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Defining the variant-phenotype correlation in patients affected by Noonan syndrome with the RAF1:c.770C>T p.(Ser257Leu) variant

Abstract

Hypertrophic cardiomyopathy (HCM) is the major contributor to morbidity and mortality in Noonan syndrome (NS). Gain-of-function variants in RAF1 are associated with high prevalence of HCM. Among these, NM_002880.4:c.770C > T, NP_002871.1:p.(Ser257Leu) accounts for approximately half of cases and has been reported as associated with a particularly severe outcome. Nevertheless, comprehensive studies on cases harboring this variant are missing. To precisely define the phenotype associated to the RAF1:c.770C > T, variant, an observational retrospective analysis on patients carrying the c.770C > T variant was conducted merging 17 unpublished patients and literature-derived ones. Data regarding prenatal findings, clinical features and cardiac phenotypes were collected to provide an exhaustive description of the associated phenotype. Clinical information was collected in 107 patients. Among them, 92% had HCM, mostly diagnosed within the first year of life. Thirty percent of patients were preterm and 47% of the newborns was admitted in a neonatal intensive care unit, mainly due to respiratory complications of HCM and/or pulmonary arterial hypertension. Mortality rate was 13%, mainly secondary to HCM-related complications (62%) at the average age of 7.5 months. Short stature had a prevalence of 91%, while seizures and ID of 6% and 12%, respectively. Two cases out of 75 (3%) developed neoplasms. In conclusion, patients with the RAF1:c.770C > T pathogenic variant show a particularly severe phenotype characterized by rapidly progressive neonatal HCM and high mortality rate suggesting the necessity of careful monitoring and early intervention to prevent or slow down the progression of HCM.

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Fig. 1: Schematic representation of RAF1 protein and RAF1 gene.
Fig. 2: Flowchart representing the process of article selection from the medical literature.
Fig. 3: Survival rate in the merged cohort.

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Data availability

Full data are available from the corresponding authors, AM and GBF, upon reasonable request. The variant under investigation has been submitted to the ClinVar repository with the accession number VCV000013957.89.

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Funding

This research was partially funded with the contribution of the Italian Association of patients affected by Noonan Syndrome and other RASopathies (Associazione Italiana Sindrome di Noonan e RASopatie ODV, www.sindromedinoonan.org), and Italian Ministry of Health (5 per 1000 2024 and RC 2022–2024).

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Authors and Affiliations

Authors

Contributions

Conceptualization: AM, AG, EA, and GBF; methodology; AM, AG, FF, and EA; validation: CL, MN, MCD, and SC; formal analysis: EA and AG; investigation: EA, AG; resources: AM and GBF; data curation: EA, AG, AM, CL, MN, MLD, EM, GL, SC, and MCD; writing—original draft preparation: AG and EA; writing—review and editing: AG, AM, DC, FF, MN, CL, EM, GL, GZ, MCD, ADL, SC, EB, AMV, GC, SM, CR, PD, MLD, MT, and GBF; supervision: AM and GBF; project administration: AM and GBF; funding acquisition: AM and GBF. All authors have read and agreed to the published version of the manuscript.

Corresponding authors

Correspondence to Giovanni Battista Ferrero or Alessandro Mussa.

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The authors declare no competing interests.

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The study was conducted in accordance with the Declaration of Helsinki and approved by the Institutional Review Board of A.O.U. Città della Salute e della Scienza di Torino (approval number 256/2022 prot 68301 approved on 17/06/2022) for studies involving humans. Informed consent was obtained from all subjects involved in the study.

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Gazzin, A., Fornari, F., Niceta, M. et al. Defining the variant-phenotype correlation in patients affected by Noonan syndrome with the RAF1:c.770C>T p.(Ser257Leu) variant. Eur J Hum Genet (2024). https://doi.org/10.1038/s41431-024-01643-6

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