Abstract

The same genetic variant found in different individuals can cause a range of diverse phenotypes, from no discernible clinical phenotype to severe disease, even among related individuals. Such variants can be said to display incomplete penetrance, a binary phenomenon where the genotype either causes the expected clinical phenotype or it does not, or they can be said to display variable expressivity, in which the same genotype can cause a wide range of clinical symptoms across a spectrum. Both incomplete penetrance and variable expressivity are thought to be caused by a range of factors, including common variants, variants in regulatory regions, epigenetics, environmental factors, and lifestyle. Many thousands of genetic variants have been identified as the cause of monogenic disorders, mostly determined through small clinical studies, and thus, the penetrance and expressivity of these variants may be overestimated when compared to their effect on the general population. With the wealth of population cohort data currently available, the penetrance and expressivity of such genetic variants can be investigated across a much wider contingent, potentially helping to reclassify variants that were previously thought to be completely penetrant. Research into the penetrance and expressivity of such genetic variants is important for clinical classification, both for determining causative mechanisms of disease in the affected population and for providing accurate risk information through genetic counseling. A genotype-based definition of the causes of rare diseases incorporating information from population cohorts and clinical studies is critical for our understanding of incomplete penetrance and variable expressivity. This review examines our current knowledge of the penetrance and expressivity of genetic variants in rare disease and across populations, as well as looking into the potential causes of the variation seen, including genetic modifiers, mosaicism, and polygenic factors, among others. We also considered the challenges that come with investigating penetrance and expressivity.

MeSH

Signs And Symptoms, Genotype, Rare Diseases, Penetrance, Phenotype

Cited by

• Prenatal diagnosis of recurrent hypoplastic left heart syndrome associated with MYH6 variants: a case report. BMC Cardiovasc Disord, 2023
• Rare variants found in multiplex families with orofacial clefts: Does expanding the phenotype make a difference? medRxiv, 2023
• Genetic determinants of blood pressure and heart rate identified through ENU-induced mutagenesis with automated meiotic mapping. Sci Adv, 2024
• Scrutinizing neurodegenerative diseases: decoding the complex genetic architectures through a multi-omics lens. Hum Genomics, 2024
• Common genetic modifiers influence cardiomyopathy susceptibility among the carriers of rare pathogenic variants. HGG Adv, 2025
• Parent-of-origin testing of prenatal copy number variations: a retrospective study of 167 family cases. Sci Rep, 2025
• Expanding the mutational spectrum of ReNU syndrome: insights into 5' Stem-loop variants. Eur J Hum Genet, 2025
• Reduced Penetrance is Common Among Predicted Loss-of-Function Variants and is Likely Driven by Residual Allelic Activity. medRxiv, 2024
• A young-onset type 2 diabetic Chinese girl with familial renal glycosuria caused by a novel mutation in SLC5A2: A case report. J Diabetes, 2023
• Late-onset sensory-motor axonal neuropathy, a novel SLC12A6-related phenotype. Brain, 2023
• A Missense Variant in CASKIN1's Proline-Rich Region Segregates with Psychosis in a Three-Generation Family. Genes (Basel), 2023
• "Incidentally" discovered Von Hippel Lindau disease: an emerging clinical phenotype. Oncologist, 2025
• The role of public health in rare diseases: hemophilia as an example. Front Public Health, 2025
• Clinical characteristics of hereditary spherocytosis with red blood cell membrane protein gene variants. Front Pediatr, 2025
• Noncoding RNAs and Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes in Cardiac Arrhythmic Brugada Syndrome. Cells, 2023
• Lack of Evidence for the Role of the p.(Ser96Ala) Polymorphism in Histidine-Rich Calcium Binding Protein as a Secondary Hit in Cardiomyopathies. Int J Mol Sci, 2023
• Protein-folding chaperones predict structure-function relationships and cancer risk in BRCA1 mutation carriers. Cell Rep, 2024
• The Excess of Carriers in Rare Disorders Suggests a Nonpathogenic Effect for Most Variants of Uncertain Significance. Clin Genet, 2025
• How do stochastic processes and genetic threshold effects explain incomplete penetrance and inform causal disease mechanisms? Philos Trans R Soc Lond B Biol Sci, 2024
• Antagonizing regulatory elements of a conserved flowering gene mediate developmental robustness. Proc Natl Acad Sci U S A, 2025