Compound heterozygous mutations in the gene PIGP are associated with early infantile epileptic encephalopathy.

Devon L Johnstone, Thi-Tuyet-Mai Nguyen, Yoshiko Murakami, Kristin D Kernohan, Martine Tétreault, Claire Goldsmith, Asif Doja, Justin D Wagner, Lijia Huang, Taila Hartley, Anik St-Denis, Françoise le Deist, Jacek Majewski, Dennis E Bulman, Taroh Kinoshita, David A Dyment, Kym M Boycott, Philippe M Campeau

There are over 150 known human proteins which are tethered to the cell surface via glycosylphosphatidylinositol (GPI) anchors. These proteins play a variety of important roles in development, and particularly in neurogenesis. Not surprisingly, mutations in the GPI anchor biosynthesis and remodeling pathway cause a number of developmental disorders. This group of conditions has been termed inherited GPI deficiencies (IGDs), a subgroup of congenital disorders of glycosylation; they present with variable phenotypes, often including seizures, hypotonia and intellectual disability. Here, we report two siblings with compound heterozygous variants in the gene phosphatidylinositol glycan anchor biosynthesis, class P (PIGP) (NM_153681.2: c.74T>C;p.Met25Thr and c.456delA;p.Glu153AsnFs*34). PIGP encodes a subunit of the enzyme that catalyzes the first step of GPI anchor biosynthesis. Both children presented with early-onset refractory seizures, hypotonia, and profound global developmental delay, reminiscent of other IGD phenotypes. Functional studies with patient cells showed reduced PIGP mRNA levels, and an associated reduction of GPI-anchored cell surface proteins, which was rescued by exogenous expression of wild-type PIGP. This work associates mutations in the PIGP gene with a novel autosomal recessive IGD, and expands our knowledge of the role of PIG genes in human development.