title: Vaccine-associated varicella and rubella infections in severe combined immunodeficiency with isolated CD4 lymphocytopenia and mutations in IL7R detected by tandem whole exome sequencing and chromosomal microarray.
abstract: In areas without newborn screening for severe combined immunodeficiency (SCID), disease-defining infections may lead to diagnosis, and in some cases, may not be 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. Immunological evaluations demonstrated neutropenia, isolated CD4 lymphocytopenia, the presence of CD8(+) T cells, poor lymphocyte proliferation, hypergammaglobulinaemia 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 pretransplant blood and buccal DNA and maternal engraftment (5-10%) demonstrated in pretransplant blood DNA. This may be responsible for the patient's unusual immunological phenotype compared to classical interleukin (IL)-7Rα deficiency. Disseminated VZV was controlled with anti-viral and immune-based therapy, and umbilical cord blood stem cell transplantation was successful. Retrospectively performed T cell receptor excision circle (TREC) analyses completed on neonatal Guthrie cards identified absent TREC. This case emphasizes the danger of live viral vaccination in severe combined immunodeficiency (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 aetiology for SCID patients.
authors.affiliation: Department of Pediatrics, Section of Immunology, Allergy, and Rheumatology, Baylor College of Medicine and Texas Children's Hospital, Houston, TX, USA.
authors.forename: D K
authors.initials: DK
authors.lastname: Bayer
authors.forename: C A
authors.initials: CA
authors.lastname: Martinez
authors.forename: H S
authors.initials: HS
authors.lastname: Sorte
authors.forename: L R
authors.initials: LR
authors.lastname: Forbes
authors.forename: G J
authors.initials: GJ
authors.lastname: Demmler-Harrison
authors.forename: I C
authors.initials: IC
authors.lastname: Hanson
authors.forename: N M
authors.initials: NM
authors.lastname: Pearson
authors.forename: L M
authors.initials: LM
authors.lastname: Noroski
authors.forename: S R
authors.initials: SR
authors.lastname: Zaki
authors.forename: W J
authors.initials: WJ
authors.lastname: Bellini
authors.forename: M S
authors.initials: MS
authors.lastname: Leduc
authors.forename: Y
authors.initials: Y
authors.lastname: Yang
authors.forename: C M
authors.initials: CM
authors.lastname: Eng
authors.forename: A
authors.initials: A
authors.lastname: Patel
authors.forename: O K
authors.initials: OK
authors.lastname: Rodningen
authors.forename: D M
authors.initials: DM
authors.lastname: Muzny
authors.forename: R A
authors.initials: RA
authors.lastname: Gibbs
authors.forename: I M
authors.initials: IM
authors.lastname: Campbell
authors.forename: C A
authors.initials: CA
authors.lastname: Shaw
authors.forename: M W
authors.initials: MW
authors.lastname: Baker
authors.forename: V
authors.initials: V
authors.lastname: Zhang
authors.forename: J R
authors.initials: JR
authors.lastname: Lupski
authors.forename: J S
authors.initials: JS
authors.lastname: Orange
authors.forename: F O
authors.initials: FO
authors.lastname: Seeborg
authors.forename: A
authors.initials: A
authors.lastname: Stray-Pedersen
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002644:Chickenpox / Q000209:etiology*; D056915:DNA Copy Number Variations; D059472:Exome; D005260:Female; D006801:Humans; D007223:Infant; D008231:Lymphopenia / Q000209:etiology*; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D020395:Receptors, Interleukin-7 / Q000235:genetics*; D012409:Rubella / Q000209:etiology*; D016511:Severe Combined Immunodeficiency / Q000235:genetics* / Q000276:immunology; D014611:Vaccination / Q000009:adverse effects*
chemical_list: D020395:Receptors, Interleukin-7
keywords: IL7R; SCID; copy number variation; revertant mosaicism; whole exome sequencing