio Sanguinetti, Luca Masucci, Alessandra Guarnaccia, Serafina Valente, Alex Di Florio, Marco Mandalà, Alessia Giorli, Lorenzo Salerni, Patrizia Zucchi, Pierpaolo Parravicini, Elisabetta Menatti, Tullio Trotta, Ferdinando Giannattasio, Gabriella Coiro, Fabio Lena, Gianluca Lacerenza, Cristina Mussini, Luisa Tavecchia, Lia Crotti, Gianfranco Parati, Roberto Menè, Maurizio Sanarico, Marco Gori, Francesco Raimondi, Alessandra Stella, Filippo Biscarini, Tiziana Bachetti, Maria Teresa La Rovere, Maurizio Bussotti, Serena Ludovisi, Katia Capitani, Simona Dei, Sabrina Ravaglia, Annarita Giliberti, Giulia Gori, Rosangela Artuso, Elena Andreucci, 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, Giulia Micheli, Marco Falcone, Donato Urso, Giusy Tiseo, 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, Alessio Bellucci, Marta Colaneri, Patrizia Casprini, Cristoforo Pomara, Massimiliano Esposito, Roberto Leoncini, Michele Cirianni, Lucrezia Galasso, Marco Antonio Bellini, Chiara Gabbi, and Nicola Picchiotti

Subjects
COVID-19, host genetics, integrated polygenic score, genetic algorithm, logistic regression, genetic science modeling, Genetics, QH426-470
Abstract

The impact of common and rare variants in COVID-19 host genetics has been widely studied. In particular, in Fallerini et al. (Human genetics, 2022, 141, 147–173), common and rare variants were used to define an interpretable machine learning model for predicting COVID-19 severity. First, variants were converted into sets of Boolean features, depending on the absence or the presence of variants in each gene. An ensemble of LASSO logistic regression models was used to identify the most informative Boolean features with respect to the genetic bases of severity. After that, the Boolean features, selected by these logistic models, were combined into an Integrated PolyGenic Score (IPGS), which offers a very simple description of the contribution of host genetics in COVID-19 severity.. IPGS leads to an accuracy of 55%–60% on different cohorts, and, after a logistic regression with both IPGS and age as inputs, it leads to an accuracy of 75%. The goal of this paper is to improve the previous results, using not only the most informative Boolean features with respect to the genetic bases of severity but also the information on host organs involved in the disease. In this study, we generalize the IPGS adding a statistical weight for each organ, through the transformation of Boolean features into “Boolean quantum features,” inspired by quantum mechanics. The organ coefficients were set via the application of the genetic algorithm PyGAD, and, after that, we defined two new integrated polygenic scores (IPGSph1 and IPGSph2). By applying a logistic regression with both IPGS, (IPGSph2 (or indifferently IPGSph1) and age as inputs, we reached an accuracy of 84%–86%, thus improving the results previously shown in Fallerini et al. (Human genetics, 2022, 141, 147–173) by a factor of 10%.

Published
2024
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2. Matrisome and Immune Pathways Contribute to Extreme Vascular Outcomes in Williams–Beuren Syndrome

Author

Delong Liu, Charles J. Billington, Neelam Raja, Zoe C. Wong, Mark D. Levin, Wulfgang Resch, Camille Alba, Daniel N. Hupalo, Elisa Biamino, Maria Francesca Bedeschi, Maria Cristina Digilio, Gabriella Maria Squeo, Roberta Villa, Pheobe C. R. Parrish, Russell H. Knutsen, Sharon Osgood, Joy A. Freeman, Clifton L. Dalgard, Giuseppe Merla, Barbara R. Pober, Carolyn B. Mervis, Amy E. Roberts, Colleen A. Morris, Lucy R. Osborne, and Beth A. Kozel

Subjects
adaptive/innate immune system, elastin (ELN), extreme phenotype, pathway analysis, supravalvar aortic stenosis, Williams–Beuren syndrome, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract

Background Supravalvar aortic stenosis (SVAS) is a characteristic feature of Williams–Beuren syndrome (WBS). Its severity varies: ~20% of people with Williams–Beuren syndrome have SVAS requiring surgical intervention, whereas ~35% have no appreciable SVAS. The remaining individuals have SVAS of intermediate severity. Little is known about genetic modifiers that contribute to this variability. Methods and Results We performed genome sequencing on 473 individuals with Williams–Beuren syndrome and developed strategies for modifier discovery in this rare disease population. Approaches include extreme phenotyping and nonsynonymous variant prioritization, followed by gene set enrichment and pathway‐level association tests. We next used GTEx v8 and proteomic data sets to verify expression of candidate modifiers in relevant tissues. Finally, we evaluated overlap between the genes/pathways identified here and those ascertained through larger aortic disease/trait genome‐wide association studies. We show that SVAS severity in Williams–Beuren syndrome is associated with increased frequency of common and rarer variants in matrisome and immune pathways. Two implicated matrisome genes (ACAN and LTBP4) were uniquely expressed in the aorta. Many genes in the identified pathways were previously reported in genome‐wide association studies for aneurysm, bicuspid aortic valve, or aortic size. Conclusions Smaller sample sizes in rare disease studies necessitate new approaches to detect modifiers. Our strategies identified variation in matrisome and immune pathways that are associated with SVAS severity. These findings suggest that, like other aortopathies, SVAS may be influenced by the balance of synthesis and degradation of matrisome proteins. Leveraging multiomic data and results from larger aorta‐focused genome‐wide association studies may accelerate modifier discovery for rare aortopathies like SVAS.

Published
2024
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4. The ubiquitin ligase TRIM32 promotes the autophagic response to Mycobacterium tuberculosis infection in macrophages

Author

Alessandra Romagnoli, Martina Di Rienzo, Elisa Petruccioli, Carmela Fusco, Ivana Palucci, Lucia Micale, Tommaso Mazza, Giovanni Delogu, Giuseppe Merla, Delia Goletti, Mauro Piacentini, and Gian Maria Fimia

Subjects
Cytology, QH573-671
Abstract

Abstract Mycobacterium tuberculosis (Mtb) is known to evade host immune responses and persist in macrophages for long periods. A mechanism that the host uses to combat Mtb is xenophagy, a selective form of autophagy that targets intracellular pathogens for degradation. Ubiquitination of Mtb or Mtb-containing compartments is a key event to recruit the autophagy machinery and mediate the bacterial delivery to the lysosome. This event relies on the coordinated and complementary activity of different ubiquitin ligases, including PARKIN, SMURF1, and TRIM16. Because each of these factors is responsible for the ubiquitination of a subset of the Mtb population, it is likely that additional ubiquitin ligases are employed by macrophages to trigger a full xenophagic response during Mtb infection. In this study, we investigated the role TRIM proteins whose expression is modulated in response to Mtb or BCG infection of primary macrophages. These TRIMs were ectopically expressed in THP1 macrophage cell line to assess their impact on Mtb replication. This screening identified TRIM32 as a novel player involved in the intracellular response to Mtb infection, which promotes autophagy-mediated Mtb degradation. The role of TRIM32 in xenophagy was further confirmed by silencing TRIM32 expression in THP1 cells, which causes increased intracellular growth of Mtb associated to impaired Mtb ubiquitination, reduced recruitment of the autophagy proteins NDP52/CALCOCO2 and BECLIN 1/BECN1 to Mtb and autophagosome formation. Overall, these findings suggest that TRIM32 plays an important role in the host response to Mtb infection through the induction of autophagy, representing a promising target for host-directed tuberculosis therapies.

Published
2023
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5. FOXI3 pathogenic variants cause one form of craniofacial microsomia

Author

Ke Mao, Christelle Borel, Muhammad Ansar, Angad Jolly, Periklis Makrythanasis, Christine Froehlich, Justyna Iwaszkiewicz, Bingqing Wang, Xiaopeng Xu, Qiang Li, Xavier Blanc, Hao Zhu, Qi Chen, Fujun Jin, Harinarayana Ankamreddy, Sunita Singh, Hongyuan Zhang, Xiaogang Wang, Peiwei Chen, Emmanuelle Ranza, Sohail Aziz Paracha, Syed Fahim Shah, Valentina Guida, Francesca Piceci-Sparascio, Daniela Melis, Bruno Dallapiccola, Maria Cristina Digilio, Antonio Novelli, Monia Magliozzi, Maria Teresa Fadda, Haley Streff, Keren Machol, Richard A. Lewis, Vincent Zoete, Gabriella Maria Squeo, Paolo Prontera, Giorgia Mancano, Giulia Gori, Milena Mariani, Angelo Selicorni, Stavroula Psoni, Helen Fryssira, Sofia Douzgou, Sandrine Marlin, Saskia Biskup, Alessandro De Luca, Giuseppe Merla, Shouqin Zhao, Timothy C. Cox, Andrew K. Groves, James R. Lupski, Qingguo Zhang, Yong-Biao Zhang, and Stylianos E. Antonarakis

Subjects
Science
Abstract

Abstract Craniofacial microsomia (CFM; also known as Goldenhar syndrome), is a craniofacial developmental disorder of variable expressivity and severity with a recognizable set of abnormalities. These birth defects are associated with structures derived from the first and second pharyngeal arches, can occur unilaterally and include ear dysplasia, microtia, preauricular tags and pits, facial asymmetry and other malformations. The inheritance pattern is controversial, and the molecular etiology of this syndrome is largely unknown. A total of 670 patients belonging to unrelated pedigrees with European and Chinese ancestry with CFM, are investigated. We identify 18 likely pathogenic variants in 21 probands (3.1%) in FOXI3. Biochemical experiments on transcriptional activity and subcellular localization of the likely pathogenic FOXI3 variants, and knock-in mouse studies strongly support the involvement of FOXI3 in CFM. Our findings indicate autosomal dominant inheritance with reduced penetrance, and/or autosomal recessive inheritance. The phenotypic expression of the FOXI3 variants is variable. The penetrance of the likely pathogenic variants in the seemingly dominant form is reduced, since a considerable number of such variants in affected individuals were inherited from non-affected parents. Here we provide suggestive evidence that common variation in the FOXI3 allele in trans with the pathogenic variant could modify the phenotypic severity and accounts for the incomplete penetrance.

Published
2023
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6. Understanding the Variability of 22q11.2 Deletion Syndrome: The Role of Epigenetic Factors

Author

Francesca Cillo, Emma Coppola, Federico Habetswallner, Francesco Cecere, Laura Pignata, Elisabetta Toriello, Antonio De Rosa, Laura Grilli, Antonio Ammendola, Paolo Salerno, Roberta Romano, Emilia Cirillo, Giuseppe Merla, Andrea Riccio, Claudio Pignata, and Giuliana Giardino

Subjects
22q11.2 deletion syndrome, epigenetics, micro-RNAs, methylation, CpG islands, Genetics, QH426-470
Abstract

Initially described as a triad of immunodeficiency, congenital heart defects and hypoparathyroidism, 22q11.2 deletion syndrome (22q11.2DS) now encompasses a great amount of abnormalities involving different systems. Approximately 85% of patients share a 3 Mb 22q11.2 region of hemizygous deletion in which 46 protein-coding genes are included. However, the hemizygosity of the genes of this region cannot fully explain the clinical phenotype and the phenotypic variability observed among patients. Additional mutations in genes located outside the deleted region, leading to “dual diagnosis”, have been described in 1% of patients. In some cases, the hemizygosity of the 22q11.2 region unmasks autosomal recessive conditions due to additional mutations on the non-deleted allele. Some of the deleted genes play a crucial role in gene expression regulation pathways, involving the whole genome. Typical miRNA expression patterns have been identified in 22q11.2DS, due to an alteration in miRNA biogenesis, affecting the expression of several target genes. Also, a methylation epi-signature in CpG islands differentiating patients from controls has been defined. Herein, we summarize the evidence on the genetic and epigenetic mechanisms implicated in the pathogenesis of the clinical manifestations of 22q11.2 DS. The review of the literature confirms the hypothesis that the 22q11.2DS phenotype results from a network of interactions between deleted protein-coding genes and altered epigenetic regulation.

Published
2024
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7. DNA Methylation in the Fields of Prenatal Diagnosis and Early Detection of Cancers

Author

Fabio Coppedè, Utsa Bhaduri, Andrea Stoccoro, Vanessa Nicolì, Eleonora Di Venere, and Giuseppe Merla

Subjects
DNA methylation, DMNT, bisulfite sequencing, RRBS, epigenetics, cancer, Biology (General), QH301-705.5, Chemistry, QD1-999
Abstract

The central objective of the metamorphosis of discovery science into biomedical applications is to serve the purpose of patients and curtail the global disease burden. The journey from the discovery of DNA methylation (DNAm) as a biological process to its emergence as a diagnostic tool is one of the finest examples of such metamorphosis and has taken nearly a century. Particularly in the last decade, the application of DNA methylation studies in the clinic has been standardized more than ever before, with great potential to diagnose a multitude of diseases that are associated with a burgeoning number of genes with this epigenetic alteration. Fetal DNAm detection is becoming useful for noninvasive prenatal testing, whereas, in very preterm infants, DNAm is also shown to be a potential biological indicator of prenatal risk factors. In the context of cancer, liquid biopsy-based DNA-methylation profiling is offering valuable epigenetic biomarkers for noninvasive early-stage diagnosis. In this review, we focus on the applications of DNA methylation in prenatal diagnosis for delivering timely therapy before or after birth and in detecting early-stage cancers for better clinical outcomes. Furthermore, we also provide an up-to-date commercial landscape of DNAm biomarkers for cancer detection and screening of cancers of unknown origin.

Published
2023
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8. Rise of TRIM8: A Molecule of Duality

Author

Utsa Bhaduri and Giuseppe Merla

Subjects
E3 ubiquitin ligases, TRIM family, TRIM8, cancer, Therapeutics. Pharmacology, RM1-950
Abstract

The human tripartite motif containing protein 8 (TRIM8), a member of TRIM family proteins, is known to play a dual role as both tumor suppressor and oncogene, and to function at the crosstalk of cancer and innate immunity. In this review, in addition to accumulating recent corroborations that endorse this dual character of TRIM8, we appraise the game-changing capacity of TRIM8 under stress conditions against the backdrop of cell proliferation, apoptosis, and cancer, and also highlight the duality of TRIM8 in multiple contexts like cellular localization, stress-induced conditions, and E3 ubiquitin ligase activity. Finally, we discuss the emerging role of TRIM8 during bipolar spindle formation and mitotic progression, and its growing sphere of influence across multiple human cancers and pathologies, and suggest TRIM8-linked axes that can be modulated further for anti-cancer therapeutics development.

