Article originally published by Boston Children's Hospital - 14/08/2017
By Catherine Brownstein, Kelsey Graber and Joseph Gonzalez-Heydrich
Precision medicine fails when new genetic discoveries aren't communicated to patients who need to know them. This case shows how two patients could have avoided having psychotic episodes if clinical institutions had a better system for communicating new gene variants associated with mental illness.
We need a better infrastructure to enable precision medicine. Research implicating rare genetic variants in medical and psychiatric diseases is quickly accumulating. This expanding knowledge should be taken into account when making treatment decisions for patients carrying these variants — as well as other family members — even when that knowledge comes after the patient is tested. But all too often, medical institutions are unable to go back and update the information given to families.
This problem recently surfaced in our psychiatry practice. It came to our attention because of a young boy with mild coordination delays and learning disabilities. At age 6, he started experiencing daily hallucinations such as voices telling him to kill his classmates. He was treated successfully with risperdone.
Through chromosomal microarray analysis (CMA), we learned that he had a deletion in interval I of the 16p13.11 region, which encompasses the genes PDXDC1, NTAN1 and RRN. This deletion is known to be linked to an increased risk for psychosis. Through further investigation, we concluded that the deletion was de novo or inherited from the boy’s father: His mother does not have it, and his father, who had probable schizophrenia, was not available for testing.
To look for more cases, we searched all CMA results within Boston Children’s Hospital medical records. We also searched the databases of Claritas Clinical Genomics, an independent company spun off from Boston Children’s in 2013, and of WuXi NextCODE, a genomics company that provides the IT, database and analytical infrastructure for large-scale genomics efforts at Boston Children’s, Claritas and beyond. This search turned up three other patients with 16p13.11 deletions.
The first had had CMA to evaluate the cause of dysregulated behavior, learning problems and a family history of intellectual disability. Review of medical records and psychiatric interviews established that this patient had experienced psychosis, as had a parent with the same deletion.
The second had a history of intellectual disability and seizures and had never developed speech so it is not known if she ever had psychotic symptoms. Her parents declined genetic testing.
The third patient, who we’ll call Jack, also had a psychotic episode, as had his father who had the same deletion. We believe the psychosis could have been averted in both father and son had updated genetic knowledge been available to them.
Jack originally had CMA testing at 16 years of age because of macrocephaly (a larger-than-normal head), a history of learning problems and early childhood seizures (now controlled with medication). When Jack was 20, his father was diagnosed with ADHD and treated with mixed amphetamine salts. The dose was increased gradually to 80 mg per day, well over the FDA-approved maximum dose of 60 mg.
After a few weeks on this dose, Jack’s father experienced a manic-psychotic break that persisted after stopping the amphetamine salts. His mania has since remitted with an antipsychotic, but eight months into his father’s psychotic episode, Jack became withdrawn and depressed. He, too, developed psychosis and was hospitalized after the hallucinations started telling him to jump out of the window.
We need to enhance our ability to search electronic medical records for genetic findings.
Jack’s hallucinations stopped on clozapine, which he continues to take, but he continues to harbor some delusional ideas about the origin of the voices. It seems likely that this episode was triggered by the stress of his father’s psychosis, and that his father’s late-onset psychosis was triggered by his high-dose amphetamine treatment.
If Jack’s father’s psychiatrist had known that he had a 16p13.11 deletion increasing the risk for psychosis, he likely wouldn’t have prescribed the amphetamine salts at such a high dose, or at all. And had Jack’s treatment team known that his deletion increased his risk for psychosis, he could have received psychological support to shield him from the stress of his father’s psychosis. Both Jack’s and his father’s psychotic episodes may have then been avoided.
Here’s the problem. The report describing Jack’s CNV was sent to his referring physician in 2009, before this CNV was linked with psychosis (in 2011). This link was known when Jack’s father began the amphetamine salt treatment, and when he and Jack had their subsequent psychotic episodes. But there was no mechanism for alerting the treatment team of the newly discovered risks.
How do we fix what’s broken here? How can we provide better care to patients based on genetic discoveries?
We propose that medical centers adopt the following practices:
To adopt these practices and provide ever more precise medical care, we will have to meet infrastructure challenges. First, we need to enhance our ability to search electronic medical records for genetic findings. Second, as the number of known at-risk genetic variants grows larger, as the list of possible risks lengthens and as more patients get genetic testing, staying up to date and recontacting families will become increasingly time-consuming.
Finally, we need global databases that medical centers can access and add to easily and securely. This will allow us to steadily accumulate a more complete picture of the range of variants linked to thousands of rare diseases.
Clinicians will need more resources to help them keep up with genetic discoveries and avoid “alert fatigue.” Costly as such changes may be, the price of failing to prevent preventable and disablinƒg illnesses could be much higher. We should take a hard look the cost of not employing precision medicine.
This blog post was originally published on the Boston Children’s Hospital blog on August 14, 2017 as “If I knew then what I know now: The need for infrastructure to enable precision medicine.” Author credit: Catherine Brownstein, Kelsey Graber and Joseph Gonzalez-Heydrich.
The case investigations were funded by the Tommy Fuss Fund, the Boston Children’s Hospital Intellectual and Developmental Disabilities Research Center (funded by National Institutes of Health P30 HD18655) and the Manton Center for Orphan Disease Research.