Are we sure we really want to go there?
As an Ashkenazi Jew and someone who was pregnant several times in the late 1990s and early 2000s, I witnessed, from the perspective of a patient, the stepwise increase in the number of Jewish genetic diseases for which carrier testing was available. When I moved into this scientific realm professionally in 2006, I realized that that was only the tip of the iceberg. What had started out as population testing for one disease only (Tay-Sachs) in the 1970s rapidly advanced gene-by-gene, to the point where now we readily can test for carrier status for at least 18 of the so-called “Ashkenazi Jewish genetic diseases.”
Until recently, testing was performed in a gene by gene manner, resulting in additive costs that reached the thousands of dollars. Fortunately, breakthroughs in technology have led to significant progress in reducing the costs associated with screening for many diseases at the same time. Now, a single DNA sample can be assessed on a “chip” or an “array” that simultaneously can survey many mutations in many disease genes . If a mutation is detected by the array, then that individual is said to be a “carrier” of the associated genetic disease. Remember, carriers themselves do not and will not exhibit symptoms of that disease, but offspring of carrier couples are at risk to be affected.
Okay, now here is where the “are we sure we really want to go there” question comes into play. Right now, we are still testing for the common mutations in the relevant disease genes with these “targeted” arrays. But there are other rarer mutations in those same genes that have been described to be disease-associated that are not being assessed routinely. So, some carriers are being missed. If we wanted to look at each disease gene in its entirety, we could instead be using a technology called gene sequencing. With gene sequencing, each position in the gene is “read” and then cross-compared to the normal sequence. Many companies and laboratories are thinking about/developing sequencing platforms for the purpose of carrier identification, with the goal of missing fewer carriers.
So what’s the downside? The downside is that we will not only pick up the common+rarer disease mutations, but we will also pick up changes that we cannot interpret properly because we have not seen them before (these changes are called “variants of unknown significance”). They could be disease-causing in offspring of carrier couples, but alternatively they could be benign. If we as professionals can’t interpret these properly, what do we tell the patients?
And you know what makes me even more anxious? The alternative concept of sequencing ALL of someone’s genes (their genome) for carrier identification, as opposed to just focusing the sequencing on a targeted subset of genes, such as the subset that causes the Ashkenazi Jewish diseases. In that scenario, not only will we be grappling with the variants of unknown clinical significance, but also with findings throughout the genome that are incidental/unanticipated. These findings could include mutations that lead to adult-onset disease in the carriers themselves, some of which diseases have no treatments or cures.
Only time will tell where the field is heading, and advances in technology coupled with decreasing costs may be the ultimate drivers here. I think we should pause and think about how vast the ocean is before taking the plunge.
Posted on November 5, 2012, in Nicole's posts and tagged array, Ashkenazi, Ashkenazi diseases, carrier, Einstein, genetic testing, genetics, Jewish genetic diseases, Program for Jewish Genetic Health, sequencing, variants. Bookmark the permalink. 2 Comments.