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.

WHY ? Because some are autosomal dominant (AD) & some are autosomal recessive (AR) ...

"Desminopathy is one of the most common intermediate filament human disorders associated with mutations in closely interacting proteins, desmin and alphaB-crystallin. Desminopathy is inherited as autosomal dominant or autosomal recessive trait, and in some patients it is caused by de novo mutations"

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!

Regarding (cf. answer 001 above) : First sentence:

"Desminopathy is one of the most common intermediate filament human disorders associated with mutations in closely interacting proteins, desmin and alphaB-crystallin." See/cf:

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"

can be found in:

https://link.springer.com/referenceworkentry/10.1007/978-3-540-29676-8_474

=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:

https://link.springer.com/referenceworkentry/10.1007/978-3-540-29676-8_474#citeas

>>Definition and Characteristics

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!

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.

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

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