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.

Berlin Institute of Health at Charité Universitätsmedizin Berlin 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

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

Childrens' Hospital Skåne University Hospital Lund Sweden

Department of Allergy and Immunology The Children's Hospital at Westmead Sydney Australia

Department of Clinical Genetics University Hospital Copenhagen Copenhagen Denmark

Department of Clinical Medicine Faculty of Health and Medical Sciences University of Copenhagen Copenhagen Denmark

Department of Human Genetics Labor Berlin Charité Vivantes GmbH Berlin Germany

Department of Immunology 2nd Faculty of Medicine Charles University and University Hospital in Motol Prague Czechia

Department of Immunology Labor Berlin Charité Vivantes GmbH Berlin Germany

Department of Immunology The Children's Memorial Health Institute Warsaw Poland

Department of Oncology St Jude Children's Research Hospital Memphis Tenn

Department of Paediatrics and Adolescent Medicine Division of Neonatology Neuropaediatrics and Paediatric Intensive Care and Center for Congenital Immunodeficiencies and Jeffrey Modell Diagnostic and Research Center Medical University of Vienna Vienna Austria

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

Department of Pediatrics and Adolescent Medicine Rigshospitalet Copenhagen Denmark

Department of Pediatrics Endocrinology Diabetology Metabolic Diseases and Cardiology of the Developmental Age Pomeranian Medical University in Szczecin Szczecin Poland

Department of Rheumatology and Immunology Hannover Medical University and Hannover Medical School Hannover Germany

Division of Immunology and Allergy Lausanne University Hospital and University of Lausanne Lausanne Switzerland

Division of Immunology and the Children's Research Center University Children's Hospital Zurich University of Zurich Zurich Switzerland

Institute of Medical Genetics University of Zurich Zurich Switzerland

Molecular Genetics Laboratory Centre for Cardiovascular Surgery and Transplantation Brno and Medical Faculty Masaryk University Brno Czechia

Unit of Pediatric Immunology Allergology and Rheumatology Department of Woman Mother Child Lausanne University Hospital and University of Lausanne Lausanne Switzerland

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