Interpretation of Genomic Sequencing Results in Healthy and Ill Newborns: Results from the BabySeq Project

Abstract

Project TeamGenomic sequencing provides many opportunities in newborn clinical care, but the challenges of interpreting and reporting newborn genomic sequencing (nGS) results need to be addressed for its broader and effective application. The BabySeq Project is a pilot randomized clinical trial that explores the medical, behavioral, and economic impacts of nGS in well newborns and those admitted to a neonatal intensive care unit (NICU). Here we present childhood-onset and actionable adult-onset disease risk, carrier status, and pharmacogenomics findings from nGS of 159 newborns in the BabySeq Project. nGS revealed a risk of childhood-onset disease in 15/159 (9.4%) newborns; none of the disease risks were anticipated based on the infants' known clinical or family histories. nGS also revealed actionable adult-onset disease risk in 3/85 (3.5%) newborns whose parents consented to receive this information. Carrier status for recessive diseases and pharmacogenomics variants were reported in 88% and 5% of newborns, respectively. Additional indication-based analyses were performed in 29/32 (91%) NICU newborns and 6/127 (5%) healthy newborns who later had presentations that prompted a diagnostic analysis. No variants that sufficiently explained the reason for the indications were identified; however, suspicious but uncertain results were reported in five newborns. Testing parental samples contributed to the interpretation and reporting of results in 13/159 (8%) newborns. Our results suggest that nGS can effectively detect risk and carrier status for a wide range of disorders that are not detectable by current newborn screening assays or predicted based on the infant's known clinical or family history, and the interpretation of results can substantially benefit from parental testing.

The Role of Extended CFTR Gene Sequencing in Newborn Screening for Cystic Fibrosis

“…Whole exome sequencing and whole genome sequencing are nowadays affordable due to a significant reduction of costs. The relevance of implementing extended NBS for numerous genetic diseases is currently debated [66][67][68], which again raises the unsolved question of the interpretation of rare variants all along the genome. In this respect, comprehensive information on genetic issues should be given to the parents prior to NBS.…”

Molecular characterization of SLC24A5 variants and evaluation of Nitisinone treatment efficacy in a zebrafish model of OCA6

“…SLC24A5, a potent K + ‐dependent Na + /Ca 2+ exchanger, plays a vital role in melanogenesis by maintaining ionic homeostasis inside the melanosomes. Genetic variants significantly impact the function of SLC24A5, resulting in the OCA6 type phenotype in humans and complete loss of pigmentation in zebrafish (Bertolotti et al., 2016; Ceyhan‐Birsoy et al., 2019; Lamason et al., 2005; Lasseaux et al., 2018; Mondal, Sengupta, Samanta, Sil, & Ray, 2012; Morice‐Picard et al., 2014; Veniani et al., 2016; Wei et al., 2013). Our study further expands the genetic repertoire of SLC24A5 variants responsible for OCA6 in humans, especially in the Pakistani population.…”

Health-care providers’ perspectives on uncertainty generated by variant forms of newborn screening targets

“…Increasingly, genotypic information is being integrated to optimize the precision of screening algorithms and to enable the identification of a broader range of screening and diagnostic targets in the newborn period. 2,3 However, barriers to using first-tier genome sequencing in NBS include high cost of sequencing infrastructure, test sensitivity, interpretive and management complexity related to uncertain penetrance and mild and/or uncertain variants, and controversy with respect to how expansive screening panels ought to be. 4 In light of these barriers, early targets for genotype-first approaches may be limited to diseases for which biochemical testing is impossible (i.e., biochemical biomarkers do not exist) or impractical (measurement of a biomarker is too costly or complex).…”