A woman and a man with no personal or family history of a severe, recessive, childhood-onset genetic disease still face a roughly 1 in 1,500 chance of giving birth to a child affected by a severe, genetic disease simply due to the chance pairing of mutations that each parent unknowingly carries.
Genetic screen result showing deletion causing Lesch-Nyhan syndrome/courtesy Stephen Kingsmore and Science Translational Medicine
Will those odds motivate prospective parents to get themselves screened before conceiving a child, to learn whether they each carry a recessive mutation in the same gene?
It’s a choice that parents-to-be may soon face, thanks to a wide-ranging carrier screening test reported today by researchers at the National Center for Genome Resources in Santa Fe and their associates.
The team, led by Dr. Stephen F. Kingsmore, report their findings with a test that screens for mutations in 448 different genes that can each lead to a severe, recessive childhood disease. Five of these diseases already have preconception screens that are usually offered to selected, higher risk people: fragile X, cystic fibrosis, Tay-Sachs disease, Canavan disease, and familial dysautonomia. By applying a panel of state-of-the-art genetic-testing technology, Dr. Kingsmore and his coworkers expanded their screening net to include 443 additional genes and diseases, including 142 metabolic disorders, 122 neurologic defects, 46 genes that affect development, 45 with cutaneous presentations, etc. In an interview, he told me that while today’s report focuses on screening 448 genes, the actual total now possible has grown to 580 different genes and resulting disorders. I’m sure over time the list will grow even longer.
In the current paper they applied the 448-gene screen to 104 people, and found that each person carried, on average, 2.8 mutations. Although several subjects had known genetic disorders, correcting for this skewing still produced the estimate that any adult carries, on average, 2.8 recessive gene mutations even if they appear completely healthy and have absolutely no personal or family history suggesting they might be a carrier. In short, everyone harbors some genetic flaws hidden within their cells that can unexpectedly appear in their children if their partner contributes a mutation in the same gene.
Mathematically, a recessive, genetic-mutation burden of 2.8 per parent out of 448 genes works out to a 1 in 25,000 risk for having an affected child, but the actual risk is much higher because everyone has some genetic skewing that boosts the risk. For example, people with Northern European ancestry have a 2.5% rate of carrying a mutated cystic fibrosis gene. As a result, the overall risk for any seemingly healthy couple with no affected family members is one in 1,500.
With a risk as significant as that, Dr. Kingsmore and his associates call for making preconception genetic screening available to everyone, not just those with a pedigree that seems to put them at higher risk. They also noted that the tests they ran cost $378 per person, a price that could drop with higher volume. But the cost of testing also must include the added fees for test interpretation, results reporting, and genetic counseling.
—Mitchel Zoler (on Twitter @mitchelzoler)
EGMN: Notes from the Road 