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A phenotypic overlap may exist in children with other RASopathies or with other genetic conditions if only multiple caf\u00e9\u2010au\u2010lait 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\u2010IMPPC 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\n                    <jats:italic>NF1<\/jats:italic>\n                    accounting for 10% of cases. Furthermore, we identified pathogenic mutations mainly in the\n                    <jats:italic>NF1<\/jats:italic>\n                    gene, but also in\n                    <jats:italic>SPRED1<\/jats:italic>\n                    , in more than 50% of children with multiple CALMs, exhibiting an\n                    <jats:italic>NF1<\/jats:italic>\n                    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\u2010defined groups outperforms previous strategies.\n                  <\/jats:p>","DOI":"10.1111\/cge.13649","type":"journal-article","created":{"date-parts":[[2019,10,1]],"date-time":"2019-10-01T08:29:19Z","timestamp":1569918559000},"page":"264-275","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Mutational spectrum by phenotype: panel\u2010based NGS testing of patients with clinical suspicion of RASopathy and children with multiple caf\u00e9\u2010au\u2010lait macules"],"prefix":"10.1111","volume":"97","author":[{"given":"Elisabeth","family":"Castellanos","sequence":"first","affiliation":[{"name":"Hereditary Cancer Group, Program of Predictive and Personalized Medicine of Cancer (PMPPC) Germans Trias &amp; Pujol Research Institute (IGTP)  Barcelona 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Biologia Universitat de Barcelona (UB), IBUB, IRSJD, CIBERER  Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"Legius","sequence":"additional","affiliation":[{"name":"Laboratory for Neurofibromatosis Research, Department of Human Genetics KU Leuven University Hospital  Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2895-9857","authenticated-orcid":false,"given":"Eduard","family":"Serra","sequence":"additional","affiliation":[{"name":"Hereditary Cancer Group, Program of Predictive and Personalized Medicine of Cancer (PMPPC) Germans Trias &amp; Pujol Research Institute (IGTP)  Barcelona Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en RED (CIBERONC) Instituto de Salud Carlos III  Madrid 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