A recent study published by members of the SHaRe Cardiomyopathy Registry found that genetic test results for HCM are more definitive and helpful to patients when testing has been carried out at a high volume HCM center – especially a center that shares genetic data with other HCM centers.
A recent paper by researchers in Australia, published this week in Circulation: Cardiovascular Genetics, found more than one rare HCM gene in 4% of patients in a 758 patient sample group.
The researchers found that those patients with multiple rare HCM genes tended to present with HCM at a younger age, were more likely to experience cardiac arrest or death from other causes, and were more likely to require a heart transplant.
In general, few patients have multiples of mutations commonly associated with HCM. See this Canadian study from April of this year which found that multiple mutations were less prevalent and harmful than previously thought.
Scientists, in a follow up to three earlier, less successful, Chinese experiments, have for the first time used a recently developed gene editing process known as “CRISPR” to remove a genetic defect from a human embryo. The specific defect that the scientists targeted was a mutation in MYBPC3, a common genetic cause of hypertrophic cardiomyopathy (HCM).
What Happened in the Study?
The study authors consisted of a multi-national team of geneticists, cardiologists, fertility experts and embryologists. Led by Dr. Shoukhrat Mitalipov of Oregon Health Sciences University, in collaboration with researchers at the Salk Institute in La Jolla, CA, China and South Korea, the researchers were able to largely remove the HCM gene MYBPC3 from very early stage human embryos.
Their research involved using eggs from 12 healthy female donors, and sperm from a male HCM patient with the MYBPC3 gene. When gene-editing components were introduced to the egg along with the sperm, prior to fertilization of the egg, approximately 3/4 of the embryos repaired themselves using the DNA blueprint provided by the normal, non-mutated copy of the gene from the unaffected female. This was somewhat surprising to researchers, who had theorized that cells would replicate using a blueprint from the repaired paternal gene – not the healthy gene of the mother.
Ultimately, genes were corrected in 42 of 58 embryos, constituting 72.4% of the total, a higher proportion than expected, and far more than any correction shown in previous experiments.
Implications for the Future
This technique is still far from general usage and will require further study and refinement. And, currently it is not legal in the United States since the Food & Drug Administration currently prohibits medical gene editing which would impact future generations.
However, it would be possible for this technique to be used alongside current technology to assist families with genetic diseases like HCM. If used in conjunction with pre-implantation genetic testing and in-vitro fertilization (PGD), the technique could repair the large proportion of embryos (roughly 50%) which must be discarded due to genetic defectiveness.
While there are critics who say that this technology will lead to “designer babies” and that it creates troubling ethical issues for society, most HCM patients believe that it provides a ray of hope, so that hopefully one day, in the not-too-distant-future, our children and grandchildren will be free of the affliction that has permeated our lives, as well as the lives of our siblings, our parents, our aunts and uncles, our cousins, our grandparents, and our great-grandparents.
As this story was reported by all major news sources, links to many of the articles can be found below.
NOTE THAT APPROXIMATELY A MONTH AFTER THE PUBLICATION OF THIS ARTICLE, THE RESULTS HAVE BEEN CALLED INTO QUESTION BY OTHER SCIENTISTS.
See this article in MIT Technology Review, this article in Science Magazine, this article in Nature, and this article in The Scientist, all of which cite this article in BioRxiv which poses alternative theories for the results claimed by the original paper.
Dr. Heidi Rehm is a human geneticist and clinical laboratory director at Harvard Medical School who has spent much of her career studying the genetics of cardiomyopathy.
Imagine her surprise when she found out that she, her mother and her daughter all have a mutation in the MYH7 gene which has been associated with dilated cardiomyopathy!
The unexpected revelation came as an indirect result of a visit to her daughter’s orthodontist. When one of her daughter’s teeth was delayed coming in, the orthodontist suggested that there might be a genetic cause for the late tooth. This provided the idea behind her high school daughter’s summer biology research project: 2 weeks in her mom’s lab sequencing her exome, looking for a genetic cause for her delayed tooth.
Though the mouth genetics turned out to be normal and the tooth eventually arrived, an totally unexpected incidental finding turned up instead: a variation in the MYH7 gene which has been associated with dilated cardiomyopathy.
Researchers from around the globe have joined together to study an unlikely subject in order to understand the genetics of HCM according to a paper published today in the journal eLIFE.
Dr. Christine Seidman, a cardiologist from Harvard Medical School, Dr. James Ware a geneticist from the MRC London Institute of Medical Sciences at Imperial College London, and Dr. Raúl Padrón, a structural biologist at the Venezuelan Institute for Scientific Research, have joined forces in order to study the tarantula.
