Posted July 2022

Pharmacogenomic testing in children with complex medical histories can help predict and prevent adverse drug reactions, improve adherence and salvage drugs with high toxicity.

The tests yield actionable results in most cases, acording to Shannon Manzi, PharmD, BCCPS, the former director of the clinical pharmacogenomics service at Boston Children’s Hospital (BCH). “More than 92% of patients tested by the BCH service” received such results, she said.

Cystic fibrosis (CF) is a condition that is particularly amenable to pharmacogenomic testing, and is one of several disorders for which the testing is mandatory, Dr. Manzi noted. She cited ivacaftor (Kalydeco, Vertex), which can only be prescribed in CF patients with CF transmembrane conductance regulator variants.

“It is also now highly encouraged that all investigational new drug applications to the FDA include pharmacogenomics information that can advise the labeling going forward,” Dr. Manzi said.

The BCH clinical pharmacogenomics service, a collaboration between the Division of Genetics & Genomics and the Department of Pharmacy at BCH, averages about six clinic visits and 10 single-gene sequencing tests sent per week as well as five inpatient consults per month, she said. “Most of our patients have a complex history involving significant failure to respond to medications or a laundry list of adverse drug reactions with the trial-and-error method,” Dr. Manzi said at ASHP’s 2021 Midyear Clinical Meeting and Exhibition.

Approximately 57% of patients have a significant finding from pharmacogenomic testing, according to internal data Dr. Manzi presented. “Another 36% of patients have no significant findings relative to the original question, but when we look at the entire panel, most of those patients have significant incidental results,” she said. “When you add it all up, over 92% of patients we see have an actionable result.”

Common Drug–Gene Pairs

In addition to ivacaftor, there are multiple common drug–gene pairs that can influence medication selection in pediatric patients, Dr. Manzi noted. “For example, no one at BCH starts abacavir without HLA testing, because a severe Stevens-Johnson syndrome–type reaction can occur,” Dr. Manzi said.

As for which drugs are good candidates for pharmacogenomic testing prior to initiation, “they should have a narrow therapeutic index, with toxicity and effective dose closely related,” Dr. Manzi said. “For example, amoxicillin can have a very wide range of dosing and is not likely to result in toxicity, so testing wouldn’t be useful. But for warfarin or phenytoin, the toxic and efficacious doses are very close and metabolism can make a difference. There should also be published dosing and a validated, reliable assay.”

She cautioned that unlike a test such as a radiograph, pharmacogenomic results are revisable over time, meaning that pharmacists may have to reach out to a patient they haven’t seen in years as new information becomes available. “Guidelines can change, pharmacogenomic clinical activity definitions can change, and as a result, you may have to change what you’re telling your patients—for example, if a variant status has a new guideline based on emerging information.”

Pharmacogenomic testing sometimes will yield a positive result for CACNA1S/RYR1, which predisposes patients to malignant hyperthermia.

What Comes After Testing?

Pharmacogenomic testing sometimes can have broader familial implications that extend beyond the patient currently being assessed, said Cyrine-Eliana Haidar, PharmD, BCPS, a clinical pharmacogenomics coordinator at St. Jude Children’s Research Hospital, in Memphis, Tenn. “Most pharmacogenes have codominant inheritance patterns that don’t have implications for the patient’s family members, but some findings do have implications for full biological relatives,” Dr. Haidar said. Among the pharmacogenes that have dominant expressions, she noted, are HLA, which predisposes patients to skin reactions with certain medications; and mt-RNR1, which predisposes to immunoglycoside-induced autotoxicity. Then there are other genes that have X-linked inheritance, such as G6PD, she noted.

Dr. Haidar also discussed CACNA1S/RYR1 and malignant hyperthermia, a potentially fatal hypermetabolic response to potent volatile anesthetic gases such as halothane, sevoflurane, desflurane and the depolarizing muscle relaxant succinylcholine. “Because it has an autosomal dominant inheritance pattern, when we see this high-risk variant as a pharmacogenomic result, this means the person with the high-risk genotype inherited the allele from one of their parents,” she explained. “So, when we counsel the patient that they should not receive certain medications, such as inhaled fluorinated anesthetics, because of their risk of developing malignant hyperthermia, we also could provide genetic counseling to family members to explain to them what the implication of this positive test result is for their biological parents and full biological siblings, and offer cascade testing to the first-degree relatives.”

Institutions should have a process set up for handling such findings and discussions, approved by institutional leaders and oversight committees. Questions to be addressed include:

• Should counseling of family members be performed?
• Should genotype testing of family members be offered?
• Should the institution follow up with family members in the event of a high-risk result?
• Who will pay for the genotype testing?

Incidental Findings

Often, when pharmacogenomic testing is done, the results include findings that are not related to the original reason the patient underwent testing. Incidental findings are more likely to be discovered when panel pharmacogenomic testing is performed rather than a single-gene test.

One example, Dr. Haidar noted, is G6PD deficiency, an X-linked recessive disorder, and Klinefelter syndrome. “G6PD deficiency affects about 400 million people across the globe,” she said. “It affects males more than females, and causes hemolytic anemia when patients receive certain medications, eat fava beans or are triggered by certain infections.”

Because male individuals have only a single copy of the X chromosome, they have a single copy of the G6PD allele, while females have two X chromosomes and two copies. If the G6PD genotype in a phenotypically male patient shows two G6PD alleles, it could suggest that the person has Klinefelter syndrome, a sex chromosome disorder in which a person has a total of 47 chromosomes instead of the normal 46. They are phenotypically male, because they have a Y chromosome, but they have two X chromosomes rather than one.

“Children with Klinefelter syndrome may have learning disabilities, delayed speech or delayed language development,” Dr. Haidar said. “They are also at higher risk of developing breast cancer, systemic lupus or osteoporosis, disorders that we consider that females should be monitored for throughout their life.”

In such circumstances, who should be informed of the findings—the patient only, the patient and their family, only the patient’s medical team?

“There’s not one right answer to this question, but the majority of the medical genomic community would agree that the family and the patient should be informed if the patient is less than 18 years of age,” Dr. Haidar said, noting that such a step allows for proactive interventions for the learning disabilities and other hallmark findings of the condition.

“Since this is an actionable finding that can help patients,” she said, “we will return that to the patient and their family members, and it’s up to them how to proceed, as is the case with so many of these disorders.”

Dr. Haidar reported no relevant financial disclosures. Dr. Manzi reported that she is a scientific advisory board member for Global Gene Corp and a consultant to Stoke Therapeutics.