Diagnostic Yield and Clinical Impact of Comprehensive WES / WGS Testing Beyond Common Genetic Causes in Hereditary Optic Atrophy

Le résumé fourni par la source

Hereditary optic atrophy is characterized by degeneration of retinal ganglion cells and may result from a wide range of genetic etiologies. While pathogenic variants in OPA1 and primary mitochondrial variants causing Leber hereditary optic neuropathy (LHON) account for a substantial proportion of cases, many patients remain genetically unsolved. We evaluated the diagnostic yield and clinical impact of comprehensive whole exome/genome sequencing (WES/WGS)-based virtual panel testing in 62 partially pre-screened individuals with suspected hereditary optic atrophy. A total of 51 genes associated with optic atrophy and mitochondrial DNA variants were analyzed. Clinical data were systematically retrieved from medical records, including information on extraocular manifestations. A genetic diagnosis was established in 21 patients (33.9%). Pathogenic or likely pathogenic variants in OPA1 accounted for 57.1% of solved cases, whereas 42.9% involved other genes, including WFS1, ACO2, NR2F1, UCHL1, CACNA1F, and COQ2. In the majority of patients with non-OPA1 findings, the genetic diagnosis prompted additional clinical evaluation, surveillance, or therapeutic intervention. Our findings demonstrate that broad WES/WGS-based testing increases diagnostic yield and expands the genetic spectrum beyond OPA1 and LHON, frequently revealing syndromic conditions with direct clinical implications. Comprehensive genomic testing with broader gene panels should therefore be considered part of the diagnostic workup when hereditary optic atrophy is suspected.

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