a. Department of Medical Genetics and Center for Rare Diseases, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, China;
b. Nanhu Brain-computer Interface Institute, Hangzhou, Zhejiang 311100, China;
c. Zhejiang Key Laboratory of Rare Diseases for Precision Medicine and Clinical Translation, Hangzhou, Zhejiang 310009, China
Funds:
This work was supported by the grant (No. 82230062) from the National Natural Science Foundation of China to Zhi-Ying Wu.
Neurogenetic disorders have been recognized clinically for decades, and advances in clinical and genetic studies have identified more than 1700 monogenic causes of neurological diseases. Various types of mutations, including missense, truncating, and repeat expansions, have been reported in patients with neurogenetic disorders. It is now recognized that incomplete penetrance is common, with some individuals carrying disease-causing mutations remaining clinically unaffected. However, there is currently no comprehensive conceptual framework to categorize or explain these observations. Here, we review and integrate decades of evidence on incomplete penetrance in neurogenetic disorders to clarify its biological and mechanistic bases. Accordingly, four major themes are identified, encompassing genetic modifiers, epigenetic modifications, mosaicism, and environmental factors. These factors may act independently or interactively to influence pathogenic burden and functional network balance, ultimately determining whether a pathogenic mutation manifests clinically. Based on these insights, we highlight emerging perspectives and propose future research to fill gaps in our understanding. A deeper understanding of incomplete penetrance will be essential for generating genetic insights to support more effective genetic counseling, therapeutic interventions, and disease prevention in neurogenetic disorders.
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