Mendelian disorders of the epigenetic machinery: a decade of insights into the molecular basis.

Abstract

The Mendelian disorders of the Epigenetic Machinery (MDEMs), or Chromatinopathies, are now understood to be a collectively common cause of childhood neurodevelopmental delays and intellectual disability. In the past decade, the chromatin and gene expression consequences of heterozygous chromatin regulator disruption have been investigated in various disease models, yielding insights into the molecular pathogenesis of MDEMs. In this review, we highlight some of these results - drawing upon studies of representative MDEMs - together with potential unifying concepts. We propose that MDEMs are characterized by distributed, often subtle chromatin and gene expression perturbations, which impact diverse cellular pathways and processes and are frequently shared between distinct disorders. In this sense, they occupy an intermediate space between classical monogenic disorders and complex traits. We propose potential explanations for the variable expressivity in MDEMs and conclude by considering how technological advances can now enable a deeper and more precise mechanistic characterization of this important Mendelian disease group.