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PIGT-CDG, a disorder of the glycosylphosphatidylinositol anchor: description of 13 novel patients and expansion of the clinical characteristics



To provide a detailed electroclinical description and expand the phenotype of PIGT-CDG, to perform genotype–phenotype correlation, and to investigate the onset and severity of the epilepsy associated with the different genetic subtypes of this rare disorder. Furthermore, to use computer-assisted facial gestalt analysis in PIGT-CDG and to the compare findings with other glycosylphosphatidylinositol (GPI) anchor deficiencies.


We evaluated 13 children from eight unrelated families with homozygous or compound heterozygous pathogenic variants in PIGT.


All patients had hypotonia, severe developmental delay, and epilepsy. Epilepsy onset ranged from first day of life to two years of age. Severity of the seizure disorder varied from treatable seizures to severe neonatal onset epileptic encephalopathies. The facial gestalt of patients resembled that of previously published PIGT patients as they were closest to the center of the PIGT cluster in the clinical face phenotype space and were distinguishable from other gene-specific phenotypes.


We expand our knowledge of PIGT. Our cases reaffirm that the use of genetic testing is essential for diagnosis in this group of disorders. Finally, we show that computer-assisted facial gestalt analysis accurately assigned PIGT cases to the multiple congenital anomalies–hypotonia–seizures syndrome phenotypic series advocating the additional use of next-generation phenotyping technology.

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Anonymized data will be shared by request with any qualified investigator for the sole purpose of replicating procedures and results presented in the article and as long as data transfer is in agreement with EU legislation on the general data protection regulation.

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Shared first authors: Allan Bayat, Alexej Knaus, Annika Wollenberg Juul.


  1. 1.

    Kinoshita T, Fujita M, Maeda Y. Biosynthesis, remodelling and functions of mammalian GPI-anchored proteins: recent progress. J Biochem. 2008;144:287–294.

  2. 2.

    Fujita M, Kinoshita T. GPI-anchor remodeling: potential functions of GPI-anchors in intracellular trafficking and membrane dynamics. Biochim Biophys Acta. 2012;1821:1050–1058.

  3. 3.

    Kinoshita T, Fujita M. Biosynthesis of GPI-anchored proteins: special emphasis on GPI lipid remodeling. J Lipid Res. 2016;57:6–24.

  4. 4.

    Park S, Lee C, Sabharwal P, et al. GDE2 promotes neurogenesis by glycosylphosphatidylinositol-anchor cleavage of RECK. Science. 2013;339:324–328.

  5. 5.

    Nozaki M, Ohishi K, Yamada N, et al. Developmental abnormalities of glycosylphosphatidylinositol-anchor-deficient embryos revealed by Cre/loxP system. Lab Invest. 1999;79:293–299.

  6. 6.

    McKean DM, Niswander L. Defects in GPI biosynthesis perturb Cripto signaling during forebrain development in two new mouse models of holoprosencephaly. Biol Open. 2012;1:874–883.

  7. 7.

    Bessler M, Mason PJ, Hillmen P, et al. Paroxysmal nocturnal haemoglobinuria (PNH) is caused by somatic mutations in the PIG-A gene. EMBO J. 1994;13:110–117.

  8. 8.

    Almeida AM, Murakami Y, Layton DM, et al. Hypomorphic promoter mutation in PIGM causes inherited glycosylphosphatidylinositol deficiency. Nat Med. 2006;12:846–851.

  9. 9.

    Krawitz PM, Schweiger MR, Rödelsperger C, et al. Identity-by-descent filtering of exome sequence data identifies PIGV mutations in hyperphosphatasia mental retardation syndrome. Nat Genet. 2010;42:827–829.

  10. 10.

    Murakami Y, Tawamie H, Maeda Y, et al. Null mutation in PGAP1 impairing Gpi-anchor maturation in patients with intellectual disability and encephalopathy. PLoS Genet. 2014;10:e1004320.

  11. 11.

    Martin HC, Kim GE, Pagnamenta AT, et al. Clinical whole-genome sequencing in severe early-onset epilepsy reveals new genes and improves molecular diagnosis. Hum Mol Genet. 2014;23:3200–3211.

  12. 12.

    Ilkovski B, Pagnamenta AT, O’Grady GL, et al. Mutations in PIGY: expanding the phenotype of inherited glycosylphosphatidylinositol deficiencies. Hum Mol Genet. 2015;24:6146–6159.

  13. 13.

    Makrythanasis P, Kato M, Zaki MS, et al. Pathogenic variants in PIGG cause intellectual disability with seizures and hypotonia. Am J Hum Genet. 2015;98:1–12.

  14. 14.

    Johnstone DL, Nguyen T-T-M, Murakami Y, et al. Compound heterozygous mutations in the gene PIGP are associated with early infantile epileptic encephalopathy. Hum Mol Genet. 2017;26:1706–1715.

  15. 15.

    Edvardson S, Murakami Y, Nguyen TTM, et al. Mutations in the phosphatidylinositol glycan C (PIGC) gene are associated with epilepsy and intellectual disability. J Med Genet. 2017;54:196–201.

  16. 16.

    Maydan G, Noyman I, Har-Zahav A, et al. Multiple congenital anomalies-hypotonia-seizures syndrome is caused by a mutation in PIGN. J Med Genet. 2011;48:383–389.

  17. 17.

    Ng BG, Hackmann K, Jones MA, et al. Mutations in the glycosylphosphatidylinositol gene PIGL cause CHIME syndrome. Am J Hum Genet. 2012;90:685–688.

