Decoding Genetic Disease Through the Skin: Lessons From the UDN

Skin findings are often among the earliest signs of genetic disease but remain underused in diagnostic evaluation, especially in complex or multisystem cases.

We aimed to examine how dermatologic features contribute to genetic diagnoses in patients evaluated through the Undiagnosed Diseases Network (UDN).

We conducted a retrospective study of 2849 individuals referred to the UDN from 2015 to 2025. All underwent comprehensive clinical evaluation and genome-wide sequencing. Skin findings were identified using Human Phenotype Ontology (HPO) terms and assessed for their association with diagnostic yield and time to diagnosis using odds ratios, Fisher's exact tests, and t-tests.

A confirmed genetic diagnosis was made in 911 individuals. Eighteen were diagnosed with a primary genodermatosis, including four with somatic mosaicism, three of whom required biopsy of affected skin for confirmation. Skin-related HPO terms were present in about one-third of both diagnosed and undiagnosed individuals. While general skin findings were not predictive, specific features were strongly associated with diagnosis. These included café au lait macules (odds ratio 6.75), decreased palmar creases (odds ratio 5.61), and prominent fingertip pads (odds ratio 2.36). In contrast, bruising susceptibility was associated with a lower likelihood of diagnosis. Diagnostic delay was shorter for primary dermatologic disorders, though not statistically significant.

Skin features, even subtle ones, can provide powerful diagnostic clues in rare diseases. Integrating focused dermatologic evaluation and tissue-specific testing, particularly for suspected mosaicism, can enhance diagnostic accuracy and shorten the path to answers for patients and families.