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Telethon Undiagnosed Disease Program: Structured approach to solving rare childhood-onset genetic diseases

Annalaura Torella1,2,3, Manuela Morleo1,2, Carmine Spampanato1,3

  • 1Telethon Institute of Genetics and Medicine, Pozzuoli, Italy.

Genetics in Medicine Open
|April 22, 2026
PubMed

Insights

The Telethon Undiagnosed Diseases Program successfully diagnosed nearly half of children with severe genetic disorders, shortening their diagnostic journey. This multicenter initiative offers a model for improving rare pediatric disease diagnosis and treatment.

Area of Science:

  • Genetics
  • Pediatrics
  • Rare Diseases

Background:

  • Many children with severe genetic disorders remain undiagnosed, hindering prognosis, genetic counseling, and treatment development.
  • Early diagnosis is crucial for managing complex pediatric cases and advancing research into disease mechanisms.

Purpose of the Study:

  • To increase diagnostic rates in children with complex, undiagnosed genetic disorders.
  • To foster research into the underlying mechanisms of rare pediatric diseases.
  • To establish a structured, multicenter approach for rare disease diagnosis.

Main Methods:

  • The Telethon Undiagnosed Diseases Program utilized a structured, multicenter approach from 2016.
  • Trio-based exome sequencing was performed on eligible children with severe, multisystemic disorders and prior negative genetic tests.
  • Regular reanalysis of unsolved cases ensured continuous diagnostic efforts.

Main Results:

  • Between 2016 and 2023, 1019 out of 1338 submitted cases were accepted.
  • A definitive genetic diagnosis was achieved in 49% of cases, identifying variants in 330 genes.
  • The majority of pathogenic variants (70.2%) were de novo, with 9% of patients showing homozygosity.

Conclusions:

  • The program significantly reduced the diagnostic odyssey for rare pediatric diseases, averaging approximately 8 years.
  • Children diagnosed after 2016 experienced faster diagnostic timelines.
  • This initiative provides a scalable and cost-effective model for improving diagnosis and guiding therapeutic innovation in rare pediatric diseases.
Abstract

Keywords:
Exome sequencingGenetic diagnosisPediatric genomicsRare diseasesUndiagnosed Diseases Program

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