CLN - Focus on Laboratory Stewardship
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As clinical lab professionals know, stewardship isn’t over when an approved test is ordered. In truth, the process never really ends. Our experience at Seattle Children’s Hospital (SCH) serves as a case in point. After SCH’s Laboratory Stewardship Committee approved the use of a sponsored genetic panel for pediatric obesity in 2020, they reassessed the test’s clinical utility 4 years later. Specifically, they revisited clinical practice guidelines, gauged patients’ changing needs, and gathered providers’ perspectives. This work resulted in SCH’s rollout of a new and improved referral algorithm in 2025.
In this article, we share how the committee partnered with other SCH healthcare and genetics professionals, with the goal of optimizing care for SCH’s pediatric patients with obesity and their families.
In March of 2020, SCH’s Laboratory Stewardship Committee approved the ordering of a sponsored test panel that sequences 87 genes associated with certain forms of obesity. A sponsored lab test is a clinical or genetic test where a pharmaceutical or biopharmaceutical company covers the cost for patients.
As a matter of policy, the committee reviews all sponsored tests to ensure they align with the standard of care, are performed in a CLIA environment, and are offered equitably to patients. This particular genetic panel is sponsored by Rhythm Pharmaceuticals, which manufactures the drug setmelanotide for the treatment of hypothalamic obesity. The sponsored pediatric obesity panel’s inclusion criteria stipulate that patients must be 18 years or younger with a body mass index (BMI) greater than or equal to the 97th percentile.
After reviewing the sponsored genetic panel, the committee assessed it to be equitable and performed in a CLIA-certified lab. Although few practice guidelines on genetic testing for pediatric obesity existed at that time, the committee found that a test to assess monogenic causes of obesity fell within the standard of care.
Once the committee was satisfied with SCH’s use of the sponsored test, a workflow was put into place. SCH providers who specialized in endocrinology and nutrition facilitated pre-test counseling, test ordering, and results delivery. In addition, they offered families a referral to experts in clinical genetics on an as-needed basis to discuss results.
In 2024, clinical genetics providers within SCH asked the Laboratory Stewardship Committee to reassess the clinical utility of the sponsored genetic panel for pediatric obesity. They shared their concern that the panel yielded a high incidence of variants of uncertain significance (VUS) that often confused families and rarely changed the medical management of patients. Additionally, they provided case examples of patients who would have qualified for testing with a broader diagnostic scope — such as exome or genome sequencing — but instead received the sponsored panel as a first-line test, potentially delaying the delivery of important diagnostic results.
In response, the committee asked SCH’s laboratory genetic counseling (LabGC) team to perform a review of 93 orders of the sponsored genetic test panel from April 2022 - April 2024. The team extracted key data from the institution’s utilization management database, including patient name, medical record number, ordering provider specialty, and order date. Then they conducted a manual chart review to document patients’ age, BMI percentile, test results, clinical genetics referral status, and documented changes in medical management.
The data supported the clinical genetics providers’ experiences of low diagnostic yield and a high incidence of uncertain results. Of the 93 sponsored genetic test orders, three (3%) were diagnostic. Two of these diagnostic orders identified pathogenic variants in the MC4R gene with autosomal dominant inheritance and no documented changes to medical management, and one order identified an incidental multi-gene deletion that led to a minor alteration in medical management.
Sixty-nine (74%) patients received uncertain results (i.e., at least one VUS) and 48 (52%) were referred to the clinical genetics team. Thirty-four (71%) of the referred patients were seen by clinical genetics providers, of which 18 (53%) were offered broader testing such as exome or genome sequencing. Overall, an average appointment for patients referred to the clinical genetics team involved the discussion of two VUSs (Figure 1).
Figure 1. Pediatric obesity case referrals to clinical genetics for uncertain results after genetic testing
After the LabGC team presented these findings to the Laboratory Stewardship Committee, the committee recommended discontinuing the sponsored genetic panel orders at SCH and creating a plan that better served patients with pediatric obesity and their families.
From there, the committee convened a multidisciplinary working group that included representatives from LabGC, endocrinology, nutrition, and clinical genetics. The group reviewed the data and discussed alternative genetic testing workflows that could improve patient care at the hospital.
Within the working group, the experts in endocrinology and nutrition shared one of their ongoing challenges: finding time to thoroughly perform pretest counseling within the time constraints of their appointments. This matched the clinical genetics providers’ experience that patients did not fully understand the purpose and possible results of the sponsored testing.
The endocrinology and nutrition providers also said it was difficult to determine when a patient would qualify for broader testing. Their fellow working-group members in clinical genetics outlined their referral process and provided contact information for individuals who could triage patient-specific questions.
hen the clinical genetics providers expressed uncertainty about how genetic testing results inform medical management, those in endocrinology and nutrition shared information on when the medication setmelanotide is indicated for patients with damaging variants in MC4R, POMC, PCSK1, LEPR, or BBS genes.
The working group also reviewed current practice guidelines and published literature to inform their workflow for genetic testing for pediatric obesity. Their discussion focused on two populations: patients with non-syndromic severe obesity and/or hyperphagia (insatiable hunger), and patients with syndromic presentations (severe obesity and/or hyperphagia in the presence of intellectual disability, developmental delay, congenital anomalies, etc.).
According to the 2023 American Academy of Pediatrics clinical practice guidelines, patients with severe obesity (defined as a BMI ≥ 120% of the 95th percentile) with onset before age 5 and/or hyperphagia may be evaluated for a genetic cause.
In December 2024, the Food and Drug Administration approved setmelanotide for use in patients as young as 2 years old with melanocortin-4 receptor (MC4R) pathway deficiencies caused by variants in MC4R, POMC, PCSK1, LEPR, or BBS genes. For patients with intellectual disability, developmental delay, and/or congenital anomalies, the 2021 American College of Medical Genetics and Genomics clinical practice guidelines recommend exome or genome sequencing.
Taken together, the stewardship data, provider experiences, and practice guidelines informed the development of an updated genetic testing workflow for pediatric obesity (Figure 2). Endocrinology and nutrition providers now refer all patients with severe obesity and/or hyperphagia to their colleagues in clinical genetics to coordinate genetic testing. Clinical genetics providers then evaluate the patient for the best first-line test, provide thorough pre-test consent, and establish continuity of care for the delivery of results and subsequent discussion. Non-syndromic patients are offered a genetic panel that includes MC4R, POMC, PCSK1, LEPR, and BBS genes to inform their eligibility for setmelanotide. Syndromic patients are offered broader genetic testing such as exome or genome sequencing, which can inform eligibility for setmelanotide and the medical management of clinical features beyond obesity.
Figure 2. Improved genetic referral algorithm for pediatric obesity
SCH providers adopted the genetic referral algorithm for pediatric obesity in March 2025, acknowledging that the sponsored test orders that were already offered to families would proceed as planned. Since the implementation of the new workflow, order volumes for the sponsored genetic test have decreased from an average of seven orders per month to one order per month.
The immediate impact of the referral algorithm demonstrates that laboratory stewardship is iterative. Approved tests require continuous stewardship to align with updated clinical practice guidelines, the changing needs of the patient population, and ordering provider perspectives.
Payton L. Gablehouse, BS, is a laboratory genetic counseling assistant at Seattle Children’s Hospital. +Email: [email protected]
Paige Haas, PhD, MS, CGC, is a laboratory genetic counselor at Seattle Children’s Hospital. +Email: [email protected]