Monday, November 9, 2009

Long QT Syndrome, location matters

I just saw a family who had Long QT with a KCNQ1 mutation ripping through them. Which is why I loved this email I received from one of my long time readers the day after I saw them.

One of my favorite lines from this paper was

"Nothing tests the tools of clinical risk prediction quite like sudden death."

Ummmm......Uh Huh.

They go on to say

"The difficulties encountered in the clinical application of genetic data, even in inherited conditions such as the long-QT syndrome (LQTS), in which the transmitted risk of sudden death is several hundred-fold greater than that in the general population, highlight some of the hurdles that must be overcome if DNA diagnosis is ever to transform cardiovascular medicine. "

The reader then went on to send me a release from ScienceDaily

But I should probably give you some background.

Long QT syndrome is a condition where the electrical activity in your heart is faulty. In fact, the conduction system has dangerous delays that can lead to dangerous heart rhythms which cause sudden death.

It is so serious that in every single patient I see, I ask "Has anyone in your family died suddenly or in their sleep? Has anyone had any crib death? Any sudden unexplainable car accidents?"

This is my lay screen for Sudden Cardiac Death (SCD).

Long QT is one of the causes of SCD. The rate is about 1 in 2000 or so. In 10% of people roughly, the first symptom is sudden death. This can be due to exertion, stress, auditory triggers.

A multicenter study was performed to evaluate genetic "noise" in 1400 controls and approximately 400 subjects (Far more than the Norovirus resistance gene for 22andSerge)

What did they find? They found some noise......of course.
This noise was present in about 4% of controls. This is surprisingly low in my estimate......

What else did they find? They found a genotype/phenotype correlation. Which in Autosomal Dominant disease is also no big surprise. Which likely will be augmented with modifier genes.

What is the "noise rate" for other genes? That, my friend is a good question.

What is noise? It could be anything we haven't classified as for certain pathogenic or benign. For BRCA we call these changes "Variants of Uncertain Significance" or affectionately known as VUSes

The VUS rate for BRCA is anywhere between 10 and 15 percent. Which is why I was so surprised about the LQTS study. Heck, there are more than 2 genes involved in LQTS

So why is this noise such a big deal? As we reach the precipitously dropping cost of the genome, we will be able to have a whole bunch of noise......

In fact, I think it will take us at least 20 years to sort out that noise. Add on layers of epigenetics and we may have another 20 years.......

Why so glum? We do have pretty valid clinical testing for Sudden Cardiac Death. It works, MOST of the time. Whole Genome Scanning?

Well, that may be a different story. I have harped on the Incidentalome several times on the blog, but this bears repeating.........

" If practitioners pursue these unexpected genomic findings without thought, there may be disastrous consequences. First, physicians will be overwhelmed by the complexity of pursuing unexpected genomic measurements. Second, patients will be subjected to unnecessary follow-up tests, causing additional morbidity. Third, the cost of genomic medicine will increase substantially with little benefit to patients or physicians (but with great financial benefits to the genomic testing industry), "

-Zak Kohane

"Mathematicians modeled sequencing the whole genome. As they get up to sequencing 10.000 people they find that the fraction of the population with a false positive result skyrockets up to 60%. What does this mean? Well, we have to carefully select who we test. Or better yet we need an immense database of "Normal Variants". At a minimum we will need 1000s of "sequence specialists" or "computer sequence analysis programs" to evaluate and decide if the "work up" is indicated or not. Personal Genomics is very complex, even more than personalized medicine."

-Steven Murphy in 2007

The Sherpa Says: In Genomics, there is going to be a whole lotta maybes........which in case you are curious, computers handle very poorly....


gojohn10 said...

Do you have a link for the math modeling of sequencing genomes?

Steve Murphy MD said...

Click the Incidentalome link.