Rosanna Asselta

Humanitas University · Biomedical Sciences

Despite substantial progress, causal variants are identified only for a minority of familial Parkinson’s disease (PD) cases, leaving high-risk pathogenic variants unidentified1,2. To identify such variants, we uniformly processed exome sequencing data of 2,184 index familial PD cases and 69,775 controls. Exome-wide analyses converged on RAB32 as a...

Background and Aims Genetic variants influence primary biliary cholangitis (PBC) risk. We established and tested an accurate polygenic risk score (PRS) using these variants. Methods Data from two Italian cohorts (OldIT 444 cases, 901 controls; NewIT 255 cases, 579 controls) were analysed. The latest international genome‐wide meta‐analysis provided...

Loss‐of‐function CHD2 (chromodomain helicase DNA‐binding protein 2) mutations are associated with a spectrum of neurodevelopmental disorders often including early‐onset generalized seizures, photosensitivity, and epileptic encephalopathies. Patients show psychomotor delay/intellectual disability (ID), autistic features, and behavior disorders, such...

The clinical manifestations of SARS-CoV-2 infection vary widely among patients, from asymptomatic to life-threatening. Host genetics is one of the factors that contributes to this variability as previously reported by the COVID-19 Host Genetics Initiative (HGI), which identified sixteen loci associated with COVID-19 severity. Herein, we investigate...

278 Background: Family history is a major prostate cancer (PCa) risk factor. Pathogenic gene variants (e.g., BRCA1/BRCA2) greatly increase PCa risk (2.5 to 8.6-fold for <65-year-olds) and affect outcomes. This study assesses an enhanced screening protocol's effectiveness and participant compliance. It combines PHI for familial cases and multiparame...

342 Background: Pathogenic variants (PVs) in DNA repair genes (DRG), such as in BRCA1, BRCA2, ATM, CHEK2, etc., have implications for prostate cancer (PCa) family genetic counselling, testing and risk stratification in men. However, understanding how to counsel patients with variants of unknown significance (VUS) is an unmet clinical need. On the o...

Blood transfusions, conducted between donors compatible in their red blood cell (RBC) antigens, play a life-saving role in transfusion medicine. Genetic differences at blood group loci between ethnicities result in diversity and altered frequency of RBC antigens that need to be considered in blood transfusion. Consequently, comprehensive, and accur...

Patients with cystic fibrosis (CF) exhibit pronounced respiratory damage and were initially considered among those at highest risk for serious harm from SARS‐CoV‐2 infection. Numerous clinical studies have subsequently reported that individuals with CF in North America and Europe—while susceptible to severe COVID‐19—are often spared from the highes...

Genome-wide association (GWA) studies of primary biliary cholangitis (PBC) have identified more than 60 risk loci for the disease. Causal variants and candidate genes at those loci remain obscure, however, limiting biological insight. We sought to address this limitation using statistical colocalisation. Accordingly, we applied coloc and HyPrColoc...

The clinical manifestations of SARS-CoV-2 infection vary widely among patients, from asymptomatic to life-threatening. Host genetics is one of the factors that contributes to this variability as a previous case-control genome-wide association study by the COVID-19 Host Genetics Initiative (HGI) identified sixteen loci associated with COVID-19 sever...

Coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may lead to life-threatening respiratory symptoms. Understanding the genetic basis of the prognosis of COVID-19 is important for risk profiling of potentially severe symptoms. Here, we conducted a genome-wide epistasis study of COVID-19 se...

Objective The aim of this study is to evaluate male awareness of developing prostate cancer (PCa) in families with germline DNA‐repair genes (DRG) variants. Materials and methods Data were collected from a prospective, monocentric cohort study. The study was conducted in a university hospital with a multidisciplinary approach to the patient (colla...

Streptococcus pneumoniae is a major pathogen in children, elderly subjects and immunodeficient patients. PTX3 is a fluid phase pattern recognition molecule (PRM) involved in resistance to selected microbial agents and in regulation of inflammation. The present study was designed to assess the role of PTX3 in invasive pneumococcal infection. In a mu...

Streptococcus pneumoniae is a major pathogen in children, elderly subjects, and immunodeficient patients. Pentraxin 3 (PTX3) is a fluid-phase pattern recognition molecule (PRM) involved in resistance to selected microbial agents and in regulation of inflammation. The present study was designed to assess the role of PTX3 in invasive pneumococcal inf...

