Genetic errors of immunity distinguish pediatric nonmalignant lymphoproliferative disorders

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dc.contributor.authorForbes, Lisa R.
dc.contributor.authorEckstein, Olive S.
dc.contributor.authorGulati, Nitya
dc.contributor.authorPeckham-Gregory, Erin C.
dc.contributor.authorOzuah, Nmazuo W.
dc.contributor.authorLubega, Joseph
dc.contributor.authorEl-Mallawany, Nader K.
dc.contributor.authorAgrusa, Jennifer E.
dc.contributor.authorPoli, Cecilia
dc.contributor.authorVogel, Tiphanie P.
dc.contributor.authorChaimowitz, Natalia S.
dc.contributor.authorRider, Nicholas L.
dc.contributor.authorMace, Emily M.
dc.contributor.authorOrange, Jordan S.
dc.contributor.authorCaldwell, Jason W.
dc.contributor.authorAldave-Becerra, Juan C.
dc.contributor.authorJolles, Stephen
dc.contributor.authorSaettini, Francesco
dc.contributor.authorChong, Hey J.
dc.contributor.authorStray-Pedersen, Asbjorg
dc.contributor.authorHeslop, Helen E.
dc.contributor.authorKamdar, Kala Y.
dc.contributor.authorRouce, R. Helen
dc.contributor.authorMuzny, Donna M.
dc.contributor.authorJhangiani, Shalini N.
dc.contributor.authorGibbs, Richard A.
dc.contributor.authorCoban-Akdemir, Zeynep H.
dc.contributor.authorLupski, James R.
dc.contributor.authorMcClain, Kenneth L.
dc.contributor.authorAllen, Carl E.
dc.contributor.authorChinn, Ivan K.
dc.date.accessioned2022-04-06T21:47:32Z
dc.date.available2022-04-06T21:47:32Z
dc.date.issued2022
dc.description.abstractBackground: 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.es
dc.identifier.citationForbes LR, Eckstein OS, Gulati N, Peckham-Gregory EC, Ozuah NW, Lubega J, El-Mallawany NK, Agrusa JE, Poli MC, 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, Rouce RH, Muzny DM, Jhangiani SN, Gibbs RA, Coban-Akdemir ZH, Lupski JR, McClain KL, Allen CE, Chinn IK. Genetic errors of immunity distinguish pediatric nonmalignant lymphoproliferative disorders. J Allergy Clin Immunol. 2022 Feb;149(2):758-766. doi: 10.1016/j.jaci.2021.07.015.es
dc.identifier.urihttps://doi.org/10.1016/j.jaci.2021.07.015es
dc.identifier.urihttp://hdl.handle.net/11447/5954
dc.language.isoenes
dc.subjectEpstein-Barr viruses
dc.subjectLymphoproliferationes
dc.subjectGenomices
dc.subjectPediatrices
dc.subjectWhole exome sequencinges
dc.titleGenetic errors of immunity distinguish pediatric nonmalignant lymphoproliferative disorderses
dc.typeArticlees
dcterms.sourceJournal of Allergy and Clinical Immunologyes

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