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.
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.
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.
After normal chromosomal microarray, RASopathies should be considered when any ultrasound finding of lymphatic dysplasia or suggestive CHD is found alone or in association.
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This study was supported, in part, by funding from European Joint Programme on Rare Diseases: EJP-RD (NSEuronet, to M.T.), Associazione Italiana per la Ricerca sul Cancro: AIRC (IG 21614, to M.T.), and the Italian Ministry of Health (Ricerca Corrente 2019 and 2020, to M.T. and A.D.L.).
The study was performed in accordance with the principles set out in the Declaration of Helsinki. The CHU Sainte-Justine Research Ethics and the Fondazione IRCCS Ethics Committees approved the study based on chart review. Because patients and clinical data were de-identified and the study was considered to have minimal risks, the need for consent was waived by the Research Ethics committee.
A.-M.L. received an honorarium for a conference given by Sobi (Swedish Orphan Biovitrum AB [publ] reg. number 556038–9321). The other authors declare no competing interests.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Scott, A., Di Giosaffatte, N., Pinna, V. et al. When to test fetuses for RASopathies? Proposition from a systematic analysis of 352 multicenter cases and a postnatal cohort. Genet Med (2021). https://doi.org/10.1038/s41436-020-01093-7