Telethon Undiagnosed Disease Program: Structured Approach to Solving Rare Childhood-Onset Genetic Diseases

Authors

• Annalaura Torella
• Manuela Morleo
• Carmine Spampanato
• Raffaele Castello
• Mariateresa Zanobio
• Giulio Piluso
• Pasquale Di Letto
• Maria Elena Onore
• Sarah Iffat Rahman
• Francesco Musacchia
• Michele Pinelli
• Giuseppina Vitiello
• Giulia De Riso
• Angelo Selicorni
• Milena Mariani
• Cecilia Daolio
• Valeria Capra
• Marcello Scala
• Francesca Nardecchia
• Serena Galosi
• Mario Mastrangelo
• Filippo Manti
• Donatella Milani
• Corrado Romano
• Donatella Greco
• Claudia Ciaccio
• Stefano D'Arrigo
• Arianna De Laurentiis
• Antonietta Coppola
• Marcella Zollino
• Domizia Pasquetti
• Federica Francesca L'Erario
• Albina Tummolo
• Claudia Santoro
• Livia Garavelli
• Carla Marini
• Stefania Bigoni
• Alfonsina Tirozzi
• Viviana Cetrangolo
• Giancarlo Parenti
• Diego Di Bernardo
• Angela Peron
• Silvia Maitz
• Andrea Accogli
• Gerarda Cappuccio
• Sandro Banfi
• Giorgio Casari
• Andrea Ballabio
• Nicola Brunetti-Pierri
• Vincenzo Nigro
• Telethon Undiagnosed Disease Study group

Language

English

Publication Date

1-1-2026

Journal

Genetics in Medicine Open

DOI

10.1016/j.gimo.2026.104394

PMID

42016445

PMCID

PMC13094511

PubMedCentral® Posted Date

3-25-2026

PubMedCentral® Full Text Version

Post-print

Abstract

Purpose: Many children with severe genetic disorders remain undiagnosed despite advanced genomic technologies. Early diagnosis is vital for prognosis, genetic counseling, and targeted treatment development. This study aims to increase diagnostic rates in complex pediatric cases and foster research into disease mechanisms.

Methods: Launched in 2016, the Telethon Undiagnosed Diseases Program provides a structured, multicenter approach to rare disease diagnosis. Standardized case submission criteria ensured consistent clinical data collection. Children with severe, multisystemic disorders and prior negative genetic tests were eligible. After case approval, trio-based exome sequencing was performed, with regular reanalysis for unsolved cases until December 2024.

Results: Between June 2016 and December 2023, 1338 cases were submitted by 60 clinicians from 22 Italian centers; 1019 were accepted. A definitive genetic diagnosis was achieved in 49% of cases, implicating 330 genes. Most pathogenic variants (70.2%) were de novo, reflecting demographic trends, such as delayed parenthood. The remainder included autosomal recessive or X-linked variants, with homozygosity observed in 9% of patients.

Conclusion: The Telethon Undiagnosed Diseases Program significantly shortened the average diagnostic odyssey of ∼8 years. Children born after 2016 benefited from faster diagnoses. This initiative offers a scalable, cost-effective model for improving diagnosis, guiding treatment, and supporting therapeutic innovation in rare pediatric diseases.

Keywords

Exome sequencing, Genetic diagnosis, Pediatric genomics, Rare diseases, Undiagnosed Diseases Program

Published Open-Access

yes

Recommended Citation

Torella, Annalaura; Morleo, Manuela; Spampanato, Carmine; et al., "Telethon Undiagnosed Disease Program: Structured Approach to Solving Rare Childhood-Onset Genetic Diseases" (2026). Duncan NRI Faculty and Staff Publications. 235.
https://digitalcommons.library.tmc.edu/duncar_nri_pub/235