Allan Bayat1,2, Alexej Knaus3, Manuela Pendziwiat4, Alexandra Afenjar5, Tahsin Stefan Barakat6, Friedrich Bosch7, Bert Callewaert8,9, Patrick Calvas10, Berten Ceulemans11, Nicolas Chassaing10, Christel Depienne12,13, Milda Endziniene14, Carlos R Ferreira15, Carolina Fischinger Moura de Souza16, Cécile Freihuber17,18, Shiva Ganesan19,20,21, Svetlana Gataullina22,23, Renzo Guerrini24, Anne-Marie Guerrot25, Lars Hansen26, Aleksandra Jezela-Stanek27, Caroline Karsenty28, Anneke Kievit6, Frank R Kooy29, Christian M Korff30, Johanne Kragh Hansen31, Martin Larsen31,32, Valérie Layet33, Gaetan Lesca34,35, Kim L McBride36,37,38, Marije Meuwissen29, Cyril Mignot39,40, Martino Montomoli24, Hannah Moore41, Sophie Naudion42, Caroline Nava40, Marie-Christine Nougues43, Elena Parrini24, Matthew Pastore36,38, Jurgen H Schelhaas44, Steven Skinner41, Krzysztoł Szczałuba45, Ashley Thomas46, Mads Thomassen31,32, Lisbeth Tranebjaerg47,48, Marjon van Slegtenhorst6, Lynne A Wolfe49,50, Dennis Lal51,52,53,54,55, Elena Gardella1,2,56, Lilian Bomme Ousager31,32, Tobias Brünger51, Ingo Helbig4,19,20,21,57, Peter Krawitz3, Rikke S Møller1,2. 1. Institute for Regional Health Services, University of Southern Denmark, Odense, Denmark. 2. Department of Epilepsy Genetics and Personalized Medicine, Danish Epilepsy Center, Dianalund, Denmark. 3. Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn, Rheinische Friedrich-Wilhelms-University Bonn, Bonn, Germany. 4. Department of Neuropediatrics, University Medical Center Schleswig-Holstein Christian Albrechts University, Kiel, Germany. 5. CRMR Congenital Malformations and Diseases of the Cerebellum and Rare Causes of Intellectual Disabilities, Department of Genetics, Sorbonne University, AP-HP, Trousseau Hospital, Paris, France. 6. Department of Clinical Genetics, Erasmus MC, University Medical Center, Rotterdam, the Netherlands. 7. Children's Hospital, Fürth, Germany. 8. Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium. 9. Department of Biomolecular Medicine, Ghent University, Ghent, Belgium. 10. UMR1056 INSERM-Université de Toulouse, Department of Genetics, University Hospital of Toulouse, Toulouse, France. 11. Department of Pediatric Neurology, University Hospital and University of Antwerp, Antwerp, Belgium. 12. Institute of Human Genetics, University Hospital Essen, University of Duisburg-Essen, Essen, Germany. 13. UMR S1127, Inserm U1127, CNRS UMR 7225, Institute of brain and spinal cord, Sorbonne University, Paris, France. 14. Neurology Department, Medical Academy, Lithuanian University of Health Sciences, Kaunas, Lithuania. 15. Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA. 16. Medical Genetics Service, Hospital de Clinicas de Porto Alegre, Porto Alegre, Brazil. 17. Department of Pediatric Neurology, AP-HP, GHUEP, Armand Trousseau University Hospital, Paris, France. 18. GRC ConCer-LD, Sorbonne University, UPMC University of Paris 06, Paris, France. 19. Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA. 20. Epilepsy NeuroGenetics Initiative, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA. 21. Department of Biomedical and Health Informatics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA. 22. Sleep Disorders Center, AP-HP, Antoine-Béclère Hospital, Clamart, France. 23. Department of Pediatrics and Neonatal Intensive Care, André Grégoire Hospital, Montreuil, France. 24. Pediatric Neurology, Neurogenetics and Neurobiology Unit and Laboratories, Department of Neuroscience, A. Meyer Children's Hospital, University of Florence, Florence, Italy. 25. Department of Genetics and Reference Center for Developmental Disorders, Normandy Center for Genomic and Personalized Medicine, Normandy University, UNIROUEN, Inserm U1245 and Rouen University Hospital, Rouen, France. 26. Department of Cellular and Molecular Medicine, Faculty of Health Science, Copenhagen Center for Glycomics, Copenhagen, Denmark. 27. Department of Genetics and Clinical Immunology, National Institute of Tuberculosis and Lung Diseases, Warsaw, Poland. 28. Neuropediatrics Department, University Hospital of Toulouse, Toulouse, France. 29. Department of Medical Genetics, University of Antwerp, Antwerp, Belgium. 30. Pediatric Neurology Unit, Department of the Woman, Child, and Adolescent, University Hospitals Geneva, Geneva, Switzerland. 31. Department of Clinical Genetics, Odense University Hospital, Odense, Denmark. 32. Human Genetics, Department of Clinical Research, University of Southern Denmark, Odense, Denmark. 33. Department of Genetics, Du Havre Hospital, Le Havre, France. 34. Department of Medical Genetics, Lyon University Hospital, Lyon, France. 35. Institut Neuromyogene, University Claude Bernard Lyon 1, Lyon University, Lyon, France. 