The reason for their focus on the tarantula is because the proteins comprising the muscles inside the furry spider are actually very similar to proteins inside the human heart.
Dr. Seidman, who had taken note of Dr. Padrón’s work with spiders, sought him out at a meeting to discuss the similarity of heart proteins to those in tarantula muscles and asked him whether they might collaborate.
By studying the way that the spider proteins interact with one another, the scientists hope that they will gain further insight into whether and how certain genes cause different types of hereditary cardiomyopathy, including hypertrophic and dilated.
I hope that they find the answers soon, before any tarantulas escape from their lab!
A study published this week by HCM researchers in Canada found that double mutations in patients with hypertrophic cardiomyopathy are much less common than previously thought. In particular, researchers found that except for those with double mutations in the gene MYBPC3, there is not much data to support the finding that there is a worse clinical course for those patients who have double HCM mutations.
Hence, in the absence of extraordinary circumstances, such as two MYBPC3 mutations, the researchers caution that double mutations should not be the sole justification for the insertion of an implantable defibrillator.
The study looked at patients >18 years of age who underwent genetic testing at the Toronto General Hospital between January 2005 and June 2016. Out of a sample of 1411 patients, 9% of those who were gene-positive patients had 2 genes, but only in 1 case (0.4%) were both genes classified as those known to cause HCM.
In addition to looking at their own patients, the researchers also re-examined data from previously published studies. Similarly, they found when they re-analyzed the data that only 0.4% of the 8% of patients previously found to have double mutations in fact carried multiple pathogenic mutations.
When a patient is the only person in the family ever diagnosed with HCM, s/he will often wonder whether their disease is, in fact, genetic. S/he will also wonder whether it will be necessary for all first degree relatives to undergo serial screenings for the rest of their lives.
In answer to this concern, Australian researchers have recently identified a subset of HCM patients who appear to have a non-familial form of the disease and whose relatives may be candidates for less stringent screening protocols.
The study, just published in Circulation: Cardiovascular Genetics by Dr. Jodie Ingles and Dr. Chris Semsarian, found that this group, having neither genetic mutation associated with HCM nor family history of HCM, comprises approximately 40% of all HCM patients. Non-familial HCM patients are more likely to be older when diagnosed, and they often present with non-asymmetric hypertrophy and hypertension. And, these HCM patients appear to have a more favorable clinical course, with a better track record of survival from major cardiovascular events.
The researchers point out that by sorting patients into more distinct subgroups, doctors will be able to provide more personalized and evidence-based care to patients and their families. In particular, their recommendation is that first-degree relatives of non-familial HCM patients need only be screened one or more times in adulthood. Less frequent follow up surveillance is also suggested, in contrast with the more intensive screening guidelines recommended for family members of patients with familial HCM.
The same study also found that gene positive children without overt signs of the disease are at relatively low risk for cardiac events.
The study included 119 children, positive for at least one HCM gene, with a median age of 12.1 years. 8 of these children (6.7%) received a HCM diagnosis within the time span of the study [which varied from 3.1 to 10.7 years]. 1 of the 8 diagnosed children suffered a cardiac event which necessitated implantation of an implantable cardioverter defibrillator or ICD.
The study did caution, however, that because severe hypertrophy and cardiac events may develop, it is important to refine risk stratification and long term follow up procedures for gene positive kids.
This informative blog article about genetic testing features practical advice about genetic testing and is taken from answers provided in a live presentation by Drs. John Jefferies and Ivan Wilmot.
Issues addressed include: how the test is administered, insurance issues related to the test and the meaning of a positive genetic test.
A study published today by Dr. Carolyn Ho, of Boston’s Brigham and Women’s Hospital, and colleagues, including Australia’s Christopher Semsarian, found that there are several factors which appear to stand out in young people who later go on to develop HCM.
The children/adolescents/young adults who participated in the study all carried at least one gene associated with HCM, and were members of families with strong histories of HCM. None of the 38 young people had clinical manifestations of HCM at the beginning of the study period, while 4 went on to develop HCM by the end of the study. In collecting the data analyzed in the study, the test results of the 4 individuals with HCM were compared to the 34 individuals that did not have HCM at the end of the study.
The factors associated with the development of overt HCM, as identified by the researchers, were: abnormal left ventricular relaxation and higher ejection fraction, EKG changes, longer mitral valve leaflets, higher NT-proBNP concentrations and troponin values.
In the conclusion, the authors acknowledged the need for further research and investigation in order to better understand the natural course and evolution of the disease.