Am J Ophthalmol. 2025 Dec;280:51-63. doi: 10.1016/j.ajo.2025.07.028. Epub 2025 Aug 6.
ABSTRACT
PURPOSE: The multicenter NIH-funded Undiagnosed Diseases Network (UDN) exists to diagnose puzzling and newly discovered conditions. We report the UDN’s assistance in diagnosing perplexing ocular disorders along with 6 case illustrations.
DESIGN: Retrospective Interventional Case Series.
SUBJECTS: Participants with ocular phenotypes who had applied and were accepted into the UDN with detailed supporting letters written by ophthalmologists or other clinicians when clinically indicated genetic and laboratory testing results were not diagnostic.
METHODS: Human Phenotype Ontology Codes were used to identify and categorize subjects with ocular phenotypes. Advanced genomic technologies (exome, genome, mitochondrial and RNA sequencing, X-inactivation analysis, immunoblot analysis) were available for diagnoses.
MAIN OUTCOME MEASURE: Proportion of cases solved by the UDN in subjects manifesting an ophthalmic component of their undiagnosed disorder.
RESULTS: The national UDN diagnostic rate for subjects with an eye phenotype was 40.2% (452 of 1123); the diagnostic rate for the other subjects (without an eye) phenotype was 27.8% (276 of 992). In univariate analysis, having an eye phenotype was significantly associated with receiving a diagnosis (odds ratio [OR] = 1.75; CI = 1.45-2.10; P = 2.28e-09). Of 58 eye diagnosed cases/104 total diagnosed cases at the Vanderbilt UDN site, 6 will be discussed more fully. Vanderbilt UDN cases include an autosomal dominant glaucoma with a variant in TEK/TIE2; a de novo heterozygous variant in PRPS1 causing microcornea and glaucoma with skewed X-inactivation affecting a female; a homozygous variant in NADK2 causing optic nerve atrophy; autosomal recessive variants in EPG5 resulting in optic nerve atrophy and cone-rod dystrophy; and a rare de novo variant in COG4 causing a cataract/ retinitis pigmentosa/ nystagmus phenotype. EPG5 and COG4 are not present on inherited retinal disease panels.
CONCLUSIONS: The UDN is a national resource available to increase solving undiagnosed diseases including those with ocular phenotypes, facilitate research on undiagnosed diseases, and create a collaboration to improve care options for patients with undiagnosed diseases. Clinicians including ophthalmologists can collaborate with the UDN to solve challenging ocular mysteries using genomic technologies.
PMID:40780579 | DOI:10.1016/j.ajo.2025.07.028