Digenic Inheritance in Rare Disorders and Mitochondrial Disease—Crossing the Frontier to a More Comprehensive Understanding of Etiology

Author:

Neuhofer Christiane M.123,Prokisch Holger12ORCID

Affiliation:

1. Institute of Human Genetics, University Medical Center, Technical University of Munich, Trogerstr. 32, 81675 Munich, Germany

2. Institute of Neurogenomics, Computational Health Center, Helmholtz Centre Munich Neuherberg, Ingolstädter Landstraße 1, 85764 Oberschleißheim, Germany

3. Institute of Human Genetics, Salzburger Landeskliniken, University Hospital of the Paracelsus Medical University, Müllner Hauptstraße 48, 5020 Salzburg, Austria

Abstract

Our understanding of rare disease genetics has been shaped by a monogenic disease model. While the traditional monogenic disease model has been successful in identifying numerous disease-associated genes and significantly enlarged our knowledge in the field of human genetics, it has limitations in explaining phenomena like phenotypic variability and reduced penetrance. Widening the perspective beyond Mendelian inheritance has the potential to enable a better understanding of disease complexity in rare disorders. Digenic inheritance is the simplest instance of a non-Mendelian disorder, characterized by the functional interplay of variants in two disease-contributing genes. Known digenic disease causes show a range of pathomechanisms underlying digenic interplay, including direct and indirect gene product interactions as well as epigenetic modifications. This review aims to systematically explore the background of digenic inheritance in rare disorders, the approaches and challenges when investigating digenic inheritance, and the current evidence for digenic inheritance in mitochondrial disorders.

Funder

BMBF

EJPRD project GENOMIT

Publisher

MDPI AG

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