Considerations in Modifying the Adult AWG Framework for the Pediatric AWG

The Pediatric AWG was developed to expand the impact of the ClinGen AWG and provide an assessment of the clinical actionability of secondary findings from genome-scale sequencing in children and adolescents. The Pediatric AWG framework was based on the previously described Adult AWG framework, with adaptations made to account for the ethical and practical considerations related to reporting presymptomatic and predictive genetic findings in children.^7–9 For the purposes of the Pediatric AWG framework, the pediatric period was defined as under the age of 18 years when the person is not responsible for their own medical decisions. Considerations made and adaptation of the framework for the pediatric context are discussed below.

When it comes to adult-onset conditions, it is important to weigh factors such as future autonomy of the child against the benefit of providing important health information.⁸ Arguments against returning genetic findings associated with adult-onset conditions include the child’s “right to an open future,” which can be violated when someone else makes the decision for them to learn about their genetic risk for an adult-onset condition.^7–9,17 Arguments for returning these findings include providing the opportunity to implement interventions that lead to disease prevention or delayed onset and improve downstream clinical outcomes for genetic conditions, particularly if these interventions can be implemented during the pediatric period.

Due to the complex ethical issues inherent in returning secondary findings in the pediatric population for adult-onset conditions, the Pediatric AWG decided to focus on conditions with evidence of clinical actionability during the pediatric period, specifically those where implementation of clinical interventions is recommended to occur during childhood or adolescence. Therefore, conditions are considered when there is either a significant risk of onset before adulthood or when adult-onset outcomes may be modified by the implementation of interventions during childhood or adolescence. Heterozygous familial hypercholesterolemia is an example of one such condition, as initiation of lipid-lowering therapy is recommended within the first decade of life, even though complications of atherosclerosis occur most commonly in middle-aged individuals (30–50 years). Conversely, a condition such as Lynch syndrome, where colorectal cancer screening is not recommended to begin until adulthood, would not be considered actionable in the pediatric period. Overall, this approach balances the principle of maintaining an open future for the child or adolescent in regard to genetic conditions that are not actionable until adulthood while providing important health information for genetic conditions that are actionable during the pediatric period.

Some genetic conditions (e.g., early onset forms of propionic acidemia) present primarily during the neonatal period, which we define as birth to 30 days. Given the clinical context of the Pediatric AWG to assess clinical actionability of a secondary finding from genome-scale sequencing, receiving this genetic information during the necessary timeframe and implementing an intervention in that timeframe for a neonatal onset condition may not be feasible. It is also unclear whether a secondary finding for a neonatal onset condition would be actionable later in life in the absence of clinical presentation during the neonatal period. Thus, we exclude from consideration any conditions that are limited almost exclusively to presentation during the neonatal period.

One of the domains assessed by the SQM is the likelihood of outcomes associated with the genetic condition to occur (penetrance); thus, it was important for the Pediatric AWG to consider whether to focus on penetrance before adulthood only or account for lifetime penetrance. Because the scope of clinical actionability includes genetic conditions with outcomes across the lifespan (i.e., onset at any age), if there is evidence that an intervention during childhood or adolescence can optimize health outcomes, lifetime penetrance, rather than age-related penetrance, will be considered when scoring likelihood of the outcome.

The Adult AWG framework includes the assessment of the effectiveness of recommendations related to family management (e.g., genetic testing of at-risk adult relatives). Some have argued that a secondary finding in a child (e.g., pathogenic variant in BRCA1) may not be actionable in the child, but that genetic testing and implementation of life-saving interventions in a parent who may also carry the genetic finding would be beneficial to the child.^11,18 Indeed, the secondary finding in the child may be the only opportunity to identify a life-threatening genetic risk factor in the parents. However, the Pediatric AWG decided that, because these recommendations are not actionable for the child or adolescent themselves¹⁹, recommendations related to family management are excluded from the Pediatric AWG assessments.