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

Elizabeth I. Pierpont, Daniel L. Kenney-Jung, Ryan Shanley, Abigail L. Zatkalik, Ashley E. Whitmarsh, Samuel J. Kroening, Amy E. Roberts, Martin Zenker

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1556-1566
Number of pages11
JournalGenetics in Medicine
Volume24
Issue number7
DOIs
StatePublished - Jul 2022

Bibliographical note

Funding Information:
The completion of this research was made possible by funding from CFC International and a microgrant from the Rare Disease Foundation. Support for E.I.P. was provided by the National Institutes of Health National Center for Advancing Translational Sciences, grants KL2TR002492 and UL1TR002494, and by the University of Minnesota Department of Pediatrics. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. M.Z. received funding from the German Federal Ministry of Education and Research (BMBF), project titles German Network of RASopathy Research (GeNeRARe; FKZ 01GM1902A) and European Network on Noonan Syndrome and Related Disorders (FKZ 01GM1921A). The funding bodies had no role in the design of the study, collection and analysis of data, or decision to publish. The authors would like to express gratitude for the commitment of the families that participated in this research and to CFC International and CFC-Syndrom e.V. for facilitating recruitment. We are grateful to our research assistants Dante Rogers and Sabrina Bui.

Funding Information:
The completion of this research was made possible by funding from CFC International and a microgrant from the Rare Disease Foundation . Support for E.I.P. was provided by the National Institutes of Health National Center for Advancing Translational Sciences, grants KL2TR002492 and UL1TR002494, and by the University of Minnesota Department of Pediatrics. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. M.Z. received funding from the German Federal Ministry of Education and Research ( BMBF ), project titles German Network of RASopathy Research (GeNeRARe; FKZ 01GM1902A) and European Network on Noonan Syndrome and Related Disorders (FKZ 01GM1921A). The funding bodies had no role in the design of the study, collection and analysis of data, or decision to publish. The authors would like to express gratitude for the commitment of the families that participated in this research and to CFC International and CFC-Syndrom e.V. for facilitating recruitment. We are grateful to our research assistants Dante Rogers and Sabrina Bui.

Publisher Copyright:
© 2022 The Authors

Keywords

  • Cardiofaciocutaneous syndrome
  • Epilepsy
  • Neurodevelopment
  • RASopathies
  • Seizures

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