The genetic landscape and clinical implication of pediatric Moyamoya angiopathy in an international cohort

Zanoni P, Steindl K, Sticht H, Oneda B, Joset P, Ivanovski I, Horn AH, Cabello EM, Laube J, Zweier M, Baumer A, Rauch A, Khan N (2023)

Publication Type: Journal article

Publication year: 2023

Journal

European Journal of Human Genetics Nature Publishing Group: Open Access Hybrid Model Option B

DOI: 10.1038/s41431-023-01320-0

Abstract

Pediatric Moyamoya Angiopathy (MMA) is a progressive intracranial occlusive arteriopathy that represents a leading cause of transient ischemic attacks and strokes in childhood. Despite this, up to now no large, exclusively pediatric MMA cohort has been subjected to systematic genetic investigation. In this study, we performed molecular karyotyping, exome sequencing and automated structural assessment of missense variants on a series of 88 pediatric MMA patients and correlated genetic, angiographic and clinical (stroke burden) findings. The two largest subgroups in our cohort consisted of RNF213 and neurofibromatosis type 1 (NF1) patients. While deleterious RNF213 variants were associated with a severe MMA clinical course with early symptom onset, frequent posterior cerebral artery involvement and higher stroke rates in multiple territories, NF1 patients had a similar infarct burden compared to non-NF1 individuals and were often diagnosed incidentally during routine MRIs. Additionally, we found that MMA-associated RNF213 variants have lower predicted functional impact compared to those associated with aortic disease. We also raise the question of MMA as a feature of recurrent as well as rare chromosomal imbalances and further support the possible association of MMA with STAT3 deficiency. In conclusion, we provide a comprehensive characterization at the genetic and clinical level of a large exclusively pediatric MMA population. Due to the clinical differences found across genetic subgroups, we propose genetic testing for risk stratification as part of the routine assessment of pediatric MMA patients.

Authors with CRIS profile

Heinrich Sticht Professur für Bioinformatik

Involved external institutions

University of Zurich / Universität Zürich (UZH) CH Switzerland (CH) Universitäts-Kinderspital Zürich CH Switzerland (CH)

How to cite

APA:

Zanoni, P., Steindl, K., Sticht, H., Oneda, B., Joset, P., Ivanovski, I.,... Khan, N. (2023). The genetic landscape and clinical implication of pediatric Moyamoya angiopathy in an international cohort. European Journal of Human Genetics. https://doi.org/10.1038/s41431-023-01320-0

MLA:

Zanoni, Paolo, et al. "The genetic landscape and clinical implication of pediatric Moyamoya angiopathy in an international cohort." European Journal of Human Genetics (2023).

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