Incomplete penetrance and variable expressivity in monogenic diabetes; a challenge but also an opportunity

Monogenic Forms of Diabetes (MFD) account for about 3% of all diabetes, and their accurate diagnosis often results in life-changing therapeutic reassignment for the patients. Like other Mendelian diseases, reduced penetrance and variable expressivity are often seen in several different types of MFD, where symptoms develop only in a portion of the persons who carry the pathogenic variant or vary widely in symptom severity and age of onset. This complicates diagnosis and disease management in MFD. In addition to its clinical importance, knowledge of genetic modifiers that confer penetrance and expressivity variability opens possibilities to identify protective genetic variants which may help probe the mechanisms of more common forms of diabetes and shed light in new therapeutic strategies. In this review, we will mainly address penetrance and expressivity variation in different types of MFD, factors that confer such variations and opportunities that come with such knowledge. Related literature was searched in PubMed, Medline and Embase. Papers with publication year from 1974 to 2023 are included. Data are either sourced from literatures or from OMIM, Clinvar and 1000 genome browser.

Automated summary

Monogenic Forms of Diabetes (MFD) account for approximately 3% of all diabetes cases and accurate diagnosis can lead to life-changing treatment adjustments. However, MFD exhibits reduced penetrance and variable expressivity, making diagnosis and management challenging. Understanding the genetic modifiers that contribute to these variations not only has clinical importance, but also provides opportunities to explore mechanisms and therapeutic strategies for more common forms of diabetes. This review discusses the penetrance and expressivity variation in different types of MFD, the factors influencing these variations, and the potential benefits of such knowledge.