Actionability of unanticipated monogenic disease risks in newborn genomic screening: Findings from the BabySeq Project

Abstract

Newborn genomic sequencing (NBSeq) to screen for medically important genetic information is of considerable interest but data characterizing the actionability of such findings, and the downstream medical efforts in response to discovery of unanticipated genetic risk variants, are lacking. From a clinical trial of comprehensive exome sequencing in 127 apparently healthy infants and 32 infants in intensive care, we previously identified 17 infants (10.7%) with unanticipated monogenic disease risks (uMDRs). In this analysis, we assessed actionability for each of these uMDRs with a modified ClinGen actionability semiquantitative metric (CASQM) and created radar plots representing degrees of penetrance of the condition, severity of the condition, effectiveness of intervention, and tolerability of intervention. In addition, we followed each of these infants for 3-5 years after disclosure and tracked the medical actions prompted by these findings. All 17 uMDR findings were scored as moderately or highly actionable on the CASQM (mean 9, range: 7-11 on a 0-12 scale) and several distinctive visual patterns emerged on the radar plots. In three infants, uMDRs revealed unsuspected genetic etiologies for existing phenotypes, and in the remaining 14 infants, uMDRs provided risk stratification for future medical surveillance. In 13 infants, uMDRs prompted screening for at-risk family members, three of whom underwent cancer-risk-reducing surgeries. Although assessments of clinical utility and cost-effectiveness will require larger datasets, these findings suggest that large-scale comprehensive sequencing of newborns will reveal numerous actionable uMDRs and precipitate substantial, and in some cases lifesaving, downstream medical care in newborns and their family members.

Keywords: genomic screening; newborn screening; newborn sequencing; population health; precision medicine.

Figure 1

Clinical actionability radar plots (A and B) Radar plots that illustrate visualization of clinical actionability. The plots utilize a modified semi-quantitative metric adapted from ClinGen as described in the material and methods. As shown in (A), the four points of the diamond on the radar graph (starting from the top and moving clockwise with each figure) represent severity of the fully expressed genetic condition, the penetrance or likelihood that the condition will manifest over an individual’s lifetime, the effectiveness of the specific intervention shown in the figure, and the tolerability of the intervention, i.e., its burden and acceptability to patients. A radar plot with maximum area within the diamond would represent a severe genetic condition that has high penetrance with a highly effective intervention that is particularly acceptable to patients because it is minimally invasive or dangerous. (B) shows sample clinical actionability radar plots for three genes from the ACMG secondary findings list.

Figure 2

Clinical actionability of the specific uMDR genes Radar plots that illustrate the pattern of clinical actionability in the 13 specific genes in which pathogenic and likely pathogenic variants (PLPVs) were identified in the 17 infants with an unanticipated monogenic disease risk. Axes labels correspond to reference diamond plot in Figure 1.