Clinical and genetic landscape of optic atrophy in 826 families: insights from 50 nuclear genes

Abstract

Hereditary optic neuropathies (HON) comprise a group of diseases caused by genetic defects in either the mitochondrial or nuclear genomes. The increasing availability of genetic testing has expanded the genetic and phenotypic spectrum of HON more broadly than previously recognized. The genetic and phenotypic landscape of HON is attributed to 50 nuclear genes, so we genetically analysed patients with suspected HON from a group of 4776 index cases following our previous study on 1516 probands with Leber's HON (LHON) who had mitochondrial DNA variants. Exome sequencing was performed in 473 probands diagnosed with nuclear gene-related HON (nHON) and 353 cases with unsolved LHON. Sequencing and variant interpretation of the 50 nuclear genes indicated that the diagnostic yield of exome sequencing for nHON was 31.50% (149/473), while it was markedly lower [1.42% (5/353)] for LHON patients without primary mtDNA mutations. The top five genes implicated in nHON in our in-house cohort were OPA1, WFS1, FDXR, ACO2 and AFG3L2, which accounted for 82.46% of probands. Although OPA1 was the most prevalent nHON-causative gene in both our cohort (53.25%) and a literature review (37.09%), the predominance of OPA1, WFS1 and FDXR differed significantly between our in-house cohort and the literature review (P-adjusted < 0.001). Fundus changes in nHON could be stratified into three categories: the most common was optic atrophy at examination (78.79%); the rarest was LHON-like optic atrophy (3.64%); and optic atrophy with concurrent retinal degeneration (17.57%), an independent risk factor for visual prognosis in nHON, occurred at an intermediate frequency. A systematic genotype-phenotype analysis highlighted different genetic contributions for ocular, extraocular neurological and extraocular non-neurological phenotypes. In addition, systemic variant analysis at the individual gene level suggested a revised interpretation of the pathogenicity of a WFS1 heterozygous truncation variant. This study provides a panoramic view of the genetic and phenotypic profiles of HON in a real-world study and the literature. The categories of nHON fundus phenotypes will benefit future studies on the molecular mechanisms underlying HON and targeted therapies. In addition to routine ophthalmic examinations, careful examination of extraocular symptoms and meaningful genetic counselling are warranted for patients with nHON.

Keywords: Leber’s hereditary optic neuropathy; dominant optic atrophy; hereditary optic neuropathy; mitochondrial.