Genetic results in a cohort of 633 patients with optic atrophy

Abstract

Purpose : Variants in both nuclear and mitochondrial (mtDNA) genes cause Optic Atrophy (OA). We investigated the yield of panel testing including nuclear and mtDNA genes, covering disease-associated noncoding variants and copy-number variants (CNVs), in a cohort of patients with OA to determine the clinical utility of this testing approach.

Methods : Clinical reports of consecutive patients who underwent Optic Atrophy Panel testing at Blueprint Genetics (a CLIA-certified laboratory) were examined. Testing included coding exons (+/-20bp from the intron/exon boundary), noncoding disease-associated variants and CNVs. MtDNA analysis was included in almost 83% (525/633) of individuals. Variant interpretation was performed in accordance with ACMG/AMP guidelines. A positive result was defined as a pathogenic (P) or likely pathogenic (LP) variant(s), and in the mtDNA genes >5% heteroplasmy was required. Chi-square (χ²) analysis was used to determine statistical significance (P<0.05).

Results : In a cohort of 633 patients, the median age at time of testing was 24 years (range: neonatal to 82 years). Of those tested, 234 (37.0%) were children (0-18 years). The cohort included 341 males (53.9%). A positive result was reported for 170 patients (26.9%). Those tested in childhood were not significantly more likely to receive a positive result (26.5%, 62/234) than those tested in adulthood (27.1%%, 108/399). However, women (32.0%, 93/291) were significantly more likely to receive a positive result compared to men (22.6%, 77/341) (χ²=7.02, P<.05). A variant of uncertain significance trending pathogenic was reported in 19 patients (3.0%). LP/P variants in 4 genes were responsible for 80% of positive results (OPA1 n=100, WFS1 n=16, MT-ND6 n=11, MT-ND4 n=9). LP/P CNVs were responsible for 10 of 170 positive results (5.9%) of which 7 (70.0%) were identified in OPA1. Two noncoding variants in OPA1 were responsible for 1.2% (2/170) of the positive results. Variants in mtDNA genes accounted for 20.4% of the positive results in the cohort (29/142).

Conclusions : This study demonstrates the clinical utility of a comprehensive approach to genetic testing for patients with OA as almost one third of patients in this cohort received a clinically significant result. Variants in mtDNA were responsible for 20.4% of the positive results while noncoding variants and CNVs were responsible for 7.1% of the positive results in this cohort.

This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.