PIGG variant pathogenicity assessment reveals characteristic features within 19 families

Camille Tremblay-Laganière, Reza Maroofian, Thi Tuyet Mai Nguyen, Ehsan Ghayoor Karimiani, Salman Kirmani, Fizza Akbar, Shahnaz Ibrahim, Bushra Afroze, Mohammad Doosti, Farah Ashrafzadeh, Meisam Babaei, Stephanie Efthymiou, Marilena Christoforou, Tipu Sultan, Roger L. Ladda, Heather M. McLaughlin, Rebecca Truty, Sonal Mahida, Julie S. Cohen, Kristin BarananoFatima Y. Ismail, Millan S. Patel, Anna Lehman, Andrew C. Edmondson, Amanda Nagy, Melissa A. Walker, Saadet Mercimek-Andrews, Yuta Maki, Rani Sachdev, Rebecca Macintosh, Elizabeth E. Palmer, Grazia M.S. Mancini, Tahsin Stefan Barakat, Robert Steinfeld, Christina T. Rüsch, Georg M. Stettner, Matias Wagner, Saskia B. Wortmann, Usha Kini, Angela F. Brady, Karen L. Stals, Naila Ismayilova, Sian Ellard, Danilo Bernardo, Kimberly Nugent, Scott D. McLean, Stylianos E. Antonarakis, Henry Houlden, Taroh Kinoshita, Philippe M. Campeau, Yoshiko Murakami

Research output: Contribution to journalArticlepeer-review

4 Citations (Scopus)


Purpose: Phosphatidylinositol Glycan Anchor Biosynthesis, class G (PIGG) is an ethanolamine phosphate transferase catalyzing the modification of glycosylphosphatidylinositol (GPI). GPI serves as an anchor on the cell membrane for surface proteins called GPI-anchored proteins (GPI-APs). Pathogenic variants in genes involved in the biosynthesis of GPI cause inherited GPI deficiency (IGD), which still needs to be further characterized. Methods: We describe 22 individuals from 19 unrelated families with biallelic variants in PIGG. We analyzed GPI-AP surface levels on granulocytes and fibroblasts for three and two individuals, respectively. We demonstrated enzymatic activity defects for PIGG variants in vitro in a PIGG/PIGO double knockout system. Results: Phenotypic analysis of reported individuals reveals shared PIGG deficiency–associated features. All tested GPI-APs were unchanged on granulocytes whereas CD73 level in fibroblasts was decreased. In addition to classic IGD symptoms such as hypotonia, intellectual disability/developmental delay (ID/DD), and seizures, individuals with PIGG variants of null or severely decreased activity showed cerebellar atrophy, various neurological manifestations, and mitochondrial dysfunction, a feature increasingly recognized in IGDs. Individuals with mildly decreased activity showed autism spectrum disorder. Conclusion: This in vitro system is a useful method to validate the pathogenicity of variants in PIGG and to study PIGG physiological functions.

Original languageEnglish
Pages (from-to)1873-1881
Number of pages9
JournalGenetics in Medicine
Issue number10
Publication statusPublished - Oct 2021


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