The researchers used the case of a
nuclear family with three children who had childhood-onset
. Using whole exome sequencing
on the parents and children
To test this out, the team created
exactly the same mutations on one copy of the gene in mice using CRISPR-Cas9
technology. The mice that had one copy of the father's two variants did not
have any heart disease. Similarly, mice that had one copy of the mother's
single variant did not present with heart disease. Mice that had all three variants as in the three children presented
with heart defects
. The mice presented with damage to the structure and
function of the heart like in the children but also with changes in expressions
of hundreds of genes involved in the development of heart and coronary systems.
Between Gene Mutations and Heart Disease
According to first author Gifford, the
findings indicated that the inheritance of the mutated gene from the mother
compounded the problem caused by the father's genes and resulted in a more
severe form of heart disease.
Finally, the research
team also generated induced pluripotent stem cells from each
of the family members and transformed the stem cells into beating heart cells.
The cells from the children with all three mutations had signs of the disease.
The parent's cells did not show any signs of disease.
The research is significant because it
proves how people with the same mutation can have different forms of the
disease with varying severity. For example, the mutation MYH7 was previously
linked to the development of both
congenital and adult-onset heart disease. The research also indicates that the
modifier gene variant NKX2-5 has an impact on MYH7 and changes how the disease
According to Professor Srivastava,
professor of Pediatrics and Biochemistry and Biophysics at UCSF; the study
explains how modifier genes have a role in changing the severity and
development of any disease caused by genetic mutations. This discovery is a
stepping stone towards identifying genetic modifiers of diseases and using it
to develop novel targeted therapeutics.
The study titled "Oligogenic inheritance
of a human heart disease involving a genetic modifier" was published on May 31, 2019, in the journal Science. Reference :
- Gifford, A. C., Ranade, S. S., Samarakoon, R, Salunga, T.H. et al. (2019). Oligogenic inheritance of a human heart disease involving a genetic modifier. Science, Vol. 364, Issue 6443, pp. 865-870. - (https://science.sciencemag.org/content/364/6443/865)