Digenic inheritance and genetic modifiers.

Area of Science:

• Genetics and Genomics
• Medical Genetics
• Molecular Biology

Background:

• Digenic inheritance (DI) represents the simplest form of multigenic etiology, involving two or more genes and potentially environmental factors.
• True DI is defined by the necessity and sufficiency of biallelic or triallelic mutations in two distinct genes (in cis or trans) to cause a specific pathology.
• In true DI, heterozygous mutations in either gene alone do not result in a recognizable phenotype, distinguishing it from other inheritance patterns.

Purpose of the Study:

• To review examples of genetic modifiers (GMs) and present recent notable cases of true digenic inheritance (DI).
• To discuss the broader literature on DI and its implications for understanding complex genetic diseases.
• To highlight the impact of high-throughput sequencing in identifying DI conditions and genetic modifiers for precision medicine.

Main Methods:

• Literature review of documented cases of digenic inheritance (DI) and genetic modifiers (GMs).
• Analysis of recent studies employing high-throughput sequencing to identify novel DI cases.
• Discussion of the genetic mechanisms underlying true DI and pseudo-DI.

Main Results:

• True digenic inheritance (DI) diseases are rare and follow non-Mendelian inheritance patterns.
• Co-inheritance of mutations in two distinct disease entities can lead to mixed phenotypes.
• Monogenic Mendelian conditions can exhibit broad phenotypic spectra due to pseudo-DI, influenced by genetic modifiers (GMs).

Conclusions:

• High-throughput sequencing is expected to uncover more cases of true digenic inheritance (DI) and genetic modifiers (GMs).
• Understanding DI and GMs is crucial for advancing precision medicine and personalized treatment strategies.
• Further research into DI mechanisms will enhance diagnostic capabilities for complex genetic disorders.