Decoding Genetic Disease Through the Skin: Lessons From the UDN

Area of Science:

• Genetics
• Dermatology
• Rare Diseases

Background:

• Skin findings are early indicators of genetic diseases but are underutilized in diagnosis.
• Complex or multisystem genetic disorders often present diagnostic challenges.

Purpose of the Study:

• To investigate the role of dermatologic features in achieving genetic diagnoses within the Undiagnosed Diseases Network (UDN).

Main Methods:

• Retrospective analysis of 2849 individuals evaluated by the UDN (2015-2025).
• Comprehensive clinical evaluation and genome-wide sequencing.
• Identification of skin findings using Human Phenotype Ontology (HPO) terms to assess diagnostic yield.

Main Results:

• A genetic diagnosis was confirmed in 911 individuals.
• Specific skin findings, including café au lait macules (OR 6.75) and decreased palmar creases (OR 5.61), were strongly associated with diagnosis.
• Bruising susceptibility was linked to a lower diagnostic likelihood.

Conclusions:

• Subtle skin features offer crucial diagnostic clues for rare genetic diseases.
• Integrating dermatologic evaluation and targeted testing, especially for mosaicism, enhances diagnostic accuracy.
• Improved diagnostic pathways can shorten the time to answers for affected individuals and families.