Compensated pathogenic variants in coagulation factors VIII and IX present complex mapping between molecular impact and hemophilia severity.

ABSTRACT: Compensated pathogenic deviations (CPDs) are sequence variants that are pathogenic in humans but neutral in other species. In recent years, our molecular understanding of CPDs has advanced substantially. For example, it is known that their impact on human proteins is generally milder than that of average pathogenic mutations and that their impact is suppressed in non-human carriers by compensatory mutations. However, prior studies have ignored the evolutionarily relevant relationship between molecular impact and organismal phenotype. Here, we explore this topic using CPDs from FVIII and FIX and data concerning carriers' hemophilia severity. We find that, regardless of their molecular impact, these mutations can be associated with either mild or severe disease phenotypes. Only a weak relati

SUBMITTER: Marin O 

PROVIDER: S-EPMC6606640 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature