TY - JOUR T1 - Mutations in the phosphatidylinositol glycan C (<em>PIGC</em>) gene are associated with epilepsy and intellectual disability JF - Journal of Medical Genetics JO - J Med Genet SP - 196 LP - 201 DO - 10.1136/jmedgenet-2016-104202 VL - 54 IS - 3 AU - Simon Edvardson AU - Yoshiko Murakami AU - Thi Tuyet Mai Nguyen AU - Maher Shahrour AU - Anik St-Denis AU - Avraham Shaag AU - Nadira Damseh AU - Françoise Le Deist AU - Yenan Bryceson AU - Bassam Abu-Libdeh AU - Philippe M Campeau AU - Taroh Kinoshita AU - Orly Elpeleg Y1 - 2017/03/01 UR - http://jmg.bmj.com/content/54/3/196.abstract N2 - Background Of our 1400 exome-studied patients, 67% originate from consanguineous families. ∼80% suffer from variable degree of intellectual disability (ID). The search for disease causing genes using homozygosity mapping was progressing slowly until 2010, then markedly accelerated by the introduction of exome analysis.Objectives To identify the disease causing mutation(s) in three patients from two unrelated families who suffered from global developmental delay, severe ID and drug-responsive seizure disorder.Methods Exome analysis was performed in DNA of the three patients. The identified PIGC variants were generated and transfected into PIGC-defective mouse cells and the restoration of the surface expression of mouse CD90, CD48 and FLAER was assessed using flow cytometry. The expression of these proteins was also studied on the surface of patients' leucocytes.Results Three PIGC mutations were identified; homozygous p.L189W in one family and compound heterozygosity for p.L212P/p.R21X variants in another. PIGC participates in the biosynthesis of the glycosylphosphatidylinositol (GPI) anchor which tethers proteins to plasma membrane. In cells lacking PIGC protein, which were transfected with each of the PIGC variants, we detected a clear reduction of surface expression of GPI-anchored proteins. Furthermore, analyses of patients' leucocytes showed significant and constant decrease of CD16 surface expression in granulocytes, and moderate decrease of CD14, CD55, CD59 and FLAER levels.Conclusions PIGC joins the list of genes in which mutations result in defective biosynthesis of GPI anchoring, manifesting by global developmental delay and seizure disorder. The lack of specific biomarker dictates exome sequencing as the diagnostic procedure of choice in similar patients. ER -