The Telethon Undiagnosed Diseases Program (TUDP) is a multicenter Italian national program that started as the Pilot Program in 2016 and a new TUDP 2.0 restarted in 2021 with the aim of identifying new genes mutated in pediatric onset monogenic rare diseases. From 2016 to date, 1188 families have been evaluated. Most cases are of major severity: these children usually show severe multisystem manifestations, neurological involvement and dysmorphism, but remain undiagnosed. To date, the TUDP have solved almost 50% of these unsolved cases. Mutations in known genes of known diseases were identified for 79% of cases, while for the remaining 21% of families disease-causing variants were identified in new genetic diseases, discovered while the TUDP study was ongoing. Compound-Heterozygous (12%) or homozygous (10%), de novo (68%) and X-linked (7% inherited from mother and 3% de novo X-linked) mutations were identified. During the Project we learned three things: first, the TUDP benefited from a highly selective and rigorous clinical evaluation, but it was of fundamental importance to produce a useful, rich, and specific list of phenotypic terms. Second point, whole exome sequencing (WES) in trio is the obligatory choice of entry, due to the enormous advantages in terms of costs / benefits compared to other strategies, but there has been a need for continuous improvement of the quality of the wet data thanks to the new kits and to re-sequence cases after some time. Finally, the periodic re-evaluation of the cases with new bioinformatics tools, new literature, and matchmaking led to the solution of about 30% more cases. We believe that the reanalysis of still unsolved cases through more expensive technologies, such as long-read WGS and RNASeq, can benefit an additional portion of patients, albeit with very small percentages. We are testing these additional tools to establish access criteria, considering the costs and the yield
Programma Telethon "Malattie senza diagnosi": aggiornamento al 2022