The frequency of rare and monogenic diseases in pediatric organ transplant recipients in Italy
Authors: Vaisitti Tiziana , Peritore Daniela , Magistroni Paola , Ricci Andrea , Lombardini Letizia , Gringeri Enrico , Catalano Silvia , Spada Marco , Sciveres Marco , Di Giorgio Angelo , Limongelli Giuseppe , Varrenti Marisa , Gerosa Gino , Terzi Amedeo , Pace Napoleone Carlo , Amodeo Antonio , Ragni Luca , Dello Strologo Luca , Benetti Elisa , Fontana Iris , Testa Sara , Peruzzi Licia , Mitrotti Adele , Abbate Serena , Comai Giorgia , Gotti Eliana , Schiavon Marco , Boffini Massimo , De Angelis Daniele , Bertani Alessandro , Pinelli Domenico , Torre Massimo , Poggi Camilla , Deaglio Silvia , Cardillo Massimo , Amoroso Antonio ,   Italian Pediatric Transplant Centers, Gringeri Enrico , Catalano Silvia , Spada Marco , Sciveres Marco , Di Giorgio Angelo , Limongelli Giuseppe , Varrenti Marisa , Gerosa Gino , Terzi Amedeo , Pace Napoleone Carlo , Amodeo Antonio , Ragni Luca , Dello Strologo Luca , Benetti Elisa , Fontana Iris , Testa Sara , Peruzzi Licia , Mitrotti Adele , Serena Abbate , Giorgia Comai , Gotti Eliana , Schiavon Marco , Boffini Massimo , De Angelis Daniele , Bertani Alessandro , Pinelli Domenico , Torre Massimo , Poggi Camilla , Deaglio Silvia , Cardillo Massimo , Amoroso Antonio 
Published: November 2021

Abstract
Background
Rare diseases are chronic and life-threatening disorders affecting < 1 person every 2,000. For most of them, clinical symptoms and signs can be observed at birth or childhood. Approximately 80% of all rare diseases have a genetic background and most of them are monogenic conditions. In addition, while the majority of these diseases is still incurable, early diagnosis and specific treatment can improve patients’ quality of life. Transplantation is among the therapeutic options and represents the definitive treatment for end-stage organ failure, both in children and adults. The aim of this paper was to analyze, in a large cohort of Italian patients, the main rare genetic diseases that led to organ transplantation, specifically pointing the attention on the pediatric cohort.

Results
To the purpose of our analysis, we considered heart, lung, liver and kidney transplants included in the Transplant Registry (TR) of the Italian National Transplantation Center in the 2002–2019 timeframe. Overall, 49,404 recipients were enrolled in the cohort, 5.1% of whom in the pediatric age. For 40,909 (82.8%) transplant recipients, a disease diagnosis was available, of which 38,615 in the adult cohort, while 8,495 patients (17.2%) were undiagnosed. There were 128 disease categories, and of these, 117 were listed in the main rare disease databases. In the pediatric cohort, 2,294 (5.6%) patients had a disease diagnosis: of the 2,126 (92.7%) patients affected by a rare disease, 1,402 (61.1%) presented with a monogenic condition. As expected, the frequencies of pathologies leading to organ failure were different between the pediatric and the adult cohort. Moreover, the pediatric group was characterized, compared to the adult one, by an overall better survival of the graft at ten years after transplant, with the only exception of lung transplants. When comparing survival considering rare vs non-rare diseases or rare and monogenic vs rare non-monogenic conditions, no differences were highlighted for kidney and lung transplants, while rare diseases had a better survival in liver as opposed to heart transplants.

Conclusions
This work represents the first national survey analyzing the main genetic causes and frequencies of rare and/or monogenic diseases leading to organ failure and requiring transplantation both in adults and children.