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


Zanoni, Paolo; Steindl, Katharina; Sticht, Heinrich; Oneda, Beatrice; Joset, Pascal; Ivanovski, Ivan; Horn, Anselm H C; Cabello, Elena María; Laube, Julia; Zweier, Markus; Baumer, Alessandra; Rauch, Anita; Khan, Nadia (2023). The genetic landscape and clinical implication of pediatric Moyamoya angiopathy in an international cohort. European Journal of Human Genetics, 31(7):784-792.

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.

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.

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Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Children's Hospital Zurich > Medical Clinic
04 Faculty of Medicine > Institute of Medical Genetics
04 Faculty of Medicine > Neuroscience Center Zurich
04 Faculty of Medicine > Zurich Center for Integrative Human Physiology (ZIHP)
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Scopus Subject Areas:Life Sciences > Genetics
Health Sciences > Genetics (clinical)
Uncontrolled Keywords:Genetics (clinical), Genetics
Language:English
Date:1 July 2023
Deposited On:13 Apr 2023 13:24
Last Modified:29 Apr 2024 01:37
Publisher:Nature Publishing Group
ISSN:1018-4813
Additional Information:DATA AVAILABILITY Protocols and code presented in this work are available upon request to the corresponding authors. Sequence and copy number variants have been deposited in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/; submission ID SUB11907061) and Decipher (https://www.deciphergenomics.org/; see Decipher-IDs in Table S2). ETHICAL APPROVAL The study was conducted under approval of the Ethical Committee of the Canton of Zurich, ID# BASEC-2016-00880. Written informed consent for genetic testing and publication of genetic and clinical data was obtained from each individual’s parents or their legal guardian.
OA Status:Hybrid
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1038/s41431-023-01320-0
PubMed ID:37012328
Project Information:
  • : FunderUniversity of Zurich
  • : Grant IDITINERARE
  • : Project TitleURPP ITINERARE Innovative Therapies in Rare Diseases
  • : Project Websitehttps://www.itinerare.uzh.ch/
  • Content: Published Version
  • Language: English
  • Licence: Creative Commons: Attribution 4.0 International (CC BY 4.0)