Since 2001 I have been involved in translational research in genetics of neuromuscular and cardiac disorders, including muscular dystrophies, Charcot-Marie-Tooth neuropathies, spastic paraparesis and cardiac arrhythmias. In particular, my research was focused in identifying and characterizing new genetic variants and disease genes in order to improve knowledge of pathogenetic mechanisms and phenotype correlations. To this purpose we employed high throughput genetic techniques, like SNPs arrays and next generation sequencing, and we generated databases integrating clinical and genetic data in collaboration with several italian centers. Our final goal is to improve patient management and in particular risk stratification for malignant arrhythmias.
EDUCATION AND TRAINING
1998 – Specialization in Medical Genetics, Università degli Studi di Milano (70/70 cum laude).
1996 – Specialization Course of the European School of Medical Genetics, Sestri Levante. Director Dr. Giovanni Romeo.
1994 – Degree in Biological Sciences, Università degli Studi di Milano (110/110 cum laude).
1994 – Specialization in chromatographic and spectrophotometric techniques, Centro per la Formazione Professionale Vigorelli, Regione Lombardia.
2007- to date: “Dirigente biologa”, Laboratory of Clinical Molecular Biology, San Raffaele Hospital, Milano. Director Prof. Maurizio Ferrari. Translational research in genetics of neuromuscular disorders and cardiac arrhythmias.
2001- 2007: Research Scientist, Laboratory of Clinical Molecular Biology, San Raffaele Hospital, Milano. Director Prof. Maurizio Ferrari. Translational research in genetics of neuromuscular disorders and cardiac arrhythmias.
1999-2001: Post-Doctoral Fellow, Laboratory of Molecular Neuro-Oncology, Emory University, Atlanta, USA. Director Dr. Erwin G. Van Meir. Gene therapy of malignant gliomas.
1994-1999: Pre-Doctoral Fellow, Laboratory of Molecular Neuro-Oncology, Istituto Neurologico C. Besta, Milano. Director Dr. Gaetano Finocchiaro. Gene therapy of malignant gliomas.
1991-1994: Bachelor Student, Center for the Study of Cellular Pathology, National Research Council, Milano. Director Prof. Sergio Ottolenghi. Regulation of the erythroid transcription factor GATA-1.
HONORS AND AWARDS
Reviewer for international genetics, neurology and cardiology journals, e.g. Clinical Genetics, Neuromuscular Disorders, Muscle Nerve, Journal of Neurology, Heart Rhythm, Journal of the American College of Cardiology
1999-2000: Winner of a one year fellowship from Fondazione Italiana per la Ricerca sul Cancro
1996-1998: Winner of a three years fellowship from Associazione Italiana per la Ricerca sul Cancro
2007- 2011: Teacher of Biology at Degree Course in Physiotherapy, Università Vita e Salute San Raffaele, Milano.
2004-2008: Teacher at Specialization School in Neurology, Università Vita e Salute San Raffaele, Milano.
My major research interests are: i) Arrhythmogenic Syndromes: genetic characterization of arrhythmogenic inherited diseases, in particular Brugada Syndrome; ii) Lamin A/C defects: improving understanding of pathogenetic mechanisms underlying laminopathies and risk stratification for defibrillator implant in of lamin A/C mutation carriers; iii) Application of high throughput molecular techniques for genetic screening of clinically-relevant genes.
Inherited cardiac disorders include arrhythmogenic primarily electrical diseases, such as Brugada Syndrome, Long and Short QT Syndromes and Catecolaminergic Polymorphic Ventricular Tachycardia, and structural disorders like dilated and hypertrophic cardiomyopathies. These disorders often cause sudden cardiac death at young age and the main effective therapy to date is prevention by implantation of an implantable cardioverter defibrillator (ICD), but often the choice is debatable. The identification of efficient risk stratification criteria for ICD implant is therefore today highly prioritary for correct patient management.
Inherited cardiac diseases are genetically complex and it has been increasingly recognized that several SNPs can contribute to phenotype modulation. However, genetic data are scarcely considered for risk stratification, because correlation between genotype and clinical phenotype is often inconclusive. A thorough genetic characterization may therefore give important informations for clinical practice and prognosis evaluation. In a pilot study we identified some genetic variants associated with the occurrence of arrhythmic events in a cohort of BS patients (Sommariva et al., 2012), which in perspective may improve clinical practice.
