Genetic Diagnosis Using Whole Exome Sequencing in Common Variable Immunodeficiency. Maffucci, P., Filion, C. A, Boisson, B., Itan, Y., Shang, L., Casanova, J., & Cunningham-Rundles, C. 7:220, 1, 2016.
Genetic Diagnosis Using Whole Exome Sequencing in Common Variable Immunodeficiency. [link]Paper  doi  abstract   bibtex   
Whole exome sequencing (WES) has proven an effective tool for the discovery of genetic defects in patients with primary immunodeficiencies (PIDs). However, success in dissecting the genetic etiology of common variable immunodeficiency (CVID) has been limited. We outline a practical framework for using WES to identify causative genetic defects in these subjects. WES was performed on 50 subjects diagnosed with CVID who had at least one of the following criteria: early onset, autoimmune/inflammatory manifestations, low B lymphocytes, and/or familial history of hypogammaglobulinemia. Following alignment and variant calling, exomes were screened for mutations in 269 PID-causing genes. Variants were filtered based on the mode of inheritance and reported frequency in the general population. Each variant was assessed by study of familial segregation and computational predictions of deleteriousness. Out of 433 variations in PID-associated genes, we identified 17 probable disease-causing mutations in 15 patients (30%). These variations were rare or private and included monoallelic mutations in NFKB1, STAT3, CTLA4, PIK3CD, and IKZF1, and biallelic mutations in LRBA and STXBP2. Forty-two other damaging variants were found but were not considered likely disease-causing based on the mode of inheritance and/or patient phenotype. WES combined with analysis of PID-associated genes is a cost-effective approach to identify disease-causing mutations in CVID patients with severe phenotypes and was successful in 30% of our cohort. As targeted therapeutics are becoming the mainstay of treatment for non-infectious manifestations in CVID, this approach will improve management of patients with more severe phenotypes.
@article{Maffucci-2016-ID239,
  title     = {Genetic Diagnosis Using Whole Exome Sequencing in Common Variable
               Immunodeficiency.},
  abstract  = {Whole exome sequencing ({WES}) has proven an effective tool for the
               discovery of genetic defects in patients with primary immunodeficiencies
               ({PID}s). However, success in dissecting the genetic etiology of common
               variable immunodeficiency ({CVID}) has been limited. We outline a practical
               framework for using {WES} to identify causative genetic defects in these
               subjects. {WES} was performed on 50 subjects diagnosed with {CVID} who had
               at least one of the following criteria: early onset,
               autoimmune/inflammatory manifestations, low B lymphocytes, and/or familial
               history of hypogammaglobulinemia. Following alignment and variant calling,
               exomes were screened for mutations in 269 {PID}-causing genes. Variants
               were filtered based on the mode of inheritance and reported frequency in
               the general population. Each variant was assessed by study of familial
               segregation and computational predictions of deleteriousness. Out of 433
               variations in {PID}-associated genes, we identified 17 probable
               disease-causing mutations in 15 patients (30\%). These variations were rare
               or private and included monoallelic mutations in {NFKB}1, {STAT}3, {CTLA}4,
               {PIK}3{CD}, and {IKZF}1, and biallelic mutations in {LRBA} and {STXBP}2.
               Forty-two other damaging variants were found but were not considered likely
               disease-causing based on the mode of inheritance and/or patient phenotype.
               {WES} combined with analysis of {PID}-associated genes is a cost-effective
               approach to identify disease-causing mutations in {CVID} patients with
               severe phenotypes and was successful in 30\% of our cohort. As targeted
               therapeutics are becoming the mainstay of treatment for non-infectious
               manifestations in {CVID}, this approach will improve management of patients
               with more severe phenotypes.},
  author    = {Maffucci, Patrick and Filion, Charles A and Boisson, Bertrand and Itan,
               Yuval and Shang, Lei and Casanova, Jean-Laurent and Cunningham-Rundles,
               Charlotte},
  volume    = {7},
  pages     = {220},
  year      = {2016},
  month     = {1},
  url       = {https://www.ncbi.nlm.nih.gov/pubmed/27379089},
  pmcid     = {4903998},
  pmid      = {27379089},
  doi       = {10.3389/fimmu.2016.00220},
  file      = {FULLTEXT:pdfs/000/000/000000239.pdf:PDF}
}
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