Autosomal dominant optic atrophy caused by six novel pathogenic OPA1 variants and genotype–phenotype correlation analysis

PURPOSE: To describe the genetic and clinical features of nineteen patients from eleven unrelated Chinese pedigrees with OPA1-related autosomal dominant optic atrophy (ADOA) and define the phenotype-genotype correlations. METHODS: Detailed ophthalmic examinations were performed. Targeted next-generation sequencing (NGS) was conducted in the eleven probands using a custom designed panel PS400. Sanger sequencing and cosegregation were used to verify the identified variants. The pathogenicity of gene variants was evaluated according to American College of Medical Genetics and Genomics (ACMG) guidelines. RESULTS: Nineteen patients from the eleven unrelated Chinese ADOA pedigrees had impaired vision and optic disc pallor. Optical coherence tomography showed significant thinning of the retinal nerve fiber layer. The visual field showed varying degrees of central or paracentral scotoma. The onset of symptoms occurred between 3 and 24 years of age (median age 6 years). Eleven variants in OPA1 were identified in the cohort, and nine novel variants were identified. Among the novel variants, two splicing variants c.984 + 1_984 + 2delGT, c.1194 + 2 T > C, two stop-gain variants c.1937C > G, c.2830G > T, and one frameshift variant c.2787_2794del8, were determined to be pathogenic based on ACMG. A novel splicing variant c.1316-10 T > G was determined to be likely pathogenic. In addition, a novel missense c.1283A > C (p.N428T) and two novel splicing variants c.2496G > A and c.1065 + 5G > C were of uncertain significance. CONCLUSIONS: Six novel pathogenic variants were identified. The findings will facilitate genetic counselling by expanding the pathogenic mutation spectrum of OPA1.