Published
2020
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9. Novel diagnostic DNA methylation episignatures expand and refine the epigenetic landscapes of Mendelian disorders

Author

Michael A. Levy, Haley McConkey, Jennifer Kerkhof, Mouna Barat-Houari, Sara Bargiacchi, Elisa Biamino, María Palomares Bralo, Gerarda Cappuccio, Andrea Ciolfi, Angus Clarke, Barbara R. DuPont, Mariet W. Elting, Laurence Faivre, Timothy Fee, Robin S. Fletcher, Florian Cherik, Aidin Foroutan, Michael J. Friez, Cristina Gervasini, Sadegheh Haghshenas, Benjamin A. Hilton, Zandra Jenkins, Simranpreet Kaur, Suzanne Lewis, Raymond J. Louie, Silvia Maitz, Donatella Milani, Angela T. Morgan, Renske Oegema, Elsebet Østergaard, Nathalie Ruiz Pallares, Maria Piccione, Simone Pizzi, Astrid S. Plomp, Cathryn Poulton, Jack Reilly, Raissa Relator, Rocio Rius, Stephen Robertson, Kathleen Rooney, Justine Rousseau, Gijs W.E. Santen, Fernando Santos-Simarro, Josephine Schijns, Gabriella Maria Squeo, Miya St John, Christel Thauvin-Robinet, Giovanna Traficante, Pleuntje J. van der Sluijs, Samantha A. Vergano, Niels Vos, Kellie K. Walden, Dimitar Azmanov, Tugce Balci, Siddharth Banka, Jozef Gecz, Peter Henneman, Jennifer A. Lee, Marcel M.A.M. Mannens, Tony Roscioli, Victoria Siu, David J. Amor, Gareth Baynam, Eric G. Bend, Kym Boycott, Nicola Brunetti-Pierri, Philippe M. Campeau, John Christodoulou, David Dyment, Natacha Esber, Jill A. Fahrner, Mark D. Fleming, David Genevieve, Kristin D. Kerrnohan, Alisdair McNeill, Leonie A. Menke, Giuseppe Merla, Paolo Prontera, Cheryl Rockman-Greenberg, Charles Schwartz, Steven A. Skinner, Roger E. Stevenson, Antonio Vitobello, Marco Tartaglia, Marielle Alders, Matthew L. Tedder, and Bekim Sadikovic

Subjects
Episignatures, Neurodevelopmental disorders, DNA methylation, Epigenetics, Clinical diagnostics, Genetics, QH426-470
Abstract

Summary: Overlapping clinical phenotypes and an expanding breadth and complexity of genomic associations are a growing challenge in the diagnosis and clinical management of Mendelian disorders. The functional consequences and clinical impacts of genomic variation may involve unique, disorder-specific, genomic DNA methylation episignatures. In this study, we describe 19 novel episignature disorders and compare the findings alongside 38 previously established episignatures for a total of 57 episignatures associated with 65 genetic syndromes. We demonstrate increasing resolution and specificity ranging from protein complex, gene, sub-gene, protein domain, and even single nucleotide-level Mendelian episignatures. We show the power of multiclass modeling to develop highly accurate and disease-specific diagnostic classifiers. This study significantly expands the number and spectrum of disorders with detectable DNA methylation episignatures, improves the clinical diagnostic capabilities through the resolution of unsolved cases and the reclassification of variants of unknown clinical significance, and provides further insight into the molecular etiology of Mendelian conditions.

Published
2022
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10. Circadian Genes Expression Patterns in Disorders Due to Enzyme Deficiencies in the Heme Biosynthetic Pathway

Author

Maria Savino, Claudio Carmine Guida, Maria Nardella, Emanuele Murgo, Bartolomeo Augello, Giuseppe Merla, Salvatore De Cosmo, Antonio Fernando Savino, Roberto Tarquini, Francesco Cei, Filippo Aucella, and Gianluigi Mazzoccoli

Subjects
heme, porphyria, circadian, rhythm, biological clock, Biology (General), QH301-705.5
Abstract

Heme is a member of the porphyrins family of cyclic tetrapyrroles and influences various cell processes and signalling pathways. Enzyme deficiencies in the heme biosynthetic pathway provoke rare human inherited metabolic diseases called porphyrias. Protein levels and activity of enzymes involved in the heme biosynthetic pathway and especially 5′-Aminolevulinate Synthase 1 are featured by 24-h rhythmic oscillations driven by the biological clock. Heme biosynthesis and circadian pathways intermingle with mutual modulatory roles. Notably, heme is a ligand of important cogs of the molecular clockwork, which upon heme binding recruit co-repressors and inhibit the transcription of numerous genes enriching metabolic pathways and encoding functional proteins bringing on crucial cell processes. Herein, we assessed mRNA levels of circadian genes in patients suffering from porphyrias and found several modifications of core clock genes and clock-controlled genes expression, associated with metabolic and electrolytic changes. Overall, our results show an altered expression of circadian genes accompanying heme biosynthesis disorders and confirm the need to deepen the knowledge of the mechanisms through which the alteration of the circadian clock circuitry could take part in determining signs and symptoms of porphyria patients and then again could represent a target for innovative therapeutic strategies.

Published
2022
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11. Clinical Utility of a Unique Genome-Wide DNA Methylation Signature for KMT2A-Related Syndrome

Author

Aidin Foroutan, Sadegheh Haghshenas, Pratibha Bhai, Michael A. Levy, Jennifer Kerkhof, Haley McConkey, Marcello Niceta, Andrea Ciolfi, Lucia Pedace, Evelina Miele, David Genevieve, Solveig Heide, Mariëlle Alders, Giuseppe Zampino, Giuseppe Merla, Mélanie Fradin, Eric Bieth, Dominique Bonneau, Klaus Dieterich, Patricia Fergelot, Elise Schaefer, Laurence Faivre, Antonio Vitobello, Silvia Maitz, Rita Fischetto, Cristina Gervasini, Maria Piccione, Ingrid van de Laar, Marco Tartaglia, Bekim Sadikovic, and Anne-Sophie Lebre

Subjects
epigenetics, DNA methylation, episignature, Wiedemann–Steiner syndrome, KMT2A gene, intellectual disability, Biology (General), QH301-705.5, Chemistry, QD1-999
Abstract

Wiedemann–Steiner syndrome (WDSTS) is a Mendelian syndromic intellectual disability (ID) condition associated with hypertrichosis cubiti, short stature, and characteristic facies caused by pathogenic variants in the KMT2A gene. Clinical features can be inconclusive in mild and unusual WDSTS presentations with variable ID (mild to severe), facies (typical or not) and other associated malformations (bone, cerebral, renal, cardiac and ophthalmological anomalies). Interpretation and classification of rare KMT2A variants can be challenging. A genome-wide DNA methylation episignature for KMT2A-related syndrome could allow functional classification of variants and provide insights into the pathophysiology of WDSTS. Therefore, we assessed genome-wide DNA methylation profiles in a cohort of 60 patients with clinical diagnosis for WDSTS or Kabuki and identified a unique highly sensitive and specific DNA methylation episignature as a molecular biomarker of WDSTS. WDSTS episignature enabled classification of variants of uncertain significance in the KMT2A gene as well as confirmation of diagnosis in patients with clinical presentation of WDSTS without known genetic variants. The changes in the methylation profile resulting from KMT2A mutations involve global reduction in methylation in various genes, including homeobox gene promoters. These findings provide novel insights into the molecular etiology of WDSTS and explain the broad phenotypic spectrum of the disease.

Published
2022
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12. The Genetic Landscape of Dystrophin Mutations in Italy: A Nationwide Study

Author

Marcella Neri, Rachele Rossi, Cecilia Trabanelli, Antonio Mauro, Rita Selvatici, Maria Sofia Falzarano, Noemi Spedicato, Alice Margutti, Paola Rimessi, Fernanda Fortunato, Marina Fabris, Francesca Gualandi, Giacomo Comi, Silvana Tedeschi, Manuela Seia, Chiara Fiorillo, Monica Traverso, Claudio Bruno, Emiliano Giardina, Maria Rosaria Piemontese, Giuseppe Merla, Milena Cau, Monica Marica, Carmela Scuderi, Eugenia Borgione, Alessandra Tessa, Guia Astrea, Filippo Maria Santorelli, Luciano Merlini, Marina Mora, Pia Bernasconi, Sara Gibertini, Valeria Sansone, Tiziana Mongini, Angela Berardinelli, Antonella Pini, Rocco Liguori, Massimiliano Filosto, Sonia Messina, Gianluca Vita, Antonio Toscano, Giuseppe Vita, Marika Pane, Serenella Servidei, Elena Pegoraro, Luca Bello, Lorena Travaglini, Enrico Bertini, Adele D'Amico, Manuela Ergoli, Luisa Politano, Annalaura Torella, Vincenzo Nigro, Eugenio Mercuri, and Alessandra Ferlini

Subjects
dystrophin, muscular dystrophy, nationwide study, exon skipping therapy, read-through therapy, Genetics, QH426-470
Abstract

Dystrophinopathies are inherited diseases caused by mutations in the dystrophin (DMD) gene for which testing is mandatory for genetic diagnosis, reproductive choices and eligibility for personalized trials. We genotyped the DMD gene in our Italian cohort of 1902 patients (BMD n = 740, 39%; DMD n =1162, 61%) within a nationwide study involving 11 diagnostic centers in a 10-year window (2008–2017). In DMD patients, we found deletions in 57%, duplications in 11% and small mutations in 32%. In BMD, we found deletions in 78%, duplications in 9% and small mutations in 13%. In BMD, there are a higher number of deletions, and small mutations are more frequent than duplications. Among small mutations that are generally frequent in both phenotypes, 44% of DMD and 36% of BMD are nonsense, thus, eligible for stop codon read-through therapy; 63% of all out-of-frame deletions are eligible for single exon skipping. Patients were also assigned to Italian regions and showed interesting regional differences in mutation distribution. The full genetic characterization in this large, nationwide cohort has allowed us to draw several correlations between DMD/BMD genotype landscapes and mutation frequency, mutation types, mutation locations along the gene, exon/intron architecture, and relevant protein domain, with effects on population genetic characteristics and new personalized therapies.

Published
2020
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13. Generation of the induced human pluripotent stem cell lines CSSi009-A from a patient with a GNB5 pathogenic variant, and CSSi010-A from a CRISPR/Cas9 engineered GNB5 knock-out human cell line

Author

Natascia Malerba, Patrizia Benzoni, Gabriella Maria Squeo, Raffaella Milanesi, Federica Giannetti, Lynette G. Sadleir, Gemma Poke, Bartolomeo Augello, Anna Irma Croce, Andrea Barbuti, and Giuseppe Merla

Subjects
Biology (General), QH301-705.5
Abstract

GNB5 loss-of-function pathogenic variants cause IDDCA, a rare autosomal recessive human genetic disease characterized by infantile onset of intellectual disability, sinus bradycardia, hypotonia, visual abnormalities, and epilepsy. We generated human induced pluripotent stem cells (hiPSCs) from skin fibroblasts of a patient with the homozygous c.136delG frameshift variant, and a GNB5 knock-out (KO) line by CRISPR/Cas9 editing. hiPSCs express common pluripotency markers and differentiate into the three germ layers. These lines represent a powerful cellular model to study the molecular basis of GNB5-related disorders as well as offer an in vitro model for drug screening.

Published
2019
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14. A Rare Case of Brachyolmia with Amelogenesis Imperfecta Caused by a New Pathogenic Splicing Variant in LTBP3

Author

Elisabetta Flex, Valentina Imperatore, Giovanna Carpentieri, Alessandro Bruselles, Andrea Ciolfi, Simone Pizzi, Maria Giovanna Tedesco, Daniela Rogaia, Amedea Mencarelli, Giuseppe Di Cara, Alberto Verrotti, Stefania Troiani, Giuseppe Merla, Marco Tartaglia, and Paolo Prontera

Subjects
brachyolmia, amelogenesis imperfecta, LTBP3, whole exome sequencing, consanguinity, Genetics, QH426-470
Abstract

In recent years, a rare form of autosomal recessive brachyolmia associated with amelogenesis imperfecta (AI) has been described as a novel nosologic entity. This disorder is characterized by skeletal dysplasia (e.g., platyspondyly, short trunk, scoliosis, broad ilia, elongated femoral necks with coxa valga) and severe enamel and dental anomalies. Pathogenic variants in the latent transforming growth factor-β binding protein 3 (LTBP3) gene have been found implicated in the pathogenesis of this disorder. So far, biallelic pathogenic LTBP3 variants have been identified in less than 10 families. We here report a young boy born from consanguineous parents with a complex phenotype including skeletal dysplasia associated with aortic stenosis, hypertrophic cardiomyopathy, hypodontia and amelogenesis imperfecta caused by a previously unreported homozygous LTBP3 splice site variant. We also compare the genotypes and phenotypes of patients reported to date. This work provides further evidence that brachyolmia with amelogenesis imperfecta is a distinct nosologic entity and that variations in LTBP3 are involved in its pathogenesis.

Published
2021
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15. Identification of a DNA Methylation Episignature in the 22q11.2 Deletion Syndrome

Author

Kathleen Rooney, Michael A. Levy, Sadegheh Haghshenas, Jennifer Kerkhof, Daniela Rogaia, Maria Giovanna Tedesco, Valentina Imperatore, Amedea Mencarelli, Gabriella Maria Squeo, Eleonora Di Venere, Giuseppe Di Cara, Alberto Verrotti, Giuseppe Merla, Matthew L. Tedder, Barbara R. DuPont, Bekim Sadikovic, and Paolo Prontera

Subjects
22q11.2 deletion, DNA methylation, episignature, diagnostic method, DiGeorge syndrome, Velocardiofacial syndrome, Biology (General), QH301-705.5, Chemistry, QD1-999
Abstract

The 22q11.2 deletion syndrome (22q11.2DS) is the most common genomic disorder in humans and is the result of a recurrent 1.5 to 2.5 Mb deletion, encompassing approximately 20–40 genes, respectively. The clinical presentation of the typical deletion includes: Velocardiofacial, Di George, Opitz G/BBB and Conotruncalanomaly face syndromes. Atypical deletions (proximal, distal or nested) are rare and characterized mainly by normal phenotype or mild intellectual disability and variable clinical features. The pathogenetic mechanisms underlying this disorder are not completely understood. Because the 22q11.2 region harbours genes coding for transcriptional factors and chromatin remodelers, in this study, we performed analysis of genome-wide DNA methylation of peripheral blood from 49 patients with 22q11.2DS using the Illumina Infinium Methylation EPIC bead chip arrays. This cohort comprises 43 typical, 2 proximal and 4 distal deletions. We demonstrated the evidence of a unique and highly specific episignature in all typical and proximal 22q11.2DS. The sensitivity and specificity of this signature was further confirmed by comparing it to over 1500 patients with other neurodevelopmental disorders with known episignatures. Mapping the 22q11.2DS DNA methylation episignature provides both novel insights into the molecular pathogenesis of this disorder and an effective tool in the molecular diagnosis of 22q11.2DS.