  18. 18.

    Krawitz PM, Murakami Y, Hecht J, et al. Mutations in PIGO, a member of the GPI-anchor-synthesis pathway, cause hyperphosphatasia with mental retardation. Am J Hum Genet. 2012;91:146–151.

  19. 19.

    Johnston JJJ, Gropman ALL, Sapp JCC, et al. The phenotype of a germline mutation in PIGA: the gene somatically mutated in paroxysmal nocturnal hemoglobinuria. Am J Hum Genet. 2012;10:295–300.

  20. 20.

    Hansen L, Tawamie H, Murakami Y, et al. Hypomorphic mutations in PGAP2, encoding a GPI-anchor-remodeling protein, cause autosomal-recessive intellectual disability. Am J Hum Genet. 2013;92:575–583.

  21. 21.

    Kvarnung M, Nilsson D, Lindstrand A, et al. A novel intellectual disability syndrome caused by GPI anchor deficiency due to homozygous mutations in PIGT. J Med Genet. 2013;50:521–528.

  22. 22.

    Chiyonobu T, Inoue N, Morimoto M, et al. Glycosylphosphatidylinositol (GPI) anchor deficiency caused by mutations in PIGW is associated with West syndrome and hyperphosphatasia with mental retardation syndrome. J Med Genet. 2014;51:203–207.

  23. 23.

    Howard MF, Murakami Y, Pagnamenta AT, et al. Mutations in PGAP3 impair GPI-anchor maturation, causing a subtype of hyperphosphatasia with mental retardation. Am J Hum Genet. 2014;94:278–287.

  24. 24.

    Ohishi K, Inoue N, Kinoshita T. PIG-S and PIG-T, essential for GPI anchor attachment to proteins, form a complex with GAA1 and GPI8. EMBO J. 2001;20:4088–4098.

  25. 25.

    Ohishi K, Nagamune K, Maeda Y, et al. Two subunits of glycosylphosphatidylinositol transamidase, GPI8 and PIG-T, form a functionally important intermolecular disulfide bridge. J Biol Chem. 2003;278:13959–13967.

  26. 26.

    Skauli N, Wallace S, Chiang S, et al. Novel PIGT variant in two brothers: expansion of the multiple congenital anomalies-hypotonia seizures syndrome 3 phenotype. Genes (Basel). 2016;7:108.

  27. 27.

    Pagnamenta AT, Murakami Y, Taylor JM, et al. Analysis of exome data for 4293 trios suggests GPI-anchor biogenesis defects are a rare cause of developmental disorders. Eur J Hum Genet. 2017;22:1–11.

  28. 28.

    Kohashi K, Ishiyama A, Yuasa S, et al. Epileptic apnea in a patient with inherited glycosylphosphatidylinositol anchor deficiency and pigt mutations. Brain Dev. 2017;40:53–57.

  29. 29.

    Yang L, Peng J, Yin X-M, et al. Homozygous PIGT mutation lead to multiple congenital anomalies-hypotonia seizures syndrome 3. Front Genet. 2018;9:153.

  30. 30.

    Gurovich Y, Hanani Y, Bar O, et al. DeepGestalt - Identifying Rare Genetic Syndromes Using Deep Learning. Nat Med. 2019;25:60–64.

  31. 31.

    Knaus A, Pantel JT, Pendziwiat M, et al. Characterization of glycosylphosphatidylinositol biosynthesis defects by clinical features, flow cytometry, and automated image analysis. Genome Med. 2018;10:3.

  32. 32.

    Pagnamenta AT, Murakami Y, Taylor JM, et al. Analysis of exome data for 4293 trios suggests GPI-anchor biogenesis defects are a rare cause of developmental disorders. Eur J Hum Genet. 2017;25:669–679.

  33. 33.

    Firth HV, Wright CF. The Deciphering Developmental Disorders (DDD) study. Dev Med Child Neurol. 2011;53:702–703.

  34. 34.

    Nakashima M, Kashii H, Murakami Y, et al. Novel compound heterozygous PIGT mutations caused multiple congenital anomalies-hypotonia-seizures syndrome 3. Neurogenetics. 2014;15:193–200.

  35. 35.

    Lam C, Golas GA, Davids M, et al. Expanding the clinical and molecular characteristics of PIGT-CDG, a disorder of glycosylphosphatidylinositol anchors. Mol Genet Metab. 2015;115:128–140.

  36. 36.

    Ng BG, Freeze HH. Human genetic disorders involving glycosylphosphatidylinositol (GPI) anchors and glycosphingolipids (GSL). J Inherit Metab Dis. 2015;38:171–178.

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We thank the families for participating in this study. We thank Malin Kvarnung for kindly sharing previously unpublished data regarding the onset of epileptic seizures in their patients. I.H. was supported by intramural funds of the University of Kiel, and by a grant from the German Research Foundation (DFG) (HE5415/6-1). Y.W. was supported by a grant from the German Research Foundation (DFG) (WE4896/3-1 and WE4896/4-1). A.C. was sponsored by Polish National Science Centre grant number 2014/15/D/NZ5/03426. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (WT098051). The research team acknowledges the support of the National Institute for Health Research, through the Comprehensive Clinical Research Network. The views expressed in this publication are those of the authors and not necessarily those of the Wellcome Trust or the Department of Health.

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The authors declare no conflicts of interest.

Correspondence to Allan Bayat MD or Rikke S. Møller MSc, PhD.

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  • congenital disorder of glycosylation
  • computer-assisted facial gestalt analysis
  • genotype–phenotype
  • epilepsy
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