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Multiple congenital anomalies-hypotonia-seizures syndrome is caused by a mutation in PIGN
  1. Gal Maydan1,
  2. Iris Noyman2,
  3. Adi Har-Zahav3,
  4. Ziva Ben Neriah4,
  5. Metsada Pasmanik-Chor5,
  6. Adva Yeheskel5,
  7. Adi Albin-Kaplanski6,
  8. Idit Maya7,
  9. Nurit Magal7,
  10. Efrat Birk3,
  11. Amos J Simon8,
  12. Ayelet Halevy2,
  13. Gideon Rechavi3,8,
  14. Mordechai Shohat3,7,9,
  15. Rachel Straussberg2,3,
  16. Lina Basel-Vanagaite3,7,10
  1. 1Department of Internal Medicine D, Rabin Medical Center, Beilinson Hospital, Petah Tikva, Israel
  2. 2Neurogenetics Clinic, Schneider Children's Medical Center of Israel, Petah Tikva, Israel
  3. 3Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
  4. 4Department of Human Genetics, Hadassah Hebrew University Hospital, Jerusalem, Israel
  5. 5Bioinformatics Unit, G.S.W. Faculty of Life Sciences, Tel-Aviv University, Tel Aviv, Israel
  6. 6Tissue Typing Laboratory, Rabin Medical Center, Petah Tikva, Israel
  7. 7Raphael Recanati Genetic Institute, Rabin Medical Center, Beilinson Hospital, Petah Tikva, Israel
  8. 8Sheba Cancer Research Center, The Chaim Sheba Medical Center, Tel Hashomer, Israel
  9. 9Felsenstein Medical Research Center, Tel Aviv University, Rabin Medical Center, Petah Tikva, Israel
  10. 10Pediatric Genetics, Schneider Children's Medical Center of Israel, Petah Tikva, Israel
  1. Correspondence to Lina Basel-Vanagaite, The Raphael Recanati Genetic Institute, Rabin Medical Center, Beilinson Hospital, and Schneider Children's Medical Center of Israel, Petah Tikva, 49100, Israel; basel{at}post.tau.ac.il

Abstract

Background This study reports on a hitherto undescribed autosomal recessive syndrome characterised by dysmorphic features and multiple congenital anomalies together with severe neurological impairment, chorea and seizures leading to early death, and the identification of a gene involved in the pathogenesis of the disease.

Methods Homozygosity mapping was performed using Affymetrix Human Mapping 250k NspI arrays. Sequencing of all coding exons of the candidate genes was performed with primer sets designed using the Primer3 program. Fluorescence activated cell sorting was performed using conjugated antibody to CD59. Staining, acquisition and analysis were performed on a FACSCalibur flow cytometer.

Results Using homozygosity mapping, the study mapped the disease locus to 18q21.32–18q22.1 and identified the disease-causing mutation, c.2126G→A (p.Arg709Gln), in PIGN, which encodes glycosylphosphatidylinositol (GPI) ethanolamine phosphate transferase 1, a protein involved in GPI-anchor biosynthesis. Arginine at the position 709 is a highly evolutionarily conserved residue located in the PigN domain. The expression of GPI linked protein CD59 on fibroblasts from patients as compared to that in a control individual showed a 10-fold reduction in expression, confirming the pathogenic consequences of the mutation on GPI dependent protein expression.

Conclusions The abundant expression of PIGN in various tissues is compatible with the diverse phenotypic features observed in the patients and with the involvement of multiple body systems. The presence of developmental delay, hypotonia, and epilepsy combined with multiple congenital anomalies, especially anorectal anomalies, should lead a clinician to suspect a GPI deficiency related disorder.

  • Neurological impairment
  • dysmorphic features
  • PIGN, glycosylphosphatidylinositol (GPI) ethanolamine phosphate transferase 1
  • clinical genetics
  • epilepsy and seizures

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Footnotes

  • Funding This study was supported by the Israeli Ministry of Health Chief Scientist Foundation (grant No 3-4963) and the Israeli Science Foundation (grant No558/09).

  • Competing interests None.

  • Patient consent Obtained.

  • Ethics approval This study was conducted with the approval of the National Committee for Genetic Studies, Israeli Ministry of Health, and the Rabin Medical Center.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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