Published
2021
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16. Ubiquitination, Biotech Startups, and the Future of TRIM Family Proteins: A TRIM-Endous Opportunity

Author

Utsa Bhaduri and Giuseppe Merla

Subjects
ubiquitination, E3 ligases, TRIM family, startups, drug discovery, Cytology, QH573-671
Abstract

Ubiquitination is a post-translational modification that has pivotal roles in protein degradation and diversified cellular processes, and for more than two decades it has been a subject of interest in the biotech or biopharmaceutical industry. Tripartite motif (TRIM) family proteins are known to have proven E3 ubiquitin ligase activities and are involved in a multitude of cellular and physiological events and pathophysiological conditions ranging from cancers to rare genetic disorders. Although in recent years many kinds of E3 ubiquitin ligases have emerged as the preferred choices of big pharma and biotech startups in the context of protein degradation and disease biology, from a surface overview it appears that TRIM E3 ubiquitin ligases are not very well recognized yet in the realm of drug discovery. This article will review some of the blockbuster scientific discoveries and technological innovations from the world of ubiquitination and E3 ubiquitin ligases that have impacted the biopharma community, from biotech colossuses to startups, and will attempt to evaluate the future of TRIM family proteins in the province of E3 ubiquitin ligase-based drug discovery.

Published
2021
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17. The alliance between genetic biobanks and patient organisations: the experience of the telethon network of genetic biobanks

Author

Chiara Baldo, Lorena Casareto, Alessandra Renieri, Giuseppe Merla, Barbara Garavaglia, Stefano Goldwurm, Elena Pegoraro, Maurizio Moggio, Marina Mora, Luisa Politano, Luca Sangiorgi, Raffaella Mazzotti, Valeria Viotti, Ilaria Meloni, Maria Teresa Pellico, Chiara Barzaghi, Chiuhui Mary Wang, Lucia Monaco, and Mirella Filocamo

Subjects
Patient organisations, Rare diseases, Biobanking, Networking, Agreements, Sample and data centralisation, Medicine
Abstract

Abstract Background Rare diseases (RDs) are often neglected because they affect a small percentage of the population (6–8 %), which makes research and development of new therapies challenging processes. Easy access to high-quality samples and associated clinical data is therefore a key prerequisite for biomedical research. In this context, Genetic Biobanks are critical to developing basic, translational and clinical research on RDs. The Telethon Network of Genetic Biobanks (TNGB) is aware of the importance of biobanking as a service for patients and has started a dialogue with RD-Patient Organisations via promotion of dedicated meetings and round-tables, as well as by including their representatives on the TNGB Advisory Board. This has enabled the active involvement of POs in drafting biobank policies and procedures, including those concerning ethical issues. Here, we report on our experience with RD-Patient Organisations who have requested the services of existing biobanks belonging to TNGB and describe how these relationships were established, formalised and maintained. Results The process of patient engagement has proven to be successful both for lay members, who increased their understanding of the complex processes of biobanking, and for professionals, who gained awareness of the needs and expectations of the people involved. This collaboration has resulted in a real interest on the part of Patient Organisations in the biobanking service, which has led to 13 written agreements designed to formalise this process. These agreements enabled the centralisation of rare genetic disease biospecimens and their related data, thus making them available to the scientific community. Conclusions The TNGB experience has proven to be an example of good practice with regard to patient engagement in biobanking and may serve as a model of collaboration between disease-oriented Biobanks and Patient Organisations. Such collaboration serves to enhance awareness and trust and to encourage the scientific community to address research on RDs.

Published
2016
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18. A NGS-Targeted Autism/ID Panel Reveals Compound Heterozygous GNB5 Variants in a Novel Patient

Author

Natascia Malerba, Shelley Towner, Katherine Keating, Gabriella Maria Squeo, William Wilson, and Giuseppe Merla

Subjects
GNB5, IDDCA, LADCI, cognitive impairment, cardiac arrhythmia, Genetics, QH426-470
Abstract

Homozygous and compound heterozygous pathogenic variants in GNB5 have been recently associated with a spectrum of clinical presentations varying from a severe multisystem form of the disorder including intellectual disability, early infantile developmental and epileptic encephalopathy, retinal abnormalities and cardiac arrhythmias (IDDCA) to a milder form with language delay, attention-deficit/hyperactivity disorder, cognitive impairment, with or without cardiac arrhythmia (LADCI). Approximately twenty patients have been described so far; here we report a novel case of a 2.5-year-old female who is a compound heterozygote for a frameshift and a missense variant in the GNB5 gene. Her clinical presentation is consistent with a moderate phenotype, corroborating the direct correlation between the type and pathogenic mechanism of the GNB5 genetic variant and the severity of related phenotype.

Published
2018
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19. Clinical Genetics Can Solve the Pitfalls of Genome-Wide Investigations: Lesson from Mismapping a Loss-of-Function Variant in KANSL1

Author

Stefania Bigoni, Giuseppe Marangi, Silvia Frangella, Arianna Panfili, Davide Ognibene, Gabriella Maria Squeo, Giuseppe Merla, and Marcella Zollino

Subjects
KANSL1, variant interpretation, clinical evaluation, copy number polymorphisms, Genetics, QH426-470
Abstract

Massive parallel sequencing of 70 genes in a girl with a suspicion of chromatinopathy detected the (NM_015443.4:)c.985_986delTT variant in exon 2 of KANSL1, which led to a diagnostic consideration of Koolen De Vries syndrome. The same variant was present in the healthy mother, consistent with either incomplete penetrance or variant mismapping. A network of second opinion was implemented among clinical geneticists first, and a diagnosis of Koolen De Vries syndrome was considered unlikely. By MLPA, a duplication spanning exons 1-3 of KANSL1 was detected in both the mother and the daughter. On cDNA sequencing, biallelic wild type mRNA was observed. We concluded that the variant affects the noncoding duplicated gene region in our family, and we finally classified it as benign. Parallel wide genomic sequencing is increasingly the first genetic investigation in individuals with intellectual disability. The c.985_986delTT variant in KANSL1 was described both in individuals with typical KdVS and in a limited number of healthy subjects. This report highlights the role of clinical genetics to correctly classify variants and to define proper clinical and diagnostic correlations.

Published
2020
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20. Loss of Function of the Gene Encoding the Histone Methyltransferase KMT2D Leads to Deregulation of Mitochondrial Respiration

Author

Consiglia Pacelli, Iolanda Adipietro, Natascia Malerba, Gabriella Maria Squeo, Claudia Piccoli, Angela Amoresano, Gabriella Pinto, Pietro Pucci, Ji-Eun Lee, Kai Ge, Nazzareno Capitanio, and Giuseppe Merla

Subjects
Kabuki syndrome, KMT2D, mitochondria, Cytology, QH573-671
Abstract

KMT2D encodes a methyltransferase responsible for histone 3 lysine 4 (H3K4) mono-/di-methylation, an epigenetic mark correlated with active transcription. Here, we tested the hypothesis that KMT2D pathogenic loss-of-function variants, which causes the Kabuki syndrome type 1, could affect the mitochondrial metabolic profile. By using Seahorse technology, we showed a significant reduction of the mitochondrial oxygen consumption rate as well as a reduction of the glycolytic flux in both Kmt2d knockout MEFs and skin fibroblasts of Kabuki patients harboring heterozygous KMT2D pathogenic variants. Mass-spectrometry analysis of intermediate metabolites confirmed alterations in the glycolytic and TCA cycle pathways. The observed metabolic phenotype was accompanied by a significant increase in the production of reactive oxygen species. Measurements of the specific activities of the mitochondrial respiratory chain complexes revealed significant inhibition of CI (NADH dehydrogenase) and CIV (cytochrome c oxidase); this result was further supported by a decrease in the protein content of both complexes. Finally, we unveiled an impaired oxidation of glucose and larger reliance on long-chain fatty acids oxidation. Altogether, our findings clearly indicate a rewiring of the mitochondrial metabolic phenotype in the KMT2D-null or loss-of-function context that might contribute to the development of Kabuki disease, and represents metabolic reprogramming as a potential new therapeutic approach.

Published
2020
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21. DNA Methylation in the Diagnosis of Monogenic Diseases

Author

Flavia Cerrato, Angela Sparago, Francesca Ariani, Fulvia Brugnoletti, Luciano Calzari, Fabio Coppedè, Alessandro De Luca, Cristina Gervasini, Emiliano Giardina, Fiorella Gurrieri, Cristiana Lo Nigro, Giuseppe Merla, Monica Miozzo, Silvia Russo, Eugenio Sangiorgi, Silvia M Sirchia, Gabriella Maria Squeo, Silvia Tabano, Elisabetta Tabolacci, Isabella Torrente, Maurizio Genuardi, Giovanni Neri, and Andrea Riccio

Subjects
dna methylation, genetic testing, high-throughput analysis, epi-signatures, developmental delay/intellectual disability disorders, imprinting disorders, hereditary tumors, neuromuscular diseases, prenatal diagnosis, Genetics, QH426-470
Abstract

DNA methylation in the human genome is largely programmed and shaped by transcription factor binding and interaction between DNA methyltransferases and histone marks during gamete and embryo development. Normal methylation profiles can be modified at single or multiple loci, more frequently as consequences of genetic variants acting in cis or in trans, or in some cases stochastically or through interaction with environmental factors. For many developmental disorders, specific methylation patterns or signatures can be detected in blood DNA. The recent use of high-throughput assays investigating the whole genome has largely increased the number of diseases for which DNA methylation analysis provides information for their diagnosis. Here, we review the methylation abnormalities that have been associated with mono/oligogenic diseases, their relationship with genotype and phenotype and relevance for diagnosis, as well as the limitations in their use and interpretation of results.

Published
2020
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22. E3 Ubiquitin Ligase TRIM Proteins, Cell Cycle and Mitosis

Author

Santina Venuto and Giuseppe Merla

Subjects
TRIMs, cell cycle, cancer, mitosis, Cytology, QH573-671
Abstract

The cell cycle is a series of events by which cellular components are accurately segregated into daughter cells, principally controlled by the oscillating activities of cyclin-dependent kinases (CDKs) and their co-activators. In eukaryotes, DNA replication is confined to a discrete synthesis phase while chromosome segregation occurs during mitosis. During mitosis, the chromosomes are pulled into each of the two daughter cells by the coordination of spindle microtubules, kinetochores, centromeres, and chromatin. These four functional units tie chromosomes to the microtubules, send signals to the cells when the attachment is completed and the division can proceed, and withstand the force generated by pulling the chromosomes to either daughter cell. Protein ubiquitination is a post-translational modification that plays a central role in cellular homeostasis. E3 ubiquitin ligases mediate the transfer of ubiquitin to substrate proteins determining their fate. One of the largest subfamilies of E3 ubiquitin ligases is the family of the tripartite motif (TRIM) proteins, whose dysregulation is associated with a variety of cellular processes and directly involved in human diseases and cancer. In this review we summarize the current knowledge and emerging concepts about TRIMs and their contribution to the correct regulation of cell cycle, describing how TRIMs control the cell cycle transition phases and their involvement in the different functional units of the mitotic process, along with implications in cancer progression.

Published
2019
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23. Clinical and Neurobehavioral Features of Three Novel Kabuki Syndrome Patients with Mosaic KMT2D Mutations and a Review of Literature

Author

Francesca Romana Lepri, Dario Cocciadiferro, Bartolomeo Augello, Paolo Alfieri, Valentina Pes, Alessandra Vancini, Cristina Caciolo, Gabriella Maria Squeo, Natascia Malerba, Iolanda Adipietro, Antonio Novelli, Stefano Sotgiu, Renzo Gherardi, Maria Cristina Digilio, Bruno Dallapiccola, and Giuseppe Merla

Subjects
kabuki syndrome, KMT2D/MLL2, mosaicism, developmental delay, Biology (General), QH301-705.5, Chemistry, QD1-999
Abstract

Kabuki syndrome (KS) is a rare disorder characterized by multiple congenital anomalies and variable intellectual disability caused by mutations in KMT2D/MLL2 and KDM6A/UTX, two interacting chromatin modifier responsible respectively for 56–75% and 5–8% of the cases. To date, three KS patients with mosaic KMT2D deletions in blood lymphocytes have been described. We report on three additional subjects displaying KMT2D gene mosaics including one in which a single nucleotide change results in a new frameshift mutation (p.L1199HfsX7), and two with already-known nonsense mutations (p.R4484X and p.R5021X). Consistent with previously published cases, mosaic KMT2D mutations may result in mild KS facial dysmorphisms and clinical and neurobehavioral features, suggesting that these characteristics could represent the handles for genetic testing of individuals with slight KS-like traits.

Published
2017
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24. Genomic and Genetic Disorders Biobank

Author

Carmela Fusco, Lucia Micale, Maria Teresa Pellico, Ester Valentina D'Addetta, Bartolomeo Augello, Barbara Mandriani, Pasquelena De Nittis, Dario Cocciadiferro, Natascia Malerba, Michele Sacco, Leopoldo Zelante, and Giuseppe Merla

Subjects
biobanking, genomic and genetic disorders, biospecimens., Medicine, Computer applications to medicine. Medical informatics, R858-859.7
Abstract

The Genomic and Genetic Disorders Biobank (GGDB, formerly Genomic Disorders Biobank) was established in 2006 as an internal bioresource supported by own database, to collect and store biospecimens from genomic-disorder (e.g. microdeletion and duplication syndromes) affected individuals. Since 2009 the Bioresource has joined the Telethon Network of Genetic Biobanks and has expanded the collection to include also genetic mendelian diseases. The GGDB gathers wholly annotated clinical and longitudinal data and biological samples from affected and healthy donors, according to standard ethical principles. Biospecimens are available to the international scientific community for research projects in the field of the pathologies collected and stored in GGDB.

Published
2015
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25. Juvenile Moyamoya and Craniosynostosis in a Child with Deletion 1p32p31: Expanding the Clinical Spectrum of 1p32p31 Deletion Syndrome and a Review of the Literature

Author

Paolo Prontera, Daniela Rogaia, Amedea Mencarelli, Valentina Ottaviani, Ester Sallicandro, Giorgio Guercini, Susanna Esposito, Anna Bersano, Giuseppe Merla, and Gabriela Stangoni

Subjects
1p32p31 deletion, moyamoya syndrome, craniosynostosis, FOXD3, FOXC1, FOX genes, Biology (General), QH301-705.5, Chemistry, QD1-999
Abstract

Moyamoya angiopathy (MA) is a rare cerebrovascular disorder characterised by the progressive occlusion of the internal carotid artery. Its aetiology is uncertain, but a genetic background seems likely, given the high MA familial rate. To investigate the aetiology of craniosynostosis and juvenile moyamoya in a 14-year-old male patient, we performed an array-comparative genomic hybridisation revealing a de novo interstitial deletion of 8.5 Mb in chromosome region 1p32p31. The deletion involved 34 protein coding genes, including NF1A, whose haploinsufficiency is indicated as being mainly responsible for the 1p32-p31 chromosome deletion syndrome phenotype (OMIM 613735). Our patient also has a deleted FOXD3 of the FOX gene family of transcription factors, which plays an important role in neural crest cell growth and differentiation. As the murine FOXD3−/− model shows craniofacial anomalies and abnormal common carotid artery morphology, it can be hypothesised that FOXD3 is involved in the pathogenesis of the craniofacial and vascular defects observed in our patient. In support of our assumption, we found in the literature another patient with a syndromic form of MA who had a deletion involving another FOX gene (FOXC1). In addition to describing the clinical history of our patient, we have reviewed all of the available literature concerning other patients with a 1p32p31 deletion, including cases from the Decipher database, and we have also reviewed the genetic disorders associated with MA, which is a useful guide for the diagnosis of syndromic form of MA.

