Mosaic variants in TNFRSF1A: an emerging cause of tumour necrosis factor receptor-associated periodic syndrome.

Autor:	Assrawi E; Sorbonne Université, INSERM, Maladies Génétiques d'Expression Pédiatrique., Louvrier C; Sorbonne Université, INSERM, Maladies Génétiques d'Expression Pédiatrique.; Unité Fonctionnelle de Génétique Moléculaire, Assistance Publique-Hôpitaux de Paris, Hôpital Trousseau., El Khouri E; Sorbonne Université, INSERM, Maladies Génétiques d'Expression Pédiatrique., Delaleu J; Sorbonne Université, INSERM, Maladies Génétiques d'Expression Pédiatrique., Copin B; Unité Fonctionnelle de Génétique Moléculaire, Assistance Publique-Hôpitaux de Paris, Hôpital Trousseau., Dastot-Le Moal F; Unité Fonctionnelle de Génétique Moléculaire, Assistance Publique-Hôpitaux de Paris, Hôpital Trousseau., Piterboth W; Unité Fonctionnelle de Génétique Moléculaire, Assistance Publique-Hôpitaux de Paris, Hôpital Trousseau., Legendre M; Unité Fonctionnelle de Génétique Moléculaire, Assistance Publique-Hôpitaux de Paris, Hôpital Trousseau., Karabina SA; Sorbonne Université, INSERM, Maladies Génétiques d'Expression Pédiatrique., Grateau G; Sorbonne Université, INSERM, Maladies Génétiques d'Expression Pédiatrique.; Service de Médecine Interne, Assistance Publique-Hôpitaux de Paris, Hôpital Tenon, Paris, France., Amselem S; Sorbonne Université, INSERM, Maladies Génétiques d'Expression Pédiatrique.; Unité Fonctionnelle de Génétique Moléculaire, Assistance Publique-Hôpitaux de Paris, Hôpital Trousseau., Giurgea I; Sorbonne Université, INSERM, Maladies Génétiques d'Expression Pédiatrique.; Unité Fonctionnelle de Génétique Moléculaire, Assistance Publique-Hôpitaux de Paris, Hôpital Trousseau.
Jazyk:	angličtina
Zdroj:	Rheumatology (Oxford, England) [Rheumatology (Oxford)] 2022 Dec 23; Vol. 62 (1), pp. 473-479.
DOI:	10.1093/rheumatology/keac274
Abstrakt:	Objective: To identify the molecular basis of a systemic autoinflammatory disorder (SAID) evocative of TNF receptor-associated periodic syndrome (TRAPS). Methods: (i) Deep next generation sequencing (NGS) through a SAID gene panel; (ii) variant allele distribution in peripheral blood subpopulations; (iii) in silico analyses of mosaic variants using TNF receptor superfamily 1A (TNFRSF1A) crystal structure; (iv) review of the very rare TNFRSF1A mosaic variants reported previously. Results: In a 36-year-old man suffering from recurrent fever for 12 years, high-depth NGS revealed a TNFRSF1A mosaic variant, c.176G>A p.(Cys59Tyr), which Sanger sequencing failed to detect. This mosaic variant displayed a variant allele fraction of 14% in whole blood; it affects both myeloid and lymphoid lineages. p.(Cys59Tyr), a recurrent germline pathogenic variant, affects a crucial cysteine located in the first cysteine-rich domain (CRD1) and involved in a disulphide bridge. Introduction of a tyrosine at this position is expected to disrupt the CRD1 structure. Review of the three previously reported TNFRSF1A mosaic variants revealed that they are all located in a small region of CRD2 and that germinal cells can be affected. Conclusion: This study expands the localization of TNFRSF1A mosaic variants to the CRD1 domain. Noticeably, residues involved in germline TNFRSF1A mutational hot spots can also be involved in post-zygotic mutational events. Including our study, only four patients have been thus far reported with TNFRSF1A mosaicism, highlighting the need for a high-depth NGS-based approach to avoid the misdiagnosis of TRAPS. Genetic counselling has to consider the potential occurrence of TNFRSF1A mosaic variants in germinal cells. (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu