Genetic errors of immunity distinguish pediatric nonmalignant lymphoproliferative disorders.

TitleGenetic errors of immunity distinguish pediatric nonmalignant lymphoproliferative disorders.
Publication TypeJournal Article
Year of Publication2022
AuthorsForbes, LR, Eckstein, OS, Gulati, N, Peckham-Gregory, EC, Ozuah, NW, Lubega, J, El-Mallawany, NK, Agrusa, JE, M Poli, C, Vogel, TP, Chaimowitz, NS, Rider, NL, Mace, EM, Orange, JS, Caldwell, JW, Aldave-Becerra, JC, Jolles, S, Saettini, F, Chong, HJ, Stray-Pedersen, A, Heslop, HE, Kamdar, KY, R Rouce, H, Muzny, DM, Jhangiani, SN, Gibbs, RA, Coban-Akdemir, ZH, Lupski, JR, McClain, KL, Allen, CE, Chinn, IK
JournalJ Allergy Clin Immunol
Date Published2022 Feb
KeywordsAdolescent, Autoimmunity, Child, Child, Preschool, Exome Sequencing, Female, Genetic Association Studies, Genetic Testing, Herpesvirus 4, Human, Humans, Immunity, Infant, Lymphoproliferative Disorders, Male, Young Adult

BACKGROUND: Pediatric nonmalignant lymphoproliferative disorders (PLPDs) are clinically and genetically heterogeneous. Long-standing immune dysregulation and lymphoproliferation in children may be life-threatening, and a paucity of data exists to guide evaluation and treatment of children with PLPD.

OBJECTIVE: The primary objective of this study was to ascertain the spectrum of genomic immunologic defects in PLPD. Secondary objectives included characterization of clinical outcomes and associations between genetic diagnoses and those outcomes.

METHODS: PLPD was defined by persistent lymphadenopathy, lymph organ involvement, or lymphocytic infiltration for more than 3 months, with or without chronic or significant Epstein-Barr virus (EBV) infection. Fifty-one subjects from 47 different families with PLPD were analyzed using whole exome sequencing.

RESULTS: Whole exome sequencing identified likely genetic errors of immunity in 51% to 62% of families (53% to 65% of affected children). Presence of a genetic etiology was associated with younger age and hemophagocytic lymphohistiocytosis. Ten-year survival for the cohort was 72.4%, and patients with viable genetic diagnoses had a higher survival rate (82%) compared to children without a genetic explanation (48%, P = .03). Survival outcomes for individuals with EBV-associated disease and no genetic explanation were particularly worse than outcomes for subjects with EBV-associated disease and a genetic explanation (17% vs 90%; P = .002). Ascertainment of a molecular diagnosis provided targetable treatment options for up to 18 individuals and led to active management changes for 12 patients.

CONCLUSIONS: PLPD defines children at high risk for mortality, and whole exome sequencing informs clinical risks and therapeutic opportunities for this diagnosis.

Alternate JournalJ Allergy Clin Immunol
PubMed ID34329649
PubMed Central IDPMC8795244
Grant ListK12 CA090433 / CA / NCI NIH HHS / United States
P50 CA126752 / CA / NCI NIH HHS / United States
R01 AI120989 / AI / NIAID NIH HHS / United States
UM1 HG006542 / HG / NHGRI NIH HHS / United States

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