Newborn Screening for Inborn Errors of Immunity via Whole-Genome Sequencing: A Pilot Study

Newborn screening by T cell receptor excision circle (TREC) measurement has transformed the care of severe combined immunodeficiency disease (SCID) by identifying babies and intervening prior to symptoms and/or infection. Many other inborn errors of immunity (IEI) could be managed similarly but cannot be identified by the TREC screen. The Genomic Uniform-screening Against Rare Disease In All Newborns (GUARDIAN) study was initiated with the aim of expanded genome-based newborn screening for actionable diseases across disciplines—including an expanded and evolving list of IEI—within a diverse population of newborns. Out of the first ∼10,000 asymptomatic newborns screened, four possible IEI were identified, none of whom had abnormalities on the standard TREC screen. These included 1) a male with hemizygous IL2RG c.664 C>A p.R222S—previously reported in 2 patients with atypical X-SCID. He had a CD3 count of 1319 (polyclonal, 63% naïve), B cell count of 704, and NK cell count of 2792 cells/µL with normal proliferation to phytohemagglutinin, but markedly decreased IL-2– and IL-7–induced pSTAT5 activation. He underwent successful haploidentical stem cell transplantation; 2) a male with compound heterozygous variants in ADA (c.454C>A p.L152M—reported in SCID, and c.548C>A p.A183D—a variant of uncertain significance [VUS]). Despite normal percentages and numbers of naïve and memory CD4 and CD8 T cells, recent thymic emigrants, B cells, and NK cells, his RBC ADA activity level was 0 with a modest elevation in dAXP—consistent with ADA-deficient combined immunodeficiency associated with a delayed onset presentation. Therapeutic intervention is under consideration; 3) a female with compound heterozygous C9 variants (- c.346 C>T p.R116* - pathogenic and c.1511 A>T p. E504V - VUS). Complement studies showed low normal C9 function and low normal CH50 indicating minimal risk for terminal complement deficiency-associated infection; and 4) a female with heterozygous STAT1 c. 181del p. L61Cfs*23 that is being evaluated now. These cases illustrate the potential for expanded genome-based newborn screening to identify newborns with medically actionable IEI at frequencies likely much higher than standard TREC screening. They also highlight the importance of efficient laboratory immunophenotying, VUS assessment, genetic counseling, and, when indicated, prompt management.