Variants in IGLL1 cause a broad phenotype from agammaglobulinemia to transient hypogammaglobulinemia
Year: 2024
Type: review
Study design: Observational Study
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 × 10 9 /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.
Authors: Maarja Soomann, Viktor Bily, Magdeldin Elgizouli, Dennis Kraemer, Gülfirde Akgül, Horst von Bernuth, Markéta Bloomfield, Nicholas Brodszki, Fabio Candotti, Elisabeth Förster-Waldl, Tomas Freiberger, Maria Giżewska, Adam Klocperk, Uwe Kölsch, Kim E. Nichols, Renate Krüger, Ninad Oak, Małgorzata Pac, Seraina Prader, Kjeld Schmiegelow, Anna Šedivá, Georgios Sogkas, Anna Stittrich, Ulrik Kristoffer Stoltze, Katerina Theodoropoulou, Karin Wadt, Melanie Wong, Maximillian Zeyda, Jana Pachlopnik Schmid, Johannes Trück
Institutions: University of Zurich, University Children's Hospital Zurich, Masaryk University, Centrum kardiovaskulární a transplantační chirurgie, Humboldt-Universität zu Berlin, Berlin-Brandenburger Centrum für Regenerative Therapien, Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Charité – Universitätsmedizin Berlin, Charles University, University Hospital in Motol, Skåne University Hospital, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Medical University of Vienna, Pomeranian Medical University, St. Jude Children's Research Hospital, Children's Memorial Health Institute, University of Copenhagen, Rigshospitalet, Medizinische Hochschule Hannover, Copenhagen University Hospital, Children's Hospital at Westmead
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $4,000
OpenAlex ID: W4401540787