Journal
CLINICAL GENETICS
Volume 97, Issue 2, Pages 264-275Publisher
WILEY
DOI: 10.1111/cge.13649
Keywords
genetic testing; multiple CALMs; neurofibromatosis type 1; NGS panel; RASopathies
Categories
Funding
- Departament d'Universitats, Recerca i Societat de la Informacio [2014 SGR 338, 2017 SGR 00496, 2014 SGR 932]
- Instituto de Salud Carlos III [PI11/1609, PI14/00577, RTICC RD12/0036/008]
- CIBERONC [U720]
- Plan Estatal de I +D+I - FEDER Program 2013-2016 - FEDER Program
- Spanish Ministry of Science and Innovation (MINECO) [SAF2016-75948-R]
- CIBERONC
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Children with neurofibromatosis type 1 (NF1) may exhibit an incomplete clinical presentation, making difficult to reach a clinical diagnosis. A phenotypic overlap may exist in children with other RASopathies or with other genetic conditions if only multiple cafe-au-lait macules (CALMs) are present. The syndromes that can converge in these inconclusive phenotypes have different clinical courses. In this context, an early genetic testing has been proposed to be clinically useful to manage these patients. We present the validation and implementation into diagnostics of a custom NGS panel (I2HCP, ICO-IMPPC Hereditary Cancer Panel) for testing patients with a clinical suspicion of a RASopathy (n = 48) and children presenting multiple CALMs (n = 102). We describe the mutational spectrum and the detection rates identified in these two groups of individuals. We identified pathogenic variants in 21 out of 48 patients with clinical suspicion of RASopathy, with mutations in NF1 accounting for 10% of cases. Furthermore, we identified pathogenic mutations mainly in the NF1 gene, but also in SPRED1, in more than 50% of children with multiple CALMs, exhibiting an NF1 mutational spectrum different from a group of clinically diagnosed NF1 patients (n = 80). An NGS panel strategy for the genetic testing of these two phenotype-defined groups outperforms previous strategies.
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