The main goal of our project is to exploit high throughput technologies to expand our knowledge on the molecular bases by identifying new disease genes and pathogenetic variants. Accordingly, we recently reported the identification of new BS candidate genes by next generation sequencing (Di Resta et al., 2015). Selected variants will be functionally studied in in vitro models including patient-derived iPS cells. In addition, genetic and clinical data will be correlated by multivariate analysis in order to evaluate genotype contribution to the expression of the pathological phenotype and the predisposition to malignant arrhythmias.
Our second goal is to identify markers of early cardiac involvement for the diagnosis of asymptomatic and pre-symptomatic patients, which is a relevant clinical issue since the first symptom may be sudden death. To this purpose, the dosage of tissue-specific cell free circulating DNA based on specific methylation patterns will be investigated.
Thanks to the close interaction between genetists and clinicians, this project will improve knowledge of pathogenetic mechanisms and increase diagnostic power, thus improving familial counselling and clinical management.
Di Resta C, Pietrelli A, Sala S, Della Bella P, De Bellis G, Ferrari M, Bordoni R, Benedetti S. High-throughput genetic characterization of a cohort of Brugada syndrome patients. Hum Mol Genet. 2015 Oct 15;24(20):5828-35.
Scarlato M, Nuara A, Gerevini S, Benedetti S, Rossi P, Ferrari M, Previtali SC. A new double-trouble phenotype: fascioscapulohumeral muscular dystrophy ameliorates hereditary spastic paraparesis due to spastin mutation. J Neurol. 2015 Feb;262(2):476-8.
Maggi L, D’Amico A, Pini A, Sivo S, Pane M, Ricci G, Vercelli L, D’Ambrosio P, Travaglini L, Sala S, Brenna G, Kapetis D, Scarlato M, Pegoraro E, Ferrari M, Toscano A, Benedetti S, Bernasconi P, Colleoni L, Lattanzi G, Bertini E, Mercuri E, Siciliano G, Rodolico C, Mongini T, Politano L, Previtali SC, Carboni N, Mantegazza R, Morandi L. LMNA-associated myopathies: The Italian experience in a large cohort of patients. Neurology. 2014 Oct 28;83(18):1634-44.
Sommariva E, Pappone C, Martinelli Boneschi F, Di Resta C, Rosaria Carbone M, Salvi E, Vergara P, Sala S, Cusi D, Ferrari M, Benedetti S. Genetics can contribute to the prognosis of the Brugada syndrome: a pilot model for risk stratification. Eur J Hum Genet, 2013; 21:911-917.
Magagnotti C, Bachi A, Zerbini G, Fattore E, Fermo I, Riba M, Previtali SC, Ferrari M, Andolfo A, Benedetti S. Protein profiling reveals energy metabolism and cytoskeletal proteins alterations in LMNA mutation carriers. Biochimica et Biophysica Acta – Molecular Basis of Disease, 2012;1822(6):970-9.
Crimella C, Baschirotto C, Arnoldi A, Tonelli A, Tenderini E, Airoldi G, Martinuzzi A, Trabacca A, Losito L, Scarlato M, Benedetti S, Scarpini E, Spinicci G, Bresolin N, Bassi M. Mutations in the motor and stalk domains of KIF5A in spastic paraplegia type 10 and in axonal Charcot-Marie-Tooth type 2. Clin Genet. 2011 May 30.
Stefano Marangoni*; Chiara Di Resta*; Lucio Barile; Marcella Rocchetti; Riccardo Rizzetto; Elena Sommariva; Maurizio Ferrari; Carlo Pappone; Sara Benedetti; Antonio Zaza. A Brugada Syndrome mutation (S216L) and its modulation by H558R polymorphism: standard and dynamic characterization. Cardiovascular Res, 2011; 91(4):606-16.
Benedetti S., Previtali S.C., Coviello S., Scarlato M., Cerri F., Di Pierri E., Piantoni L., Spiga I., Fazio R., Riva N., Natali-Sora m.G., Dacci P., Malaguti M.C., Munerati E., Grimaldi L.M.E., Marrosu M.G., De Pellegrin M., Ferrari M., Comi G., Quattrini A., Bolino A. Analyzing Histopathological Features of Rare Charcot-Marie-Tooth Neuropathies to Unravel Their Pathogenesis. Arch Neurol, 2010 67(12):1498-1505.
