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Isidor, B., Ebstein, F., Hurst, A., Vincent, M., Bader, I., Rudy, N. L., Cogne, B., Mayr, J., Brehm, A., Warren, K., Bacino, C. A., Gerard, A., Ranells, J. D., Metcalfe, K. A., van Bever, Y., Jiang, Y-H., Mendelssohn, B. A., Cope, H., Besnard, T., ... Undiagnosed Diseases Network (2022). Stankiewicz-Isidor syndrome: Expanding the clinical and molecular phenotype. Genetics in Medicine, 24(1), 179-191. https://doi.org/10.1016/j.gim.2021.09.005
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.