Published
2017
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26. Associations between genetic polymorphisms in IL-33, IL1R1 and risk for inflammatory bowel disease.

Author

Anna Latiano, Orazio Palmieri, Luca Pastorelli, Maurizio Vecchi, Theresa T Pizarro, Fabrizio Bossa, Giuseppe Merla, Bartolomeo Augello, Tiziana Latiano, Giuseppe Corritore, Alessia Settesoldi, Maria Rosa Valvano, Renata D'Incà, Laura Stronati, Vito Annese, and Angelo Andriulli

Subjects
Medicine, Science
Abstract

BackgroundRecent evidence suggests that the IL-33/IL1RL1 axis plays a critical role in several autoimmune and inflammatory disorders; however, its mechanistic role in inflammatory bowel disease (IBD) has not been clearly defined. We investigated the contribution of IL-33 and IL1RL1 polymorphisms to IBD risk, and possible correlations with phenotype in an Italian cohort of adult and pediatric patients.MethodsWe evaluated the association of six SNPs in IL-33 and IL1RL1 genes, in 805 Crohn's disease (CD), 816 ulcerative colitis (UC), and 752 controls, using Taqman. IL-33 and IL1RL1 mRNA expression was also analyzed.ResultsSignificant allele and genotype associations with IL-33 rs3939286 were found in CD (P = 0.004; P = 0.035) and UC patients (P = 0.002; P = 0.038). After stratifying the cohort for age at diagnosis, the differences remained significant only in the IBD adult-onset. Significant associations were also obtained in CD patients with two IL1RL1 polymorphisms (rs13015714 and rs2058660, PConclusionsCommon IL-33 and IL1RL1 polymorphisms contribute to the risk of IBD in an Italian cohort of adult and pediatric patients, with some influence on sub-phenotypes.

Published
2013
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27. A fish-specific transposable element shapes the repertoire of p53 target genes in zebrafish.

Author

Lucia Micale, Maria Nicla Loviglio, Marta Manzoni, Carmela Fusco, Bartolomeo Augello, Eugenia Migliavacca, Grazia Cotugno, Eugenio Monti, Giuseppe Borsani, Alexandre Reymond, and Giuseppe Merla

Subjects
Medicine, Science
Abstract

Transposable elements, as major components of most eukaryotic organisms' genomes, define their structural organization and plasticity. They supply host genomes with functional elements, for example, binding sites of the pleiotropic master transcription factor p53 were identified in LINE1, Alu and LTR repeats in the human genome. Similarly, in this report we reveal the role of zebrafish (Danio rerio) EnSpmN6_DR non-autonomous DNA transposon in shaping the repertoire of the p53 target genes. The multiple copies of EnSpmN6_DR and their embedded p53 responsive elements drive in several instances p53-dependent transcriptional modulation of the adjacent gene, whose human orthologs were frequently previously annotated as p53 targets. These transposons define predominantly a set of target genes whose human orthologs contribute to neuronal morphogenesis, axonogenesis, synaptic transmission and the regulation of programmed cell death. Consistent with these biological functions the orthologs of the EnSpmN6_DR-colonized loci are enriched for genes expressed in the amygdala, the hippocampus and the brain cortex. Our data pinpoint a remarkable example of convergent evolution: the exaptation of lineage-specific transposons to shape p53-regulated neuronal morphogenesis-related pathways in both a hominid and a teleost fish.

Published
2012
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28. The E3-ubiquitin ligase TRIM50 interacts with HDAC6 and p62, and promotes the sequestration and clearance of ubiquitinated proteins into the aggresome.

Author

Carmela Fusco, Lucia Micale, Mikhail Egorov, Maria Monti, Ester Valentina D'Addetta, Bartolomeo Augello, Flora Cozzolino, Alessia Calcagnì, Andrea Fontana, Roman S Polishchuk, Gerard Didelot, Alexandre Reymond, Piero Pucci, and Giuseppe Merla

Subjects
Medicine, Science
Abstract

In this study we report that, in response to proteasome inhibition, the E3-Ubiquitin ligase TRIM50 localizes to and promotes the recruitment and aggregation of polyubiquitinated proteins to the aggresome. Using Hdac6-deficient mouse embryo fibroblasts (MEF) we show that this localization is mediated by the histone deacetylase 6, HDAC6. Whereas Trim50-deficient MEFs allow pinpointing that the TRIM50 ubiquitin-ligase regulates the clearance of polyubiquitinated proteins localized to the aggresome. Finally we demonstrate that TRIM50 colocalizes, interacts with and increases the level of p62, a multifunctional adaptor protein implicated in various cellular processes including the autophagy clearance of polyubiquitinated protein aggregates. We speculate that when the proteasome activity is impaired, TRIM50 fails to drive its substrates to the proteasome-mediated degradation, and promotes their storage in the aggresome for successive clearance.

Published
2012
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29. Influence of pentraxin 3 (PTX3) genetic variants on myocardial infarction risk and PTX3 plasma levels.

Author

Elisa Barbati, Claudia Specchia, Massimo Villella, Marco Luciano Rossi, Simona Barlera, Barbara Bottazzi, Luisa Crociati, Carmela d'Arienzo, Raffaele Fanelli, Cecilia Garlanda, Francesca Gori, Ruggiero Mango, Alberto Mantovani, Giuseppe Merla, Enrico B Nicolis, Silvia Pietri, Patrizia Presbitero, Yukio Sudo, Alessandro Villella, and Maria Grazia Franzosi

Subjects
Medicine, Science
Abstract

PTX3 is a long pentraxin of the innate immune system produced by different cell types (mononuclear phagocytes, dendritic cells, fibroblasts and endothelial cells) at the inflammatory site. It appears to have a cardiovascular protective function by acting on the immune-inflammatory balance in the cardiovascular system. PTX3 plasma concentration is an independent predictor of mortality in patients with acute myocardial infarction (AMI) but the influence of PTX3 genetic variants on PTX3 plasma concentration has been investigated very little and there is no information on the association between PTX3 variations and AMI. Subjects of European origin (3245, 1751 AMI survivors and 1494 controls) were genotyped for three common PTX3 polymorphisms (SNPs) (rs2305619, rs3816527, rs1840680). Genotype and allele frequencies of the three SNPs and the haplotype frequencies were compared for the two groups. None of the genotypes, alleles or haplotypes were significantly associated with the risk of AMI. However, analysis adjusted for age and sex indicated that the three PTX3 SNPs and the corresponding haplotypes were significantly associated with different PTX3 plasma levels. There was also a significant association between PTX3 plasma concentrations and the risk of all-cause mortality at three years in AMI patients (OR 1.10, 95% CI: 1.01-1.20, p = 0.02). Our study showed that PTX3 plasma levels are influenced by three PTX3 polymorphisms. Genetically determined high PTX3 levels do not influence the risk of AMI, suggesting that the PTX3 concentration itself is unlikely to be even a modest causal factor for AMI. Analysis also confirmed that PTX3 is a prognostic marker after AMI.

Published
2012
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30. Using transcription modules to identify expression clusters perturbed in Williams-Beuren syndrome.

Author

Charlotte N Henrichsen, Gábor Csárdi, Marie-Thérèse Zabot, Carmela Fusco, Sven Bergmann, Giuseppe Merla, and Alexandre Reymond

Subjects
Biology (General), QH301-705.5
Abstract

The genetic dissection of the phenotypes associated with Williams-Beuren Syndrome (WBS) is advancing thanks to the study of individuals carrying typical or atypical structural rearrangements, as well as in vitro and animal studies. However, little is known about the global dysregulations caused by the WBS deletion. We profiled the transcriptomes of skin fibroblasts from WBS patients and compared them to matched controls. We identified 868 differentially expressed genes that were significantly enriched in extracellular matrix genes, major histocompatibility complex (MHC) genes, as well as genes in which the products localize to the postsynaptic membrane. We then used public expression datasets from human fibroblasts to establish transcription modules, sets of genes coexpressed in this cell type. We identified those sets in which the average gene expression was altered in WBS samples. Dysregulated modules are often interconnected and share multiple common genes, suggesting that intricate regulatory networks connected by a few central genes are disturbed in WBS. This modular approach increases the power to identify pathways dysregulated in WBS patients, thus providing a testable set of additional candidates for genes and their interactions that modulate the WBS phenotypes.

Published
2011
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31. PIGN encephalopathy: Characterizing the epileptology

Author

Allan Bayat, Guillem de Valles‐Ibáñez, Manuela Pendziwiat, Alexej Knaus, Kerstin Alt, Elisa Biamino, Annette Bley, Sophie Calvert, Patrick Carney, Alfonso Caro‐Llopis, Berten Ceulemans, Janice Cousin, Suzanne Davis, Vincent des Portes, Patrick Edery, Eleina England, Carlos Ferreira, Jeremy Freeman, Blanca Gener, Magali Gorce, Delphine Heron, Michael S. Hildebrand, Aleksandra Jezela‐Stanek, Pierre‐Simon Jouk, Boris Keren, Katja Kloth, Gerhard Kluger, Marius Kuhn, Johannes R. Lemke, Hong Li, Francisco Martinez, Caroline Maxton, Heather C. Mefford, Giuseppe Merla, Hanna Mierzewska, Alison Muir, Sandra Monfort, Joost Nicolai, Jennifer Norman, Gina O'Grady, Barbara Oleksy, Carmen Orellana, Laura Elena Orec, Charlotte Peinhardt, Ewa Pronicka, Monica Rosello, Fernando Santos‐Simarro, Eva Maria Christina Schwaibold, Alexander P. A. Stegmann, Constance T. Stumpel, Elzbieta Szczepanik, Iwona Terczyńska, Julien Thevenon, Andreas Tzschach, Patrick Van Bogaert, Roberta Vittorini, Sonja Walsh, Sarah Weckhuysen, Barbara Weissman, Lynne Wolfe, Alexandre Reymond, Pasquelena De Nittis, Annapurna Poduri, Heather Olson, Pasquale Striano, Gaetan Lesca, Ingrid E. Scheffer, Rikke S. Møller, Lynette G. Sadleir, RS: MHeNs - R1 - Cognitive Neuropsychiatry and Clinical Neuroscience, Klinische Neurowetenschappen, MUMC+: MA Med Staf Spec Neurologie (9), and MUMC+: DA KG Lab Specialisten (9)

Subjects
Epilepsy/diagnostic imaging, Drug Resistant Epilepsy, PROTEINS, Electroencephalography, Intellectual Disability/diagnostic imaging, HYPOTONIA-SEIZURES SYNDROME, PHENOTYPE, congenital disorder of glycosylation, CONGENITAL-ANOMALIES, Phenotype, Neurology, Seizures, intellectual disability, Humans, epilepsy, Female, Human medicine, Neurology (clinical), developmental and epileptic encephalopathy, PRENATAL-DIAGNOSIS, Seizures/genetics, GPI-anchoring disorder, MUTATION
Abstract

OBJECTIVE: Epilepsy is common in patients with PIGN diseases due to biallelic variants; however, limited epilepsy phenotyping data have been reported. We describe the epileptology of PIGN encephalopathy. METHODS: We recruited patients with epilepsy due to biallelic PIGN variants and obtained clinical data regarding age at seizure onset/offset and semiology, development, medical history, examination, electroencephalogram, neuroimaging, and treatment. Seizure and epilepsy types were classified. RESULTS: Twenty six patients (13 female) from 26 families were identified, with mean age 7 years (range = 1 month to 21 years; three deceased). Abnormal development at seizure onset was present in 25 of 26. Developmental outcome was most frequently profound (14/26) or severe (11/26). Patients presented with focal motor (12/26), unknown onset motor (5/26), focal impaired awareness (1/26), absence (2/26), myoclonic (2/26), myoclonic-atonic (1/26), and generalized tonic-clonic (2/26) seizures. Twenty of 26 were classified as developmental and epileptic encephalopathy (DEE): 55% (11/20) focal DEE, 30% (6/20) generalized DEE, and 15% (3/20) combined DEE. Six had intellectual disability and epilepsy (ID+E): two generalized and four focal epilepsy. Mean age at seizure onset was 13 months (birth to 10 years), with a lower mean onset in DEE (7 months) compared with ID+E (33 months). Patients with DEE had drug-resistant epilepsy, compared to 4/6 ID+E patients, who were seizure-free. Hyperkinetic movement disorder occurred in 13 of 26 patients. Twenty-seven of 34 variants were novel. Variants were truncating (n = 7), intronic and predicted to affect splicing (n = 7), and missense or inframe indels (n = 20, of which 11 were predicted to affect splicing). Seven variants were recurrent, including p.Leu311Trp in 10 unrelated patients, nine with generalized seizures, accounting for nine of the 11 patients in this cohort with generalized seizures. SIGNIFICANCE: PIGN encephalopathy is a complex autosomal recessive disorder associated with a wide spectrum of epilepsy phenotypes, typically with substantial profound to severe developmental impairment.

Published
2022

32. Supplementary Table s1 from AQP4 Aggregation State Is a Determinant for Glioma Cell Fate

Author

Grazia P. Nicchia, Maria Svelto, Angelo L. Vescovi, Antonio Frigeri, Lucia Micale, Giuseppe Merla, Manuela De Bellis, Maria G. Mola, Francesco Pisani, and Laura Simone

Abstract

Supplementary Table s1. M23-AQP4 mutants. Mutant names, WT and mutated amino acid sequences, position and references are reported. The amino acid positions refer to M1-AQP4.

Published
2023

33. Data from AQP4 Aggregation State Is a Determinant for Glioma Cell Fate

Author

Grazia P. Nicchia, Maria Svelto, Angelo L. Vescovi, Antonio Frigeri, Lucia Micale, Giuseppe Merla, Manuela De Bellis, Maria G. Mola, Francesco Pisani, and Laura Simone

Abstract

The glial water channel protein aquaporin-4 (AQP4) forms heterotetramers in the plasma membrane made of the M23-AQP4 and M1-AQP4 isoforms. The isoform ratio controls AQP4 aggregation into supramolecular structures called orthogonal arrays of particles (AQP4-OAP). The role of AQP4 aggregation into OAP in malignant gliomas is still unclear. In this study, we demonstrate that AQP4 aggregation/disaggregation into OAP influences the biology of glioma cells. Selective expression of the OAP-forming isoform M23-AQP4 (AQP4-OAP) triggered cell shape changes in glioma cells associated with alterations to the F-actin cytoskeleton that affected apoptosis. By contrast, expression of M1-AQP4 (AQP4-tetramers), which is unable to aggregate into OAP, ameliorated glioma cell invasiveness, improved cell migration, and increased methalloproteinase-9 activity. Two prolines (254 and 296) at the C-terminus tail were shown to be important in mediating the relationship between the actin cytoskeleton and AQP4-OAP and AQP4-tetramers. In conclusion, this study demonstrates that AQP4 aggregation state might be an important determinant in orienting glioma cells to persist or perish. AQP4 disaggregation may potentiate invasiveness potential, whereas AQP4 aggregation may activate the apoptotic path. This study shows a new perspective on the role of AQP4 in brain tumors not necessarily associated with edema formation but with AQP4 aggregation/disaggregation dynamics and their link with the actin cytoskeleton.Significance:This study demonstrates how AQP4 aggregation influences plasma membrane dynamics to alter cell proliferation, invasiveness, migration, and apoptotic potential in glioma cells.

