Background

Patients with rare diseases often experience a 'diagnostic odyssey,' where they visit multiple clinics and undergo various tests before a diagnosis is reached. Early identification of causative variants can reduce unnecessary tests and inappropriate treatments, and in treatable diseases, it can even improve prognosis. With the decreasing cost of whole-genome and exome analysis, there is growing support for large-scale genetic screening of asymptomatic newborns and the general population.

However, identifying genetic abnormalities is not the same as diagnosing a disease. Rare diseases have diverse genetic causes and clinical manifestations, and effective treatments are not available for all diseases. Even in hospitalized patients, a pathogenic variant strongly associated with a disease may have a lower penetrance in the general population, meaning that the probability of individuals with the variant actually developing symptoms is lower. Ignoring these differences can lead to overestimating the risk of disease in healthy individuals or causing long-term follow-up and anxiety due to uncertain results.

Key Findings

The article published in Nature Medicine on July 28, 2026, by Caroline Wright, Professor of Medical Genetics at the University of Exeter, and colleagues, is not a new clinical trial or cohort analysis, but a review article. The authors argue that reducing the time to diagnosis for rare diseases should not be reduced to a single solution, namely 'whole-population genomic screening,' based on a review of 15 articles and policy documents.

The review organizes the problem around three axes. First, rare diseases should be categorized based on whether they have a known genetic cause and whether they are treatable. Early identification of gene variants has limited direct clinical benefit if there are no prevention, treatment, or follow-up strategies. Second, the penetrance of pathogenic variants derived from clinical patient populations cannot be directly applied to the general population. This is because the group of individuals who visit the hospital due to symptoms is, by definition, a selected sample with a higher probability of having the disease.

Third, the starting points of screening and diagnostic testing should be distinguished. Screening is the process of identifying high-risk individuals in an asymptomatic population, while diagnosis is the process of confirming a disease by integrating symptoms, family history, and test results. The authors propose that newborn blood spot screening, symptom-based early referral, family cascade screening, and clinical genomic testing and reanalysis should be considered complementary pathways rather than competing options. The three diagrams in the review illustrate the genetic basis and treatability of the disease, the differences in penetrance in clinical and population cohorts, and the relationship between screening and diagnostic pathways.

Significance and Outlook

The key to this proposal is that the diagnostic outcome depends more on who is tested, when, and how the results are linked to clinical decision-making, rather than on the genetic technology itself. Healthcare systems can expand targeted screening for treatable diseases while streamlining referral pathways to ensure that patients with unexplained developmental delays or multi-organ system symptoms have early access to clinical geneticists and genetic testing. For patients with negative results, regular reanalysis incorporating new disease genes and variant interpretation criteria is also effective.

However, this review does not directly compare the diagnostic rate, cost-effectiveness, or patient outcomes of specific strategies. More large-scale, long-term follow-up data are also needed to accurately estimate variant-specific penetrance in the general population. There is also a need for consensus on how to communicate and manage false positives, uncertain variants, and incidentally detected secondary findings. Whether to expand screening should be evaluated not only based on technical detection capabilities but also on treatability, follow-up care capacity, health inequalities, and patient and family preferences.