Use of Next-Generation Sequencing for the Molecular Diagnosis of 1,102 Patients With a Autosomal Optic Neuropathy

Abstract

Advances in next-generation sequencing (NGS) facilitate the diagnosis of genetic disorders. To evaluate its use for the molecular diagnosis of inherited optic neuropathy (ION), a blinding disease caused by the degeneration of retinal ganglion cells, we performed genetic analysis using targeted NGS of 22 already known and candidate genes in a cohort of 1,102 affected individuals. The panel design, library preparation, and sequencing reactions were performed using the Ion AmpliSeq technology. Pathogenic variants were detected in 16 genes in 245 patients (22%), including 186 (17%) and 59 (5%) dominant and recessive cases, respectively. Results confirmed that OPA1 variants are responsible for the majority of dominant IONs, whereas ACO2 and WFS1 variants are also frequently involved in both dominant and recessive forms of ION. All pathogenic variants were found in genes encoding proteins involved in the mitochondrial function, highlighting the importance of mitochondria in the survival of retinal ganglion cells.

Genetic Spectrum and Characteristics of Hereditary Optic Neuropathy in Taiwan

“…In our cohort, OPA1 was responsible for seven probands (50% of probands with a genetic diagnosis of autosomal HON) and was the most common disease-causing gene. This percentage was similar to that observed in previous studies [ 15 , 21 ]. OPA1 contains 30 exons spread over 100 Kb of genomic DNA [ 22 ].…”

“…Therefore, in this study, we focused on exploring autosomal HON with a panel-based NGS test containing 52 HON-associated genes. Recently, two large-scale NGS-based genetic surveys for HON have been published [ 14 , 15 ]. Although the numbers and ranges of the target genes differed, these studies have reported a detection rate of 22–40% in identifying the disease-causing variants.…”

“…Our project identified 14 disease-causing variants among 42 probands, with a diagnostic rate of 33.3%, which is comparable with those of previous studies. Previous studies have shown that AD was much more common than AR in patients with HON [ 14 , 15 ]. Our results also verified this observation because only two patients were classified as having AR-pattern among 14 patients with a diagnosis.…”

“…In recent years, next-generation sequencing (NGS) has been demonstrated to be a cost-effective and time-saving technique that has revolutionized medical genetics. Some large-scale NGS-based genetic screening studies for HON have been published [ 14 , 15 ].…”

EyeG2P: an automated variant filtering approach improves efficiency of diagnostic genomic testing for inherited ophthalmic disorders

“…1,2 Obtaining a genetic diagnosis in affected individuals can inform management, and clinical genomic testing is increasingly being used as a frontline diagnostic tool for these disorders. [3][4][5][6][7][8] Notably, the more widespread availability of gene-directed interventions including gene therapy and preimplantation genetic testing has increased both the value and risk of genomic testing. [9][10][11][12][13][14] This places substantial demands on the delivery of testing in a timely and accurate manner.…”