Arriving at a diagnosis: Effective strategies used by the Undiagnosed Diseases Network.

Strategies to resolve diagnostic odysseys — reanalysis and reinterpretation of exome and genome data, case matching, aggregation of clinical information

This study describes the diagnostic strategies of the second cohort of the US Undiagnosed Diseases Network (UDN, 24 May 2017 – 30 June 2023). The proportion of participants with prior exome or genome sequencing before enrolment rose from 40.2% to 75.0% over time. The diagnostic rate was 22.1% (379/1,713), and reanalysis or reinterpretation of sequencing data yielded the greatest number of diagnoses — 21.4% via prior exome, 17.3% via UDN genome sequencing. Case matching was the most frequent supporting strategy (25.6%); for the 26 non-genetic diagnoses, aggregation of clinical information (57.7%) and clinical testing (42.3%) predominated. Overall, 235 diagnoses (59.9%) required research efforts beyond standard clinical approaches.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The number to remember is not the 22% but the fact that most diagnoses came from data already generated: sequencing data ages better than the report attached to it. This argues for scheduled reanalysis of negative exomes and genomes and for genuine access to case-matching platforms, rather than for a new test order. The flip side is that nearly 60% of diagnoses required research-grade resources that a routine laboratory cannot easily reproduce.

Analysis by Dr Thibaut Benquey