Impacts on Genetic of Complex Diseases

Incomplete penetrance refers to a situation where not all individuals carrying a specific genetic mutation express the associated phenotype or disease. In other words, despite having the genetic predisposition for a certain condition, some individuals do not exhibit the traits or symptoms of the condition. This phenomenon is seen in both autosomal dominant and autosomal recessive conditions and contrasts with Mendelian genetics, where a specific genotype is expected to result in a predictable phenotype​​.

Incomplete penetrance is closely linked to the concepts of penetrance and expressivity in molecular genetics. Penetrance is about whether there is a clinical expression of the genotype in an individual, while expressivity describes the differences observed in the clinical phenotype among individuals with the same genotype​​. The variability in gene expression underlies incomplete penetrance, as demonstrated in studies where large variations in gene expression during development lead to different outcomes​​.

In the context of complex diseases like Multiple Sclerosis (MS), incomplete penetrance is particularly significant. These diseases often have a genetic component, but their expression can be influenced by a combination of genetic, environmental, and lifestyle factors. Understanding incomplete penetrance helps explain the variability in disease expression even among individuals with similar genetic backgrounds. For example, in congenital Long QT Syndrome (LQTS), incomplete penetrance and variable expressivity have become clinical hallmarks, with disease penetrance varying among individuals carrying the same genetic marker​​.

Our study explores the role of common and rare genetic variants in multiplex MS families. It reveals that about half of MS heritability remains unexplained despite identifying numerous common risk variants and candidate low-frequency and rare variants. The study involved seven multiplex MS families, focusing on genetic factors that increase MS risk. The researchers used linkage analysis, homozygosity mapping, and exome sequencing to identify these factors. They also conducted weighted sum score and polygenic risk score (PRS) analyses in MS families, sporadic MS cases, non-MS control families, and independent, ancestry-matched controls.

Key findings from the study include:
Familial MS cases exhibited a significantly higher burden of common risk variation compared to population controls and control families.
Sporadic MS cases tend to have a higher PRS compared to familial MS cases, suggesting a higher rare risk variation burden in the families.
The study identified several fully penetrant, rare, or low-frequency variants in MS families. Some families showed higher sum score and PRS values in MS cases compared to unaffected family members, while others did not exhibit this pattern, indicating the role of intra-familial genetic differences in MS risk.
In some families, the increased MS risk was largely attributable to common MS-associated variants, while in others, rarer variants further modified the risk.
The study emphasizes the complexity of MS heritability, highlighting the interplay of common and rare genetic variants and the need for further investigation to fully understand the genetic basis of MS.
In summary, incomplete penetrance is a key factor in understanding the genetic basis of complex diseases like MS. Its investigation in familial studies helps unravel the intricate interplay of genetic factors that lead to the development or absence of disease in individuals carrying specific mutations. This knowledge is crucial for advancing personalized medicine, genetic counseling, and targeted therapies, especially in diseases with a strong genetic component. Understanding incomplete penetrance provides a more nuanced view of how genetics influences disease risk and expression, moving beyond the simplistic one-gene-one-disease model to a more comprehensive understanding of human health and disease.