36. Division of Genetic and Genomic Medicine, Nationwide Children's Hospital, Columbus, Ohio, USA. 37. Center for Cardiovascular Research, Nationwide Children's Hospital, Columbus, Ohio, USA. 38. Department of Pediatrics, Ohio State University, Columbus, Ohio, USA. 39. APHP, Department of Genetics, Pitié-Salpêtrière Hospital, Reference Center for Rare Causes of Intellectual Disabilities, Paris, France. 40. Department of Genetics, Inserm U1127, CNRS UMR 7225, Institute for brain and spinal cord, ICM, AP-HP, De la Pitié Salpêtrière Hospital, Sorbonne University, Paris, France. 41. Greenwood Genetic Center, Greenwood, South Carolina, USA. 42. Department of Genetics, University of Bordeaux, Bordeaux, France. 43. Department of Neuropaediatrics, Armand Trousseau Hospital, APHP, Paris, France. 44. Department of Epilepsy, Zwolle, the Netherlands. 45. Department of Medical Genetics, Warsaw Medical University, Warsaw, Poland. 46. Department of Neurology, University of Alabama at Birmingham, Birmingham, Alabama, USA. 47. Department of Clinical Genetics, Rigshospitalet/Kennedy Center, Glostrup, Denmark. 48. Institute of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark. 49. Undiagnosed Diseases Program, Common Fund, National Institutes of Health, Bethesda, Maryland, USA. 50. Section of Human Biochemical Genetics, National Human Genome Research Institute, Bethesda, Maryland, USA. 51. Cologne Center for Genomics, University Hospital Cologne, University of Cologne, Cologne, Germany. 52. Stanley Center for Psychiatric Research, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts, USA. 53. Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts, USA. 54. Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, Ohio, USA. 55. Genomic Medicine Institute, Lerner Research Institute Cleveland Clinic, Cleveland, Ohio, USA. 56. Department of Clinical Neurophysiology, Danish Epilepsy Center, Dianalund, Denmark. 57. Department of Neurology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
Abstract
OBJECTIVE: To define the phenotypic spectrum of phosphatidylinositol glycan class A protein (PIGA)-related congenital disorder of glycosylation (PIGA-CDG) and evaluate genotype-phenotype correlations. METHODS: Our cohort encompasses 40 affected males with a pathogenic PIGA variant. We performed a detailed phenotypic assessment, and in addition, we reviewed the available clinical data of 36 previously published cases and assessed the variant pathogenicity using bioinformatical approaches. RESULTS: Most individuals had hypotonia, moderate to profound global developmental delay, and intractable seizures. We found that PIGA-CDG spans from a pure neurological phenotype at the mild end to a Fryns syndrome-like phenotype. We found a high frequency of cardiac anomalies including structural anomalies and cardiomyopathy, and a high frequency of spontaneous death, especially in childhood. Comparative bioinformatical analysis of common variants, found in the healthy population, and pathogenic variants, identified in affected individuals, revealed a profound physiochemical dissimilarity of the substituted amino acids in variant constrained regions of the protein. SIGNIFICANCE: Our comprehensive analysis of the largest cohort of published and novel PIGA patients broadens the spectrum of PIGA-CDG. Our genotype-phenotype correlation facilitates the estimation on pathogenicity of variants with unknown clinical significance and prognosis for individuals with pathogenic variants in PIGA.
OBJECTIVE: To define the phenotypic spectrum of phosphatidylinositol glycan class A protein (PIGA)-related congenital disorder of glycosylation (PIGA-CDG) and evaluate genotype-phenotype correlations. METHODS: Our cohort encompasses 40 affected males with a pathogenic PIGA variant. We performed a detailed phenotypic assessment, and in addition, we reviewed the available clinical data of 36 previously published cases and assessed the variant pathogenicity using bioinformatical approaches. RESULTS: Most individuals had hypotonia, moderate to profound global developmental delay, and intractable seizures. We found that PIGA-CDG spans from a pure neurological phenotype at the mild end to a Fryns syndrome-like phenotype. We found a high frequency of cardiac anomalies including structural anomalies and cardiomyopathy, and a high frequency of spontaneous death, especially in childhood. Comparative bioinformatical analysis of common variants, found in the healthy population, and pathogenic variants, identified in affected individuals, revealed a profound physiochemical dissimilarity of the substituted amino acids in variant constrained regions of the protein. SIGNIFICANCE: Our comprehensive analysis of the largest cohort of published and novel PIGApatients broadens the spectrum of PIGA-CDG. Our genotype-phenotype correlation facilitates the estimation on pathogenicity of variants with unknown clinical significance and prognosis for individuals with pathogenic variants in PIGA.