Kelly Ormond, MS, CGC, program director, associate professor, Department of Genetics, Stanford School of Medicine, provided an overview of the challenges in the clinical application of whole-genome sequencing.
She noted that the ethics of diagnostic testing obviously differ from pre-dispositional testing. In the early days of testing, Ormond said, the field generally focused on rare Mendelian conditions.
Roughly half of these conditions remain undiagnosed, she said, though she predicted that figure would decrease over time. There are almost 20,000 known Mendelian genes, she said, and clinicians can test for a couple thousand on a clinical basis.
The field accelerated with the development of the comparative genomic hybridization assay, but that process also leads to a lot of incidental findings. Single gene mutations are where a lot of the testing is nowadays
So, then, why can’t physicians just sequence the gene and be done with it? Problems with that, she said, are:
- It’s expensive and time consuming
- You must test the proper gene
- It does not detect large deletions
- There are variants of uncertain significance
- It can lead to false negatives in unaffected relatives
- New short read-read technologies may make triple repeat expansions and other in/dels more difficult to interpret
The advent of testing panels in recent years, she said, “I think have changed the dynamic a little bit.” This is especially helpful, she said, when a disorder has significant locus heterogeneity that clinicians cannot differentiate or that has significant overlap.
Newborn screening, she said, started about 40 years ago with a handful of conditions that met traditional public health screening criteria. It expanded dramatically with the introduction of mass spectrometry.
Early thinking on conveying the information to parents, she said, was “I can find this stuff out, so I probably should tell you,” even if clinicians were unsure about what the findings meant.
That made parents anxious, and it wasn’t clear if medical treatment would have been any different whether physicians knew the results or not. So, she said, the field “backtracked a lot.”
The American College of Medical Genetics and Genomics (ACMG) recommends testing on about 30 conditions on a primary list and another roughly 25 that tests can diagnose with less confidence. While most of those are “genetic” conditions, she said, they don’t usually do DNA testing on the first pass.
She said that incidental findings are not unique to genetics. Geneticists, she said, just need to figure out what is different about their field.
One example involved an aCGH test from her clinical practice. In doing the test in a child, they found a large deletion that put the child at higher risk of colon cancer, and they had to decide whether to disclose that to the family.
In newborn screening and prenatal diagnosis, screeners are typically informing parents about carrier status, despite conservative recommendations against carrier testing in children.
She said there are three key points to consider in genetic testing of children:
- The developing competency of children
- The best interest of the child
- The inextricable role and impact of parents and family
In 1995, she said, the original report from the American Society of Human Genetics and the ACMG issued a number of recommendations. The first recommendation is the key, she said: timely medical benefit to the child should be the primary justification for genetic testing.
Currently, practitioners feel comfortable testing when it offers an immediate medical benefit.
They are typically deferring when the test offers no medical benefit but may offer reproductive benefit, and when medical benefit and reproductive benefits are not immediate.
They are also being quite cautious about testing when it only benefits other family members and not the child.
Another question about revealing results revolves around the age of onset for the potential condition, Ormond said.
For childhood onset, she said, benefits could include influencing future childbearing for parents and decreased risk of morbidity.
For adult onset, she said, things to consider are: whether the knowledge could positively influence health behaviors of the child and whether divulging is worth the potential psychological effects of knowing.
In the last two decades, FAP is one of the conditions where geneticists have seen a change in thinking. In this condition, physicians can see polyps in the colon and usually begin screening kids around the ages of 10 or 12.
In FAP testing, studies have not shown much harmful psychosocial effects of knowing either in parents or children.
People are treading more cautiously when it comes to adult onset conditions, such as testing for BRCA in adolescent girls. One study found only about 20% to 30% of geneticists expressed a willingness to offer or consider testing adolescents on a case-by-case basis for BRCA.
In summary, she said:
- Little data exists
- There’s more data on the impacts/effects of childhood onset predictive testing vs. adult onset predictive testing
- Most data suggests that changes in anxiety, depression and other adjustment measures are transient and minor in most children and adults
- Most researchers suggest that negative results in high-risk families alleviate and anxiety and reduce depression
- Professional statements are still cautious about predictive testing for adult onset conditions
The situation is similar when it comes to genome sequencing. A lot of information is available, but many times researchers do not know what the findings mean. “We kind of shrug our shoulders and say, ‘I don’t know what is going on.’”
She said, “It is really hard to know what to do with all this (data), because we don’t know what most of it means.”