Non-Mendelian Factors of Inheritance in Huntington’s Disease

Navigating the scientific aspects of Huntington’s disease can be a bit overwhelming, with research sometimes feeling like a maze. Rest assured, we are here to simplify it for you. Our goal is to provide information in a way that not only keeps you informed but also helps you grasp the complexities of Huntington’s disease. Below, we dive into the fascinating non-mendelian factors of inheritance. If you have not had the chance yet, we recommend reading the “Mechanisms of HD” content to build a solid foundation. Huntington’s disease, characterised by the abnormal expansion of CAG repeats in the HTT gene, was initially associated with mendelian genetics. However, our understanding has evolved to uncover additional layers of complexity. In this section, we discuss three crucial aspects: Reduced Penetrance, Anticipation, and Non-CAG Modifiers. These factors challenge traditional views by demonstrating that predicting the course of Huntington’s disease involves more than just counting CAG repeats.

Reduced penetrance

The term “penetrance” measures the proportion of people who develop the symptoms of any condition as opposed to the individuals who live their entire life without developing any symptoms associated to the gene mutation. Surprisingly, some individuals carrying the mutated form of the HTT gene (with 36-39 CAG repeats) never show symptoms of Huntington’s disease. Reduced penetrance is likely influenced by genetics, environment, and lifestyle, making it challenging to predict a person’s risk of passing on the condition.

Figure 1: Reduced penetrance

In Figure 1, the lighter shade represents an individual with a CAG repeat between 36-41, who does not exhibit any symptoms of Huntington’s Disease throughout their lifetime, despite having a sibling with the same number of CAG repeats who does exhibit symptoms similar to their parent. However, the non-symptomatic sibling will still produce abnormal protein and is at a 50% risk of having children who can develop Huntington’s Disease.

Anticipation

In families with Huntington’s disease, it’s observed that the disease’s onset occurs earlier in successive generations. This phenomenon, called anticipation, may be linked to increased instability in the CAG repeats during reproduction, leading to earlier symptom appearance.

Figure 2: Anticipation

In figure 2, the increasing intensity of the colour with each passing generation signifies increase in CAG repeats, a phenomenon that occurs during reproduction. This increase in the CAG repeats is assumed to result in early onset and severe symptoms in each passing generation.

Non-CAG modifiers

Recent studies suggest that factors such as age, lifestyle, and other genes beyond the CAG repeats can impact symptom development in Huntington’s Disease. For instance, individuals with 38 CAG repeats may begin experiencing symptoms in their early 50s, while others with the same number of CAG repeats may not show any symptoms until their late 60s. This variation is believed to be influenced by factors such as lifestyle choices, mental health, and gut health. Additionally, genes involved in DNA repair mechanisms and other adjacent genetic factors also play a role in determining the age of symptom onset.

Understanding these non-mendelian factors sheds light on the complexity of Huntington’s disease. Contrary to earlier beliefs, the number of CAG repeats might not directly correlate with the disease’s progression, symptoms, or duration.