Henri Margot1, Guilaine Boursier2,3, Claire Duflos4, Elodie Sanchez2,3, Jeanne Amiel5, Jean-Christophe Andrau6, Stéphanie Arpin7, Elise Brischoux-Boucher8, Odile Boute9, Lydie Burglen10, Charlotte Caille11, Yline Capri12, Patrick Collignon13, Solène Conrad14, Valérie Cormier-Daire5, Geoffroy Delplancq8, Klaus Dieterich15, Hélène Dollfus16, Mélanie Fradin17, Laurence Faivre18, Helder Fernandes19,20,21, Christine Francannet22, Vincent Gatinois2,3, Marion Gerard23, Alice Goldenberg24, Jamal Ghoumid9, Sarah Grotto12, Anne-Marie Guerrot24, Agnès Guichet25, Bertrand Isidor14, Marie-Line Jacquemont26,27, Sophie Julia28, Philippe Khau Van Kien29, Marine Legendre1,27, K H Le Quan Sang30, Bruno Leheup31, Stanislas Lyonnet5, Virginie Magry22, Sylvie Manouvrier9, Dominique Martin32, Godelieve Morel33, Arnold Munnich5, Sophie Naudion1,27, Sylvie Odent17, Laurence Perrin12, Florence Petit9, Nicole Philip34, Marlène Rio5, Julie Robbe34, Massimiliano Rossi35, Elisabeth Sarrazin27, Annick Toutain7, Julien Van Gils1,27,36, Gabriella Vera24, Alain Verloes12, Sacha Weber23, Sandra Whalen37, Damien Sanlaville35, Didier Lacombe1,27,36, Nathalie Aladjidi19,20,21, David Geneviève38,39. 1. Service de génétique médicale, CHU de Bordeaux, Bordeaux, France. 2. Département de génétique médicale, Maladies rares et médecine personnalisée, CHU de Montpellier, Montpellier, France. 3. INSERM U1183, Université de Montpellier, Montpellier, France. 4. Département d'Information Médicale, CHU Montpellier, Montpellier, France. 5. Fédération de Génétique et Institut Imagine, Hôpital Necker-Enfants Malades, AP-HP et INSERM UMR1163, Paris Descartes-Sorbonne Paris Cité University, Paris, France. 6. Institut de Génétique Moléculaire de Montpellier (IGMM), Univ Montpellier, Montpellier, France. 7. Service de génétique, CHU de Tours, UMR 1253, iBrain, Université de Tours, Inserm, Tours, France. 8. Centre de Génétique Humaine, Université de Franche-Comté, Besançon, France. 9. Centre de référence maladies rares pour les anomalies du développement Nord-Ouest, Clinique de Génétique médicale, CHU de Lille et EA7364, Université de Lille, Lille, France. 10. Centre de référence des malformations et maladies congénitales du cervelet, département de génétique et embryologie médicale, APHP, GHUEP, Hôpital Trousseau, Paris, France. 11. Service de génétique médicale, CHU de Brest, Brest, France. 12. Service de génétique médicale, AP-HP Robert-Debré, Paris, France. 13. Service de génétique médicale, CHI de Toulon, Toulon, France. 14. Service de génétique médicale, CHU de Nantes, Nantes, France. 15. Service de génétique médicale, CHU de Grenoble, Grenoble, France. 16. Service de génétique médicale, CHU de Strasbourg, Strasbourg, France. 17. Service de génétique clinique, CHU de Rennes, Univ. Rennes, Institute of Genetics and Development of Rennes (IGDR) UMR6290 CNRS, Rennes, France. 18. Service de génétique médicale et centre de référence Anomalies du Développement et Syndromes Malformatifs, CHU de Dijon, Dijon, France. 19. Service d'onco hématologie pédiatrique, CHU de Bordeaux, Bordeaux, France. 20. Centre de référence des cytopénies auto-immunes de l'enfant, CHU de Bordeaux, Bordeaux, France. 21. INSERM CICP, Université de Bordeaux, Bordeaux, France. 22. Service de génétique médicale, CHU de Clemont-Ferrand, Clermont-Ferrand, France. 23. Service de génétique médicale, CHU de Caen, Caen, France. 24. Normandie Univ, UNIROUEN, Inserm U1245 and Rouen University Hospital, Department of Genetics and Reference Center for Developmental Disorders, F 76000, Normandy Center for Genomic and Personalized Medicine, Rouen, France. 25. Service de génétique médicale, CHU d'Angers, Angers, France. 26. Service de génétique médicale, CHU de la Reunion, Saint-Pierre, France. 27. Centre de Référence Anomalies du développement et Syndromes malformatifs du Sud-Ouest Occitanie Réunion, Saint-Pierre, France. 