Streptococcus pneumoniae is a major pathogen in children, elderly subjects, and immunodeficient patients. Pentraxin 3 (PTX3) is a fluid-phase pattern recognition molecule (PRM) involved in resistance to selected microbial agents and in regulation of inflammation. The present study was designed to assess the role of PTX3 in invasive pneumococcal inf...

Streptococcus pneumoniae is a major pathogen in children, elderly subjects, and immunodeficient patients. Pentraxin 3 (PTX3) is a fluid-phase pattern recognition molecule (PRM) involved in resistance to selected microbial agents and in regulation of inflammation. The present study was designed to assess the role of PTX3 in invasive pneumococcal inf...

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiologic agent of the coronavirus disease 2019 (COVID-19) pandemic. Clinical manifestations of the disease range from an asymptomatic condition to life-threatening events and death, with more severe courses being associated with age, male sex, and comorbidities. Besides these risk...

328 Background: Although one of the most important risk factors for prostate cancer (PCa) is a family history of the disease, there is a poor awareness of genetic risk. The aim of the current study is to investigate the awareness of genetic risk for PCa in men belonging to female families with germline variants in DNA-repair genes (DRGs). Methods:...

Diaphanous related formins are regulatory cytoskeletal protein involved in actin elongation and microtubule stabilization. In humans, defects in two of the three diaphanous genes (DIAPH1 and DIAPH3) have been associated with different types of hearing loss. Here, we investigate the role of the third member of the family, DIAPH2, in nonsyndromic hea...

Autoimmune liver diseases (AiLDs) are rare autoimmune conditions of the liver and the biliary tree with unknown etiology and limited treatment options. AiLDs are inherently characterized by a high degree of complexity, which poses great challenges in understanding their etiopathogenesis, developing novel biomarkers and risk-stratification tools, an...

Background Circular RNAs (circRNAs) are a class of non-coding RNAs increasingly emerging as crucial actors in the pathogenesis of human diseases, including autoimmune and neurological disorders as multiple sclerosis (MS). Despite several efforts, the mechanisms regulating circRNAs expression are still largely unknown and the circRNA profile and reg...

Background: The application of Machine Learning (ML) to genetic individual-level data represents a foreseeable advancement for the field, which is still in its infancy. Here, we aimed to evaluate the feasibility and accuracy of an ML-based model for disease risk prediction applied to Primary Biliary Cholangitis (PBC). Methods: Genome-wide signif...

Alternative Splicing (AS) is crucial for generating protein-coding isoforms and circular RNAs (circRNAs), stable non-coding RNA’s produced by circularization of exons through the back-splicing process. Here, taking advantage of Htt CAG knock-in mouse in vitro and in vivo models, we demonstrate a strong correlation between Htt CAG repeat length and...

Objectives To test the hypothesis of a relationship between a specific genetic lesion (T2:ERG) and imaging scores, such as PI-RADS and PRI-MUS, and to test the effectiveness of these parameters for the diagnosis of prostate cancer (PCa) and clinically significant PCa (csPCa). Materials and methods This is a prospective study of men with suspected...

Primary biliary cholangitis (PBC) is a rare disease of the liver characterized by an autoimmune attack on the small bile ducts. PBC is a complex trait, meaning that a large list of genetic factors interacts with environmental agents to determine its onset. Genome-wide association studies have had a huge impact in fostering research in PBC, but many...

Primary Biliary Cholangitis (PBC) is a rare autoimmune cholangiopathy. Genetic studies have shown that the strongest statistical association with PBC has been mapped in the human leukocyte antigen (HLA) locus, a highly polymorphic area that mostly contribute to the genetic variance of the disease. Furthermore, PBC presents high variability througho...

Beta-glucocerebrosidase is a lysosomal hydrolase involved in the catabolism of the sphin-golipid glucosylceramide. Biallelic loss of function mutations in this enzyme are responsible for the onset of Gaucher disease, while monoallelic β-glucocerebrosidase mutations represent the first genetic risk factor for Parkinson's disease. Despite this eviden...

ImportanceThere is growing awareness of sex-related differences in cardiovascular risk profiles, but less is known about whether these extend to pre-menopausal females experiencing an early-onset myocardial infarction (MI), who may benefit from the protective effects of estrogen exposure.MethodsA nationwide study involving 125 Italian Coronary Care...

Niemann-Pick type A disease (NPA) is a rare lysosomal storage disorder caused by mutations in the gene coding for the lysosomal enzyme acid sphingomyelinase (ASM). ASM deficiency leads to the consequent accumulation of its uncatabolized substrate, the sphingolipid sphingomyelin (SM), causing severe progressive brain disease. To study the effect of...

