Mol Genet Genomic Med 2019 Jul 24;7(7):e00743. Epub 2019 May 24.
CHU Sainte-Justine Research Center, University of Montreal, Montreal, Quebec, Canada.
Background: Glycophosphatidylinositol-anchored proteins (GPI-APs) mediate several physiological processes such as embryogenesis and neurogenesis. Germline variants in genes involved in their synthesis can disrupt normal development and result in a variety of clinical phenotypes. With the advent of new sequencing technologies, more cases are identified, leading to a rapidly growing number of reported genetic variants. With this number expected to rise with increased accessibility to molecular tests, an accurate and up-to-date database is needed to keep track of the information and help interpret results.
Methods: We therefore developed an online resource (www.gpibiosynthesis.org) which compiles all published pathogenic variants in GPI biosynthesis genes which are deposited in the LOVD database. It contains 276 individuals and 192 unique public variants; 92% of which are predicted as damaging by bioinformatics tools.
Results: A significant proportion of recorded variants was substitution variants (81%) and resulted mainly in missense and frameshift alterations. Interestingly, five patients (2%) had deleterious mutations in untranslated regions. CADD score analysis placed 97% of variants in the top 1% of deleterious variants in the human genome. In genome aggregation database, the gene with the highest frequency of reported pathogenic variants is PIGL, with a carrier rate of 1/937.
Conclusion: We thus present the GPI biosynthesis database and review the molecular genetics of published variants in GPI-anchor biosynthesis genes.