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<p><i>PIGC</i> encodes a protein essential for the biosynthesis of glycophosphatidylinositol-anchored proteins (GPI-APs). So far, three families with biallelic <i>PIGC</i> variants have been reported to exhibit developmental delay/intellectual disability and seizures. Our aim was to further elucidate the clinical and biomolecular characteristics of <i>PIGC</i> 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 <i>PIGC</i> 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 <i>PIGC</i> 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.</p>

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PIGC-related encephalopathy: Lessons learned from 18 new probands

  • 期刊论文

  • 发表日期：

    2025年9月17日

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  • Allan Bayat,
  • Maria Carla Borroto,
  • Smrithi Salian,
  • Maha S. Zaki,
  • Hind Benkerroum,
  • Hasnaa M. Elbendary,
  • Thi Tuyet Mai Nguyen,
  • Abdelrahim A. Sadek,
  • Diana Carli,
  • Alfredo Brusco,
  • Giovanni Battista Ferrero,
  • Marco Tartaglia,
  • Eleanor Hay,
  • Ilona Krey,
  • Rami A. Jamra,
  • Tobias Bartolomaeus,
  • Alexej Knaus,
  • Joseph G. Gleeson,
  • Henry Houlden,
  • Natalia Dominik,
  • Adam Jackson,
  • Sofia Douzgou Houge,
  • Siddharth Banka,
  • Javad Mohammadi-asl,
  • Mohammadreza Hajjari,
  • Reza Azizimalamiri,
  • Pardis Nourbakhsh,
  • Mostafa Neissi,
  • Annarita Scardamaglia,
  • Dianfan Li,
  • Taroh Kinoshita,
  • Reza Maroofian,
  • Yoshiko Murakami,
  • Philippe M. Campeau

摘要

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.