Multilocus inheritance and variable disease expressivity in rare disease

Abstract One of the prominent challenges of rare disease diagnosis and discovery has been the increasing observations of seemingly non-Mendelian inheritance. Such observations often offer a foothold by which to investigate novel molecular mechanisms underlying rare disease traits. In this chapter, the characteristics of multiple molecular diagnoses, mutational load, compound inheritance of rare and common variants, and how they contribute to blended phenotypes, apparent phenotypic expansion, variable expressivity, and incomplete penetrance are discussed. The Clan Genomics hypothesis provides an intellectual framework through which to conceptualize these molecular mechanisms and consequent variants and variant combinations that are private to a studied family unit.