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

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

doi:10.1038/s41436-020-01093-7

Cited by 22 publications

(23 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…found that the overall diagnostic yield for RASopathy testing after a normal CMA and increased NT was 14% (50/352), however the yield was much lower for isolated increased NT (1/90) compared with increased NT with other typical ultrasound abnormalities (16%, 27/167) (Table 4). 39 These findings are consistent with the large study on prenatal RASopathy testing by Stuurman et al., which recommended that RASopathy testing only be offered for very large isolated NTs (≥5.0 mm), or if at least one other typical ultrasound feature was present 36 …”

Section: Genomic Testingsupporting

confidence: 83%

“…reported the overall rate of a single gene condition in fetuses with NT >99th centile (including those with structural abnormalities) to be 3.3%, of which Noonan's syndrome made up almost half (1.4%) (Table 4). 10 When there are multiple ultrasound features associated with RASopathies, an overall yield of 10%–14% has been reported after a normal CMA 36–40 . Recently Scott et al.…”

Section: Genomic Testingmentioning

confidence: 99%

See 1 more Smart Citation

Increased nuchal translucency after low‐risk noninvasive prenatal testing: What should we tell prospective parents?

et al. 2021

View full text Add to dashboard Cite

Three decades ago, the observation that first trimester fetuses with excess fluid accumulation at the back of the neck were more likely to be aneuploid, gave rise to a new era of prenatal screening. The nuchal translucency (NT) measurement in combination with serum biomarkers and maternal age, resulted in the first trimester combined screening (FTCS) program. The introduction of noninvasive prenatal testing (NIPT) over the past decade has introduced the option for parents to receive highly sensitive and specific screening information for common trisomy from as early as 10 weeks gestation, altering the traditional pathway FTCS pathway. The retention of the 11–13‐week NT ultrasound remains important in the detection of structural anomalies; however, the optimal management of pregnancies with a low‐risk NIPT result and an isolated increased NT measurement in an era of advanced genomic testing options is a new dilemma for clinicians. For parents, the prolonged period between the initial diagnosis in first trimester, and prognostic information at each successive stage of investigations up to 22–24 weeks, can be emotionally challenging. This article addresses the common questions from parents and clinicians as they navigate the uncertainty of having a fetus diagnosed with an increased NT after a low‐risk NIPT result and presents suggested approaches to management.

show abstract

Section: Genomic Testingsupporting

confidence: 83%

Section: Genomic Testingmentioning

confidence: 99%

Increased nuchal translucency after low‐risk noninvasive prenatal testing: What should we tell prospective parents?

et al. 2021

View full text Add to dashboard Cite

show abstract

“…The overlapping features can include short stature, dysmorphic facial features, congenital heart disease, lymphatic dysfunction and intellectual disability. RASopathies are a common cause of non-immune hydrops fetalis ( Sparks et al, 2020 ), as well as other features that can be observed on prenatal ultrasound such as increased nuchal translucency, cystic hygroma, congenital heart disease or pleural effusions ( Scott et al, 2021 ). Each of the RASopathies are single-gene inheritance disorders.…”

Section: Introductionmentioning

confidence: 99%

The RASopathies: from pathogenetics to therapeutics

Hebron

Hernandez

Yohe

2022

Disease Models &Amp; Mechanisms

View full text Add to dashboard Cite

The RASopathies are a group of disorders caused by a germline mutation in one of the genes encoding a component of the RAS/MAPK pathway. These disorders, including neurofibromatosis type 1, Noonan syndrome, cardiofaciocutaneous syndrome, Costello syndrome and Legius syndrome, among others, have overlapping clinical features due to RAS/MAPK dysfunction. Although several of the RASopathies are very rare, collectively, these disorders are relatively common. In this Review, we discuss the pathogenesis of the RASopathy-associated genetic variants and the knowledge gained about RAS/MAPK signaling that resulted from studying RASopathies. We also describe the cell and animal models of the RASopathies and explore emerging RASopathy genes. Preclinical and clinical experiences with targeted agents as therapeutics for RASopathies are also discussed. Finally, we review how the recently developed drugs targeting RAS/MAPK-driven malignancies, such as inhibitors of RAS activation, direct RAS inhibitors and RAS/MAPK pathway inhibitors, might be leveraged for patients with RASopathies.

show abstract

“…In addition, no articles were included on patients with a pathogenic variant in LZTR1. Prenatal lymphatic anomalies were recently also reported in patients with pathogenic KRAS, BRAF, NRAS and LZTR1 variants (Scott et al, 2021).…”

Section: Discussionmentioning

confidence: 92%

Lymphatic anomalies during lifetime in patients with Noonan syndrome: Retrospective cohort study

Swarts¹,

Kleimeier²,

Leenders

et al. 2022

American J of Med Genetics Pt A

View full text Add to dashboard Cite

Noonan syndrome (NS) has been associated with an increased risk of lymphatic anomalies, with an estimated prevalence of 20%. The prevalence of lymphatic anomalies seems to differ between pathogenic variants. Therefore, this study aims to describe the clinical presentation, prevalence and genotype-phenotype correlations of lymphatic anomalies during life in patients with NS. This retrospective cohort study included patients (n = 115) who were clinically and genetically diagnosed with NS and visited the Noonan expertise Center of the Radboud University Medical Center between January 2015 and March 2021. Data on lymphatic anomalies during lifetime were obtained from medical records. Lymphatic anomalies most often presented as an increased nuchal translucency, chylothorax and/or lymphedema. Prenatal lymphatic anomalies increased the risk of lymphatic anomalies during infancy (OR 4.9, 95% CI 1.7-14.6). The lifetime prevalence of lymphatic anomalies was 37%.Genotype-phenotype correlations showed an especially high prevalence of lymphatic anomalies during infancy and childhood in patients with a pathogenic SOS2 variant (p = 0.03 and p < 0.01, respectively). This study shows that patients with NS have a high predisposition for developing lymphatic anomalies during life. Especially patients with prenatal lymphatic anomalies have an increased risk of lymphatic anomalies during infancy. Genotype-phenotype correlations were found in pathogenic variants in SOS2.

show abstract

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

Cited by 22 publications

References 37 publications

Increased nuchal translucency after low‐risk noninvasive prenatal testing: What should we tell prospective parents?

Increased nuchal translucency after low‐risk noninvasive prenatal testing: What should we tell prospective parents?

The RASopathies: from pathogenetics to therapeutics

Lymphatic anomalies during lifetime in patients with Noonan syndrome: Retrospective cohort study

Contact Info

Product

Resources

About