When to test fetuses for RASopathies? Proposition from a systematic analysis of 352 multicenter cases and a postnatal cohort

Alexandra Scott, Niccolò Di Giosaffatte, Valentina Pinna, Paola Daniele, Sara Corno, Valentina D’Ambrosio, Elena Andreucci, Annabella Marozza, Fabio Sirchia, Giada Tortora, Daniela Mangiameli, Chiara Di Marco, Maria Romagnoli, Ilaria Donati, Andrea Zonta, Enrico Grosso, Valeria Giorgia Naretto, Gioia Mastromoro, Paolo Versacci, Francesca PantaleoniFrancesca Clementina Radio, Tommaso Mazza, Giuseppe Damante, Laura Papi, Teresa Mattina, Antonella Giancotti, Antonio Pizzuti, Anne Marie Laberge, Marco Tartaglia, Marie Ange Delrue, Alessandro De Luca

Research output: Contribution to journalArticlepeer-review


Purpose: Recent studies have identified suggestive prenatal features of RASopathies (e.g., increased nuchal translucency [NT], cystic hygroma [CH], hydrops, effusions, congenital heart diseases [CHD], polyhydramnios, renal anomalies). Our objective is to clarify indications for RASopathy prenatal testing. We compare genotype distributions between pre- and postnatal populations and propose genotype–phenotype correlations. Methods: Three hundred fifty-two chromosomal microarray–negative cases sent for prenatal RASopathy testing between 2012 and 2019 were collected. For most, 11 RASopathy genes were tested. Postnatal cohorts (25 patients with available prenatal information and 108 institutional database genotypes) and the NSeuroNet database were used for genotypic comparisons. Results: The overall diagnostic yield was 14% (50/352), with rates >20% for effusions, hydrops, and CHD. Diagnostic yield was significantly improved in presence of hypertrophic cardiomyopathy (HCM), persistent or associated CH, any suggestive finding combined with renal anomaly or polyhydramnios, or ≥2 ultrasound findings. Largest prenatal contributors of pathogenic variants were PTPN11 (30%), RIT1 (16%), RAF1 (14%), and HRAS (12%), which considerably differ from their prevalence in postnatal populations. HRAS, LZTR1, and RAF1 variants correlated with hydrops/effusions, and RIT1 with prenatal onset HCM. Conclusion: After normal chromosomal microarray, RASopathies should be considered when any ultrasound finding of lymphatic dysplasia or suggestive CHD is found alone or in association.

Original languageEnglish
Pages (from-to)1116-1124
Number of pages9
JournalGenetics in Medicine
Issue number6
Publication statusPublished - Jun 2021

ASJC Scopus subject areas

  • Genetics(clinical)


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