RT Journal Article SR Electronic T1 Mutations in the phosphatidylinositol glycan C (PIGC) gene are associated with epilepsy and intellectual disability JF Journal of Medical Genetics JO J Med Genet FD BMJ Publishing Group Ltd SP 196 OP 201 DO 10.1136/jmedgenet-2016-104202 VO 54 IS 3 A1 Simon Edvardson A1 Yoshiko Murakami A1 Thi Tuyet Mai Nguyen A1 Maher Shahrour A1 Anik St-Denis A1 Avraham Shaag A1 Nadira Damseh A1 Françoise Le Deist A1 Yenan Bryceson A1 Bassam Abu-Libdeh A1 Philippe M Campeau A1 Taroh Kinoshita A1 Orly Elpeleg YR 2017 UL http://jmg.bmj.com/content/54/3/196.abstract AB 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.