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Micale L, Morlino S, Carbone A, et al. Loss-of-function variants in exon 4 of TAB2 cause a recognizable multisystem disorder with cardiovascular, facial, cutaneous, and musculoskeletal involvement. Genet Med. 2021;doi: 10.1016/j.gim.2021.10.009.
Micale, L., Morlino, S., Carbone, A., Carissimo, A., Nardella, G., Fusco, C., Palumbo, O., Schirizzi, A., Russo, F., Mazzoccoli, G., Breckpot, J., De Luca, C., Ferraris, A., Giunta, C., Grammatico, P., Haanpää, M. K., Mancano, G., Forzano, G., Cacchiarelli, D., Van Esch, H., Callewaert, B., Rohrbach, M., & Castori, M. (2021). Loss-of-function variants in exon 4 of TAB2 cause a recognizable multisystem disorder with cardiovascular, facial, cutaneous, and musculoskeletal involvement. Genetics in medicine : official journal of the American College of Medical Genetics, . https://doi.org/10.1016/j.gim.2021.10.009
Micale, Lucia, et al. "Loss-of-function variants in exon 4 of TAB2 cause a recognizable multisystem disorder with cardiovascular, facial, cutaneous, and musculoskeletal involvement." Genetics in medicine : official journal of the American College of Medical Genetics vol. (2021). doi: https://doi.org/10.1016/j.gim.2021.10.009
Micale L, Morlino S, Carbone A, Carissimo A, Nardella G, Fusco C, Palumbo O, Schirizzi A, Russo F, Mazzoccoli G, Breckpot J, De Luca C, Ferraris A, Giunta C, Grammatico P, Haanpää MK, Mancano G, Forzano G, Cacchiarelli D, Van Esch H, Callewaert B, Rohrbach M, Castori M. Loss-of-function variants in exon 4 of TAB2 cause a recognizable multisystem disorder with cardiovascular, facial, cutaneous, and musculoskeletal involvement. Genet Med. 2021 Nov 30; doi: 10.1016/j.gim.2021.10.009. Epub 2021 Nov 30. PMID: 34906501.
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Genet Med. 2021 Nov 30; doi: 10.1016/j.gim.2021.10.009. Epub 2021 Nov 30.

Loss-of-function variants in exon 4 of TAB2 cause a recognizable multisystem disorder with cardiovascular, facial, cutaneous, and musculoskeletal involvement.

Genetics in medicine : official journal of the American College of Medical Genetics

Lucia Micale, Silvia Morlino, Annalucia Carbone, Annamaria Carissimo, Grazia Nardella, Carmela Fusco, Orazio Palumbo, Annalisa Schirizzi, Federica Russo, Gianluigi Mazzoccoli, Jeroen Breckpot, Chiara De Luca, Alessandro Ferraris, Cecilia Giunta, Paola Grammatico, Maria K Haanpää, Giorgia Mancano, Giulia Forzano, Davide Cacchiarelli, Hilde Van Esch, Bert Callewaert, Marianne Rohrbach, Marco Castori

Affiliations

  1. Division of Medical Genetics, Fondazione IRCCS-Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy.
  2. Unit of Chronobiology, Division of Internal Medicine, Fondazione IRCCS-Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy.
  3. Institute for Applied Mathematics "Mauro Picone" National Research Council, Naples, Italy.
  4. Center for Human Genetics, University Hospital Leuven, Leuven, Belgium.
  5. Laboratory of Medical Genetics, Department of Molecular Medicine, Sapienza University, San Camillo-Forlanini Hospital, Rome, Italy.
  6. Division of Metabolism and Children's Research Center, University Children's Hospital Zurich and University of Zurich, Zurich, Switzerland.
  7. Department of Clinical Genetics and Genomics, Turku University Hospital and University of Turku, Turku, Finland.
  8. Medical Genetics Unit, Meyer Children's University Hospital, Florence, Italy.
  9. Medical Genetics Unit, University of Florence, Florence, Italy.
  10. Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy; Department of Translational Medicine, University of Naples "Federico II", Naples, Italy.
  11. Center for Medical Genetics and Department of Biomolecular Medicine, Ghent University Hospital, Ghent, Belgium.
  12. Division of Medical Genetics, Fondazione IRCCS-Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy. Electronic address: [email protected].

PMID: 34906501 DOI: 10.1016/j.gim.2021.10.009

Abstract

PURPOSE: This study aimed to describe a multisystemic disorder featuring cardiovascular, facial, musculoskeletal, and cutaneous anomalies caused by heterozygous loss-of-function variants in TAB2.

METHODS: Affected individuals were analyzed by next-generation technologies and genomic array. The presumed loss-of-function effect of identified variants was assessed by luciferase assay in cells transiently expressing TAB2 deleterious alleles. In available patients' fibroblasts, variant pathogenicity was further explored by immunoblot and osteoblast differentiation assays. The transcriptomic profile of fibroblasts was investigated by RNA sequencing.

RESULTS: A total of 11 individuals from 8 families were heterozygotes for a novel TAB2 variant. In total, 7 variants were predicted to be null alleles and 1 was a missense change. An additional subject was heterozygous for a 52 kb microdeletion involving TAB2 exons 1 to 3. Luciferase assay indicated a decreased transcriptional activation mediated by NF-κB signaling for all point variants. Immunoblot analysis showed a reduction of TAK1 phosphorylation while osteoblast differentiation was impaired. Transcriptomic analysis identified deregulation of multiple pleiotropic pathways, such as TGFβ-, Ras-MAPK-, and Wnt-signaling networks.

CONCLUSION: Our data defined a novel disorder associated with loss-of-function or, more rarely, hypomorphic alleles in a restricted linker region of TAB2. The pleiotropic manifestations in this disorder partly recapitulate the 6q25.1 (TAB2) microdeletion syndrome and deserve the definition of cardio-facial-cutaneous-articular syndrome.

Copyright © 2021 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.

Keywords: Congenital heart defect; Connective tissue; Ehlers-Danlos syndrome; Osteoblast; TAK1

Conflict of interest statement

Conflict of Interest The authors declare no conflict of interest related to this article. D.C. is the founder and shareholder of and consultant for Next Generation Diagnostics srl. Some of the authors

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