Two Cases of B Cell Lymphopenia Associated with IGLL1 Variants Identified Through Newborn Screening in Ukraine

Résumé fourni par la source

The kappa-deleting recombination excision circles (KREC) assay in newborn screening (NBS) facilitates the identification of conditions associated with B cell lymphopenia. The use of the KREC assay has been controversial and less commonly implemented compared with the TREC assay. We present two cases of children with positive KREC screening results to highlight the importance of early detection and support the consideration of this assay for global indication. Case presentation Case 1: A full-term, healthy female newborn had a positive NBS result with undetectable KREC but normal TREC levels at birth. Follow-up revealed low B cell counts (70 cells/μL) but preserved T and NK cell subsets at 3 months. Immunoglobulin levels (IgA, IgM, and IgG) remained within normal ranges at 3, 6, and 11 months of age. No severe infections occurred until 1 year. Vaccine responses were notable for normal tetanus antibody titers but borderline diphtheria titers. Genetic testing identified variants of uncertain significance (VUS) in the IGLL1 gene: the one allele with c.425C>T (p.Pro142Leu) and the other with c.368C>G (p.Ser123Cys) and c.377T>C (p.Leu126Pro). Case 2: A full-term healthy male newborn also presented with undetectable KREC but normal TREC. B cell counts were low at one month (97 cells/μL) and decreased at seven months (68 cells/μL), with normal T and NK cell subsets. A transient IgG decline was noted at 3.5 months and increased to low normal by 7 months. Genetic testing revealed two IGLL1 variants on separate alleles: a missense VUS c.425C>T (p.Pro142Leu) and a likely pathogenic nonsense variant c.258del (p. Gln88Asnfs∗7). Immunoglobulin replacement therapy (IRT) was recommended but not administered due to low compliance. Over one year, the child experienced mild respiratory symptoms and transient fever episodes. Conclusions Both patients carried the c.425C>T variant, and one also had the c.258del variant in the IGLL1 gene, which have been recently reported with high allele frequency in the general population but also linked to cases of B cell lymphopenia and low KRECs. These cases highlight the potential underdiagnosis of B cell deficiencies secondary to IGLL1. Early detection via KREC screening enabled close monitoring and consideration of IRT. The broader impact of KREC assay for IGLL1-related disorders remains to be determined.

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.