Abstract
PIGC encodes a protein essential for the biosynthesis of glycophosphatidylinositol-anchored proteins (GPI-APs). So far, three families with biallelic PIGC variants have been reported to exhibit developmental delay/intellectual disability and seizures. Our aim was to further elucidate the clinical and biomolecular characteristics of PIGC pathogenic or likely pathogenic variants. We established a cohort of 18 previously unreported probands. Clinical data were collected, and causative variants were identified though genome/exome sequencing. Variants were modelled in silico using AlphaFold2. Flow cytometry was performed to analyze the cell-surface expression of GPI-APs. The probands displayed a severe neurodevelopmental disorder characterized by developmental and cognitive impairment, early-onset and treatment-resistant seizures, and premature death affecting 10 out of 18 individuals (median age of 40 months, ranging from 40 days to 7 years). Additional features included brain imaging abnormalities (14/15), hypotonia (15/18), and skeletal anomalies (5/17). One patient exhibited mildly elevated alkaline phosphatase levels. All harbored biallelic PIGC variants, with 14 out of 18 of those being homozygous variants. Analysis of samples derived from probands and cellular models showed reduced cell surface levels of GPI-APs. This study confirms the association of PIGC biallelic variants with refractory seizures, severe developmental and cognitive impairments, and highlights their association with childhood-onset mortality. Additionally, it shows that dysfunctional PIGC results in defective biosynthesis of GPI-AP.
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All clinical data generated or analyzed during this study are included in this published article.
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Acknowledgements
The authors are grateful to the families for cooperating in this study. This research was made possible through access to data in the National Genomic Research Library, which is managed by Genomics England Limited (a wholly owned company of the Department of Health and Social Care). The National Genomic Research Library holds data provided by patients and collected by the NHS as part of their care and data collected as part of their participation in research. The National Genomic Research Library is funded by the National Institute for Health Research and NHS England. The Wellcome Trust, Cancer Research UK and the Medical Research Council have also funded research infrastructure.
Funding
AB is funded by a BRIDGE - Translational Excellence Programme grant funded by the Novo Nordisk Foundation, grant agreement number: NNF20SA0064340. PMC is supported by awards from the CIHR and the FRQS. MZ is supported by Science and Technology Development Fund (STDF) grant 33650. MIUR project “Dipartimenti di Eccellenza 2023-2027” to the Department of Neurosciences “Rita Levi Montalcini” (University of Turin); Italian Ministry for Education, University and Research (Ministero dell’Istruzione, dell’Università e della Ricerca - MIUR) PRIN2020 code 20203P8C3X. The whole-exome sequencing was performed as part of the Autism Sequencing Consortium and was supported by the NIMH (MH111661). This research was supported by the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC) Programme and the Wellcome Trust (203141/Z/16/Z). This study has been delivered through the NIHR Manchester BRC (NIHR203308). The views expressed are those of the author(s) and not necessarily those of the, the NIHR or the Department of Health and Social Care. Dr Adam Jackson is supported by Solve-RD. The Solve-RD project has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement No 779257.
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Conceptualization: A.B., P.M.C.; Writing-review & editing: A.B., M.C.B., P.M.C.; Methodology: S.S., H.B., T.T.M.N.; Investigation – functional experiments: S.S., H.B., T.T.M.N., T.K., Y.M., D.L., P.M.C.; Writing-original draft: S.S.; Reviewed the final draft: A.B., M.C.B., S.S., H.B., M.S.Z., T.T.M.N., A.A.S., D.C., A.B., G.B.F., E.H., I.K., T.B., A.K., J.G.G., H.H., N.D., A.J., S.D., G.E.R.C., S.B., T.K., R.M., Y.M., P.M.C.; Investigation - proband recruitment, clinical and diagnostic evaluation: M.C.B., M.S.Z., A.A.S., D.C., A.B., G.B.F., E.H., I.K., T.B., A.K., J.G.G., H.H., N.D., A.J., S.D.H., S.B., A.J.M, A.S., H.M.E., M.T., M.H., M.N., P.N., R.A.J., R.A., P.M.C.; Funding acquisition: P.M.C., A.B.
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We declare that the authors do not have any conflict of interest, and all have read and approved the final manuscript.
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The study protocol was approved by CHU Sainte-Justine Research Ethics Board (#MP-21-2016-962). Samples were collected from probands and families after written informed consent was obtained from the parents or legal guardians, and the data was de-identified. A written medical photography consent was obtained from the parents of P6, P9, P10, P11, and P12.
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Bayat, A., Borroto, M.C., Salian, S. et al. PIGC-related encephalopathy: Lessons learned from 18 new probands. Eur J Hum Genet 33, 1636–1646 (2025). https://doi.org/10.1038/s41431-025-01923-9
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DOI: https://doi.org/10.1038/s41431-025-01923-9
