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Exploring Ophthalmological Diagnoses in the Undiagnosed Diseases Network: Insights and Implications 

Clinical Genetics and Therapeutics
  • Primary Categories:
    • Clinical Genetics
  • Secondary Categories:
    • Clinical Genetics
Introduction:
Inherited ocular diseases are characterized by numerous conditions, including inherited retinal disorders (IRDs) and congenital ocular malformations. These conditions can present as non-syndromic or syndromic, and identifying the genetic causes of these conditions is complicated by allelic and locus heterogeneity. Access to whole genome sequencing (WGS) is limited for individuals with these phenotypes and is often pursued after gene panels and whole exome sequencing (WES). However, WGS is known to resolve cases by addressing non-coding/structural variants, poor gene coverage missed by exon-based testing and mitochondrial genome analysis. One of the goals of the Undiagnosed Diseases Network (UDN) is to provide undiagnosed individuals with access to robust clinical evaluations and testing, which includes WES/WGS, regardless of a participant’s phenotype. We aimed to investigate the individuals who apply to the study with ocular phenotypes to determine if WGS is warranted in these cases.

 

Methods:
This was a retrospective review of individuals who applied to the UDN who had an ophthalmologic phenotype as their primary indication for applying. Participants who had not received an evaluation were excluded. Applicants recieved a completed medical records case review performed by the clinical site to which they were assigned. Data was obtained from the UDN Gateway, including phenotype and diagnostic outcome. Reasons for rejecting participants were reviewed. Accepted participants were categorized into syndromic and non-syndromic categories. Genomic results and outcomes for those who received a diagnosis were obtained.

 

Results:
Applicants who had ophthalmology listed as their primary phenotype made up 1.0% (n=79) of all UDN applicants (n=7622). Of the total ophthalmology cohort, 45.6% (n=36) were accepted to the study. One applicant was lost to follow up. Of those not accepted (n=42),  45.0% (n=20) had previously had some form of genetic testing. The most common recommendation for the denied applicants was to receive a genetics consultation and initiate genetic testing or pursue more extensive genetic testing than was previously performed. At the time of analysis, 29 ocular participants had received a UDN evaluation. Ten participants had non-syndromic phenotypes (37%). The diagnostic rate was 25.9% (n=7) in this ocular cohort. All diagnoses were made by WES/WGS. The reasons these diagnoses were not previously made included a lack of genetic testing prior to the UDN, previously receiving incorrect or insufficient gene panels, reanalysis of previously identified variants with new insights or gene discoveries, and the failure to detect intronic variants that were missed by earlier testing. Three of the diagnosed participants had a non-syndromic genetic cause (IFT172, TEK, CTNNA1) and the remaining 4 participants had a syndromic genetic cause of their phenotype (ALMS1, TUB, ALPK1, WFS1). 

Conclusion:
Here we describe the individuals with ophthalmologic phenotypes who applied to the UDN. Individuals with ophthalmology phenotypes were a small portion (1.0%) of the total UDN cohort. This indicates that individuals with ocular phenotypes may not be seeking the resources provided by the UDN. Further, less than half of these patients were accepted, however, individuals with syndromic phenotypes who had preveiously received genetic testing were more likely to be accepted. The most common recommendations given to denied applicants were to pursue consultation with a geneticist and to undergo further genetic testing, indicating more traditional genetic testing methods would be expected to achieve a diagnosis for these individuals. The diagnostic rate for those with primary ophthalmological phenotypes was lower than the overall diagnostic rate of the UDN, however, this data indicates WGS is able to diagnose individuals who previously had negative panels and WES, even in non-syndromic cases, highlighting the opportunity for additional genes discovery and novel variant identification with this improved technology.

 

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