Exome sequencing identifies targets in the treatment-resistant ophthalmoplegic subphenotype of myasthenia gravis

- Extreme phenotype sampling was used to study ophthalmoplegic MG (OP-MG).
- Whole exome sequencing defines a unique genetic signature in OP-MG.
- Discovered candidate genes implicate myogenesis and gangliosphingolipid biosynthesis pathways.

Treatment-resistant ophthalmoplegia (OP-MG) is not uncommon in individuals with African genetic ancestry and myasthenia gravis (MG). To identify OP-MG susceptibility genes, extended whole exome sequencing was performed using extreme phenotype sampling (11 OP-MG vs 4 control-MG) all with acetylcholine receptor-antibody positive MG. This approach identified 356 variants that were twice as frequent in OP-MG compared to control-MG individuals. After performing probability test estimates and filtering variants according to those 'suggestive' of association with OP-MG (p < 0.05), only three variants remained which were expressed in extraocular muscles. Validation in 25 OP-MG and 50 control-MG cases supported the association of DDX17delG (p = 0.014) and SPTLC3insACAC (p = 0.055) with OP-MG, but ST8SIA1delCCC could not be verified by Sanger sequencing. A parallel approach, using a semantic model informed by current knowledge of MG-pathways, identified an African-specific interleukin-6 receptor (IL6R) variant, IL6R c.*3043 T>C, that was more frequent in OP-MG compared to control-MG cases (p = 0.069) and population controls (p = 0.043). A weighted genetic risk score, derived from the odds ratios of association of these variants with OP-MG, correlated with the OP-MG phenotype as opposed to control MG. This unbiased approach implicates several potentially functional gene variants in the gangliosphingolipid and myogenesis pathways in the development of the OP-MG subphenotype.