Why do some relatives with the same desmin mutation have bradycardia and others do not?

This may be due to incomplete penetrance, which has been described for other types of desmin mutations, e.g. https://www.ahajournals.org/doi/10.1161/01.cir.100.5.461, https://www.nmd-journal.com/article/S0960-8966(02)00271-7/abstract

If you need help getting started with the terminology, try reading about pedigrees & incomplete penetrance in a textbook (lots of good free ones).

If you need specifics of the T341P DES mutation, start with OMIM. There will be links to medical studies & scientific publications.

Dear Sabine Strehl, Katie A S Burnette and Sinan Ibaguner, thank you very much for your answers and links!

Usually reduced penetrance refers to the observation that not everybody the caries a mutation, dominant or recessive, develops the associated disease.

Variation in disease phenotype or onset or severity is often the result of modifier genes. Also, allelic effects can be the cause when different mutations are located in different functional domains of the protein. Finally, environmental effects cannot be excluded as a cause of variation.

Dear Jurgen Naggert, thank you very much for your reply!

è https://onlinelibrary.wiley.com/doi/10.1002/cm.21118 : =

Intrinsic Structural Disorder in Cytoskeletal Proteins by :

Mainak Guharoy, Beata Szabo, Sara Contreras Martos, Simone Kosol, Peter Tompa

First published: 12 June 2013 https://doi.org/10.1002/cm.21118

Citations: 50

Cytoskeleton, Volume70, Issue10

Special Issue:Biophysical Approaches for Investigation of the Cytoskeleton Part I October 2013 Pages 550-571

In: Section: Involvement in Disease

„….Desminopathy is one of the most common intermediate filament human disorders associated with mutations in closely interacting proteins, desmin and alpha B-crystallin [Clemen et al., 2009]. …“

Clemen CS, Fischer D, Reimann J, Eichinger L, Muller CR, Muller HD, Goebel HH, Schroder R. 2009. How much mutant protein is needed to cause a protein aggregate myopathy in vivo? Lessons from an exceptional desminopathy. Hum Mutat 30: E490–E499.

Volume 30 Issue 3 Page E490-E499 DOI: 10.1002/humu.20941 è https://onlinelibrary.wiley.com/doi/10.1002/humu.20941

Second sentence: See / cf.:

„Desminopathy is inherited as autosomal dominant or autosomal recessive trait, and in some patients it is caused by de novo mutations"

=Encyclopedia of Molecular Mechanisms of Disease,

Desminopathy Reference work entry pp 518–519

Cite as: Goldfarb, L.G. (2009). Desminopathy. In: Lang, F. (eds) Encyclopedia of Molecular Mechanisms of Disease. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-540-29676-8_474:

Desminopathy is a systemic disorder in which dysfunctional mutations in desmin or α B-crystallin severely affect the intracellular filamentous network in cardiac and skeletal muscle cells, leading to accumulation of insoluble granulo-filamentous material. Desminopathy is inherited as autosomal dominant or autosomal recessive trait, and in some patients it is caused by de novo mutations.

Dear Wolfgang H. Muss, thank you very much for your detailed answer and links to articles!

The presence of different symptoms, like bradycardia, in relatives with the same desmin mutation can be explained by several factors:

1. **Genetic Penetrance**:

- Penetrance refers to the proportion of individuals with a particular genetic mutation who actually exhibit symptoms. A mutation may not always lead to disease in every individual carrying it. Some relatives may have the desmin mutation but do not manifest bradycardia due to incomplete penetrance.

2. **Variable Expressivity**:

- Even with the same genetic mutation, the severity and specific symptoms can vary. This is called variable expressivity, where some individuals may experience bradycardia, while others with the same mutation may not.

3. **Modifier Genes**:

- Other genes in an individual’s genome, known as modifier genes, can influence the way a mutation is expressed. In some people, modifier genes might mitigate the impact of the desmin mutation on heart function, preventing bradycardia from developing.

4. **Environmental Factors**:

- Lifestyle, diet, exercise, and other external factors may influence how the mutation manifests. For instance, an individual with a heart-healthy lifestyle might reduce stress on the heart and may not show symptoms like bradycardia as quickly or at all.

5. **Epigenetic Factors**:

- Epigenetic modifications, such as DNA methylation or histone modification, can affect how genes are expressed without changing the DNA sequence. Different epigenetic patterns in relatives with the same mutation could lead to differences in whether bradycardia develops.

6. **Age of Onset**:

- Desmin-related cardiac issues, including bradycardia, may have varying onset times. Some relatives might develop bradycardia later in life, while others show symptoms earlier.

7. **Stochastic Factors**:

- Random biological events can sometimes influence gene expression and disease progression. Even with the same genetic mutation, unpredictable factors might explain why some relatives develop bradycardia and others do not.