Solla P., Vannelli A., Bolino A., Marrosu G., Coviello S., Murru M.R., Tranquilli S., Corongiu D., Benedetti S., Marrosu M.G. Heat shock protein 27 R127W mutation: evidence of a continuum between axonal Charcot-Marie-Tooth and distal hereditary motor neuropathy. J Neurol Neurosurg Psychiatry, 2010 Sep;81(9):958-62.
Bordoni R, Bonnal R, Rizzi E, Carrera P, Benedetti S, Cremonesi L, Stenirri S, Colombo A, Montrasio C, Bonalumi S, Albertini A, Rossi Bernardi L, Ferrari M, de Bellis G. Evaluation of human gene variant detection in amplicon pools by the GS-FLX parallel Pyrosequencer. BMC Genomics. 2008 Oct 8;9(1):464.
Benedetti S, Menditto I, Degano M, Rodolico C, Merlini L, D’Amico A, Palmucci L, Berardinelli A, Pegoraro E, Trevisan CP, Morandi L, Moroni I, Galluzzi G, Bertini E, Toscano A, Olive M, Bonne G, Mari F, Caldara R, Fazio R, Mammi I, Carrera P, Toniolo D, Comi G, Quattrini A, Ferrari M, and Previtali SC. Phenotypic clustering of lamin A/C mutations in neuromuscular patients. Neurology 2007 Sep 18;69(12):1285-92.
Bione S, Benedetti S, Goegan M, Menditto I, Marozzi A, Ferrari M, Toniolo D. Skewed X-chromosome inactivation is not associated with premature ovarian failure in a large cohort of Italian patients. Am J Med Genet (2006) Jun 15;140(12):1349-51.
D’Amico A, Benedetti S, Petrini S, Sambuughin N, Boldrini R, Menditto I, Ferrari M, Verardo M, Goldfarb L, Bertini E. Major myofibrillar changes in early onset myopathy due to de novo heterozygous missense mutation in lamin A/C gene. Neuromuscul Disord. (2005) Dec;15(12):847-50.
Benedetti S, Bertini E, Iannaccone S, Angelini C, Trisciani M, Toniolo D, Sferrazza B, Carrera P, Comi G, Ferrari M, Quattrini A, Previtali S. Dominant LMNA mutations can cause combined muscular dystrophy and peripheral neuropathy. J Neurol Neurosurg Psychiatry. (2005) Jul; 76(7):1019-21.
Benedetti S., Merlini L. Laminopathies: from the heart of the cell to the clinics. Curr Opin Neurol. (2004) Oct;17(5):553-60.
Vytopil M, Benedetti S, Ricci E, Galluzzi G, Dello Russo A, Merlini L, Boriani G, Gallina M, Morandi L, Politano L, Moggio M, Chiveri L, Hausmanova-Petrusewicz I, Ricotti R, Vohanka S, Toman J, Toniolo D. Mutation analysis of the lamin A/C gene (LMNA) among patients with different cardiomuscular phenotypes. J Med Genet. (2003) Dec;40(12):e132.
Benedetti, S., Pirola, B., Pollo, B., Magrassi, L., Bruzzone, M.G., Rigamonti, D., Galli, R., Selleri, S., Di Meco, F., De Fraja, C., Vescovi, A., Cattaneo, E., and Finocchiaro, G. Gene therapy of experimental brain tumors using neural progenitor cells. Nature Med (2000) 6(4): 447-450.
Benedetti, S., Bruzzone, M.G., Pollo, B., Di Meco, F., Magrassi, L., Pirola, B., Cirenei, N., Colombo, M.P., and Finocchiaro, G. Eradication of rat malignant gliomas by retroviral-mediated, in vivo delivery of the interleukin-4 gene. Cancer Res. (1999) 59:645-652.
Benedetti, S., DiMeco, F., Cirenei, N., Pollo, B., Cattaneo, E., Colombo, B.M., Bruzzone, M.G., Vescovi, A., Colombo, M.P., DiDonato, S., and Finocchiaro, G. Limits of the HSV-tk/GCV system for gene therapy of malignant gliomas: perspectives for combined transduction of the IL-4 gene. Hum Gene Ther (1997) 8:1345-1353.
Colombo BM, Benedetti S, Ottolenghi S, Mora M, Pollo B, Poli E, and Finocchiaro G. The “bystander effect”: association od U87 cell death with ganciclovir-mediated apoptosis of nearby cells and lack of effect in athymic mice. Hum. Gene Ther. (1995) 6, 763-772.