Published
2023

34. Supplementary Figure s1 from AQP4 Aggregation State Is a Determinant for Glioma Cell Fate

Author

Grazia P. Nicchia, Maria Svelto, Angelo L. Vescovi, Antonio Frigeri, Lucia Micale, Giuseppe Merla, Manuela De Bellis, Maria G. Mola, Francesco Pisani, and Laura Simone

Abstract

Supplementary Figure s1. M23-AQP4 C-terminus analysis for the ability to induce morphological changes in glioma cells. a) Schematic representation of the untagged and mCherry-tagged M23-AQP4 isoforms used for the analysis in (b). b) Immuno fluorescence analysis of U87 and U251 cells transfected with tagged and untagged M23-AQP4 isoforms. AQP4 (red) and Phallodin (green) to visualize F-actin. No morphological changes were induced by M23-AQP4 when M23-AQP4 with mCherry tagged C-terminus was used. Scale bar 50 µm. c) Quantification analysis of morphological alterations observed in the experiments described in (a). The histobar shows the percentage of cells with altered morphology. Values are expressed as mean {plus minus} SEM of % of cells with altered cell morphology on the total number of transfected cells per field (**** P

Published
2023

35. Ultra-rare RTEL1 gene variants associate with acute severity of COVID-19 and evolution to pulmonary fibrosis as a specific long COVID disorder

Author

Bergantini, Laura, Baldassarri, Margherita, D'Alessandro, Miriana, Brunelli, Giulia, Fabbri, Gaia, Zguro, Kristina, Degl'Innocenti, Andrea, Fallerini, Chiara, Bargagli, Elena, Renieri, Alessandra GEN-COVID Multicenter study: Francesca Mari, Sergio, Daga, Ilaria, Meloni, Mirella, Bruttini, Susanna, Croci, Mirjam, Lista, Debora, Maffeo, Elena, Pasquinelli, Viola Bianca Serio, Enrica, Antolini, Simona Letizia Basso, Samantha, Minetto, Rossella, Tita, Maria Antonietta Mencarelli, Caterina Lo Rizzo, Anna Maria Pinto, Francesca, Ariani, Francesca, Montagnani, Mario, Tumbarello, Ilaria, Rancan, Massimiliano, Fabbiani, 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, Arianna, Emiliozzi, 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, Maria, Lorubbio, Alessandro, Pancrazzi, Massimo, Vaghi, Antonella, D 'Arminio Monforte, Federica Gaia Miraglia, Mario, U Mondelli, Stefania, Mantovani, Raffaele, Bruno, Marco, Vecchia, Marcello, Maffezzoni, Enrico, Martinelli, Massimo, Girardis, Stefano, Busani, Sophie, Venturelli, Andrea, Cossarizza, Andrea, Antinori, Alessandra, Vergori, Stefano, Rusconi, Matteo, Siano, Arianna, Gabrieli, Agostino, Riva, Daniela, Francisci, Elisabetta, Schiaroli, Carlo, Pallotto, Saverio Giuseppe Parisi, Monica, Basso, Sandro, Panese, Stefano, Baratti, Pier Giorgio Scotton, Francesca, Andretta, Mario, Giobbia, Renzo, Scaggiante, Francesca, Gatti, 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, Giuseppe, Merla, Gabriella Maria Squeo, Filippo, Aucella, Pamela, Raggi, Rita, Perna, Matteo, Bassetti, Antonio Di Biagio, Maurizio, Sanguinetti, Luca, Masucci, Alessandra, Guarnaccia, Serafina, Valente, Alex Di Florio, Marco, Mandalà, Alessia, Giorli, Lorenzo, Salerni, Patrizia, Zucchi, Pierpaolo, Parravicini, Elisabetta, Menatti, Tullio, Trotta, Ferdinando, Giannattasio, Gabriella, Coiro, Fabio, Lena, Gianluca, Lacerenza, Cristina, Mussini, Luisa, Tavecchia, Lia, Crotti, Gianfranco, Parati, Roberto, Menè, Maurizio, Sanarico, Marco, Gori, Francesco, Raimondi, Alessandra, Stella, Filippo, Biscarini, Tiziana, Bachetti, Maria Teresa La Rovere, Maurizio, Bussotti, Serena, Ludovisi, Katia, Capitani, Simona, Dei, Sabrina, Ravaglia, Annarita, Giliberti, Giulia, Gori, Rosangela, Artuso, Elena, Andreucci, 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, Micheli, Giulia, Marco, Falcone, Donato, Urso, Giusy, Tiseo, 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, Alessio, Bellucci, Marta, Colaneri, Patrizia, Casprini, Cristoforo, Pomara, Massimiliano, Esposito, Roberto, Leoncini, Michele, Cirianni, Lucrezia, Galasso, Marco Antonio Bellini, Chiara, Gabbi, Nicola, Picchiotti, and Simone, Furini

Subjects
COVID-19, Long COVID, Pulmonary fibrosis, RTEL1
Published
2023

36. Novel biallelic variants expand the phenotype of NAA20-related syndrome

Author

Gianluca D'Onofrio, Claudia Cuccurullo, Silje Kathrine Larsen, Mariasavina Severino, Alessandra D'Amico, Kirsten Brønstad, Mohammed AlOwain, Jennifer L. Morrison, Patricia G. Wheeler, Bryn D. Webb, Abdullah Alfalah, Michele Iacomino, Paolo Uva, Antonietta Coppola, Giuseppe Merla, Vincenzo Damiano Salpietro, Federico Zara, Pasquale Striano, Andrea Accogli, Thomas Arnesen, Leonilda Bilo, D'Onofrio, Gianluca, Cuccurullo, Claudia, Larsen, Silje Kathrine, Severino, Mariasavina, D'Amico, Alessandra, Brønstad, Kirsten, Alowain, Mohammed, Morrison, Jennifer L, Wheeler, Patricia G, Webb, Bryn D, Alfalah, Abdullah, Iacomino, Michele, Uva, Paolo, Coppola, Antonietta, Merla, Giuseppe, Salpietro, Vincenzo Damiano, Zara, Federico, Striano, Pasquale, Accogli, Andrea, Arnesen, Thoma, and Bilo, Leonilda

Subjects
acetyltransferase, N-terminal acetylation, NAA20, Genetics, NatB, neurodevelopmental disorder, Genetics (clinical)
Abstract

NAA20 is the catalytic subunit of the NatB complex, which is responsible for N-terminal acetylation of approximately 20% of the human proteome. Recently, pathogenic biallelic variants in NAA20 were associated with a novel neurodevelopmental disorder in five individuals with limited clinical information. We report two sisters harboring compound heterozygous variant (c.100C>T (p.Gln34Ter) and c.11T>C p.(Leu4Pro)) in the NAA20 gene, identified by exome sequencing. In vitro studies showed that the missense variant p.Leu4Pro resulted in a reduction of NAA20 catalytic activity due to weak coupling with the NatB auxiliary subunit. In addition, unpublished data of the previous families were reported, outlining the core phenotype of the NAA20-related disorder mostly characterized by cognitive impairment, microcephaly, ataxia, brain malformations, dysmorphism and variable occurrence of cardiac defect and epilepsy. Remarkably, our two patients featured epilepsy onset in adolescence suggesting this may be a part of syndrome evolution. Functional studies are needed to better understand the complexity of NAA20 variants pathogenesis as well as of other genes linked to N-terminal acetylation.

Published
2023

37. Functional correlation of genome-wide DNA methylation profiles in genetic neurodevelopmental disorders

Author

Michael A. Levy, Raissa Relator, Haley McConkey, Erinija Pranckeviciene, Jennifer Kerkhof, Mouna Barat‐Houari, Sara Bargiacchi, Elisa Biamino, María Palomares Bralo, Gerarda Cappuccio, Andrea Ciolfi, Angus Clarke, Barbara R. DuPont, Mariet W. Elting, Laurence Faivre, Timothy Fee, Marco Ferilli, Robin S. Fletcher, Florian Cherick, Aidin Foroutan, Michael J. Friez, Cristina Gervasini, Sadegheh Haghshenas, Benjamin A. Hilton, Zandra Jenkins, Simranpreet Kaur, Suzanne Lewis, Raymond J. Louie, Silvia Maitz, Donatella Milani, Angela T. Morgan, Renske Oegema, Elsebet Østergaard, Nathalie R. Pallares, Maria Piccione, Astrid S. Plomp, Cathryn Poulton, Jack Reilly, Rocio Rius, Stephen Robertson, Kathleen Rooney, Justine Rousseau, Gijs W. E. Santen, Fernando Santos‐Simarro, Josephine Schijns, Gabriella M. Squeo, Miya St John, Christel Thauvin‐Robinet, Giovanna Traficante, Pleuntje J. van der Sluijs, Samantha A. Vergano, Niels Vos, Kellie K. Walden, Dimitar Azmanov, Tugce B. Balci, Siddharth Banka, Jozef Gecz, Peter Henneman, Jennifer A. Lee, Marcel M. A. M. Mannens, Tony Roscioli, Victoria Siu, David J. Amor, Gareth Baynam, Eric G. Bend, Kym Boycott, Nicola Brunetti‐Pierri, Philippe M. Campeau, Dominique Campion, John Christodoulou, David Dyment, Natacha Esber, Jill A. Fahrner, Mark D. Fleming, David Genevieve, Delphine Heron, Thomas Husson, Kristin D. Kernohan, Alisdair McNeill, Leonie A. Menke, Giuseppe Merla, Paolo Prontera, Cheryl Rockman‐Greenberg, Charles Schwartz, Steven A. Skinner, Roger E. Stevenson, Marie Vincent, Antonio Vitobello, Marco Tartaglia, Marielle Alders, Matthew L. Tedder, Bekim Sadikovic, Human genetics, Amsterdam Reproduction & Development (AR&D), Pediatrics, Levy M.A., Relator R., McConkey H., Pranckeviciene E., Kerkhof J., Barat-Houari M., Bargiacchi S., Biamino E., Palomares Bralo M., Cappuccio G., Ciolfi A., Clarke A., DuPont B.R., Elting M.W., Faivre L., Fee T., Ferilli M., Fletcher R.S., Cherick F., Foroutan A., Friez M.J., Gervasini C., Haghshenas S., Hilton B.A., Jenkins Z., Kaur S., Lewis S., Louie R.J., Maitz S., Milani D., Morgan A.T., Oegema R., Ostergaard E., Pallares N.R., Piccione M., Plomp A.S., Poulton C., Reilly J., Rius R., Robertson S., Rooney K., Rousseau J., Santen G.W.E., Santos-Simarro F., Schijns J., Squeo G.M., John M.S., Thauvin-Robinet C., Traficante G., van der Sluijs P.J., Vergano S.A., Vos N., Walden K.K., Azmanov D., Balci T.B., Banka S., Gecz J., Henneman P., Lee J.A., Mannens M.M.A.M., Roscioli T., Siu V., Amor D.J., Baynam G., Bend E.G., Boycott K., Brunetti-Pierri N., Campeau P.M., Campion D., Christodoulou J., Dyment D., Esber N., Fahrner J.A., Fleming M.D., Genevieve D., Heron D., Husson T., Kernohan K.D., McNeill A., Menke L.A., Merla G., Prontera P., Rockman-Greenberg C., Schwartz C., Skinner S.A., Stevenson R.E., Vincent M., Vitobello A., Tartaglia M., Alders M., Tedder M.L., Sadikovic B., Levy, Michael A, Relator, Raissa, Mcconkey, Haley, Pranckeviciene, Erinija, Kerkhof, Jennifer, Barat-Houari, Mouna, Bargiacchi, Sara, Biamino, Elisa, Bralo, María Palomare, Cappuccio, Gerarda, Ciolfi, Andrea, Clarke, Angu, Dupont, Barbara R, Elting, Mariet W, Faivre, Laurence, Fee, Timothy, Ferilli, Marco, Fletcher, Robin S, Cherick, Florian, Foroutan, Aidin, Friez, Michael J, Gervasini, Cristina, Haghshenas, Sadegheh, Hilton, Benjamin A, Jenkins, Zandra, Kaur, Simranpreet, Lewis, Suzanne, Louie, Raymond J, Maitz, Silvia, Milani, Donatella, Morgan, Angela T, Oegema, Renske, Østergaard, Elsebet, Pallares, Nathalie Ruiz, Piccione, Maria, Plomp, Astrid S, Poulton, Cathryn, Reilly, Jack, Rius, Rocio, Robertson, Stephen, Rooney, Kathleen, Rousseau, Justine, Santen, Gijs W E, Santos-Simarro, Fernando, Schijns, Josephine, Squeo, Gabriella Maria, John, Miya St, Thauvin-Robinet, Christel, Traficante, Giovanna, van der Sluijs, Pleuntje J, Vergano, Samantha A, Vos, Niel, Walden, Kellie K, Azmanov, Dimitar, Balci, Tugce B, Banka, Siddharth, Gecz, Jozef, Henneman, Peter, Lee, Jennifer A, Mannens, Marcel M A M, Roscioli, Tony, Siu, Victoria, Amor, David J, Baynam, Gareth, Bend, Eric G, Boycott, Kym, Brunetti-Pierri, Nicola, Campeau, Philippe M, Campion, Dominique, Christodoulou, John, Dyment, David, Esber, Natacha, Fahrner, Jill A, Fleming, Mark D, Genevieve, David, Heron, Delphine, Husson, Thoma, Kernohan, Kristin D, Mcneill, Alisdair, Menke, Leonie A, Merla, Giuseppe, Prontera, Paolo, Rockman-Greenberg, Cheryl, Schwartz, Charle, Skinner, Steven A, Stevenson, Roger E, Vincent, Marie, Vitobello, Antonio, Tartaglia, Marco, Alders, Marielle, Tedder, Matthew L, Sadikovic, Bekim, Human Genetics, General Paediatrics, Graduate School, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, ARD - Amsterdam Reproduction and Development, ANS - Cellular & Molecular Mechanisms, ANS - Complex Trait Genetics, and ACS - Pulmonary hypertension & thrombosis

Subjects
DNA methylation, clinical diagnostics, Syndrome, DNA methylation, clinical diagnostics, episignatures, neurodevelopmental syndromes, neurodevelopmental syndromes, Epigenesis, Genetic, Neurodevelopmental Disorders, Genetics, Humans, CpG Islands, DNA, Intergenic, episignatures, Episignature, Genetics (clinical)
Abstract

An expanding range of genetic syndromes are characterized by genome-wide disruptions in DNA methylation profiles referred to as episignatures. Episignatures are distinct, highly sensitive and specific biomarkers that have recently been applied in clinical diagnosis of genetic syndromes. Episignatures are contained within the broader disorder-specific genome-wide DNA methylation changes which can share significant overlap amongst different conditions. In this study we performed functional genomic assessment and comparison of disorder-specific and overlapping genome-wide DNA methylation changes related to 65 genetic syndromes with previously described episignatures. We demonstrate evidence of disorder-specific and recurring genome-wide differentially methylated probes (DMPs) and regions (DMRs). The overall distribution of DMPs and DMRs across the majority of the neurodevelopmental genetic syndromes analyzed showed substantial enrichment in gene promoters and CpG islands, and under-representation of the more variable intergenic regions. Analysis showed significant enrichment of the DMPs and DMRs in gene pathways and processes related to neurodevelopment, including neurogenesis, synaptic signaling and synaptic transmission. This study expands beyond the diagnostic utility of DNA methylation episignatures by demonstrating correlation between the function of the mutated genes and the consequent genomic DNA methylation profiles as a key functional element in the molecular etiology of genetic neurodevelopmental disorders. This article is protected by copyright. All rights reserved.