These factors contribute to why people with the same genetic mutation can exhibit different symptoms, such as bradycardia.

Dear Shler Ali Khorsheed, thank you very much for your detailed answer!

I am flabbergasted by the answers provided here (penetrance) which in fact means, we don't understand the mechanism by which genotype and phenotypes diverge!

This is similar to the term idiopathic used in too many diseases.

We have a term, therefore it is acknowledged (but not understood), next question, please 😁

Dear Samy Kijner, thank you very much for your answer!

I assume that in the next 3 years the mechanism of progression of desminopathy T341P will be revealed, then there will be no questions.

The difference in clinical presentation between the son & the father, despite both having the T341P DES mutation in a heterozygous state, is dependent on other genetic variations, which can influence the expression & impact of the desmin mutation. These genetic modifiers can either exacerbate or mitigate the effects of the primary mutation, leading to different clinical outcomes. Epigenetic changes, like DNA methylation & histone modifications can also affect gene expression without altering the DNA sequence & can be influenced by environmental factors as well. Differences in lifestyle, diet, physical activity, exposure to environmental stressors can also impact how the mutation manifests. For example, factors like physical activity levels along with overall cardiovascular health can influence the development of bradycardia. The age at which symptoms appear can vary. The son might be at an age where the mutation's effects are more pronounced, while the father might not have exhibited symptoms at the same age or might have developed compensatory mechanisms over time. These factors highlight the complexity of genetic conditions and the importance of considering both genetic and non-genetic influences when assessing clinical presentations as such.

Dear Tanupriya Mukherjee, thank you very much for your reply!

In the identified case of desminopathy T341P in father and son, the manifestation of the disease was found to be from the age of 30. They had the same following factors (they lived together): nutrition, environment, lifestyle, physical activity. The obvious difference was that the father smoked, and the son does not smoke. Skeletal muscle atrophy in the son develops in the same way as in the father.

The father died at 49, and he did not have bradycardia. And the son developed bradycardia from the age of 40, now he is 45 years old.

The variation in symptoms, such as bradycardia, among relatives with the same **desmin mutation** can be attributed to several factors:

1. **Genetic Background**: Even with the same mutation, individuals may have other genetic differences (called genetic modifiers) that influence how the desmin mutation affects their heart. These modifiers can either exacerbate or mitigate the effects of the mutation, leading to variations in symptoms like bradycardia.

2. **Epigenetic Factors**: Epigenetic modifications, such as DNA methylation and histone modification, can regulate how genes are expressed without altering the underlying DNA sequence. This can result in different clinical manifestations even in individuals with the same genetic mutation.

3. **Environmental and Lifestyle Factors**: Factors like physical activity, diet, and other external influences can affect heart health and potentially modify the impact of the desmin mutation on the development of bradycardia.

4. **Penetrance and Expressivity**: Some genetic mutations show **incomplete penetrance**, meaning not everyone with the mutation will display the trait or symptom (in this case, bradycardia). Additionally, **variable expressivity** refers to how severe or mild the symptoms may be among individuals with the same mutation.

5. **Age of Onset and Disease Progression**: Some individuals may develop symptoms later in life or may not yet have progressed to the point where bradycardia manifests, especially if the disease has a delayed onset.

These factors combine to create a situation where some family members with the same desmin mutation develop bradycardia, while others do not.

Dear Shler Ali Khorsheed, thank you very much for your detailed answer!

Bradycardia is a condition in which the heart rate is below the normal range and is often associated with a variety of factors, including genetic mutations, environmental factors, and individual physiological characteristics. Although some relatives may carry the same desmin mutation, their clinical manifestations may vary, which can be attributed to several factors:

1. Variation in gene expression: Even with the same mutation, gene expression levels may vary between individuals, which may lead to different physiological responses.

2. Genetic background: Each person's genetic background is unique. Variants, mutations, or polymorphisms in other genes may affect heart function and heart rate, so bradycardia may vary from person to person even with the same desmin mutation.

3. Environmental factors: Lifestyle, diet, exercise habits, medication use, and other environmental factors can also affect heart health and may cause some relatives to show bradycardia while others are not affected.

4. Age and gender differences: Age and gender may affect the physiological function of the heart and its response to the mutation. The same mutation may affect people of different ages or genders differently.

5. Comorbidity: Other health problems or underlying diseases (such as high blood pressure, diabetes or other heart diseases) may affect an individual's heart rate, so even if they have the same gene mutation, their bradycardia may be different.

In summary, although relatives with the same desmin mutation may share certain genetic characteristics, the interaction of multiple factors may cause them to show different clinical features in bradycardia.

Dear Seraphina Seraphina Seraphina, thank you very much for your detailed answer!