Immunopathological manifestations in Kabuki syndrome: a registry study of 177 individuals

Margot, Henri; Boursier, Guilaine; Duflos, Claire; Sanchez, Elodie; Amiel, Jeanne; Andrau, Jean-Christophe; Arpin, Stéphanie; Brischoux‐Boucher, Elise; Boute, Odile; Bürglen, Lydie; Caille, Charlotte; Capri, Yline; Collignon, P.; Conrad, Solène; Cormier‐Daire, Valérie; Delplancq, Geoffroy; Dieterich, Klaus; Dollfus, Hélène; Fradin, Mélanie; Faivre, Laurence; Fernandes, Helder; Francannet, Christine; Gatinois, Vincent; Gérard, Marion; Goldenberg, Alice; Ghoumid, Jamal; Grotto, Sarah; Guerrot, Anne‐Marie; Guichet, Agnès; Isidor, Bertrand; Jacquemont, Marie‐Line; Julia, Sophie; Kien, Philippe Khau Van; Legendre, Marine; Sang, Kim Hanh Le Quan; Leheup, Bruno; Lyonnet, Stanislas; Magry, Virginie; Manouvrier, Sylvie; Martin, Dominique; Morel, Godelieve; Münnich, Arnold; Naudion, Sophie; Odent, Sylvie; Perrin, Laurence; Petit, Florence; Philip, Nicole; Rio, Marlène; Robbe, Julie; Rossi, Massimiliano; Sarrazin, Elisabeth; Toutain, Annick; Gils, Julien Van; Vera, Gabriella; Verloès, Alain; Weber, Sacha; Whalen, Sandra; Sanlaville, Damien; Lacombe, Didier; Aladjidi, Nathalie; Geneviève, David

doi:10.1038/s41436-019-0623-x

Cited by 38 publications

(65 citation statements)

References 39 publications

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“…3,33 However, routine screening of patients with Kabuki syndrome for antibody deficiency or GLILD is not frequently performed. 34 Our findings show that patients with Kabuki syndrome and CVID-like PID should be screened for GLILD.…”

Section: Discussionmentioning

confidence: 66%

Rituximab and antimetabolite treatment of granulomatous and lymphocytic interstitial lung disease in common variable immunodeficiency

Verbsky

Hintermeyer

Simpson

et al. 2021

Journal of Allergy and Clinical Immunology

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Section: Discussionmentioning

confidence: 66%

Rituximab and antimetabolite treatment of granulomatous and lymphocytic interstitial lung disease in common variable immunodeficiency

Verbsky

Hintermeyer

Simpson

et al. 2021

Journal of Allergy and Clinical Immunology

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“…Schott et al analyzed the growth data of 39 genetically confirmed KS individuals and all subjects showed a growth retardation during childhood and lack of the pubertal growth spurt (Schott et al, 2016). From a nationwide study of the genetically confirmed 177 KS individuals by Margot et al, almost half of them had features of immunodeficiency and prevalence of autoimmune disease such as immune thrombocytopenic purpura and autoimmune hemolytic anemia increased with age, with one in four adults having at least one disease (Margot et al, 2020). This observation is consistent with our result.…”

Section: Discussionmentioning

confidence: 99%

Clinical and molecular characterization study of Chinese Kabuki syndrome in Hong Kong

Luk

et al. 2020

American J of Med Genetics Pt A

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Kabuki syndrome (OMIM #147920 and 300867) is a rare genetic disorder characterized by a distinctive facial gestalt, intellectual disability and multiple congenital anomalies. We summarized the clinical features and molecular findings of the Kabuki syndrome (KS) patients diagnosed in Hong Kong between January 1991 and December 2019. There were 21 molecularly confirmed KS. Twenty of them were due to pathogenic KMT2D variants and one patient had KDM6A deletion. Nine KMT2D variants were novel. The clinical phenotype of our Chinese KS patients was largely comparable with that reported in patients of other ethnicities. This study expands the mutation spectrum but also provide important natural history information of Chinese KS in literature.

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“…This mouse reliably models KS phenotypes, [8][9][10] and we show that many of the immune phenotypes observed in patients (IgA deficiency, impaired response to vaccination, and splenomegaly) are also recapitulated in these mice. [11][12][13] We also uncover novel phenotypes including decreased size and numbers of Peyer patches (PPs), as well as abnormalities of the peritoneal cavity, bone marrow, and intestinal B-cell/plasma-cell compartments. We further demonstrate decreased expression of Itgb7 (integrin subunit beta 7), an adhesion factor that mediates lymphocyte homing to the gut, and we show by in vitro and in vivo assays that Itgb7 dysregulation is mechanistically tied to KMT2D haploinsufficiency.…”

mentioning

confidence: 97%

Abnormal Peyer patch development and B-cell gut homing drive IgA deficiency in Kabuki syndrome

Pilarowski

Cazares

Zhang

et al. 2020

Journal of Allergy and Clinical Immunology

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Background: Kabuki syndrome (KS) is commonly caused by mutations in the histone-modifying enzyme lysine methyltransferase 2D (KMT2D). Immune dysfunction is frequently observed in individuals with KS, but the role of KMT2D in immune system function has not been identified. Objective: We sought to understand the mechanisms driving KS-associated immune deficiency (hypogammaglobulinemia [low IgA], splenomegaly, and diminished immunization responses). Methods: We performed a comprehensive evaluation of humoral immunity and secondary lymphoid tissues in an established KS (Kmt2d 1/bGeo) mouse model and validated select findings in a patient with KS. Results: Compared with wild-type littermates, Kmt2d 1/bGeo mice demonstrated deficiencies in multiple B-cell lineages and reduced serum IgA and elevated IgM levels across multiple ages. The bone marrow, spleen, and intestine of Kmt2d 1/bGeo mice contained diminished numbers of IgA-secreting cells, while elevated germinal center B cells were found in the mesenteric lymph node and Peyer patches. Kmt2d 1/bGeo mice have decreased size and numbers of Peyer patches, a finding confirmed in human samples. We identified deficiency of Itgb7 RNA and protein expression, a gene encoding an adhesion protein that mediates intestinal homing, and we demonstrated KMT2D-dependent control of ITGB7 expression in a human cell line. Conclusions: Kmt2d haploinsufficiency has broad deleterious effects on B-cell differentiation, specifically hampering gut lymphocyte homing and IgA 1 plasma cell differentiation. Intestinal lymphoid defects caused by ITGB7 deficiency have not previously been recognized in KS, and these results provide new mechanistic insights into the pathogenesis of KS-associated immune deficiency.

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Immunopathological manifestations in Kabuki syndrome: a registry study of 177 individuals

Cited by 38 publications

References 39 publications

Rituximab and antimetabolite treatment of granulomatous and lymphocytic interstitial lung disease in common variable immunodeficiency

Rituximab and antimetabolite treatment of granulomatous and lymphocytic interstitial lung disease in common variable immunodeficiency

Clinical and molecular characterization study of Chinese Kabuki syndrome in Hong Kong

Abnormal Peyer patch development and B-cell gut homing drive IgA deficiency in Kabuki syndrome

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