Hearing relies on the proper functioning of auditory hair cells and on actin-based cytoskeletal structures. Diaphanous-related formins (DRFs) are evolutionarily conserved cytoskeletal proteins that regulate the nucleation of linear unbranched actin filaments. They play key roles during metazoan development, and they seem particularly pivotal for th...

Tuberous breast (TB) deformity is a condition characterized by alterations in breast morphology and tissue structure with high prevalence in the general population. The literature provides sparse descriptions of TB, as not many investigations on the condition have been conducted. The aim of this review was to analyze and provide a holistic overview...

Primary Biliary Cholangitis (PBC) is a rare autoimmune disease of the liver, affecting mostly females. There is evidence that epigenetic changes have a pathogenic role in PBC. Epigenetic modifications are related to methylation of CpG DNA islands, post-translational modifications of histone proteins, and non-coding RNAs. In PBC, there are data show...

Introduction: Autoimmune diseases mostly affect females. Besides hormones, several factors related to chromosome X have been called in action to explain this sex predominance. Areas covered: This paper provides an overview on the role of chromosome X (chrX) in explaining why females have higher susceptibility to autoimmunity. The work outlines s...

Background: To date, variants in the GBA gene represent the most frequent large-effect genetic factor associated with Parkinson's disease (PD). However, the reason why individuals with the same GBA variant may or may not develop neurodegeneration and PD is still unclear. Objectives: Therefore, we evaluated the contribution of rare variants in ge...

The humoral arm of innate immunity includes diverse molecules with antibody-like functions, some of which serve as disease severity biomarkers in coronavirus disease 2019 (COVID-19). The present study was designed to conduct a systematic investigation of the interaction of human humoral fluid-phase pattern recognition molecules (PRMs) with severe a...

Background Acute myocardial infarction with non-obstructive coronary artery disease (MINOCA) is frequent in patients experiencing an early-onset MI, but data concerning its long-term prognosis are limited and conflicting. Methods The Italian Genetic Study on Early-onset MI enrolled 2000 patients experiencing a first MI before the age of 45 years,...

Aims Data regarding long-term prognosis of MINOCA are very limited and conflicting. Methods and results The Italian Genetic Study on early-onset MI enrolled 2000 patients who had a first MI before they were 45. The median follow-up was 19.9 years, the equivalent of 39 535 person-years. The composite primary endpoint was cardiovascular (CV) death,...

Erratum for An international genome-wide meta-analysis of primary biliary cholangitis: Novel risk loci and candidate drugs. Cordell HJ, Fryett JJ, Ueno K, Darlay R, Aiba Y, Hitomi Y, Kawashima M, Nishida N, Khor SS, Gervais O, Kawai Y, Nagasaki M, Tokunaga K, Tang R, Shi Y, Li Z, Juran BD, Atkinson EJ, Gerussi A, Carbone M, Asselta R, Cheung A, de...

Background: Psoriatic disease is a multifactorial inflammatory condition spanning from skin and nail psoriasis (Pso) to spine and joint involvement characterizing psoriatic arthritis (PsA). Monozygotic twins provide a model to investigate genetic, early life environmental exposure and stochastic influences to complex diseases, mainly mediated by ep...

Congenital fibrinogen disorders are rare pathologies of the hemostasis, comprising quantitative (afibrinogenemia, hypofibrinogenemia) and qualitative (dysfibrinogenemia and hypodysfibrinogenemia) disorders. The clinical phenotype is highly heterogeneous, being associated with bleeding, thrombosis, or absence of symptoms. Afibrinogenemia and hypofib...

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiologic agent of the coronavirus disease 2019 (COVID-19) pandemic. Besides virus intrinsic characteristics, the host genetic makeup is predicted to account for the extreme clinical heterogeneity of the disease, which is characterized, among other manifestations, by a derangement...

Objective The objectives of our study were to assess the association of radiomic and genomic data with histology and patient outcome in non-small cell lung cancer (NSCLC). Methods In this retrospective single-centre observational study, we selected 151 surgically treated patients with adenocarcinoma or squamous cell carcinoma who performed baselin...

Background: There is considerable variability in COVID-19 outcomes amongst younger adults-and some of this variation may be due to genetic predisposition. Methods: We combined individual level data from 13,888 COVID-19 patients (N=7,185 hospitalized) from 17 cohorts in nine countries to assess the association of the major common COVID-19 genetic...

