Clinical and molecular spectra of BRAF-associated RASopathy

Abstract

Noonan syndrome (NS) and cardio-facio-cutaneous (CFC) syndrome are the most common subtypes of RASopathy. As an effector of Ras, BRAF is one of the molecules responsible for RASopathy. We investigated the phenotypic and genotypic features of 26 patients with BRAF-associated RASopathy. The clinical diagnoses were CFC (n = 21, 80.8%), NS (n = 3, 11.5%), NS/CFC (n = 1, 3.8%), and undefined syndromic intellectual disability (ID) (n = 1, 3.8%). The mostly shared phenotypes were ID (90.5%), cutaneous manifestations (84.6%), congenital heart defects (76.9%), short stature (76.9%), and dysmorphic features such as short neck (65.4%) and low-set ears (65.4%). Importantly, moderate to severe ID (57.1%) and epilepsy (26.9%) were noted. Eighteen different missense mutations were found, including a novel mutation, p.Phe498Tyr. p.Gln257Arg (n = 9, 34.6%) was the most common mutation, and the mutations were clustered in the cysteine-rich domain or protein kinase domain. A review of previously reported cases along with our findings revealed the existence of multiple sub-phenotypes of RASopathy within a single genotype, indicating that BRAF-associated RASopathy is not variant-specific. Our study further delineated the diverse and expanded clinical phenotypes of BRAF-associated RASopathy with their molecular genetic characteristics.

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Fig. 1
Fig. 2
Fig. 3: BRAF protein domain structure and the location of mutations identified in the study patients.

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Acknowledgements

We are deeply grateful to the patients and their families for providing their clinical information. We would like to give particular thanks to subject 21 and his family for allowing us to publish his photograph.

Funding

This work was supported by the Institute for Information and Communications Technology Promotion (IITP) and by a grant from the government of South Korea (MSIT) (Grant Number 2018-0-00861; Intelligent SW Technology Development for Medical Data Analysis) and the Bio & Medical Technology Development Program of the National Research Foundation (NRF) funded by the Korean government (NRF-2018M3A9H1078335).

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Correspondence to Beom Hee Lee.

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Lee, Y., Choi, Y., Seo, G.H. et al. Clinical and molecular spectra of BRAF-associated RASopathy. J Hum Genet (2020). https://doi.org/10.1038/s10038-020-00852-3

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