Utilization of genomic sequencing for population screening of immunodeficiencies in the newborn

Abstract

PurposeImmunodeficiency screening has been added to many state-directed newborn screening programs. The current methodology is limited to screening for severe T-cell lymphopenia disorders. We evaluated the potential of genomic sequencing to augment current newborn screening for immunodeficiency, including identification of non-T cell disorders.MethodsWe analyzed whole-genome sequencing (WGS) and clinical data from a cohort of 1,349 newborn-parent trios by genotype-first and phenotype-first approaches. For the genotype-first approach, we analyzed predicted protein-impacting variants in 329 immunodeficiency-related genes in the WGS data. As a phenotype-first approach, electronic health records were used to identify children with clinical features suggestive of immunodeficiency. Genomes of these children and their parents were analyzed using a separate pipeline for identification of candidate pathogenic variants for rare Mendelian disorders.ResultsWGS provides adequate coverage for most known immunodeficiency-related genes. 13,476 distinct variants and 8,502 distinct predicted protein-impacting variants were identified in this cohort; five individuals carried potentially pathogenic variants requiring expert clinical correlation. One clinically asymptomatic individual was found genomically to have complement component 9 deficiency. Of the symptomatic children, one was molecularly identified as having an immunodeficiency condition and two were found to have other molecular diagnoses.ConclusionNeonatal genomic sequencing can potentially augment newborn screening for immunodeficiency.

Newborn Screening for Primary Immunodeficiency Diseases: The Past, the Present and the Future

“…Three of these children had pathogenic mutations in other (non-PID) genes which correlated clinically. No additional causative variants were found in the other children, the majority of whom were considered to be unlikely to have a PID [32]. These findings are consistent with results of a survey conducted by Boyle et al, who determined a PID prevalence of 1 in 1200 in the US [33].…”

“…Pavey et al recently reported the results of WGS-based screening for PID in a cohort of 1349 newborn and parent trios, who were analyzed for variants in 329 known immunodeficiency genes [32]. A genotype-first pipeline resulted in identification of 396 newborns with pathogenic/likely pathogenic mutations, however on further analysis, only one individual was found to have a genomically predicted immunodeficiency (complement component C9 deficiency).…”

“…In terms of screening for PID, an approach similar to that adopted by Pavey et al [32] involving interrogation of a gene panel inclusive of the currently-described 300+ PID genes is an appropriate starting point. However, such panels would need to be regularly updated to include newly identified genes.…”

What Genomic Sequencing Can Offer Universal Newborn Screening Programs

“…For conditions like cystic fibrosis and lysosomal storage disorders, sequencing can help to confirm a diagnosis and can provide additional prognostic information . For nonspecific disorders, such as immunodeficiencies and hearing loss, gene panels or whole‐exome sequencing can help determine the underlying cause of the condition, information that is critical for appropriate medical management, surveillance, and treatment . In the future, widespread use of sequencing as a diagnostic follow‐up to existing screening tests could also decrease the number of false positives generated in public health programs, thereby lessening the emotional and financial burden on parents and the health care system.…”

“…4 For nonspecific disorders, such as immunodeficiencies and hearing loss, gene panels or whole-exome sequencing can help determine the underlying cause of the condition, information that is critical for appropriate medical management, surveillance, and treatment. 5 In the future, widespread use of sequencing as a diagnostic follow-up to existing screening tests could also decrease the number of false positives generated in public health programs, thereby lessening the emotional and financial burden on parents and the health care system. As one example, elevated phenylalanine levels detected using today's main newborn screening technology (tandem mass spectrometry) are associated with phenylketonuria (PKU) disease, the disorder that drove the establishment of newborn screening programs worldwide.…”