Hippocrates (Kos, c.460–c.370 BC) reminds us that “It is more important to know what sort of person has a disease than to know what sort of disease a person has”. This is still true today and reflects the emerging role of personalized medicine for patient-specific risk stratification and treatment programs. This report documents my personal experie...

Background With the development of new therapies entering clinical trials for HD, there is an increasing need to develop and validate biomarkers in accessible biofluids, such as blood, to follow disease progression and predict treatment outcomes. Some biomarkers do exist; however, reliable and readily available additional ones will be crucial in as...

Primary biliary cholangitis (PBC) is a rare autoimmune disease of the liver affecting the small bile ducts. From a genetic point of view, PBC is a complex trait and several genetic and environmental factors have been called in action to explain its etiopathogenesis. Similarly to other complex traits, PBC has benefited from the introduction of genom...

Clonal hematopoiesis of indeterminate potential (CHIP) is associated with increased risk of cancers and inflammation-related diseases. This phenomenon becomes very common in oldest-old individuals, in whom the implications of CHIP are not well defined. We performed a mutational screening in 1794 oldest-old individuals enrolled in two population-bas...

The humoral arm of innate immunity includes diverse molecules with antibody-like functions, some of which serve as disease severity biomarkers in COVID-19. The present study was designed to conduct a systematic investigation of the interaction of humoral fluid phase pattern recognition molecules (PRM) with SARS-CoV-2. Out of 10 PRM tested, the long...

Background Psoriatic disease is a chronic inflammatory disorder spanning from skin disease (psoriasis) to psoriatic arthritis (PsA). The genetic background is insufficient to explain disease onset as illustrated by not very informative Genome Wide Association Studies and monozygotic (MZ) twin studies recently performed. It is strongly assumed that...

Circulating cell-free DNA (ccfDNA), released from normal and cancerous cells, is a promising biomarker for cancer detection as in neoplastic patients it is enriched in tumor-derived DNA (ctDNA). ctDNA contains cancer-specific mutations and epigenetic modifications, which can have diagnostic/prognostic value. However, in primary tumors, and in parti...

Background & aims: Primary biliary cholangitis (PBC) is a chronic liver disease in which autoimmune destruction of the small intra-hepatic bile ducts eventually leads to cirrhosis. Many patients have inadequate response to licensed medications, motivating the search for novel therapies. Previous genome-wide association studies (GWAS) and meta-anal...

Background: There is considerable variability in COVID-19 outcomes amongst younger adults and some of this variation may be due to genetic predisposition. We characterized the clinical implications of the major genetic risk factor for COVID-19 severity, and its age-dependent effect, using individual-level data in a large international multi-centre...

Background Significant efforts have been made to investigate the molecular pathways involved in thymic carcinogenesis. However, genetic findings have still not impacted clinical practice. The aim of this exploratory trial was to evaluate the immunoscore and molecular profile of a series of thymic carcinomas (TCs), correlating this data with clinica...

Background & aims Genome-wide association studies (GWAS) in primary biliary cholangitis (PBC) have failed to find X chromosome (chrX) variants associated with the disease. Here, we specifically explore the chrX contribution to PBC, a sexually-dimorphic complex autoimmune disease. Methods We performed a chrX-wide association study (XWAS), including...

Inherited hearing loss is extremely heterogeneous both clinically and genetically. In addition, the spectrum of deafness-causing genetic variants differs greatly among geographical areas and ethnicities. The identification of the causal mutation in affected families allows early diagnosis, clinical follow-up, and genetic counseling. A large consang...

Objectives The objectives of our study were to assess the association of radiomic and genomic data with histology and patient outcome in non-small cell lung cancer (NSCLC). Methods In this retrospective single-centre observational study, we selected 151 surgically treated patients with adenocarcinoma or squamous cell carcinoma who performed baselin...

Background Circulating cell-free DNA (ccfDNA), released from normal and cancerous cells, is a promising biomarker for cancer detection as in neoplastic patients it is enriched in tumor-derived DNA (ctDNA). ctDNA contains cancer-specific mutations and epigenetic modifications, which can have diagnostic/prognostic value. However, in primary tumors, a...

Background: There are sex differences in vulnerability to Coronavirus disease 2019 (COVID-19). The coronavirus S protein mediates viral entry into target cells employing the host cellular serine protease TMPRSS2 for S-protein priming. The TMPRSS2 gene expression is responsive to androgen stimulation and it could partially explain sex differences....

