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Keywords:

  • Immunodeficiency;
  • IL7R;
  • SCID;
  • whole exome sequencing;
  • chromosomal microarray;
  • copy number variation;
  • reverse mutation

Summary

In areas without newborn screening for severe combined immunodeficiency (SCID), disease-defining infections may lead to diagnosis, and not identified prior to the first year of life. We describe a female infant who presented with disseminated vaccine-acquired varicella (VZV) and vaccine-acquired rubella infections at 13 months of age. Immunologic evaluations demonstrated neutropenia, isolated CD4 lymphocytopenia, presence of CD8+ T cells, poor lymphocyte proliferation, hypergammaglobulinemia, and poor specific antibody production to VZV infection and routine immunizations. A combination of whole exome sequencing and custom-designed chromosomal microarray with exon coverage of primary immunodeficiency genes detected compound heterozygous mutations (one single nucleotide variant and one intragenic copy number variant involving one exon) within the IL7R gene. Mosaicism for wild-type allele (20-30%) was detected in pre-transplant blood and buccal DNA, and maternal engraftment (5-10%) demonstrated in pre-transplant blood DNA. This may be responsible for the patient's unusual immunologic phenotype compared to classical IL7Ralpha deficiency. Disseminated VZV was controlled with antiviral and immune-based therapy, and umbilical cord blood stem cell transplantation was successful. Retrospectively performed T-cell receptor excision circles (TREC) analyses completed on neonatal Guthrie cards from the patient identified absent TRECs. This case emphasizes the danger of live viral vaccination in SCID patients and the importance of newborn screening to identify patients prior to high-risk exposures. It also illustrates the value of aggressive pathogen identification and treatment, the influence newborn screening can have on morbidity and mortality, and the significant impact of newer genomic diagnostic tools in identifying the underlying genetic etiology for SCID patients.