Published
2022

38. Clinical heterogeneity of Kabuki syndrome in a cohort of Italian patients and review of the literature

Author

Mariateresa Falco, Pietro Strisciuglio, Ilaria De Maggio, Fortunato Lonardo, Daniela Melis, Gabriella Maria Squeo, Giuseppe Merla, Gerarda Cappuccio, Gioacchino Scarano, Carmen Rosano, Maria Siano, Claudia Mandato, Carmelo Piscopo, Paolo Fontana, Francesca Di Candia, P. Paglia, Daniele De Brasi, Matteo Della Monica, Di Candia, Francesca, Fontana, Paolo, Paglia, Pamela, Falco, Mariateresa, Rosano, Carmen, Piscopo, Carmelo, Cappuccio, Gerarda, Siano, Maria Anna, De Brasi, Daniele, Mandato, Claudia, De Maggio, Ilaria, Squeo, Gabriella Maria, Monica, Matteo Della, Scarano, Gioacchino, Lonardo, Fortunato, Strisciuglio, Pietro, Merla, Giuseppe, and Melis, Daniela

Subjects
0301 basic medicine, Adult, Male, Microcephaly, Pediatrics, medicine.medical_specialty, Adolescent, Neurological features, Autoimmunity, Vitiligo, 030105 genetics & heredity, Brain anomalie, 03 medical and health sciences, Young Adult, Intellectual disability, Medicine, Humans, Brain anomalies, Kabuki syndrome, Child, Face, Female, Retrospective Studies, Abnormalities, Multiple, Hematologic Diseases, Vestibular Diseases, Hypertelorism, Strabismus, Immunodeficiency, business.industry, medicine.disease, 030104 developmental biology, Pediatrics, Perinatology and Child Health, Cohort, Original Article, medicine.symptom, Abnormalities, business, Multiple
Abstract

Kabuki syndrome (KS) is a well-recognized disorder characterized by postnatal growth deficiency, dysmorphic facial features, skeletal anomalies, and intellectual disability. The syndrome is caused by KMT2D gene mutations or less frequently KDM6A gene mutations or deletions. We report a systematic evaluation of KS patients from Campania region of Italy; data were also compared with literature ones. We collected data of 15 subjects (8 males and 7 females with age range 10–26 years; mean age 16.9 years) with confirmed diagnosis of KS, representing the entire cohort of patients from Campania Region. Each patient performed biochemical testing and instrumental investigation. Neuro-intellectual development, cranio-facial dysmorphisms, and multisystem involvement data were collected retrospectively. For each category, type of defects and frequency of the anomalies were analyzed. Our observation shows that KS patients from Campania region have some particular and previously underscored, neurological and immunological findings. We found high prevalence of EEG’s abnormalities (43%) and MRI brain abnormalities (60%). Microcephaly resulted more common in our series (33%), if compared with major cohorts described in literature. Biochemical features of immunodeficiency and autoimmune diseases including thyroid autoimmunity, polyserositis, and vitiligo were observed with high prevalence (54.5%). Low immunoglobulins levels were a frequent finding. Lymphocyte class investigation showed significantly reduced CD8 levels in one patient.Conclusions: These data confirm great heterogeneity of clinical manifestations in KS and suggest to introduce further clinical diagnostic criteria in order to perform a correct and precocious diagnosis. What is Known• Kabuki syndrome is characterized by growth deficiency, dysmorphic facial features, skeletal anomalies, and intellectual disability• Immune dysfunction is a common finding but autoimmune diseases are rarely seen• Neurological features are common What is New• Some particular facial features could help gestalt diagnosis (hypertelorism, broad nasal bridge, micrognathia, tooth agenesis, cutaneous haemangiomas and strabismus)• Higher prevalence of autoimmune disorders than previously reported• Particular neurological features are present in this cohort (EEG and MRI brain abnormalities)

Published
2021

39. Carriers of ADAMTS13 Rare Variants Are at High Risk of Life-Threatening COVID-19

Author

Zguro, Kristina, Baldassarri, Margherita, Fava, Francesca, Beligni, Giada, Daga, Sergio, Leoncini, Roberto, Galasso, Lucrezia, Cirianni, Michele, Rusconi, Stefano, Siano, Matteo, Francisci, Daniela, Schiaroli, Elisabetta, Luchi, Sauro, Morelli, Giovanna, Martinelli, Enrico, Girardis, Massimo, Busani, Stefano, Parisi, Saverio Giuseppe, Panese, Sandro, Piscopo, Carmelo, Capasso, Mario, Tacconi, Danilo, Spertilli Raffaelli, Chiara, Giliberti, Annarita, Gori, Giulia, Katsikis, Peter D, Lorubbio, Maria, Calzoni, Paola, Ognibene, Agostino, Bocchia, Monica, Tozzi, Monica, Bucalossi, Alessandro, Marotta, Giuseppe, Furini, Simone, Gen-Covid Multicenter Study, Null, Renieri, Alessandra, Fallerini, Chiara, GEN-COVID Multicenter Study, Mari, Francesca, Bruttini, Mirella, Meloni, Ilaria, Croci, Susanna, Gabriella, Doddato, Serio, VIOLA BIANCA, Mirjam, Lista, Maffeo, Debora, Pasquinelli, Elena, Ludovica, Mercuri, Brunelli, Giulia, Rossella, Tita, Maria Antonietta Mencarelli, LO RIZZO, Caterina, Pinto, ANNA MARIA, Ariani, Francesca, Montagnani, Francesca, Tumbarello, Mario, Ilaria, Rancan, Massimiliano, Fabbiani, Bargagli, Elena, Bergantini, Laura, D'Alessandro, Miriana, Cameli, Paolo, Bennett, David, Federico, Anedda, Simona, Marcantonio, Scolletta, Sabino, Franchi, Federico, Mazzei, MARIA ANTONIETTA, Susanna, Guerrini, Edoardo, Conticini, Cantarini, Luca, Frediani, Bruno, 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, Alessandro, Pancrazzi, Massimo, Vaghi, Antonella D’Arminio Monforte, Federica Gaia Miraglia, Mondelli, Mario U., Stefania, Mantovani, Raffaele, Bruno, Marco, Vecchia, Marcello, Maffezzoni, Sophie, Venturelli, Andrea, Cossarizza, Andrea, Antinori, Alessandra, Vergori, Arianna, Emiliozzi, Arianna, Gabrieli, Agostino, Riva, Andrea, Tommasi, Pier Giorgio Scotton, Francesca, Andretta, Stefano, Baratti, Renzo, Scaggiante, Francesca, Gatti, Francesco, Castelli, Eugenia, Quiros-Roldan, Melania Degli Antoni, Isabella, Zanella, Matteo della Monica, Roberta, Russo, Immacolata, Andolfo, Achille, Iolascon, Giuseppe, Fiorentino, Massimo, Carella, Marco, Castori, Giuseppe, Merla, Gabriella Maria Squeo, Filippo, Aucella, Pamela, Raggi, Rita, Perna, Matteo, Bassetti, Antonio Di Biagio, Maurizio, Sanguinetti, Luca, Masucci, Alessandra, Guarnaccia, Valente, Serafina, Alex Di Florio, Mandala', Marco, Giorli, Alessia, Salerni, Lorenzo, Patrizia, Zucchi, Pierpaolo, Parravicini, Elisabetta, Menatti, Tullio, Trotta, Ferdinando, Giannattasio, Gabriella, Coiro, Fabio, Lena, Gianluca, Lacerenza, Cristina, Mussini, Luisa, Tavecchia, Lia, Crotti, Gianfranco, Parati, Roberto, Menè, Maurizio, Sanarico, Gori, Marco, Nicola, Picchiotti, Francesco, Raimondi, Alessandra, Stella, Filippo, Biscarini, Tiziana, Bachetti, Maria Teresa La Rovere, Maurizio, Bussotti, Serena, Ludovisi, Katia, Capitani, Chiara, Gabbi, Simona, Dei, Sabrina, Ravaglia, Rosangela, Artuso, Elena, Andreucci, Angelica, Pagliazzi, Erika, Fiorentini, Antonio, Perrella, Francesco, Bianchi, Paola, Bergomi, Emanuele, Catena, Riccardo, Colombo, Paola, Petrocelli, Sarah, Iacopini, Sara, Modica, Silvia, Baroni, Giulia, Micheli, 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, Alessio, Bellucci, Marta, Colaneri, Patrizia, Casprini, Cristoforo, Pomara, Massimiliano, Esposito, Marco Antonio Bellini, Zguro, Kristina, Baldassarri, Margherita, Fava, Francesca, Beligni, Giada, Daga, Sergio, Leoncini, Roberto, Galasso, Lucrezia, Cirianni, Michele, Rusconi, Stefano, Siano, Matteo, Francisci, Daniela, Schiaroli, Elisabetta, Luchi, Sauro, Morelli, Giovanna, Martinelli, Enrico, Girardis, Massimo, Busani, Stefano, Parisi, Saverio Giuseppe, Panese, Sandro, Piscopo, Carmelo, Capasso, Mario, Tacconi, Danilo, Spertilli Raffaelli, Chiara, Giliberti, Annarita, Gori, Giulia, Katsikis, Peter D, Lorubbio, Maria, Calzoni, Paola, Ognibene, Agostino, Bocchia, Monica, Tozzi, Monica, Bucalossi, Alessandro, Marotta, Giuseppe, Furini, Simone, Gen-Covid Multicenter Study, Null, Renieri, Alessandra, Fallerini, Chiara, Gen-Covid Multicenter Study, null, and Immunology

Subjects
Thrombotic Thrombocytopenic, Purpura, Thrombotic Thrombocytopenic, SARS-CoV-2, COVID-19, ADAMTS13, thromboembolism, add-on therapy, ADAMTS13 Protein, ADAM Proteins, Infectious Diseases, SDG 3 - Good Health and Well-being, Virology, von Willebrand Factor, Humans, Purpura
Abstract

Thrombosis of small and large vessels is reported as a key player in COVID-19 severity. However, host genetic determinants of this susceptibility are still unclear. Congenital Thrombotic Thrombocytopenic Purpura is a severe autosomal recessive disorder characterized by uncleaved ultra-large vWF and thrombotic microangiopathy, frequently triggered by infections. Carriers are reported to be asymptomatic. Exome analysis of about 3000 SARS-CoV-2 infected subjects of different severities, belonging to the GEN-COVID cohort, revealed the specific role of vWF cleaving enzyme ADAMTS13 (A disintegrin-like and metalloprotease with thrombospondin type 1 motif, 13). We report here that ultra-rare variants in a heterozygous state lead to a rare form of COVID-19 characterized by hyper-inflammation signs, which segregates in families as an autosomal dominant disorder conditioned by SARS-CoV-2 infection, sex, and age. This has clinical relevance due to the availability of drugs such as Caplacizumab, which inhibits vWF–platelet interaction, and Crizanlizumab, which, by inhibiting P-selectin binding to its ligands, prevents leukocyte recruitment and platelet aggregation at the site of vascular damage.

Published
2022

40. 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

41. Genome-wide DNA methylation profiling and exome sequencing resolved a long-time misdiagnosed case

Author

Annalisa Paparella, Gabriella Maria Squeo, Eleonora Di Venere, Erica Cardea, Tommaso Mazza, Stefano Castellana, Jennifer Kerkhof, Haley McConkey, Bekim Sadikovic, Lorenzo Sinibaldi, Maria Cristina Digilio, Giuseppe Merla, Paparella, Annalisa, Squeo, Gabriella Maria, Di Venere, Eleonora, Cardea, Erica, Mazza, Tommaso, Castellana, Stefano, Kerkhof, Jennifer, Mcconkey, Haley, Sadikovic, Bekim, Sinibaldi, Lorenzo, Digilio, Maria Cristina, and Merla, Giuseppe

Subjects
Phenotype, Vestibular Diseases, Face, Intellectual Disability, Exome Sequencing, Genetics, Humans, Abnormalities, Multiple, Exome, DNA Methylation, Diagnostic Errors, Hematologic Diseases, Genetics (clinical)
Abstract

The search for aetiology of Mendelian disorders is traditionally based on the observation of clinical phenotypes and molecular screening of associated genes. However, a disease-specific diagnosis can be challenging. In this study we detail how the combinatorial genomic and epigenomic assessment allowed to find the underlying molecular event of a clinical case that remained misdiagnosed for years. The individual was referred as affected by an atypical form of Kabuki syndrome with a variant of uncertain significance in the KMT2D gene. However, significant inconsistencies with this diagnosis emerged upon familial segregation of the variant and after the clinical re-evaluation. Therefore, we applied an epigenomic strategy by studying the DNA methylation profile which resulted not consistent with the Kabuki syndrome episignature or with any other disorder-specific episignature described so far, providing strong evidence that the Kabuki syndrome diagnosis does not apply. This result led us to further investigate for epigenetic machinery diseases by using a multigene panel for chromatinopathies. Since this analysis yielded negative results, we applied a whole exome sequencing and identified a de novo pathogenic variant in the CTNNB1 gene associated to NEDSDV syndrome, a neurodevelopmental disorder characterized by intellectual disability and craniofacial anomalies. Based on molecular results and the updated clinical features, we confirmed the NEDSDV diagnosis. Our findings show that the combination of genomic and epigenomics strategies, along with a deeper analysis of clinical phenotype, may provide a significant improvement in the diagnostic protocols for rare genetic disorders and help resolve long-time misdiagnosed and unsolved case.

