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- Title
Digenic Inheritance in Rare Disorders and Mitochondrial Disease—Crossing the Frontier to a More Comprehensive Understanding of Etiology.
- Authors
Neuhofer, Christiane M.; Prokisch, Holger
- 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.
- Subjects
HEREDITY; MITOCHONDRIAL pathology; HUMAN genetics; PHENOTYPIC plasticity; ETIOLOGY of diseases; PHYLOGEOGRAPHY
- Publication
International Journal of Molecular Sciences, 2024, Vol 25, Issue 9, p4602
- ISSN
1661-6596
- Publication type
Article
- DOI
10.3390/ijms25094602