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Clinical and molecular spectra of BRAF-associated RASopathy

Journal of Human Genetics volume 66, pages 389–399 (2021)Cite this article

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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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Authors and Affiliations

  1. Department of Pediatrics, Asan Medical Center Children’s Hospital, University of Ulsan College of Medicine, Seoul, South Korea

    Yena Lee, Yunha Choi, Jin-Ho Choi, Han-Wook Yoo & Beom Hee Lee

  2. 3billion Inc., Seoul, South Korea

    Go Hun Seo & Changwon Keum

  3. Medical Genetics Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea

    Gu-Hwan Kim, In Hee Choi, Han-Wook Yoo & Beom Hee Lee

  4. Department of Pediatrics, Seoul National University College of Medicine, Seoul, South Korea

    Jung Min Ko

  5. Department of Pediatrics, Pusan National University School of Medicine, Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan, South Korea

    Chong Kun Cheon

  6. Department of Pediatrics, CHA Gangnam Medical Center, CHA University School of Medicine, Seoul, South Korea

    Jihyun Jeon

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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 66, 389–399 (2021). https://doi.org/10.1038/s10038-020-00852-3

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