Variants in IGLL1 cause a broad phenotype from agammaglobulinemia to transient hypogammaglobulinemia

Maarja Soomann¹, Viktor Bily², Magdeldin Elgizouli³, Dennis Kraemer³, Gülfirde Akgül³, Horst von Bernuth⁴, Markéta Bloomfield⁵, Nicholas Brodszki⁶, Fabio Candotti⁷, Elisabeth Förster-Waldl⁸, Tomas Freiberger², Maria Giżewska⁹, Adam Klocperk⁵, Uwe Kölsch¹⁰, Kim E Nichols¹¹, Renate Krüger¹², Ninad Oak¹¹, Małgorzata Pac¹³, Seraina Prader¹⁴, Kjeld Schmiegelow¹⁵, Anna Šedivá⁵, Georgios Sogkas¹⁶, Anna Stittrich¹⁷, Ulrik Kristoffer Stoltze¹⁸, Katerina Theodoropoulou¹⁹, Karin Wadt²⁰, Melanie Wong²¹, Maximillian Zeyda²², Jana Pachlopnik Schmid¹⁴, Johannes Trück¹⁴

Affiliations

¹ Division of Immunology and the Children's Research Center, University Children's Hospital Zurich, University of Zurich, Zurich, Switzerland. Electronic address: Maarja.Soomann@kispi.uzh.ch.
² Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation Brno and Medical Faculty, Masaryk University, Brno, Czechia.
³ Institute of Medical Genetics, University of Zurich, Zurich, Switzerland.
⁴ Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Department of Pediatric Respiratory Medicine, Immunology, and Critical Care Medicine, University Hospital Center, Berlin, Germany; Berlin Institute of Health at Charité-Universitätsmedizin Berlin, Berlin, Germany; Department of Immunology, Labor Berlin-Charité Vivantes GmbH, Berlin, Germany; Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin-Brandenburg Center for Regenerative Therapies, Berlin, Germany.
⁵ Department of Immunology, 2nd Faculty of Medicine, Charles University and University Hospital in Motol, Prague, Czechia.
⁶ Childrens' Hospital, Skåne University Hospital, Lund, Sweden.
⁷ Division of Immunology and Allergy, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
⁸ Department of Paediatrics and Adolescent Medicine, Division of Neonatology, Neuropaediatrics, and Paediatric Intensive Care and Center for Congenital Immunodeficiencies and Jeffrey Modell Diagnostic & Research Center, Medical University of Vienna, Vienna, Austria.
⁹ Department of Pediatrics, Endocrinology, Diabetology, Metabolic Diseases, and Cardiology of the Developmental Age, Pomeranian Medical University in Szczecin, Szczecin, Poland.
¹⁰ Department of Immunology, Labor Berlin-Charité Vivantes GmbH, Berlin, Germany.
¹¹ Department of Oncology, St Jude Children's Research Hospital, Memphis, Tenn.
¹² Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Department of Pediatric Respiratory Medicine, Immunology, and Critical Care Medicine, University Hospital Center, Berlin, Germany.
¹³ Department of Immunology, The Children's Memorial Health Institute, Warsaw, Poland.
¹⁴ Division of Immunology and the Children's Research Center, University Children's Hospital Zurich, University of Zurich, Zurich, Switzerland.
¹⁵ Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Department of Pediatrics and Adolescent Medicine, Rigshospitalet, Copenhagen, Denmark.
¹⁶ Department of Rheumatology and Immunology, Hannover Medical University, and Hannover Medical School, Hannover, Germany.
¹⁷ Department of Human Genetics, Labor Berlin-Charité Vivantes GmbH, Berlin, Germany.
¹⁸ Department of Pediatrics and Adolescent Medicine, Rigshospitalet, Copenhagen, Denmark.
¹⁹ Unit of Pediatric Immunology, Allergology and Rheumatology, Department of Woman, Mother, Child, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
²⁰ Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Department of Clinical Genetics, University Hospital Copenhagen, Copenhagen, Denmark.
²¹ Department of Allergy and Immunology, The Children's Hospital at Westmead, Sydney, Australia.
²² Department of Pediatrics and Adolescent Medicine, Austrian Newborn Screening, Clinical Division of Pediatric Pulmonology, Allergology and Endocrinology, Comprehensive Center for Pediatrics, Medical University of Vienna, Vienna, Austria.

PMID: 39147326
DOI: 10.1016/j.jaci.2024.08.002

Free article

Review

Variants in IGLL1 cause a broad phenotype from agammaglobulinemia to transient hypogammaglobulinemia

Maarja Soomann et al. J Allergy Clin Immunol. 2024 Nov.

Free article

. 2024 Nov;154(5):1313-1324.e7.

doi: 10.1016/j.jaci.2024.08.002. Epub 2024 Aug 13.

