IGLL1 – Agammaglobulinemia

IGLL1 has emerged as an important gene underlying a rare form of agammaglobulinemia characterized primarily by absent or markedly reduced B cells. The disorder follows an autosomal recessive mode of inheritance, which is well‑aligned with the clinical observations in affected families. In one case report, a two‑month‑old male with an IGLL1 defect presented with recurrent sinusitis, bronchitis, and pneumonia, and additional family members with the same mutation displayed a variable clinical phenotype (PMID:39549297).

A multi‑patient study further expanded the clinical spectrum, reporting a total of 15 probands identified by newborn screening and clinical diagnosis who exhibited severe B‑cell deficiency. This study underscored that, despite profoundly low CD19+ B‑cell counts, some patients maintained residual immunoglobulin production and experienced favorable outcomes with immunoglobulin substitution (PMID:39147326).

The genetic evidence is reinforced by the identification of key variants, including the missense change c.425C>T (p.Pro142Leu) and a frameshift mutation c.258del (p.Gln88AsnfsTer7), which segregate with the disease phenotype in multiple unrelated families (PMID:39147326). Such recurrent findings provide robust support for the gene–disease association.

Although direct functional assessments are somewhat limited, the predicted disruption in pre‑B cell receptor assembly due to IGLL1 deficiency aligns well with the immunological defects observed in patients. This mechanistic insight, albeit supported by inference rather than extensive experimental validation, adds further plausibility to the pathogenicity of the reported variants.

Overall, the combined genetic and clinical data from case reports and multi‑patient series converge to support a strong gene–disease association between IGLL1 and agammaglobulinemia. The consistent autosomal recessive inheritance pattern, the segregation of multiple deleterious variants, and the corresponding clinical phenotype provide a firm basis for incorporating IGLL1 analysis in diagnostic decision‑making and genetic counseling.

Key take‑home: The evidence for IGLL1 involvement in agammaglobulinemia is robust, supporting its use as a reliable genetic marker in clinical and commercial diagnostic settings.

References

• Iranian journal of allergy, asthma, and immunology • 2024 • Single Mutation Different Clinical Findings: IGLL1 Defect. PMID:39549297
• The Journal of allergy and clinical immunology • 2024 • Variants in IGLL1 cause a broad phenotype from agammaglobulinemia to transient hypogammaglobulinemia. PMID:39147326

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