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Utility of DNA, RNA, Protein, and Functional Approaches to Solve Cryptic Immunodeficiencies.
Cousin, Margot A; Smith, Matthew J; Sigafoos, Ashley N; Jin, Jay J; Murphree, Marine I; Boczek, Nicole J; Blackburn, Patrick R; Oliver, Gavin R; Aleff, Ross A; Clark, Karl J; Wieben, Eric D; Joshi, Avni Y; Pichurin, Pavel N; Abraham, Roshini S; Klee, Eric W.
Afiliación
  • Cousin MA; Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA.
  • Smith MJ; Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
  • Sigafoos AN; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
  • Jin JJ; Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA.
  • Murphree MI; Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, USA.
  • Boczek NJ; Department of Allergy and Immunology, Mayo Clinic, Rochester, MN, USA.
  • Blackburn PR; Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA.
  • Oliver GR; Department of Clinical Genomics, Mayo Clinic, Rochester, MN, USA.
  • Aleff RA; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
  • Clark KJ; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
  • Wieben ED; Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA.
  • Joshi AY; Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
  • Pichurin PN; Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, USA.
  • Abraham RS; Medical Genome Facility, Mayo Clinic, Rochester, MN, USA.
  • Klee EW; Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA.
J Clin Immunol ; 38(3): 307-319, 2018 04.
Article en En | MEDLINE | ID: mdl-29671115
PURPOSE: We report a female infant identified by newborn screening for severe combined immunodeficiencies (NBS SCID) with T cell lymphopenia (TCL). The patient had persistently elevated alpha-fetoprotein (AFP) with IgA deficiency, and elevated IgM. Gene sequencing for a SCID panel was uninformative. We sought to determine the cause of the immunodeficiency in this infant. METHODS: We performed whole-exome sequencing (WES) on the patient and parents to identify a genetic diagnosis. Based on the WES result, we developed a novel flow cytometric panel for rapid assessment of DNA repair defects using blood samples. We also performed whole transcriptome sequencing (WTS) on fibroblast RNA from the patient and father for abnormal transcript analysis. RESULTS: WES revealed a pathogenic paternally inherited indel in ATM. We used the flow panel to assess several proteins in the DNA repair pathway in lymphocyte subsets. The patient had absent phosphorylation of ATM, resulting in absent or aberrant phosphorylation of downstream proteins, including γH2AX. However, ataxia-telangiectasia (AT) is an autosomal recessive condition, and the abnormal functional data did not correspond with a single ATM variant. WTS revealed in-frame reciprocal fusion transcripts involving ATM and SLC35F2 indicating a chromosome 11 inversion within 11q22.3, of maternal origin. Inversion breakpoints were identified within ATM intron 16 and SLC35F2 intron 7. CONCLUSIONS: We identified a novel ATM-breaking chromosome 11 inversion in trans with a pathogenic indel (compound heterozygote) resulting in non-functional ATM protein, consistent with a diagnosis of AT. Utilization of several molecular and functional assays allowed successful resolution of this case.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Genómica / Proteómica / Síndromes de Inmunodeficiencia Tipo de estudio: Diagnostic_studies / Prognostic_studies Límite: Female / Humans / Infant Idioma: En Revista: J Clin Immunol Año: 2018 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Países Bajos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Genómica / Proteómica / Síndromes de Inmunodeficiencia Tipo de estudio: Diagnostic_studies / Prognostic_studies Límite: Female / Humans / Infant Idioma: En Revista: J Clin Immunol Año: 2018 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Países Bajos