Multiplexed Functional Assessment of Genetic Variants in CARD11

Iana Meitlis, Eric J. Allenspach, Bradly M. Bauman, Isabelle Q. Phan, Gina Dabbah, Erica G. Schmitt, Nathan D. Camp, Troy R. Torgerson, Deborah A. Nickerson, Michael J. Bamshad, David Hagin, Christopher R. Luthers, Jeffrey R. Stinson, Jessica Gray, Ingrid Lundgren, Joseph A. Church, Manish J. Butte, Mike B. Jordan, Seema S. Aceves, Daniella M. SchwartzJoshua D. Milner, Susan Schuval, Suzanne Skoda-Smith, Megan A. Cooper, Lea M. Starita, David J. Rawlings, Andrew L. Snow, Richard G. James

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Genetic testing has increased the number of variants identified in disease genes, but the diagnostic utility is limited by lack of understanding variant function. CARD11 encodes an adaptor protein that expresses dominant-negative and gain-of-function variants associated with distinct immunodeficiencies. Here, we used a “cloning-free” saturation genome editing approach in a diploid cell line to simultaneously score 2,542 variants for decreased or increased function in the region of CARD11 associated with immunodeficiency. We also described an exon-skipping mechanism for CARD11 dominant-negative activity. The classification of reported clinical variants was sensitive (94.6%) and specific (88.9%), which rendered the data immediately useful for interpretation of seven coding and splicing variants implicated in immunodeficiency found in our clinic. This approach is generalizable for variant interpretation in many other clinically actionable genes, in any relevant cell type.

Original languageEnglish
Pages (from-to)1029-1043
Number of pages15
JournalAmerican journal of human genetics
Volume107
Issue number6
DOIs
StatePublished - Dec 3 2020

Keywords

  • B cells
  • CARD11
  • gene editing
  • immune dysregulation
  • lymphoma
  • primary immune deficiency
  • saturation genome editing
  • variant interpretation

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