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Application of Next-Generation Sequencing in Noonan Spectrum Disorders

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Next Generation Sequencing Based Clinical Molecular Diagnosis of Human Genetic Disorders

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Abstract

Noonan spectrum disorders (NSDs) are a group of disorders with aberrant signal transduction in the RAS/mitogen-activated protein kinase (MAPK) pathway, and therefore they are also known as RASopathies. All NSDs known to date are caused by germline dominant mutations in genes encoding proteins participating in the RAS-MAPK pathway. The molecular characterization thus far explains approximately 80% of individuals affected with a NSD. Pathogenic variants in the PTPN11 gene cause about 50% of all NSD cases. The other 17 genes account for an additional 20–30% NDS cases. High genetic heterogeneity in NSDs and their considerable overlap in clinical presentations had made the diagnosis of these disorders expensive and time consuming in a gene by gene approach. In this chapter, we provide a brief overview of clinical features of Noonan syndrome and closely related conditions, the molecular mechanisms underlying pathogenesis, and the advantages and challenges in implementing next generation sequencing (NGS) in clinical laboratories for the molecular diagnosis of NSDs.

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Authors and Affiliations

  1. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, 77030, TX, USA

    Hui Mei PhD, Hongzheng Dai, Jinglan Zhang, Lee-Jun Wong & Pilar L. Magoulas

  2. Division of Genetic Counseling, Texas Children’s Hospital, 6701 Fannin St. suite 1560, Houston, TX, 77030, USA

    Pilar L. Magoulas

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    Lee-Jun C. Wong

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Mei, H., Dai, H., Zhang, J., Wong, LJ., Magoulas, P.L. (2017). Application of Next-Generation Sequencing in Noonan Spectrum Disorders. In: Wong, LJ. (eds) Next Generation Sequencing Based Clinical Molecular Diagnosis of Human Genetic Disorders. Springer, Cham. https://doi.org/10.1007/978-3-319-56418-0_9

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