Deeper Analysis of Parents Who Carry Mutations May Predict Serious Genetic Conditions in Offspring

Prenatal testing of people of reproductive age using an expanded carrier screening may increase the detection of hypothetical future fetuses at risk for up to 94 severe or profound conditions including cystic fibrosis, compared to the current recommendations by professional organizations, according to a recent study.

Severe conditions are defined as those that can lead to substantially shortened lifespan or intellectual disability if not treated. Profound diseases are those causing both outcomes.

The study, “Modeled Fetal Risk of Genetic Diseases Identified by Expanded Carrier Screening,” published in The Journal of the American Medical Association, revealed that expanded carrier screening could identify three times more hypothetical fetuses with severe or profound conditions than professional guidelines-based screening panels.

Genetic testing of people at reproductive age help identify future parents who carry gene mutations that could lead to the development of specific diseases in their children if the baby inherits a mutated gene from the father and another mutated copy from the mother. The current genetic tests are part of routine obstetrical practice and assess a limited number of diseases based in part on self-reported racial and ethnic background.

The new advances in genetic screening allow future parents to be assessed for mutations that cause many severe and profound conditions independent of racial or ethnic background.

For the new study, the research team analyzed 346,790 individuals in reproductive age mainly from the United States and without known indications for genetic screening. The expanded carrier tests, which assessed the carrier status for up to 94 conditions, were offered by clinicians providing reproductive care. The risk for developing diseases was defined as the probability that a hypothetical fetus would inherit two mutated copies of a specific gene (one from the father and one from the mother), either with the same mutation in both copies or with a different mutation in each copy.

The researchers found that the frequency of having affected fetuses varied widely among racial and ethnic categories, ranging from 95 per 100,000 for Hispanic couples to 392 per 100,000 for Ashkenazi Jewish couples. The most important finding revealed that in most racial and ethnic categories the expanded carrier screening resulted in more hypothetical fetuses at risk for severe or profound conditions than screening based on professional guidelines. For example, for Northern European couples the professional guidelines-based screening resulted in 55 affected fetuses per 100,000, while the expanded carrier screening resulted in 159 per 100,000.

“The findings showed that an expanded testing panel identified more hypothetical fetuses at risk for severe or profound phenotypes than did testing based on current screening guidelines. This was not only because expanded carrier screening included additional disorders but also because guideline-based testing was based in part on self-identified racial/ethnic categories,” the authors wrote in the study.

Researchers believe that before the expanded screening is adopted in the clinic, prospective studies should be performed to further validate the advantages of the expanded screening for populations at risk compared to the standard of care screening.

In an editorial comment to the study, titled “Where to Draw the Boundaries for Prenatal Carrier Screening,” Dr. Wayne W. Grody, PhD, of UCLA Medical Center, in Los Angeles, wrote: “The study by Haque and colleagues is an important contribution in the evolving field of prenatal testing. It provides a wealth of data on the frequency of genetic variants that can be detected in individuals of childbearing age from a diversity of racial/ethnic backgrounds.”

“The large number of silent but potentially damaging sequence variants in every human genome went unnoticed until the last few years when high-throughput DNA sequencing technology became widely available. However, just because these variants can now be detected, there needs to be convincing evidence before they all are tested for and possibly acted upon,” Grody added.