Browsing by Author "Frede, N"
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- Characterization of the Clinical and Immunologic Phenotype and Management of 157 Individuals with 56 Distinct Heterozygous NFKB1 MutationsPublication . Lorenzini, T; Fliegauf, M; Klammer, N; Frede, N; Proietti, M; Bulashevska, A; Camacho-Ordonez, N; Varjosalo, M; Kinnunen, M; de Vries, E; van der Meer, JW; Ameratunga, R; Roifman, CM; Schejter, YD; Kobbe, R; Hautala, T; Atschekzei, F; Schmidt, RE; Schröder, C; Stepensky, P; Shadur, B; Pedroza, LA; van der Flier, M; Martínez-Gallo, M; Gonzalez-Granado, LI; Allende, LM; Shcherbina, A; Kuzmenko, N; Zakharova, V; Neves, JF; Svec, P; Fischer, U; Ip, W; Bartsch, O; Barış, S; Klein, C; Geha, R; Chou, J; Alosaimi, M; Weintraub, L; Boztug, K; Hirschmugl, T; Dos Santos Vilela, MM; Holzinger, D; Seidl, M; Lougaris, V; Plebani, A; Alsina, L; Piquer-Gibert, M; Deyà-Martínez, A; Slade, CA; Aghamohammadi, A; Abolhassani, H; Hammarström, L; Kuismin, O; Helminen, M; Allen, HL; Thaventhiran, JE; Freeman, AF; Cook, M; Bakhtiar, s; Christiansen, M; Cunningham-Rundles, C; Patel, NC; Rae, W; Niehues, T; Brauer, N; Syrjänen, J; Seppänen, MJ; Burns, SO; Tuijnenburg, P; Kuijpers, TW; Warnatz, K; Grimbacher, BBackground: An increasing number of NFKB1 variants are being identified in patients with heterogeneous immunologic phenotypes. Objective: To characterize the clinical and cellular phenotype as well as the management of patients with heterozygous NFKB1 mutations. Methods: In a worldwide collaborative effort, we evaluated 231 individuals harboring 105 distinct heterozygous NFKB1 variants. To provide evidence for pathogenicity, each variant was assessed in silico; in addition, 32 variants were assessed by functional in vitro testing of nuclear factor of kappa light polypeptide gene enhancer in B cells (NF-κB) signaling. Results: We classified 56 of the 105 distinct NFKB1 variants in 157 individuals from 68 unrelated families as pathogenic. Incomplete clinical penetrance (70%) and age-dependent severity of NFKB1-related phenotypes were observed. The phenotype included hypogammaglobulinemia (88.9%), reduced switched memory B cells (60.3%), and respiratory (83%) and gastrointestinal (28.6%) infections, thus characterizing the disorder as primary immunodeficiency. However, the high frequency of autoimmunity (57.4%), lymphoproliferation (52.4%), noninfectious enteropathy (23.1%), opportunistic infections (15.7%), autoinflammation (29.6%), and malignancy (16.8%) identified NF-κB1-related disease as an inborn error of immunity with immune dysregulation, rather than a mere primary immunodeficiency. Current treatment includes immunoglobulin replacement and immunosuppressive agents. Conclusions: We present a comprehensive clinical overview of the NF-κB1-related phenotype, which includes immunodeficiency, autoimmunity, autoinflammation, and cancer. Because of its multisystem involvement, clinicians from each and every medical discipline need to be made aware of this autosomal-dominant disease. Hematopoietic stem cell transplantation and NF-κB1 pathway-targeted therapeutic strategies should be considered in the future.
- Targeted Gene Panel Sequencing for Early-onset Inflammatory Bowel Disease and Chronic DiarrheaPublication . Petersen, BS; August, D; Abt, R; Alddafari, M; Atarod, L; Baris, S; Bhavsar, H; Brinkert, F; Buchta, M; Bulashevska, A; Chee, R; Cordeiro, AI; Dara, N; Dückers, G; Elmarsafy, A; Frede, N; Galal, N; Gerner, P; Glocker, EO; Goldacker, S; Hammermann, J; Hasselblatt, P; Havlicekova, Z; Hübscher, K; Jesenak, M; Karaca, NE; Karakoc-Aydiner, E; Kharaghani, MM; Kilic, SS; Kiykim, A; Klein, C; Klemann, C; Kobbe, R; Kotlarz, D; Laass, MW; Leahy, TR; Mesdaghi, M; Mitton, S; Farela Neves, J; Öztürk, B; Pereira, LF; Rohr, J; Restrepo, JLR; Ruzaike, G; Saleh, N; Seneviratne, S; Senol, E; Speckmann, C; Tegtmeyer, D; Thankam, P; van der Werff ten Bosch, J; von Bernuth, H; Zeissig, S; Zeissig, Y; Franke, A; Grimbacher, BBackground: In contrast to adult-onset inflammatory bowel disease (IBD), where many genetic loci have been shown to be involved in complex disease etiology, early-onset IBD (eoIBD) and associated syndromes can sometimes present as monogenic conditions. As a result, the clinical phenotype and ideal disease management in these patients often differ from those in adult-onset IBD. However, due to high costs and the complexity of data analysis, high-throughput screening for genetic causes has not yet become a standard part of the diagnostic work-up of eoIBD patients. Methods: We selected 28 genes of interest associated with monogenic IBD and performed targeted panel sequencing in 71 patients diagnosed with eoIBD or early-onset chronic diarrhea to detect causative variants. We compared these results to whole-exome sequencing (WES) data available for 25 of these patients. Results: Target coverage was significantly higher in the targeted gene panel approach compared with WES, whereas the cost of the panel was considerably lower (approximately 25% of WES). Disease-causing variants affecting protein function were identified in 5 patients (7%), located in genes of the IL10 signaling pathway (3), WAS (1), and DKC1 (1). The functional effects of 8 candidate variants in 5 additional patients (7%) are under further investigation. WES did not identify additional causative mutations in 25 patients. Conclusions: Targeted gene panel sequencing is a fast and effective screening method for monogenic causes of eoIBD that should be routinely established in national referral centers.