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Exome sequencing identifies a PLCG2 mutation in a dominantly inherited systemic inflammatory disease

Tuesday, October 25, 2011 — Poster Session II

Noon – 2:00 p.m.

Natcher Conference Center




  • Q Zhou
  • G Lee
  • J Brady
  • A Sheikh
  • J Khan
  • D Kastner
  • I Aksentijevich


We have identified a family with a chronic inflammatory disease characterized by recurrent blistering skin lesions, arthralgia, inflammatory eye and bowel disease, and a mild immunodeficiency with a paucity of circulating antibodies (IgG or IgA). We performed exome sequencing using Agilent SureSelect Human All Exon 50 Mb Kit on the affected father and daughter, and the unaffected mother. Exonic variants were filtered to exclude common variants identified in the dbSNP130 or 1000 Genomes databases along with benign variants as predicted based on the GERP score. A total of 33 transcripts were identified as possible candidate genes including the PLCG2 gene that encodes phospholipase Cγ2 (PLCγ2), an enzyme responsible for ligand-mediated signaling in B, NK, and mast cells. The candidate missense variant, S707Y, is a de novo mutation in the father and was passed only to his affected daughter but not to an unaffected son. The S707Y mutation was not detected in 376 Ashkenazi Jewish and 368 Caucasian controls and affects a highly conserved residue in an autoinhibitory SH2 domain. Preliminary overexpression study with mutant protein showed an increase in IP3 production relative to wild type protein suggesting a gain-of function mutation in the PLCγ2-mediated signal pathway.

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