VarClot – Effect of DNA non-coding variants in the MYH9 gene region in the regulation of blood clotting.

Study code
NBR36

Lead researcher
Dr Mattia Frontini

Study type
Participant re-contact

Institution or company
University of Cambridge

Speciality area
Haematology

Summary

Variants in the MYH9 gene are the cause of several syndomes (May Hegglin, Sebastian, Fechtner and Epstein).  The syndromes share features (thrombocytopenia, giant platelets, leucocytes with cytoplasmic inclusion bodes and often hearing loss and nephritis) which can be misdiagnosed as immune thrombocytopenia.

This study looks at rare variants within the MYH9 gene.  The MYH9 gene plays an important role in cell motility and shape.  The next step is to see if rare variants within this gene (with large effects) effectively act as ‘dimmers & switches’ affecting the features of the gene.  Correct identification could result in improvements in the DNA test for this group of conditions.  This is turn could potentially provide a genetic explanation for the 2,400 patients within 10,000 who currently do not have a confirmed molecular diagnosis.

The MYH9 gene encodes for a protein belonging to the conventional non-muscle myosin family and it plays an important role in cell motility and in maintaining cell shape. Coding variants changing the amino acids sequence of MYH9 are the cause of several syndromes (May-Hegglin, Sebastian, Fechtner and Epstein) sharing the following features: thrombocytopenia, giant platelets, leucocytes with cytoplasmic inclusion bodies and often, but not always, hearing loss and nephritis. These are often misdiagnosed as immune thrombocytopenia and inappropriately treated when treatment with a thrombopoietin mimetic has been shown to be extremely effective. A similar phenotype is presented also in a mouse model where one of the two copies of the gene has been deleted. We postulate that the same situation can happen when one of the two copies is not expressed or both are expressed at sub-optimal levels, because of non-coding variants in the regulatory elements of the gene that act as ‘dimmers & switches’ modulating the amount of gene product made. Having identified the regulatory elements of MYH9, our next step is to investigate whether rare variants, with large effects, in these regulatory elements, result in the above described symptoms. This could result in improvements in the DNA test for this group of conditions, potentially providing a genetic explanation to some of the 2,400 out of 10,000 bleeding disorders patients who currently do not have a confirmed molecular diagnosis.