Published
2022

42. A perspective on diet, epigenetics and complex diseases: where is the field headed next?

Author

Fabio Coppedè, Marica Franzago, Emiliano Giardina, Cristiana Lo Nigro, Giuseppe Matullo, Chiara Moltrasio, Benedetta Nacmias, Silvana Pileggi, Silvia Maria Sirchia, Andrea Stoccoro, Clelia Tiziana Storlazzi, Liborio Stuppia, Rossella Tricarico, and Giuseppe Merla

Subjects
Epigenomics, cancer, cardiovascular diseases, diet, epigenetics, inflammatory skin diseases, neurobehavioral disorders, neurodegenerative diseases, obesity and Type 2 diabetes, Cancer Research, DNA Methylation, Epigenesis, Genetic, Diabetes Mellitus, Type 2, Pregnancy, Genetics, Humans, Female
Abstract

Dietary factors can regulate epigenetic processes during life, modulating the intracellular pools of metabolites necessary for epigenetic reactions and regulating the activity of epigenetic enzymes. Their effects are strong during the prenatal life, when epigenetic patterns are written, allowing organogenesis. However, interactions between diet and the epigenome continue throughout life and likely contribute to the onset and progression of various complex diseases. Here, we review the contribution of dietary factors to the epigenetic changes observed in complex diseases and suggest future steps to better address this issue, focusing on neurobehavioral, neuropsychiatric and neurodegenerative disorders, cardiovascular diseases, obesity and Type 2 diabetes, cancer and inflammatory skin diseases.

Published
2022

43. DNA methylation episignature testing improves molecular diagnosis of Mendelian chromatinopathies

Author

Bekim Sadikovic, Maria Accadia, Gabriella Maria Squeo, Maria Rosaria Piemontese, Maria Piccione, Michael A. Levy, Marco Castori, Paolo Prontera, Daniela Melis, Elisa Biamino, Silvia Maitz, Haley McConkey, Angelo Selicorni, Cristina Gervasini, Matteo Della Monica, Jennifer Kerkhof, Marilena Carmela Di Giacomo, Giuseppe Merla, Donatella Milani, Kerkhof, J., Squeo, G. M., Mcconkey, H., Levy, M. A., Piemontese, M. R., Castori, M., Accadia, M., Biamino, E., Della Monica, M., Di Giacomo, M. C., Gervasini, C., Maitz, S., Melis, D., Milani, D., Piccione, M., Prontera, P., Selicorni, A., Sadikovic, B., Merla, G., Kerkhof J., Squeo G.M., McConkey H., Levy M.A., Piemontese M.R., Castori M., Accadia M., Biamino E., Della Monica M., Di Giacomo M.C., Gervasini C., Maitz S., Melis D., Milani D., Piccione M., Prontera P., Selicorni A., Sadikovic B., and Merla G.

Subjects
Chromatinopathies, DNA methylation, Epigenetics, Chromatinopathie, Biology, EPIC, DNA sequencing, symbols.namesake, medicine, Humans, Abnormalities, Multiple, Genetics (clinical), Sequence (medicine), Genetics, DNA Methylation, Genome, Hematologic Diseases, Vestibular Diseases, Epigenetic, Methylation, Hematologic Disease, medicine.disease, Chromatin, Mendelian inheritance, symbols, Abnormalities, Kabuki syndrome, Multiple, Human
Abstract

Purpose Chromatinopathies include more than 50 disorders caused by disease-causing variants of various components of chromatin structure and function. Many of these disorders exhibit unique genome-wide DNA methylation profiles, known as episignatures. In this study, the methylation profile of a large cohort of individuals with chromatinopathies was analyzed for episignature detection. Methods DNA methylation data was generated on extracted blood samples from 129 affected individuals with the Illumina Infinium EPIC arrays and analyzed using an established bioinformatic pipeline. Results The DNA methylation profiles matched and confirmed the sequence findings in both the discovery and validation cohorts. Twenty-five affected individuals carrying a variant of uncertain significance, did not show a methylation profile matching any of the known episignatures. Three additional variant of uncertain significance cases with an identified KDM6A variant were re-classified as likely pathogenic (n = 2) or re-assigned as Wolf-Hirschhorn syndrome (n = 1). Thirty of the 33 Next Generation Sequencing negative cases did not match a defined episignature while three matched Kabuki syndrome, Rubinstein-Taybi syndrome and BAFopathy respectively. Conclusion With the expanding clinical utility of the EpiSign assay, DNA methylation analysis should be considered part of the testing cascade for individuals presenting with clinical features of Mendelian chromatinopathy disorders.

Published
2022

44. A restricted spectrum of missense KMT2D variants cause a multiple malformations disorder distinct fromKabuki syndrome

Author

Karen Stals, Sara Cuvertino, Víctor Faundes, Frances Flinter, Lihadh Al-Gazali, Santina Venuto, Vagheesh M. Narasimhan, Laura Southgate, Colin A. Johnson, Eamonn Sheridan, Nisha Nair, Anne Barton, Alice Colyer, Susan J. Kimber, Brian R. Jackson, Adam Stevens, Daniel Weisberg, Natalie Canham, Giuseppe Merla, Gabriella Maria Squeo, Richard C. Trembath, Sally Ann Lynch, Fatima Nadat, Terence Garner, Robert Sellers, Sian Ellard, Muriel Holder-Espinasse, David A. van Heel, Michelle Peckham, Francesca Montanari, Siddharth Banka, Verity L. Hartill, Marco Seri, Jozef Hertecant, Cuvertino, S., Hartill, V., Colyer, A., Garner, T., Nair, N., Al-Gazali, L., Canham, N., Faundes, V. Flinter F., Hertecant, J., Holder-Espinasse, M., Jackson, B., Lynch, Sa, Nadat, F., Narasimhan, V., Peckham, M., Sellers, R., Seri, M., Montanari, F., Southgate, L., Squeo, Gm, Trembath, R., van Heel, D., Venuto, S., Weisberg, D., Stals, K., Ellard, S., The, 100, Barton, A., Kimber, S., Sheridan, E., Merla, G, Stevens, A., Johnson, Ca, Banka, S., Cuvertino S., Hartill V., Colyer A., Garner T., Nair N., Al-Gazali L., Canham N., Faundes V., Flinter F., Hertecant J., Holder-Espinasse M., Jackson B., Lynch S.A., Nadat F., Narasimhan V.M., Peckham M., Sellers R., Seri M., Montanari F., Southgate L., Squeo G.M., Trembath R., van Heel D., Venuto S., Weisberg D., Stals K., Ellard S., Barton A., Kimber S.J., Sheridan E., Merla G., Stevens A., Johnson C.A., and Banka S.

Subjects
Genetics, 0303 health sciences, Kabuki syndrome, Hearing loss, KMT2D, Choanal atresia, Biology, intrinsically disordered region, medicine.disease, Article, Human genetics, multiple congenital anomaly, 03 medical and health sciences, Exon, 0302 clinical medicine, 030220 oncology & carcinogenesis, DNA methylation, medicine, Missense mutation, medicine.symptom, histone 3 lysine 4 methyltransferase, Haploinsufficiency, Genetics (clinical), 030304 developmental biology
Abstract

Purpose: To investigate if specific exon 38 or 39 KMT2D missense variants (MVs) cause a condition distinct from Kabuki syndrome type 1 (KS1). Methods: Multiple individuals, with MVs in exons 38 or 39 of KMT2D that encode a highly conserved region of 54 amino acids flanked by Val3527 and Lys3583, were identified and phenotyped. Functional tests were performed to study their pathogenicity and understand the disease mechanism. Results: The consistent clinical features of the affected individuals, from seven unrelated families, included choanal atresia, athelia or hypoplastic nipples, branchial sinus abnormalities, neck pits, lacrimal duct anomalies, hearing loss, external ear malformations and thyroid abnormalities. None of the individuals had intellectual disability. The frequency of clinical features, objective software-based facial analysis metrics and genome-wide peripheral blood DNA methylation patterns in these patients were significantly different from that of KS1. Circular dichroism spectroscopy indicated that these MVs perturb KMT2D secondary structure through an increased disordered to alpha helical transition. Conclusion: KMT2D MVs located in a specific region spanning exons 38 and 39 and affecting highly conserved residues cause a novel multiple malformations syndrome distinct from KS1. Unlike KMT2D haploinsufficiency in KS1, these MVs likely result in disease through a dominant negative mechanism.

Published
2020

45. Clinical Utility of a Unique Genome-Wide DNA Methylation Signature for

Author

Aidin, Foroutan, Sadegheh, Haghshenas, Pratibha, Bhai, Michael A, Levy, Jennifer, Kerkhof, Haley, McConkey, Marcello, Niceta, Andrea, Ciolfi, Lucia, Pedace, Evelina, Miele, David, Genevieve, Solveig, Heide, Mariëlle, Alders, Giuseppe, Zampino, Giuseppe, Merla, Mélanie, Fradin, Eric, Bieth, Dominique, Bonneau, Klaus, Dieterich, Patricia, Fergelot, Elise, Schaefer, Laurence, Faivre, Antonio, Vitobello, Silvia, Maitz, Rita, Fischetto, Cristina, Gervasini, Maria, Piccione, Ingrid, van de Laar, Marco, Tartaglia, Bekim, Sadikovic, and Anne-Sophie, Lebre

Subjects
Craniofacial Abnormalities, Phenotype, Intellectual Disability, Hypertrichosis, Facies, Humans, Abnormalities, Multiple, DNA, Syndrome, DNA Methylation, Growth Disorders
Abstract

Wiedemann-Steiner syndrome (WDSTS) is a Mendelian syndromic intellectual disability (ID) condition associated with hypertrichosis cubiti, short stature, and characteristic facies caused by pathogenic variants in the

Published
2021

46. Common, low-frequency, rare, and ultra-rare coding variants contribute to COVID-19 severity

Author

Fallerini, Chiara, Picchiotti, Nicola, Baldassarri, Margherita, Zguro, Kristina, Daga, Sergio, Fava, Francesca, Benetti, Elisa, Amitrano, Sara, Bruttini, Mirella, Palmieri, Maria, Croci, Susanna, Lista, Mirjam, Beligni, Giada, Valentino, Floriana, Meloni, Ilaria, Tanfoni, Marco, Minnai, Francesca, Colombo, Francesca, Cabri, Enrico, Fratelli, Maddalena, Gabbi, Chiara, Mantovani, Stefania, Frullanti, Elisa, Gori, Marco, Crawley, Francis P, Butler-Laporte, Guillaume, Richards, Brent, Zeberg, Hugo, Lipcsey, Miklos, Hultström, Michael, Ludwig, Kerstin U, Schulte, Eva C, Pairo-Castineira, Erola, Baillie, John Kenneth, Schmidt, Axel, Frithiof, Robert, Mari, Francesca, Renieri, Alessandra, Furini, Simone Simone Furini, 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, Maurizio, Spagnesi, 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, Mario, U Mondelli, 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, 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, Gabriella, Doddato, Rossella, Tita, Annarita, Giliberti, Maria Antonietta Mencarelli, Caterina Lo Rizzo, Anna Maria Pinto, Valentina, Perticaroli, Francesca, Ariani, Miriam Lucia Carriero, Laura Di Sarno, Diana, Alaverdian, Elena, Bargagli, Marco, Mandalà, Alessia, Giorli, Lorenzo, Salerni, Patrizia, Zucchi, Pierpaolo, Parravicini, Elisabetta, Menatti, Tullio, Trotta, Ferdinando, Giannattasio, Gabriella, Coiro, Fabio, Lena, Leonardo Gianluca Lacerenza, Domenico, A Coviello, Cristina, Mussini, Enrico, Martinelli, Sandro, Mancarella, Luisa, Tavecchia, Mary Ann Belli, Lia, Crotti, Gianfranco, Parati, Maurizio, Sanarico, Francesco, Raimondi, 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, Menè, Roberto, Umberto, Zuccon, Lucia, Vietri, Stefano, Ceri, Pietro, Pinoli, Patrizia, Casprini, Giuseppe, Merla, Gabriella Maria Squeo, Marcello, Maffezzoni, Raffaele, Bruno, Marco, Vecchia, Marta, Colaneri, Serena, Ludovisi, Yanara, Marincevic-Zuniga, Jessica, Nordlund, Tomas, Luther, Anders, Larsson, Katja Hanslin Anna Gradin, Sarah, Galien, Sara Bulow Anderberg, Jacob, Rosén, Sten, Rubertsson, Hugo, Zeberg, Robert, Frithiof, Miklós, Lipcsey, Michael, Hultström, Sara Clohisey Peter Horby, Johnny, Millar, Julian, Knight, Hugh, Montgomery, David, Maslove, Lowell, Ling, Alistair, Nichol, Charlotte, Summers, Tim, Walsh, Charles, Hinds, Malcolm, G Semple, Peter J, M Openshaw, Manu, Shankar-Hari, Antonia, Ho, Danny, Mcauley, Chris, Ponting, Kathy, Rowan, J Kenneth Baillie, Fiona, Griffiths, Wilna, Oosthuyzen, Jen, Meikle, Paul, Finernan, James, Furniss, Ellie, Mcmaster, Andy, Law, Sara, Clohisey, Trevor, Paterson, Tony, Wackett, Ruth, Armstrong, Lee, Murphy, Angie, Fawkes, 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Mohamed Ali, Rangarajan, H, Sarathy, V, Selvanayagam, S, Vedage, D, White, M, Smith, M, Truman, N, Chukkambotla, S, Keith, S, Cockerill-Taylor, J, Ryan-Smith, J, Bolton, R, Springle, P, Dykes, J, Thomas, J, Khan, M, T Hijazi, M, Massey, E, Croston, G, Reschreiter, H, Camsooksai, J, Patch, S, Jenkins, S, Humphrey, C, Wadams, B, Bhatia, N, Msiska, M, Adanini, O, Attwood, B, Parsons, P, Tatham, K, Jhanji, S, Black, E, A Dela Rosa, Howle, R, Thomas, B, Bemand, T, Raobaikady, R, Saha, R, Staines, N, Daniel, A, Finn, J, Hutter, J, Doble, P, Shovelton, C, Pawley, C, Kannan, T, Hill, M, Combes, E, Monnery, S, Joefield, T, Popescu, M, Thankachen, M, Oblak, M, Little, J, Mcivor, S, Brady, A, Whittle, H, Prady, H, Chan, R, Ahmed, A, Morris, A, Gibson, C, Gordon, E, Keenan, S, Quinn, H, Benyon, S, Marriott, S, Zitter, L, Park, L, Baines, K, Lyons, M, Holland, M, Keenan, N, Young, M, Garrioch, S, Dawson, J, Tolson, M, Scholefield, B, R, Bi, Richardson, N, Schumacher, N, Cosier, T, Millen, G, Higham, A, Turki, S, Allen, L, Crisp, N, Hazleton, T, Knight, A, Deery, J, Price, C, Turney, S, Tilbey, S, Beranova, E, Wright, D, Georg, L, Twiss, S, Wadd, S, Postlethwaite, K, Gondo, P, Masunda, B, Kayani, A, Hadebe, B, Whiteside, J, Clarke, N, Donnison, P, Trim, F, Leadbitter, I, Butcher, D, O'Sullivan, S, Purewal, B, Bell, S, Rivers', V, O'Leary, R, Birch, J, Collins, E, Anderson, S, Hammerton, K, Andrews, E, Burns, K, Edmond, I, Todd, A, Donnachie, J, Turner, P, Prentice, L, Symon, L, Runciman, N, Auld, F, Halkes, M, Mercer, P, Thornton, L, Debreceni, G, Wilkins, J, Brown, A, Crickmore, V, Subramanian, G, Marshall, R, Jennings, C, Latif, M, Bunni, L, Spivey, M, Bean, S, Burt, K, Linnett, V, Ritzema, J, Sanderson, A, Mccormick, W, Bokhari, M, Kapoor, R, Loader, D, Ayers, A, Harrison, W, North, J, Belagodu, Z, Parasomthy, R, Olufuwa, O, Gherman, A, Fuller, B, Stuart, C, Kelsall, O, Davis, C, Wild, L, Wood, H, Thrush, J, Durie, A, Austin', K, Archer, K, Anderson, P, Vigurs, C, Thorpe, C, Knights, E, Boyle, N, Price, A, Kubisz-Pudelko, A, Wood, D, Lewis, A, Board, S, Pippard, L, Perry, J, Beesley, K, Rattray, A, Lee, E, Lennon, L, Douglas, K, Bell, D, Boyle, R, Glass, L, M Nauman Akhtar, Dent, K, Potoczna, D, Pearson, S, Horsley, E, Spencer, S, Mullan, D, Skinner, D, Gaylard, J, Ortiz-Ruizdegordoa, L, Barber, R, Hewitt, C, Hilldrith, A, Shepardson, S, Wills, M, Jackson-Lawrence, K, Gupta, A, Easthope, A, Timlick, E, Gorman, C, Otaha, I, Gales, A, Coetzee, S, Raj, M, Peiu, M, Quaid, S, Watson, E, Elliott, K, Mallinson, J, Chandler, B, Turnbull, A, Finch, C, Holl, C, Cooper, J, Evans, A, Khaliq, W, Collins, A, E Treus Gude, Love, N, L van Koutrik, Hunt, J, Kaye, D, Fisher, E, Brayne, A, Tuckey, V, Jackson, P, Parkin, J, Raith, E, 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, M Genetu, R, Otahal, I, 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, Hanson, K, 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, Axel, Schmidt, Kerstin, U Ludwig, Selina, Rolker, Markus, M Nöthen, Julia, Fazaal, Verena, Keitel, Björn, Jensen, Torsten, Feldt, Lisa, Knopp, Julia, Schröder, Carlo, Maj, Fabian, Brand, Marc, M Berger, Thorsten, Brenner, Anke, Hinney, Oliver, Witzke, Robert, Bals, Christian, Herr, Nicole, Ludwig, Jörn, Walter, Jochen, Schneider, Johanna, Erber, Christoph, D Spinner, Clemens, M Wendtner, Christof, Winter, Ulrike, Protzer, Nicolas, Casadei, Stephan, Ossowski, Olaf, H Riess, Eva, C Schulte, J Brent Richards, Guillaume, Butler-Laporte, Mirosław, Kwasniewski, Urszula, Korotko, Karolina, Chwialkowska, Magdalena, Niemira, Jerzy, Jaroszewicz, Barbara, Sobala-Szczygiel, Beata, Puzanowska, Anna, Parfieniuk-Kowerda, Diana, Martonik, Anna, Moniuszko-Malinowska, Sławomir, Pancewicz, Dorota, Zarębska-Michaluk, Krzysztof, Simon, Monika, Pazgan-Simon, Iwona, Mozer-Lisewska, Maciej, Bura, Agnieszka, Adamek, Krzysztof Tomasiewicz Małgorzata Pawłowska, Anna, Piekarska, Aleksandra, 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Repository, NIHR, Fallerini, C, Picchiotti, N, Baldassarri, M, Zguro, K, Daga, S, Fava, F, Benetti, E, Amitrano, S, Bruttini, M, Palmieri, M, Croci, S, Lista, M, Beligni, G, Valentino, F, Meloni, I, Tanfoni, M, Minnai, F, Colombo, F, Cabri, E, Fratelli, M, Gabbi, C, Mantovani, S, Frullanti, E, Gori, M, Crawley, F, Butler-Laporte, G, Richards, B, Zeberg, H, Lipcsey, M, Hultström, M, Ludwig, K, Schulte, E, Pairo-Castineira, E, Baillie, J, Schmidt, A, Frithiof, R, Mari, F, Renieri, A, Furini, S, and Crotti, L

