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PIGG variant pathogenicity assessment reveals characteristic features within 19 families



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.


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.


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.


This in vitro system is a useful method to validate the pathogenicity of variants in PIGG and to study PIGG physiological functions.

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Fig. 1: Pedigrees and genotypes of families with biallelic PIGG variants.
Fig. 2: Clinical findings.
Fig. 3: PIGG protein structure and location of variants.
Fig. 4: Functional analysis of PIGG variants.

Data availability statement

Data and materials developed in support of the paper are available upon request.


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This work is supported by Canadian Institutes of Health Research (CIHR) and Fonds de Recherche du Québec–Santé (FRQS) awards to P.M.C. We thank Keiko Kinoshita, Saori Umeshita, Kae Imanishi (Osaka University) for technical help. T.S.B. is supported by the Netherlands Organisation for Scientific Research (ZonMW Veni, grant 91617021), a NARSAD Young Investigator Grant from the Brain & Behavior Research Foundation, an Erasmus MC Fellowship 2017, and Erasmus MC Human Disease Model Award 2018. This work was supported by JSPS and MEXT KAKENHI grants (JP16H04753 and JP17H06422), and grants from AMED (20ek0109418h0002) and MHLW of Japan. Some families were collected as part of the SYNaPS Study Group collaboration funded by the Welcome Trust and strategic award (Synaptopathies) funding (WT093205 MA and WT104033AIA). This research was conducted as part of the Queen Square Genomics group at University College London, supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre. Family 13 was identified in the CAUSES Study, funded by British Columbia Children’s Hospital Foundation and Genome BC.

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Conceptualization: P.M.C., Y. Murakami, T.K. Formal analysis: C.T-L., Y. Murakami, T.T.M.N., Y. Maki. Funding acquisition: P.M.C., T.S.B., Y. Murakami, T.K., H.H., A.L. Investigation: R. Maroofian, T.T.M.N., E.G.K., S.K., F. Akbar, S.I., B.A., M.D., F. Ashrafzadeh, M.B., S. Efthymiou, M.C., T.S., R.L.L., H.M.M., R.T., S.M., J.S.C., K.B., F.Y.I., M.S.P., A.L, A.C.E., A.N., M.A.W., S.M.A, Y. Maki, R. Sachdev, R. Macintosh, E.E.P., G.M.S.M., T.S.B., R. Steinfeld, C.T.R., G.M.S., M.W., S.B.W., U.K., A.F.B., K.L.S., N.I., S.E.I., D.B., K.N., S.D.M., S.E.A. Methodology: P.M.C., Y. Murakami. Project administration: C.T-L., P.M.C., Y. Murakami. Resources: P.M.C., Y. Murakami, T.K., R. Maroofian, E.G.K., S.K., F. Akbar, S.I., B.A., M.D., F. Ashrafzadeh, M.B., T.S., R.L.L., H.M.M., R.T., S.M., J.S.C., K.B., F.Y.I., M.S.P., A.L, A.C.E., M.A.W., S.M.A, R. Sachdev, R. Macintosh, E.E.P., G.M.S.M., T.S.B., R. Steinfeld, C.T.R., G.M.S., M.W., S.B.W., U.K., A.F.B., K.L.S., N.I., S.E.I., D.B., K.N., S.D.M., S.E.A., H.H. Supervision: P.M.C., Y. Murakami. Visualization: C.T-L., Y. Murakami. Writing—original draft: C.T.-L. Writing—review & editing: C.T-L., P.M.C., Y. Murakami, T.K., R. Maroofian, M.W., E.E.P., T.S.B., R. Steinfeld, G.M.S.M.

Corresponding authors

Correspondence to Philippe M. Campeau or Yoshiko Murakami.

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Informed written consent was obtained for every participant either from themselves or their parents. Ethical approval was granted by Centre Hospitalier Universitaire Sainte-Justine Research Center and Sick Kids Hospital. Consent was received for the use of identifying patient photographs.

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The authors declare no competing interests.

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Tremblay-Laganière, C., Maroofian, R., Nguyen, T.T.M. et al. PIGG variant pathogenicity assessment reveals characteristic features within 19 families. Genet Med (2021).

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