Immune deficiency, autoimmune disease and intellectual disability: A pleiotropic disorder caused by biallelic variants in the TPP2 gene.

Clinical genetics 2021 Jun

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Four individuals from two families presented with a multisystemic condition of suspected genetic origin that was diagnosed only after genome analysis. The main phenotypic features were immune system dysregulation (severe immunodeficiency with autoimmunity) and intellectual disability. The four individuals were found to be homozygous for a 4.4 Kb deletion removing exons 20-23 (NM_003291.4) of the TPP2 gene, predicting a frameshift with premature termination of the protein. The deletion was located on a shared chromosome 13 haplotype indicating a Swiss founder mutation. Tripeptidyl peptidase 2 (TPP2) is a protease involved in HLA/antigen complex processing and amino acid homeostasis. Biallelic variants in TPP2 have been described in 10 individuals with variable features including immune deficiency, autoimmune cytopenias, and intellectual disability or chronic sterile brain inflammation mimicking multiple sclerosis. Our observations further delineate this severe condition not yet included in the OMIM catalog. Timely recognition of TPP2 deficiency is crucial since (1) immune surveillance is needed and hematopoietic stem cell transplantation may be necessary, and (2) for provision of genetic counselling. Additionally, enzyme replacement therapy, as already established for TPP1 deficiency, might be an option in the future. © 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Citation

Isis Atallah, Mathieu Quinodoz, Belinda Campos-Xavier, Virginie G Peter, Athina Fouriki, Christophe Bonvin, Armand Bottani, Camille Kumps, Federica Angelini, Felicitas Bellutti Enders, Stéphanie Christen-Zaech, Mattia Rizzi, Raffaele Renella, Maja Beck-Popovic, Claudia Poloni, Valérie Frossard, Jean-Louis Blouin, Carlo Rivolta, Orbicia Riccio, Fabio Candotti, Michael Hofer, Sheila Unger, Andrea Superti-Furga. Immune deficiency, autoimmune disease and intellectual disability: A pleiotropic disorder caused by biallelic variants in the TPP2 gene. Clinical genetics. 2021 Jun;99(6):780-788