Clinical Implications of Concurrent Heterozygous LRBA and RTEL1 Variants: A Case Study

We present the case of a 43-year-old male who presented to pulmonology with 3 years of chronic cough and recurrent sinopulmonary infections. He was diagnosed with bronchiectasis and found to have mild thrombocytopenia and agammaglobulinemia (IgG 44 mg/dL, IgA and IgM undetectable). Further immunologic evaluation revealed normal lymphocyte subsets (T/B/NK), decreased class-switched memory B cells, and low specific antibody titers, consistent with common variable immune deficiency (CVID). Genetic testing identified heterozygous likely pathogenic variants in LRBA (c.216+1G>C) and RTEL1 variant (c.2869C>T; p.R957W). Patient’s father was diagnosed with pulmonary fibrosis and carried the same variants. Patient’s telomeres were <1st percentile in all leukocyte subsets.Comprehensive organ evaluation of the patient revealed bone marrow hypocellularity, increased liver stiffness (9.6 kPa), further supporting a diagnosis of an inherited telomere biology disorder. Mature bone marrow plasma cells were essentially absent. CT chest showed interstitial changes most consistent with granulomatous lymphocytic interstitial lung disease (ILD) related to CVID. Additionally, he was found to have an expanded CD21lo B cell population (16.8%, risk ratio [RR] 0.2–8.6%) and an increased follicular helper T cell count (46%, RR 4–23%) for which a trial of abatacept has been suggested.The two genetic variants in this case are noteworthy. The RTEL1 variant, short telomeres, cytopenia, hepatic fibrosis, and ILD are consistent with a telomere biology disorders (TBD) phenotype, though ILD and cytopenias can also be seen in CVID. However, while RTEL1 has been linked to hypogammaglobulinemia, it is usually in the setting of decreased B/T/NK cell numbers and bone marrow failure, not present in this case. While the clinical significance of the heterozygous LRBA variant remains uncertain, the numerous features of the patient’s presentation mirror those seen in LRBA deficiency (hypogammaglobulinemia, lymphoproliferation, elevated CD21lo B cells, and elevated follicular helper T cells). This raises the provocative possibility of a digenic model to explain the patient’s disease—with telomere dysfunction due to the RTEL1 variant exacerbating the immunologic aberrations of heterozygous loss of LBRA. Alternatively, the patient may have a second unidentified deleterious LBRA variant and additional genetic and functional testing is underway to evaluate this possibility.