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The Multidisciplinary Ophthalmic Genetics Clinic (MOGC) at the University of Michigan Kellogg Eye Center aims to provide medical and ophthalmic genetics care to patients with inherited ocular conditions. We have developed a clinical and referral workflow where each patient undergoes coordinated evaluation by our multidisciplinary team followed by discussions on diagnosis, prognosis, and genetic testing. Testing approaches are specific to each patient and can be targeted (single-gene, gene panel), broad (chromosomal microarray, whole-exome sequencing), or a combination. We hypothesize that this clinic model improves patient outcomes and quality of care. A retrospective chart review of patients in the MOGC from July 2020 to October 2022 revealed that the most common referral diagnoses were congenital cataracts, optic neuropathy, and microphthalmia, with 52% syndromic cases. Within this patient cohort, we saw a 76% uptake for genetic testing, among which 33% received a diagnostic test result. Our results support a tailored approach to genetic testing for specific conditions. Through case examples, we highlight the power and impact of our clinic. By integrating ophthalmic care with medical genetics and counseling, the MOGC has not only helped solve individual patient diagnostic challenges but has aided the greater population in novel genetic discoveries and research towards targeted therapeutics.

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Background: Genetic eye disorders, affecting around one in 1000 people, encompass a diverse group of diseases causing severe visual deficiency. The recent adoption of next-generation sequencing techniques, including whole-exome sequencing (WES), in medicine has greatly enhanced diagnostic rates of genetically heterogeneous diseases. Objectives: The objectives of the study were to assess the diagnostic yield of WES in a cohort of Mexican individuals with suspected genetic eye disorders and to evaluate the improvement of diagnostic rates by reanalysis of WES data in patients without an initial molecular diagnosis. Methods: A total of 90 probands with ocular anomalies of suspected genetic origin were ascertained. Patients underwent WES in leukocytic DNA. Bioinformatics analysis and Sanger sequencing were used to confirm the disease-causing variants. Only variants identified as pathogenic or likely pathogenic were considered as causal. Results: Initial analysis revealed causal mutations in 46 cases (51%). Reanalysis of WES data 12 months after first analysis resulted in the identification of additional causal variants in 6 patients (7%), increasing the molecular diagnostic yield to 58%. The highest diagnostic rates by disease categories corresponded to hereditary retinal dystrophies (77%) and to anomalies of the anterior segment of the eye (47%). Conclusions: Our study demonstrates that WES is an effective approach for genetic diagnosis of genetic ocular diseases and that reanalysis of WES data can improve the diagnostic yield.

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ABSTRACT Background: Genetic eye disorders, affecting around one in 1000 people, encompass a diverse group of diseases causing severe visual deficiency. The recent adoption of next-generation sequencing techniques, including whole-exome sequencing (WES), in medicine has greatly enhanced diagnostic rates of genetically heterogeneous diseases. Objectives: The objectives of the study were to assess the diagnostic yield of WES in a cohort of Mexican individuals with suspected genetic eye disorders and to evaluate the improvement of diagnostic rates by reanalysis of WES data in patients without an initial molecular diagnosis. Methods: A total of 90 probands with ocular anomalies of suspected genetic origin were ascertained. Patients underwent WES in leukocytic DNA. Bioinformatics analysis and Sanger sequencing were used to confirm the disease-causing variants. Only variants identified as pathogenic or likely pathogenic were considered as causal. Results: Initial analysis revealed causal mutations in 46 cases (51%). Reanalysis of WES data 12 months after first analysis resulted in the identification of additional causal variants in 6 patients (7%), increasing the molecular diagnostic yield to 58%. The highest diagnostic rates by disease categories corresponded to hereditary retinal dystrophies (77%) and to anomalies of the anterior segment of the eye (47%). Conclusion: Our study demonstrates that WES is an effective approach for genetic diagnosis of genetic ocular diseases and that reanalysis of WES data can improve the diagnostic yield.