Giulio Calcagni1, Giuseppe Limongelli2, Angelo D'Ambrosio3, Francesco Gesualdo3, M Cristina Digilio4, Anwar Baban5, Sonia B Albanese5, Paolo Versacci6, Enrica De Luca6, Giovanni B Ferrero7, Giuseppina Baldassarre7, Gabriella Agnoletti7, Elena Banaudi7, Jan Marek8, Juan P Kaski9, Giulia Tuo8, M Giovanna Russo2, Giuseppe Pacileo2, Ornella Milanesi10, Daniela Messina10, Maurizio Marasini11, Francesca Cairello11, Roberto Formigari12, Maurizio Brighenti12, Bruno Dallapiccola4, Marco Tartaglia4, Bruno Marino6. 1. Department of Pediatric Cardiology and Cardiac Surgery, Bambino Gesù Children's Hospital and Research Institute, Rome, Italy. Electronic address: giulio.calcagni@opbg.net. 2. Cardiologia SUN, Monaldi Hospital, II University of Naples, Naples, Italy. 3. Multifactorial Disease and Complex Phenotype Research Division, Bambino Gesù Children's Hospital and Research Institute, Rome, Italy. 4. Genetics and Rare Diseases Research Division, Bambino Gesù Children's Hospital and Research Institute, Rome, Italy. 5. Department of Pediatric Cardiology and Cardiac Surgery, Bambino Gesù Children's Hospital and Research Institute, Rome, Italy. 6. Pediatric Cardiology, Department of Pediatrics, Sapienza University, Rome, Italy. 7. Department of Pediatric and Public Health Sciences, Città della Salute e della Scienza, University of Turin, Italy. 8. Cardiorespiratory Unit, Great Ormond Street Hospital for Children, London, UK; UCL Institute of Cardiovascular Science, London, UK. 9. Centre for Inherited Cardiovascular Diseases, Great Ormond Street Hospital, London, UK; UCL Institute of Cardiovascular Science, London, UK. 10. Department of Woman and Child's Health, Pediatric Cardiology, University of Padova, Padua, Italy. 11. Cardiovascular Department, Giannina Gaslini Institute, Genoa, Italy. 12. Cardiology and Cardiac Surgery, Sant'Orsola Malpighi Hospital, Bologna, Italy.
Abstract
BACKGROUND: RASopathies are developmental disease caused by mutations in genes encoding for signal transducers of the RAS-MAPK cascade. The aim of the present study was to provide a comprehensive description of morbidity and mortality in patients with molecularly confirmed RASopathy. METHODS: A multicentric, observational, retrospective study was conducted in seven European cardiac centres participating to the CArdiac Rasopathy NETwork (CARNET). Clinical records of 371 patients with confirmed molecular diagnosis of RASopathy were reviewed. Mortality was described as crude mortality, cumulative survival and restricted estimated mean survival. Multivariable regression analysis was used to assess the impact of mutated genes on number of interventions and overall prognosis. RESULTS: Cardiac defects occurred in 80.3% of cases, almost half of them underwent at least one intervention. Overall, crude mortality was 0.29/100 patients-year. Cumulative survival was 98.8%, 98.2%, 97.7%, 94.3%, at 1, 5, 10, and 20years, respectively. Restricted estimated mean survival at 20years follow-up was 19.6years. Ten patients died (2.7% of the entire cohort; 3.4% of patients with cardiac defect). Patients with hypertrophic cardiomyopathy (HCM) and age <2years or young adults, as well as subjects with biventricular obstruction and PTPN11 mutations had a higher risk of cardiac death. CONCLUSIONS: The risk of intervention was higher in individuals with Noonan syndrome and pulmonary stenosis carrying PTPN11 mutations. Overall, mortality was relatively low, even though the specific association between HCM, biventricular outflow tract obstructions and PTPN11 mutations appeared to be associated with early mortality, including immediate post-operative events and sudden death.
BACKGROUND: RASopathies are developmental disease caused by mutations in genes encoding for signal transducers of the RAS-MAPK cascade. The aim of the present study was to provide a comprehensive description of morbidity and mortality in patients with molecularly confirmed RASopathy. METHODS: A multicentric, observational, retrospective study was conducted in seven European cardiac centres participating to the CArdiac Rasopathy NETwork (CARNET). Clinical records of 371 patients with confirmed molecular diagnosis of RASopathy were reviewed. Mortality was described as crude mortality, cumulative survival and restricted estimated mean survival. Multivariable regression analysis was used to assess the impact of mutated genes on number of interventions and overall prognosis. RESULTS:Cardiac defects occurred in 80.3% of cases, almost half of them underwent at least one intervention. Overall, crude mortality was 0.29/100 patients-year. Cumulative survival was 98.8%, 98.2%, 97.7%, 94.3%, at 1, 5, 10, and 20years, respectively. Restricted estimated mean survival at 20years follow-up was 19.6years. Ten patients died (2.7% of the entire cohort; 3.4% of patients with cardiac defect). Patients with hypertrophic cardiomyopathy (HCM) and age <2years or young adults, as well as subjects with biventricular obstruction and PTPN11 mutations had a higher risk of cardiac death. CONCLUSIONS: The risk of intervention was higher in individuals with Noonan syndrome and pulmonary stenosis carrying PTPN11 mutations. Overall, mortality was relatively low, even though the specific association between HCM, biventricular outflow tract obstructions and PTPN11 mutations appeared to be associated with early mortality, including immediate post-operative events and sudden death.
Authors: K Nicole Weaver; Jing Chen; Amy Shikany; Pete S White; Carlos E Prada; Bruce D Gelb; James F Cnota Journal: Circ Genom Precis Med Date: 2022-06-06
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Authors: Jussi Leppävirta; Roope A Kallionpää; Elina Uusitalo; Tero Vahlberg; Minna Pöyhönen; Juha Peltonen; Sirkku Peltonen Journal: Orphanet J Rare Dis Date: 2018-01-15 Impact factor: 4.123
Authors: Giulio Calcagni; Giuseppe Limongelli; Angelo D'Ambrosio; Francesco Gesualdo; Maria Cristina Digilio; Anwar Baban; Sonia B Albanese; Paolo Versacci; Enrica De Luca; Giovanni B Ferrero; Giuseppina Baldassarre; Gabriella Agnoletti; Elena Banaudi; Jan Marek; Juan P Kaski; Giulia Tuo; Maria Giovanna Russo; Giuseppe Pacileo; Ornella Milanesi; Daniela Messina; Maurizio Marasini; Francesca Cairello; Roberto Formigari; Maurizio Brighenti; Bruno Dallapiccola; Marco Tartaglia; Bruno Marino Journal: Data Brief Date: 2017-12-02
Authors: Joseane Biso de Carvalho; Guilherme Loss de Morais; Thays Cristine Dos Santos Vieira; Natana Chaves Rabelo; Juan Clinton Llerena; Sayonara Maria de Carvalho Gonzalez; Ana Tereza Ribeiro de Vasconcelos Journal: Front Genet Date: 2019-11-13 Impact factor: 4.599