In order to reconstruct the phenotypical and clinical implications of the Italian genetic structure, we thoroughly analyzed a whole‐exome sequencing dataset comprised of 1,686 healthy Italian individuals. We found six previously unreported variants with remarkable frequency differences between Northern and Southern Italy in the HERC2, OR52R1, ADH1B...

Objective To provide a variant-specific estimate of incidence, penetrance, sex distribution, and association with dementia of the 4 most common Parkinson disease (PD)-associated GBA variants, we analyzed a large cohort of 4,923 Italian unrelated patients with primary degenerative parkinsonism (including 3,832 PD) enrolled in a single tertiary care...

Autoimmune liver diseases (AILDs) have an important genetic background. This is supported by different lines of evidence, that is, clustering in families, high concordance rates in monozygotic twins, increased risk of the disease in siblings compared to general population, and association with other autoimmune conditions. In this chapter, we summar...

Fibrinogen is a 340-kDa plasma glycoprotein constituted by two sets of symmetrical trimers, each formed by the Aα, Bβ, and γ chains (respectively coded by the FGA, FGB, and FGG genes). Quantitative fibrinogen deficiencies (hypofibrinogenemia, afibrinogenemia) are rare congenital disorders characterized by low or unmeasurable plasma fibrinogen antig...

Introduction: Deleterious variants in the GBA gene confer a 2- to 20-fold increased risk of Parkinson's disease (PD) and are associated with a more severe disease course. The presence of a highly-similar pseudogene complicates genetic screening, both by Sanger and next-generation sequencing (NGS). Among PD-associated GBA variants, four missense su...

Fibrinogen is a hexameric plasmatic glycoprotein composed of pairs of three chains (Aα, Bβ, and γ), which play an essential role in hemostasis. Conversion of fibrinogen to insoluble polymer fibrin gives structural stability, strength, and adhesive surfaces for growing blood clots. Equally important, the exposure of its non-substrate thrombin-bindin...

Background There is considerable variation in disease behavior among patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 (Covid-19). Genomewide association analysis may allow for the identification of potential genetic factors involved in the development of Covid-19. M...

As the outbreak of coronavirus disease 2019 (COVID-19) progresses, prognostic markers for early identification of high-risk individuals are an urgent medical need. Italy has one of the highest numbers of SARS-CoV-2-related deaths and one of the highest mortality rates. Worldwide, a more severe course of COVID-19 is associated with older age, comorb...

Background. Respiratory failure is a key feature of severe Covid-19 and a critical driver of mortality, but for reasons poorly defined affects less than 10% of SARS-CoV-2 infected patients. Methods. We included 1,980 patients with Covid-19 respiratory failure at seven centers in the Italian and Spanish epicenters of the SARS-CoV-2 pandemic in Europ...

Importance There are gender differences in vulnerability to the Coronavirus disease 2019 (COVID-19), with men experiencing more severe disease at any age. The use of anti-androgen drugs, like 5-alpha reductase inhibitors (5ARIs), could protect from severe pulmonary disease. Objective To determine whether men who received 5ARIs for benign prostatic...

Background: As the outbreak of coronavirus disease 2019 (COVID-19) progresses, prognostic markers for early identification of high-risk individuals are an urgent medical need. Italy has the highest rate of SARS-CoV-2 infection, the highest number of deaths, and the highest mortality rate among large countries. Worldwide, a more severe course of COV...

Background: As the outbreak of coronavirus disease 2019 (COVID-19) progresses, prognostic markers for early identification of high-risk individuals are an urgent medical need. Italy has the highest rate of SARS-CoV-2 infection, the highest number of deaths, and the highest mortality rate among large countries. Worldwide, a more severe course of COV...

284 Background: The TMPRSS2:ERG gene fusion (T:E) is found in up to 70% of prostate cancers (PCa) and results in androgen dependent overexpression of ERG, promoting tumor growth. The early identification of T:E may be helpful even in low-risk PCa. Although T:E can be non-invasively detected in urine, its correlation with new imaging tools (MRI and...

Background Collagenous colitis (CC) is a common cause of chronic diarrhoea and highly associated with immune-mediated diseases. The aetiology of CC may involve a dysregulated immune response in genetically predisposed individuals. Our preliminary data identified ancestral HLA haplotype 8.1 and non-HLA CC risk loci being associated with CC. We here...

In human tuberculosis (TB) neutrophils represent the most commonly infected phagocyte but their role in protection and pathology is highly contradictory. Moreover, a subset of low-density neutrophils (LDNs) has been identified in TB, but their functions remain unclear. Here, we have analyzed total neutrophils and their low-density and normal-densit...