Neurologic and neurodevelopmental complications in cardiofaciocutaneous syndrome are associated with genotype: A multinational cohort study.

Autor:	Pierpont EI; Division of Clinical Behavioral Neuroscience, Department of Pediatrics, University of Minnesota Medical School, Minneapolis, MN. Electronic address: pier0053@umn.edu., Kenney-Jung DL; Department of Neurology, University of Minnesota Medical School, Minneapolis, MN., Shanley R; Biostatistical Design and Analysis Center, Clinical & Translational Science Institute, University of Minnesota, Minneapolis, MN., Zatkalik AL; Division of Clinical Behavioral Neuroscience, Department of Pediatrics, University of Minnesota Medical School, Minneapolis, MN., Whitmarsh AE; Division of Clinical Behavioral Neuroscience, Department of Pediatrics, University of Minnesota Medical School, Minneapolis, MN., Kroening SJ; Division of Clinical Behavioral Neuroscience, Department of Pediatrics, University of Minnesota Medical School, Minneapolis, MN., Roberts AE; Division of Genetics and Genomics, Department of Cardiology and Department of Pediatrics, Boston Children's Hospital, Boston, MA., Zenker M; Institute of Human Genetics, University Hospital Magdeburg, Otto-von-Guericke University Magdeburg, Magdeburg, Germany.
Jazyk:	angličtina
Zdroj:	Genetics in medicine : official journal of the American College of Medical Genetics [Genet Med] 2022 Jul; Vol. 24 (7), pp. 1556-1566. Date of Electronic Publication: 2022 May 07.
DOI:	10.1016/j.gim.2022.04.004
Abstrakt:	Purpose: Dysregulation of RAS or its major effector pathway is the molecular mechanism of RASopathies, a group of multisystemic congenital disorders. Neurologic complications are especially challenging in the management of the rare RASopathy cardiofaciocutaneous (CFC) syndrome. This study evaluated clinical neurologic and neurodevelopmental features and their associations with CFC syndrome gene variants. Methods: A multinational cohort of 138 individuals with CFC syndrome (BRAF = 90, MAP2K1 = 36, MAP2K2 = 10, KRAS = 2) was recruited. Neurologic presentation was captured via clinician review of medical records and caregiver-completed electronic surveys. Validated measures of seizure severity, adaptive function, and gross motor function were obtained. Results: The overall frequency of intellectual disability and seizures was 82% and 55%, respectively. The frequency and severity of seizures was higher among individuals with BRAF or MAP2K1 variants than in those with MAP2K2 variants. A disproportionate incidence of severe, treatment-resistant seizures was observed in patients with variants in the catalytic protein kinase domain of BRAF and at the common p.Y130 site of MAP2K1. Neurodevelopmental outcomes were associated with genotype as well as seizure severity. Conclusion: Molecular genetic testing can aid in prediction of epilepsy and neurodevelopmental phenotypes in CFC syndrome. Study results identified potential CFC syndrome-associated variants in the development of relevant animal models for neurologic, neurocognitive, and motor function impairment. Competing Interests: Conflict of Interest The authors declare no conflicts of interest. (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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