Stankiewicz-Isidor syndrome: expanding the clinical and molecular phenotype

Bertrand Isidor*, Frédéric Ebstein, Anna Hurst, Marie Vincent, Ingrid Bader, Natasha L. Rudy, Benjamin Cogne, Johannes Mayr, Anja Brehm, Caleb Bupp, Kathryn Warren, Carlos A. Bacino, Amanda Gerard, Judith D. Ranells, Kay A. Metcalfe, Yolande van Bever, Yong Hui Jiang, Bryce A. Mendelssohn, Heidi Cope, Jill A. RosenfeldPatrick R. Blackburn, McKinsey L. Goodenberger, Hutton M. Kearney, Joanna Kennedy, Ingrid Scurr, Krzysztof Szczaluba, Rafal Ploski, Anne de Saint Martin, Yves Alembik, Amélie Piton, Ange Line Bruel, Christel Thauvin-Robinet, Alanna Strong, Karin E.M. Diderich, Dominique Bourgeois, Karin Dahan, Virginie Vignard, Dominique Bonneau, Estelle Colin, Magalie Barth, Caroline Camby, Geneviève Baujat, Ignacio Briceño, Alberto Gómez, Wallid Deb, Solène Conrad, Thomas Besnard, Stéphane Bézieau, Elke Krüger, Sébastien Küry, PaweƗ Stankiewicz

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

1 Citation (Scopus)

Abstract

Purpose: Haploinsufficiency of PSMD12 has been reported in individuals with neurodevelopmental phenotypes, including developmental delay/intellectual disability (DD/ID), facial dysmorphism, and congenital malformations, defined as Stankiewicz-Isidor syndrome (STISS). Investigations showed that pathogenic variants in PSMD12 perturb intracellular protein homeostasis. Our objective was to further explore the clinical and molecular phenotypic spectrum of STISS. Methods: We report 24 additional unrelated patients with STISS with various truncating single nucleotide variants or copy-number variant deletions involving PSMD12. We explore disease etiology by assessing patient cells and CRISPR/Cas9-engineered cell clones for various cellular pathways and inflammatory status. Results: The expressivity of most clinical features in STISS is highly variable. In addition to previously reported DD/ID, speech delay, cardiac and renal anomalies, we also confirmed preaxial hand abnormalities as a feature of this syndrome. Of note, 2 patients also showed chilblains resembling signs observed in interferonopathy. Remarkably, our data show that STISS patient cells exhibit a profound remodeling of the mTORC1 and mitophagy pathways with an induction of type I interferon-stimulated genes. Conclusion: We refine the phenotype of STISS and show that it can be clinically recognizable and biochemically diagnosed by a type I interferon gene signature.

Original languageEnglish
Pages (from-to)179-191
Number of pages13
JournalGenetics in Medicine
Volume24
Issue number1
Early online date30 Nov 2021
DOIs
Publication statusPublished - 1 Jan 2022

Bibliographical note

Funding Information:
We are grateful to all patients and families who participated in this study. This work was supported by grants of the German Research Foundation under grants DFG RTG PRO 2719/ B4 , SFBTR 186 TP A13 , and SFBTR 167 TP A4 to E.K.

Publisher Copyright:
© 2021 American College of Medical Genetics and Genomics

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