Utilizing Next Generation Sequencing to Screen for Inborn Errors of Immunity in Pediatric Patients with a History of Lymphoma: A Single Institution Experience

Abstract

BackgroundLymphoma risk, as well as malignancy-related morbidity and mortality, is significantly increased in individuals with inborn errors of immunity (IEI). Importantly, lymphoma can also be the first IEI-related manifestation, yet no standard screening recommendations for IEI in pediatric patients presenting with lymphoma exist. We hypothesized that pathogenic IEI-related variants occur more frequently in pediatric lymphoma patients than the general population (estimated 1/1000 patients). Here we describe IEI-focused next-generation sequencing (NGS) results on pediatric patients with a history of lymphoma. MethodsA single center, retrospective study of patients diagnosed with lymphoma at age 25 years or less between 2012 and 2021 was performed. Following informed consent, a biospecimen was sent to Invitae for clinical NGS (Inborn Errors of Immunity and Cytopenias 574-gene panel). Genetic testing was funded through the Navigate APDS program, sponsored by Pharming Healthcare. Results were reviewed by a board-certified geneticist and genetic counselor and categorized as definitive, probable, possible, or unlikely. Variants of uncertain significance (VUS) resolution testing was performed when indicated. Immune-focused family history survey and electronic medical record review were also completed. ResultsThere were 163 eligible patients, 151 of whom were still alive. Eighty-five patients were approached for this study, the remainder unable to be reached. A total of 52 patients consented to the study, with results available for 49. The study population had an average age at diagnosis of 13.4 years (range 4–21), was 63% male and 53% had non-Hodgkin lymphoma. Genetic results are depicted in Figure 1. There was a likely pathogenic IEI variant in 8.16% of subjects (4/49), which was higher than the published estimated incidence of IEI in the general population (p = 0.044). [Display omitted] ConclusionDespite the study limitations inherent to the retrospective design and inability to include deceased or allogenic stem cell transplant patients, this study demonstrated that genetic variants associated with IEI have a higher incidence in pediatric lymphoma patients compared to in the general population. Development of IEI screening guidelines for pediatric patients presenting with lymphoma as well as further prospective studies to illuminate the true incidence of IEI in this population are warranted.