Mutational spectrum by phenotype: panel-based NGS testing of patients with clinical suspicion of RASopathy and children with multiple café-au-lait macules.

Castellanos E1, Rosas I1, Negro A1, Gel B1, Alibés A2, Baena N3, Pineda M4, Pi G5, Pintos G6, Salvador H7, Lazaro C8,9, Blanco I10, Vilageliu L11, Brems H12, Grinberg D11, Legius E12, Serra E1,9.

Author information

1: Hereditary Cancer Group, Program of Predictive and Personalized Medicine of Cancer (PMPPC), Germans Trias & Pujol Research Institute (IGTP), Badalona, Barcelona, Spain.
2: Program of Predictive and Personalized Medicine of Cancer (PMPPC), Germans Trias & Pujol Research Institute (IGTP), Badalona, Barcelona, Spain.
3: Genetics Laboratory of the UDIAT-CD, Parc Tauli Health Corporation, Sabadell, Barcelona, Spain.
4: Neuropaediatrics Unit, Hospital Sant Joan de Déu, Esplugues, Barcelona, Spain.
5: Neuropaediatrics Unit, La Ribera Hospital, Valencia, Spain.
6: Department of Pediatrics, Germans Trias i Pujol University Hospital and Research Institute (IGTP), Badalona, Universitat de Barcelona, Spain.
7: Paediatrics Oncology Unit, Hospital Sant Joan de Déu, Esplugues, Barcelona, Spain.
8: Hereditary Cancer Program, Catalan Institute of Oncology (ICO-IDIBELL-ONCOBELL), CIBERONC, L'Hospitalet de Llobregat, Barcelona, Spain.
9: Centro de Investigación Biomédica en RED (CIBERONC), Instituto de Salud Carlos III, Madrid, Spain.
10: Clinical Genetics and Genetic Counseling Program, Germans Trias i Pujol Hospital, Can Ruti Campus, Badalona, Barcelona, Spain.
11: Department of Genetics, Microbiology and Statistics, Facultat de Biologia, Universitat de Barcelona (UB), IBUB, IRSJD, CIBERER, Barcelona, Spain.
12: Laboratory for Neurofibromatosis Research, Department of Human Genetics, KU Leuven University Hospital, Belgium.

Abstract

Children with Neurofibromatosis Type 1 (NF1) may exhibit an incomplete clinical presentation, making difficult to reach a clinical diagnosis. A phenotypic overlap may exist with children with other RASopathies or with other genetic conditions if only multiple café-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) 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 a 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. This article is protected by copyright. All rights reserved.