Improving the Yield of Genetic Diagnosis through Additional Genetic Panel Testing in Hereditary Ophthalmic Diseases

Abstract

Numerous hereditary ophthalmic diseases display significant genetic diversity. Consequently, the utilization of gene panel sequencing allows a greater number of patients to receive a genetic diagnosis for their clinical manifestations. We investigated how to improve the yield of genetic diagnosis through additional gene panel sequencing in hereditary ophthalmic diseases. A gene panel sequencing consisting of a customized hereditary retinopathy panel or hereditary retinitis pigmentosa (RP) panel was prescribed and referred to a CAP-accredited clinical laboratory. If no significant mutations associated with hereditary retinopathy and RP were detected in either panel, additional gene panel sequencing was requested for research use, utilizing the remaining panel. After additional gene panel sequencing, a total of 16 heterozygous or homozygous variants were identified in 15 different genes associated with hereditary ophthalmic diseases. Of 15 patients carrying any candidate variants, the clinical symptoms could be tentatively accounted for by genetic mutations in seven patients. However, in the remaining eight patients, given the in silico mutation predictive analysis, variant allele frequency in gnomAD, inheritance pattern, and genotype–phenotype correlation, fully elucidating the clinical manifestations with the identified rare variant was challenging. Our study highlights the utility of gene panel sequencing in achieving accurate diagnoses for hereditary ophthalmic diseases and enhancing the diagnostic yield through additional gene panel sequencing. Thus, gene panel sequencing can serve as a primary tool for the genetic diagnosis of hereditary ophthalmic diseases, even in cases where a single genetic cause is suspected. With a deeper comprehension of the genetic mechanisms underlying these diseases, it becomes feasible.

Keywords

• massively parallel sequencing
• gene panel sequencing
• genetic diagnosis
• hereditary ophthalmic diseases
• precision medicine