Low frequency of treatable pediatric disease alleles in gnomAD: An opportunity for future genomic screening of newborns

Abstract

Summary: Hematopoietic stem cell transplant (HSCT) can prevent progression of several genetic disorders. Although a subset of these disorders are identified on newborn screening panels, others are not identified until irreversible symptoms develop. Genetic testing is an efficient methodology to ascertain pre-symptomatic children, but the penetrance of risk-associated variants in the general population is not well understood. We developed a list of 127 genes associated with disorders treatable with HSCT. We identified likely pathogenic or pathogenic (LP/P) and loss-of-function (LoF) variants in these genes in the Genome Aggregation Database (gnomAD), a dataset containing exome and genome sequencing data from 141,456 healthy adults. Within gnomAD, we identified 59 individuals with a LP/P or LoF variant in 15 genes. Genes were associated with bone marrow failure syndromes, bleeding disorders, primary immunodeficiencies, osteopetrosis, metabolic disorders, and epidermolysis bullosa. In conclusion, few ostensibly healthy adults had genotypes associated with pediatric disorders treatable with HSCTs. Given that most of these disorders do not have biomarkers that could be cheaply and universally assessed on a standard newborn screen, our data suggest that genetic testing may be a complementary approach to traditional newborn screening methodology that has the potential to improve mortality and is not expected to lead to a high burden of false-positive results.

Keywords

• stem cell transplant
• penetrance
• genomic screening
• newborn screening
• rare disease