28. Service de génétique médicale, CHU de Toulouse, Toulouse, France. 29. Service de génétique médicale, CHU de Nîmes, Nîmes, France. 30. Institut Imagine, Paris Descartes-Sorbonne Paris Cité University, Paris, France. 31. Service de génétique médicale, CHU de Nancy, Nancy, France. 32. Service de génétique médicale, CH du Mans, Le Mans, France. 33. Service de génétique médicale, CHU de Nice, Nice, France. 34. Service de génétique médicale, CHU de Marseille, Marseille, France. 35. Service de génétique médicale, CHU de Lyon, Lyon, France. 36. INSERM U1211, Université de Bordeaux, Bordeaux, France. 37. Service de génétique médicale, AP-HP Pitié Salpétrière, Paris, France. 38. Département de génétique médicale, Maladies rares et médecine personnalisée, CHU de Montpellier, Montpellier, France. d-genevieve@chu-montpellier.fr. 39. INSERM U1183, Université de Montpellier, Montpellier, France. d-genevieve@chu-montpellier.fr.
Abstract
PURPOSE: Kabuki syndrome (KS) (OMIM 147920 and 300867) is a rare genetic disorder characterized by specific facial features, intellectual disability, and various malformations. Immunopathological manifestations seem prevalent and increase the morbimortality. To assess the frequency and severity of the manifestations, we measured the prevalence of immunopathological manifestations as well as genotype-phenotype correlations in KS individuals from a registry. METHODS: Data were for 177 KS individuals with KDM6A or KMT2D pathogenic variants. Questionnaires to clinicians were used to assess the presence of immunodeficiency and autoimmune diseases both on a clinical and biological basis. RESULTS: Overall, 44.1% (78/177) and 58.2% (46/79) of KS individuals exhibited infection susceptibility and hypogammaglobulinemia, respectively; 13.6% (24/177) had autoimmune disease (AID; 25.6% [11/43] in adults), 5.6% (10/177) with ≥2 AID manifestations. The most frequent AID manifestations were immune thrombocytopenic purpura (7.3% [13/177]) and autoimmune hemolytic anemia (4.0% [7/177]). Among nonhematological manifestations, vitiligo was frequent. Immune thrombocytopenic purpura was frequent with missense versus other types of variants (p = 0.027). CONCLUSION: The high prevalence of immunopathological manifestations in KS demonstrates the importance of systematic screening and efficient preventive management of these treatable and sometimes life-threatening conditions.
PURPOSE: Kabuki syndrome (KS) (OMIM 147920 and 300867) is a rare genetic disorder characterized by specific facial features, intellectual disability, and various malformations. Immunopathological manifestations seem prevalent and increase the morbimortality. To assess the frequency and severity of the manifestations, we measured the prevalence of immunopathological manifestations as well as genotype-phenotype correlations in KS individuals from a registry. METHODS: Data were for 177 KS individuals with KDM6A or KMT2D pathogenic variants. Questionnaires to clinicians were used to assess the presence of immunodeficiency and autoimmune diseases both on a clinical and biological basis. RESULTS: Overall, 44.1% (78/177) and 58.2% (46/79) of KS individuals exhibited infection susceptibility and hypogammaglobulinemia, respectively; 13.6% (24/177) had autoimmune disease (AID; 25.6% [11/43] in adults), 5.6% (10/177) with ≥2 AID manifestations. The most frequent AID manifestations were immune thrombocytopenic purpura (7.3% [13/177]) and autoimmune hemolytic anemia (4.0% [7/177]). Among nonhematological manifestations, vitiligo was frequent. Immune thrombocytopenic purpura was frequent with missense versus other types of variants (p = 0.027). CONCLUSION: The high prevalence of immunopathological manifestations in KS demonstrates the importance of systematic screening and efficient preventive management of these treatable and sometimes life-threatening conditions.