Authors

Affiliations

¹ Division of Immunology and the Children's Research Center, University Children's Hospital Zurich, University of Zurich, Zurich, Switzerland. Electronic address: Maarja.Soomann@kispi.uzh.ch.
² Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation Brno and Medical Faculty, Masaryk University, Brno, Czechia.
³ Institute of Medical Genetics, University of Zurich, Zurich, Switzerland.
⁴ Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Department of Pediatric Respiratory Medicine, Immunology, and Critical Care Medicine, University Hospital Center, Berlin, Germany; Berlin Institute of Health at Charité-Universitätsmedizin Berlin, Berlin, Germany; Department of Immunology, Labor Berlin-Charité Vivantes GmbH, Berlin, Germany; Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin-Brandenburg Center for Regenerative Therapies, Berlin, Germany.
⁵ Department of Immunology, 2nd Faculty of Medicine, Charles University and University Hospital in Motol, Prague, Czechia.
⁶ Childrens' Hospital, Skåne University Hospital, Lund, Sweden.
⁷ Division of Immunology and Allergy, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
⁸ Department of Paediatrics and Adolescent Medicine, Division of Neonatology, Neuropaediatrics, and Paediatric Intensive Care and Center for Congenital Immunodeficiencies and Jeffrey Modell Diagnostic & Research Center, Medical University of Vienna, Vienna, Austria.
⁹ Department of Pediatrics, Endocrinology, Diabetology, Metabolic Diseases, and Cardiology of the Developmental Age, Pomeranian Medical University in Szczecin, Szczecin, Poland.
¹⁰ Department of Immunology, Labor Berlin-Charité Vivantes GmbH, Berlin, Germany.
¹¹ Department of Oncology, St Jude Children's Research Hospital, Memphis, Tenn.
¹² Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Department of Pediatric Respiratory Medicine, Immunology, and Critical Care Medicine, University Hospital Center, Berlin, Germany.
¹³ Department of Immunology, The Children's Memorial Health Institute, Warsaw, Poland.
¹⁴ Division of Immunology and the Children's Research Center, University Children's Hospital Zurich, University of Zurich, Zurich, Switzerland.
¹⁵ Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Department of Pediatrics and Adolescent Medicine, Rigshospitalet, Copenhagen, Denmark.
¹⁶ Department of Rheumatology and Immunology, Hannover Medical University, and Hannover Medical School, Hannover, Germany.
¹⁷ Department of Human Genetics, Labor Berlin-Charité Vivantes GmbH, Berlin, Germany.
¹⁸ Department of Pediatrics and Adolescent Medicine, Rigshospitalet, Copenhagen, Denmark.
¹⁹ Unit of Pediatric Immunology, Allergology and Rheumatology, Department of Woman, Mother, Child, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
²⁰ Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Department of Clinical Genetics, University Hospital Copenhagen, Copenhagen, Denmark.
²¹ Department of Allergy and Immunology, The Children's Hospital at Westmead, Sydney, Australia.
²² Department of Pediatrics and Adolescent Medicine, Austrian Newborn Screening, Clinical Division of Pediatric Pulmonology, Allergology and Endocrinology, Comprehensive Center for Pediatrics, Medical University of Vienna, Vienna, Austria.

PMID: 39147326
DOI: 10.1016/j.jaci.2024.08.002

Abstract

Background: Agammaglobulinemia due to variants in IGLL1 has traditionally been considered an exceedingly rare form of severe B-cell deficiency, with only 8 documented cases in the literature. Surprisingly, the first agammaglobulinemic patient identified by newborn screening (NBS) through quantification of kappa-deleting recombination excision circles harbored variants in IGLL1.

Objective: We comprehensively reviewed clinical and immunologic findings of patients with B-cell deficiency attributed to variants in IGLL1.

Methods: NBS programs reporting the use of kappa-deleting recombination excision circle assays, the European Society for Immunodeficiencies Registry, and authors of published reports featuring patients with B-cell deficiency linked to IGLL1 variants were contacted. Only patients with (likely) pathogenic variants, reduced CD19⁺ counts, and no alternative diagnosis were included.

Results: The study included 13 patients identified through NBS, 2 clinically diagnosed patients, and 2 asymptomatic siblings. All had severely reduced CD19⁺ B cells (< 0.1 × 10⁹/L) at first evaluation, yet subsequent follow-up assessments indicated residual immunoglobulin production. Specific antibody responses to vaccine antigens varied, with a predominant reduction observed during infancy. Clinical outcomes were favorable with IgG substitution. Two patients successfully discontinued substitution therapy without developing susceptibility to infections and while maintaining immunoglobulin levels. The pooled incidence of homozygous or compound heterozygous pathogenic IGLL1 variants identified by NBS in Austria, Czechia, and Switzerland was 1.3:100,000, almost double of X-linked agammaglobulinemia.

Conclusion: B-cell deficiency resulting from IGLL1 variants appears to be more prevalent than initially believed. Despite markedly low B-cell counts, the clinical course in some patients may be milder than reported in the literature so far.

Keywords: Agammaglobulinemia; B-cell deficiency; IGLL1; KREC; NBS; kappa-deleting recombination excision circles; lamba5; newborn screening; predominantly antibody deficiencies; vaccine response.

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Conflict of interest statement

Disclosure statement Funding was provided by the Georg and Bertha Schwyzer-Winiker Foundation, the Wolfermann-Nägeli Foundation, and the EMDO Foundation (to M.S. and J.T.). Funding was also provided by the Swiss National Science Foundation (320030_205097) and ITINERARE, a University Research Priority Program of the University of Zurich, Zurich, Switzerland (to J.P.S.). Funding was also received from the Jeffrey Modell Foundation and the Fund for the Support of Strategic Partnerships between Charles University in Prague, Czechia, and the University of Zurich (to M.B., A.K., and A.S.). Funding was also received from the Ministry of Health, Czechia (NU23-05-00097 to A.K.; and NU-007-00170 to V.B. and T.F.), and Masaryk University, Czechia (MUNI/A/1566/2023 to V.B. and T.F.). The funding agencies did not influence the study design; the collection, analysis, or interpretation of data; the writing of the report; or the decision to submit the report for publication. Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest.

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Variants in IGLL1 cause a broad phenotype from agammaglobulinemia to transient hypogammaglobulinemia

Affiliations

Variants in IGLL1 cause a broad phenotype from agammaglobulinemia to transient hypogammaglobulinemia

Authors

Affiliations

Abstract

Conflict of interest statement

Publication types

MeSH terms

LinkOut - more resources

Full Text Sources

Research Materials

Miscellaneous