Investigating penetrance of severe combined immunodeficiency variants in an adult population cohort: implications for genomic newborn screening

Abstract

Severe combined immunodeficiency (SCID) is a heterogeneous, recessive disorder, associated with the onset of severe, recurrent infections in the first few months of life. SCID is fatal if left untreated, but outcomes can be significantly improved by prompt diagnosis and treatment, particularly prior to onset of infection. Consequently, SCID is already included in many newborn screening programmes around the world, as well as multiple international genomic newborn screening (gNBS) research programmes. However, there is a vital need to estimate penetrance of SCID variants in population cohorts, to mitigate the potential consequences of reporting low penetrance variants in a genotype-first gNBS setting. This study aimed to assess the penetrance and prevalence of these variants in the UK Biobank population cohort. Whole genome sequencing data from 490,640 individuals was used to interrogate 16 SCID genes for potentially causal variation. We identified 4206 carriers of single heterozygous pathogenic variants ([~]1% of cohort), but only 6 individuals double heterozygous, homozygous or hemizygous for relevant pathogenic variants. 3 individuals would be expected to require further testing had they been identified by gNBS, suggesting that fewer than 1 in 100,000 newborns might require follow-up testing due to SCID variants. Following detailed variant curation, we were able to identify only 2 unabected individuals likely to be harbouring biallelic pathogenic variants, potentially indicative of reduced penetrance. Nonetheless, SCID remains an excellent candidate for inclusion in gNBS studies, due its severity, clinical actionability and expected low false positive rate, although care should be taken when reporting hypomorphic variants.