Due to the recent advancements in genome-scale sequencing, complete genomic sequencing of a newborn can be performed shortly after birth. Analysis of this sequence enables the detection of deleterious variants linked to monogenic diseases. Even though such a screening tool is currently available, it is associated with several ethical, evidentiary, and cost-related issues.
A recent American Journal of Human Genetics study investigated the medical conditions of infants with unanticipated monogenic disease risks (uMDRs) and mapped them into a standardized semi-quantitative measure of potential actionability.
Study: Actionability of unanticipated monogenic disease risks in newborn genomic screening: Findings from the BabySeq Project. Image Credit: metamorworks / Shutterstock
What is the BabySeq Project?
The BabySeq Project encompasses a series of clinical trials on newborns that have been funded by the National Institute of Health (NIH). These clinical trials are associated with newborn screening using genomic sequencing (GS), which provides empirical data on mechanisms of consent, disclosure methods, gene curation, and variant interpretation. Furthermore, these trials also focus on behavioral, medical, and economic outcomes.
Initially, the BabySeq Project recruited both healthy and sick infants for the study. The healthy infants were recruited from a newborn nursery (NBN), while sick infants were from intensive care units (ICUs). These candidates were randomly assigned to receive either standard-of-care newborn screening (NBS) or NBS along with GS.
Infants assigned to GS were subjected to whole-exome sequencing. Here, the exomes were annotated and filtered, and the results were analyzed to identify pathogenic or likely pathogenic variants (PLPVs). Clinical data on PLPVs for any genetic condition were described.
These data were related to genetic conditions that could be expressed during childhood and were highly penetrant or childhood actionable and were moderately penetrant. It was noted that penetrance is most likely to be underestimated when genetic disorders present milder or subclinical features. The concept of penetrance is based on which particular phenotype is analyzed and over what time. In epidemiological studies, the penetrance of hereditary cardiomyopathy is described as asymptomatic thickening of the cardiac septum.
A total of 325 newborns were initially enrolled in the BabySeq Project. Out of 325, 159 were randomized to the GS arm, and 11.3% of these were associated with PLPV. However, only one infant with PLPV represented monogenic disease risk, which could be retrospectively associated with their clinical symptoms. Out of 159 infants, 17 had PLPVs characterized as uMDRs.
The sequence results were shared with the participants’ parents in a counseling session. A disclosure letter was provided to the parents and the newborn’s clinicians. In 17 infants with uMDRs, PLPVs were found in 13 unique genes that were heritable. In addition, two carried pathogenic variants in BRCA2, and one carried a pathogenic variant in MSH2.
The BabySeq Project was involved with actionability analysis, where the clinical severity of potential conditions was identified. Subsequently, the available interventions were graded based on the ClinGen actionability semi-quantitative metric (CASQM). A visual representation of these scores for each infant was generated.
The outcome-intervention pair evaluated by the CASQM is on four axes, namely, severity, likelihood, effectiveness, and nature of the intervention. In the context of the visual representation of data, a perfect diamond shape represents the most favorable actionable condition. Here, instead of assessing actionability specifically during childhood or adulthood, the authors assessed actionability throughout the lifetime.
All infants at-risk with uMDRs were referred for surveillance, specialty consultation, and treatment. Among the seventeen infants with uMDRs, three had unrecognized phenotypes, and uMDRs were not considered risky variants. However, these were discovered to be penetrant with mild or subclinical features. This finding indicates the difficulty of detecting the true penetrance of most monogenic conditions. It is also important to detect the difference in genetic expressivity over time.
The BabySeq Project only focussed on variants from genes that are strongly associated with disease manifestation with high penetrance irrespective of actionability and moderate evidence of penetrance but high actionability in childhood or adolescence. It is difficult to describe the concept of actionability, as in certain cases, actionability accounts for enhanced surveillance or even knowledgeable anticipation of a disease. However, some scientists describe actionability as an effective treatment that can slow disease progression or improve disease prognosis.
The most actionable manifestation of a condition was represented by a full diamond with a score of 3 in each domain. However, alternative shapes indicate signal variation, where penetrance is expected to be lower or treatment could be more burdensome. This visual dashboard could help policymakers, parents, and clinicians intuitively understand the effectiveness of the chosen intervention for a specific genetic disease.
In the BabySeq Project, the majority of infants identified with uMDRs obtained prompt specialist evaluations and follow-up procedures, which could be a life-saving approach. Thereby, the importance of alerting family members about possible genetic diseases could be extremely beneficial.