Subjects
Male, Medicin och hälsovetenskap, Linkage disequilibrium, Medizin, severity, Genome-wide association study, Disease, WES/WGS Working Group Within the HGI, Logistic regression, Severity of Illness Index, Medical and Health Sciences, Whole Exome Sequencing, Cohort Studies, 0302 clinical medicine, Lasso (statistics), GEN-COVID Multicenter Study, Germany, 80 and over, Genetics (clinical), Exome sequencing, Original Investigation, Genetics & Heredity, Aged, 80 and over, 0303 health sciences, Adult, Aged, COVID-19, Female, Humans, Italy, Middle Aged, Polymorphism, Single Nucleotide, Quebec, SARS-CoV-2, Sweden, United Kingdom, Genetic Predisposition to Disease, Phenotype, Single Nucleotide, covid-19, 1104 Complementary and Alternative Medicine, GenOMICC Consortium, Human, coding variants, Computational biology, Biology, 03 medical and health sciences, Exome Sequencing, Genetics, Polymorphism, Gene, 030304 developmental biology, 0604 Genetics, 1114 Paediatrics and Reproductive Medicine, Cohort Studie, 030217 neurology & neurosurgery, Coding (social sciences)
Abstract

The combined impact of common and rare exonic variants in COVID-19 host genetics is currently insufficiently understood. Here, common and rare variants from whole-exome sequencing data of about 4000 SARS-CoV-2-positive individuals were used to define an interpretable machine-learning model for predicting COVID-19 severity. First, variants were converted into separate sets of Boolean features, depending on the absence or the presence of variants in each gene. An ensemble of LASSO logistic regression models was used to identify the most informative Boolean features with respect to the genetic bases of severity. The Boolean features selected by these logistic models were combined into an Integrated PolyGenic Score that offers a synthetic and interpretable index for describing the contribution of host genetics in COVID-19 severity, as demonstrated through testing in several independent cohorts. Selected features belong to ultra-rare, rare, low-frequency, and common variants, including those in linkage disequilibrium with known GWAS loci. Noteworthily, around one quarter of the selected genes are sex-specific. Pathway analysis of the selected genes associated with COVID-19 severity reflected the multi-organ nature of the disease. The proposed model might provide useful information for developing diagnostics and therapeutics, while also being able to guide bedside disease management. Supplementary Information The online version contains supplementary material available at 10.1007/s00439-021-02397-7.

Published
2021

47. A Rare Case of Brachyolmia with Amelogenesis Imperfecta Caused by a New Pathogenic Splicing Variant in LTBP3

Author

Simone Pizzi, Daniela Rogaia, Amedea Mencarelli, Giuseppe Merla, Maria Giovanna Tedesco, Valentina Imperatore, Alessandro Bruselles, Elisabetta Flex, Giuseppe Di Cara, Marco Tartaglia, Andrea Ciolfi, Stefania Troiani, Alberto Verrotti, Paolo Prontera, Giovanna Carpentieri, Flex, E., Imperatore, V., Carpentieri, G., Bruselles, A., Ciolfi, A., Pizzi, S., Tedesco, M. G., Rogaia, D., Mencarelli, A., Di Cara, G., Verrotti, A., Troiani, S., Merla, G., Tartaglia, M., and Prontera, P.

Subjects
Male, Adolescent, Consanguinity, Biology, QH426-470, whole exome sequencing, Pathogenesis, Genotype-phenotype distinction, consanguinity, Rare Disease, Latent TGF-beta Binding Protein, Peru, medicine, Genetics, Amelogenesis imperfecta, Osteochondrodysplasia, Genetics (clinical), Exome sequencing, Coxa valga, amelogenesis imperfecta, medicine.disease, Pedigree, LTBP3, Hypodontia, stomatognathic diseases, Phenotype, Dysplasia, brachyolmia, medicine.symptom, Human
Abstract

In recent years, a rare form of autosomal recessive brachyolmia associated with amelogenesis imperfecta (AI) has been described as a novel nosologic entity. This disorder is characterized by skeletal dysplasia (e.g., platyspondyly, short trunk, scoliosis, broad ilia, elongated femoral necks with coxa valga) and severe enamel and dental anomalies. Pathogenic variants in the latent transforming growth factor-β binding protein 3 (LTBP3) gene have been found implicated in the pathogenesis of this disorder. So far, biallelic pathogenic LTBP3 variants have been identified in less than 10 families. We here report a young boy born from consanguineous parents with a complex phenotype including skeletal dysplasia associated with aortic stenosis, hypertrophic cardiomyopathy, hypodontia and amelogenesis imperfecta caused by a previously unreported homozygous LTBP3 splice site variant. We also compare the genotypes and phenotypes of patients reported to date. This work provides further evidence that brachyolmia with amelogenesis imperfecta is a distinct nosologic entity and that variations in LTBP3 are involved in its pathogenesis.

Published
2021

48. Identification of a dna methylation episignature in the 22q11.2 deletion syndrome

Author

Gabriella Maria Squeo, Eleonora Di Venere, Paolo Prontera, Matthew L. Tedder, Sadegheh Haghshenas, Kathleen Rooney, Giuseppe Merla, Daniela Rogaia, Amedea Mencarelli, Jennifer Kerkhof, Michael A. Levy, Bekim Sadikovic, Alberto Verrotti, Maria Giovanna Tedesco, Valentina Imperatore, Giuseppe Di Cara, Barbara R. DuPont, Rooney, K., Levy, M. A., Haghshenas, S., Kerkhof, J., Rogaia, D., Tedesco, M. G., Imperatore, V., Mencarelli, A., Squeo, G. M., Di Venere, E., Di Cara, G., Verrotti, A., Merla, G., Tedder, M. L., Dupont, B. R., Sadikovic, B., and Prontera, P.

Subjects
Male, 22q11.2 deletion, Velocardiofacial syndrome, QH301-705.5, Biology, Article, Catalysis, Inorganic Chemistry, Epigenome, DiGeorge syndrome, Intellectual disability, diagnostic method, medicine, Humans, Biology (General), Physical and Theoretical Chemistry, Episignature, QD1-999, Molecular Biology, Transcription factor, Gene, Spectroscopy, Conotruncalanomaly face syndrome, Genetics, DNA methylation, Organic Chemistry, Infant, General Medicine, Methylation, medicine.disease, Phenotype, Computer Science Applications, Chromatin, episignature, Chemistry, Female, Diagnostic method, Human
Abstract

The 22q11.2 deletion syndrome (22q11.2DS) is the most common genomic disorder in humans and is the result of a recurrent 1.5 to 2.5 Mb deletion, encompassing approximately 20–40 genes, respectively. The clinical presentation of the typical deletion includes: Velocardiofacial, Di George, Opitz G/BBB and Conotruncalanomaly face syndromes. Atypical deletions (proximal, distal or nested) are rare and characterized mainly by normal phenotype or mild intellectual disability and variable clinical features. The pathogenetic mechanisms underlying this disorder are not completely understood. Because the 22q11.2 region harbours genes coding for transcriptional factors and chromatin remodelers, in this study, we performed analysis of genome-wide DNA methylation of peripheral blood from 49 patients with 22q11.2DS using the Illumina Infinium Methylation EPIC bead chip arrays. This cohort comprises 43 typical, 2 proximal and 4 distal deletions. We demonstrated the evidence of a unique and highly specific episignature in all typical and proximal 22q11.2DS. The sensitivity and specificity of this signature was further confirmed by comparing it to over 1500 patients with other neurodevelopmental disorders with known episignatures. Mapping the 22q11.2DS DNA methylation episignature provides both novel insights into the molecular pathogenesis of this disorder and an effective tool in the molecular diagnosis of 22q11.2DS.

Published
2021

49. KMT2D haploinsufficiency in Kabuki syndrome disrupts neuronal function through transcriptional and chromatin rewiring independent of H3K4-monomethylation

Author

Franconi C, Erika Tenderini, Pierre-Luc Germain, Pereira Mf, Capocefalo D, Alessandro Vitriolo, Natascia Malerba, Tjitske Kleefstra, Nael Nk, Tom S. Koemans, Susan J. Kimber, Sara Cuvertino, Nitin Sabherwal, Monica Frega, Bèchet Nb, Michele Gabriele, van Bokhoven H, Orazio Palumbo, Massimo Carella, Squeo Gm, Giuseppe Merla, C. T. R. M. Stumpel, Catherine B. Millar, Castaldi D, Giuseppe Testa, and Siddharth Banka

Subjects
Histone, medicine, biology.protein, Transcriptional regulation, Neural crest, Biology, Stem cell, medicine.disease, Haploinsufficiency, Kabuki syndrome, Embryonic stem cell, Cell biology, Chromatin
Abstract

Kabuki syndrome (KS) is a rare multisystem disorder, characterized by intellectual disability, growth delay, and distinctive craniofacial features. It is mostly caused by de novo mutations of KMT2D, which is responsible for histone H3lysine 4 mono-methylation (H3K4me1) that marks active and poised enhancers. We assessed the impact of KMT2D mutations on chromatin and transcriptional regulation in a cohort of multiple KS1 tissues, including primary patient samples and disease-relevant lineages, namely cortical neurons (iN), neural crest stem cells (NCSC), and mesenchymal cells (MC). In parallel, we generated an isogenic line derived from human embryonic stem cells (hESC) for the stepwise characterization of neural precursors and mature neurons. We found that transcriptional dysregulation was particularly pronounced in cortical neurons and widely affected synapse activity pathways. This was consistent with highly specific alterations of spontaneous network-bursts patterns evidenced by Micro-electrode-array (MEA)-based neural network. Profiling of H3K4me1 unveiled the almost complete uncoupling between this chromatin mark and the effects on transcription, which is instead reflected by defects in H3K27ac. Finally, we identified the direct targets of KMT2D in mature cortical neurons, uncovering TEAD2 as the main mediator of KMT2D haploinsufficiency. Our results uncover the multi-tissue architecture of KS1 dysregulation and define a unique electrical phenotype and its molecular underpinnings for the cortical neuronal lineage.

Published
2021

50. A small 7q11.23 microduplication involving <scp> GTF2I </scp> in a family with intellectual disability

Author

Nicola Brunetti-Pierri, Michele Pinelli, Floriana Imperati, Flavia Troglio, Rita Genesio, Gerarda Cappuccio, Gabriella Maria Squeo, Ennio Del Giudice, Giuseppe Merla, Gaetano Terrone, Giuseppe Testa, Piero Pignataro, Lucio Nitch, Pinelli, M., Terrone, G., Troglio, F., Squeo, G. M., Cappuccio, G., Imperati, F., Pignataro, P., Genesio, R., Nitch, L., Del Giudice, E., Merla, G., Testa, G., and Brunetti-Pierri, N.

Subjects
medicine.medical_specialty, Intellectual impairment, Chromosome 7q, GTF2I gene, medicine.disease, Abdominal Radiography, Chronic kidney failure, Intellectual disability, Learning disability, Genetics, medicine, medicine.symptom, Letters to the Editor, Psychology, Psychiatry, Letter to the Editor, Genetics (clinical)
Published
2020

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