Submission Details

PIGB was first reported in related to DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 80 (MONDO:0032822) in 1996 (Takahashi et al., 1996, PMID:8861954). DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 80 is an autosomal recessive neurologic disorder characterized by the onset of refractory seizures in the first year of life. Patients have severe global developmental delay and may have additional variable features, including dysmorphic or coarse facial features, distal skeletal abnormalities, and impaired hearing or vision. At the cellular level, the disorder is caused by a defect in the synthesis of glycosylphosphatidylinositol (GPI) and thus affects the expression of GPI-anchored proteins at the cell surface (summary by Murakami et al., 2019). The PIGB gene encodes a transmembrane protein that is located in the endoplasmic reticulum and is involved in GPI-anchor biosynthesis. The GPI anchor is a glycolipid found on many blood cells and serves to anchor proteins to the cell surface. This gene is thought to encode a member of a family of dolichol-phosphate-mannose (Dol-P-Man) dependent mannosyltransferases. [provided by RefSeq, Jul 2008].

More than 350 unique variants (e.g., frameshift, missense, in-frame indel, nonsense and splice sites) have been reported in humans by ClinVar. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Ten variants that have been reported in 8 probands in 1 publication (Murakami et al., 2019; PMID: 31256876), are included in this curation. A model system that describes restored function of the GPI anchor synthesis pathway in a mutant mouse cell line (Takahashi et al., 1996, PMID:8861954) also supports this gene-disease relationship. In summary, there is moderate evidence to support PIGB in association with DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 80. This classification was approved by the ClinGen Congenital Disorders of Glycosylation GCEP on meeting date December 5, 2024 (SOP Version 10).