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.
Highlights
Inherited optic neuropathies (IONs), the most common cause of underlying blindness of genetic origin, are mitochondrial diseases that cause degeneration of retinal ganglion cells (RGCs) and optic nerves with varying levels of vision loss
DOA begins in childhood or in young adults, next-generation sequencing (NGS) for the Diagnosis of Optic Neuropathy leading to a chronic and slow progression of changes in vision, whereas recessive forms affect younger children more severely [3, 7]
We looked for causative variants using the following prioritization strategy: first, we checked for reported pathogenic variants in ION genes, and we looked for novel loss-of-function or novel missense variants in these genes, and eventually, we selected new variants in candidate genes, which should be classified as being of “uncertain significance” according to the American College of Medical Genetics and Genomics, until additional evidence is supporting their pathogenicity
Summary
Inherited optic neuropathies (IONs), the most common cause of underlying blindness of genetic origin, are mitochondrial diseases that cause degeneration of retinal ganglion cells (RGCs) and optic nerves with varying levels of vision loss. Their clinical presentation can be isolated, without extraocular symptoms, or syndromic, in which the optic atrophy is the primary symptom associated with a wide variety of secondary symptoms, mainly of neuromuscular origin [1,2,3]. DOA begins in childhood or in young adults, NGS for the Diagnosis of Optic Neuropathy leading to a chronic and slow progression of changes in vision, whereas recessive forms affect younger children more severely [3, 7]. Maternally transmitted LHON leads, in general, to acute loss of vision in one eye, followed by the other eye on average 2 months later
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