Incomplete Penetrance and Variable Expressivity: From Clinical Studies to Population Cohorts

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.

Keywords: expressivity; genomic sequencing; penetrance; rare disease; variant intepretation.

FIGURE 1

Conceptual representation of penetrance, expressivity, and pleiotropy. Squares represent individuals with the same genotype, with shaded squares indicating the individual displays the related phenotype and non-shaded squares indicating the individual does not display the related disease phenotype. Line one shows incomplete penetrance, where 60% of the individuals display the related phenotype. Line two shows that all individuals display the related phenotype, from severe manifestations to milder presentations. Line three shows incomplete penetrance and variable expressivity, where the genotype varies both in the severity of presentation and in penetrance across the population. Line four shows pleiotropy, whereby different phenotypes are caused by variants (represented by different shapes) in one gene.

FIGURE 2

Factors affecting penetrance and expressivity. (A) Examples of different biological mechanisms that can affect the overall penetrance and expressivity of monogenic disease-causing genetic variants. Figure created using BioRender.com. (B) Summary of factors affecting penetrance and expressivity across the genome, from global modifiers that can have wide-ranging overall effects to expression of the gene containing causal variants and to specific causal variants that have more distinctive effects.

FIGURE 3

Penetrance in clinical versus population cohorts. Penetrance of genetic variants identified in clinical cohorts tends to be higher than the same variants identified in population cohorts, which can manifest as earlier disease onset, less severe disease, or a larger proportion of affected individuals. Due to inherent ascertainment biases in both types of cohorts, the penetrance of variants in the general unselected population is likely to lie somewhere in-between.

FIGURE 4

Threshold model of disease. Some deleterious monogenic variants are sufficient to cause the disease alone and do not need any genetic modifiers to cause the disease phenotype. Other monogenic variants may be incompletely penetrant and only display a disease phenotype when accompanied by other genetic or non-genetic factors that raise them above the clinical threshold for disease presentation. In the latter scenario, individuals may have the same underlying causal variant but have very different phenotypic presentations depending upon their modifying factors.