Exome sequencing combined with semantic discovery identifies strong disease-associated candidates in a single case of relapsing remitting multiple sclerosis

Abstract

As known disease-associated variants identified through large cohort-based studies often explain only a small percentage of genetic risk in multifactorial disorders such as multiple sclerosis (MS), alternative methods for identification and prioritization of variants that directly and/or indirectly play a role in disease development have become increasingly important. We were tasked with identifying possible genetic causes in a case of atypical relapsing remitting MS (RRMS) that also presented with porphyrialike symptoms and where demyelination was halted in the patient upon iron supplementation. As the patient had no parents or siblings that could be used as references for filtering exome variants, we aimed to develop a new prioritization strategy based on the combination of a predicted deleterious effect on the protein and existing knowledge of the biological roles of the genes and their contribution to relevant phenotypes.