A curated gene list for reporting results of newborn genomic sequencing

Abstract

Purpose: Genomic sequencing (GS) for newborns may enable detection of conditions for which early knowledge can improve health outcomes. One of the major challenges hindering its broader application is the time it takes to assess the clinical relevance of detected variants and the genes they impact so that disease risk is reported appropriately.

Methods: To facilitate rapid interpretation of GS results in newborns, we curated a catalog of genes with putative pediatric relevance for their validity based on the ClinGen clinical validity classification framework criteria, age of onset, penetrance, and mode of inheritance through systematic evaluation of published evidence. Based on these attributes, we classified genes to guide the return of results in the BabySeq Project, a randomized, controlled trial exploring the use of newborn GS (nGS), and used our curated list for the first 15 newborns sequenced in this project.

Results: Here, we present our curated list for 1,514 gene-disease associations. Overall, 954 genes met our criteria for return in nGS. This reference list eliminated manual assessment for 41% of rare variants identified in 15 newborns.

Conclusion: Our list provides a resource that can assist in guiding the interpretive scope of clinical GS for newborns and potentially other populations.Genet Med advance online publication 12 January 2017.

Conflict of interest statement

DISCLOSURE

O.C.-B. is an employee of the Mount Sinai Genetic Testing Laboratory, Icahn School of Medicine at Mount Sinai. T.W.Y. reports receiving consulting fees from and equity in Claritas Genomics outside of the submitted work. R.C.G. is supported by NIH grants and reports that he receives personal compensation for speaking or consulting from AIA, Helix, Illumina, Invitae, and Prudential. The other authors declare no conflict of interest.

Figures

Figure 1. Return of results criteria in the BabySeq project

(a) All newborns in the sequencing group receive a newborn genomic sequencing report (NGSR) that returns risk and carrier status for childhood-onset disease and pharmacogenomics variants that may be relevant to the pediatric population. In addition, sick newborns receive an indication-based analysis (IBA) that returns all variants with evidence to cause or contribute to the infant’s disease, with an option to query pharmacogenomics variants related to the infant’s care. (b) Criteria for genes to be included in the NGSR and IBA. NGSR was limited to genes with strong evidence to cause highly penetrant childhood-onset disorders; while genes related to the infant’s clinical features with moderate evidence or moderate penetrance or typically present at later ages were also included in IBA. When a specific disease is suspected based on the infant’s presentation, genes associated with that disease with limited evidence or low penetrance may also be returned. (c) Criteria for variants to be included in the NGSR and IBA. Only pathogenic and likely pathogenic variants were returned in the NGSR, whereas IBA also included variants of uncertain significance in genes associated with the infant’s indication.

Figure 2. Summary of curated data for 1,514 gene—disease associations

The level of evidence that the gene is associated with disease, age of onset, and penetrance for all gene—disease pairs curated (top) and statistics for those with strong and definitive evidence (bottom) are demonstrated. Overall, 884 genes that have strong/definitive evidence to cause highly penetrant childhood-onset disease and 70 additional genes that are actionable in childhood met the BabySeq Project NGSR criteria, ~59.3% of which are typically inherited in an autosomal recessive manner and ~6.4% are inherited in an X-linked recessive manner.