Defining the variant-phenotype correlation in patients affected by Noonan syndrome with the RAF1:c.770C>T p.(Ser257Leu) variant.
Journal
European journal of human genetics : EJHG
ISSN: 1476-5438
Titre abrégé: Eur J Hum Genet
Pays: England
ID NLM: 9302235
Informations de publication
Date de publication:
01 Jun 2024
01 Jun 2024
Historique:
received:
16
02
2024
accepted:
20
05
2024
revised:
14
05
2024
medline:
2
6
2024
pubmed:
2
6
2024
entrez:
1
6
2024
Statut:
aheadofprint
Résumé
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 T variant was conducted merging 17 unpublished patients and literature-derived ones.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.
Identifiants
pubmed: 38824260
doi: 10.1038/s41431-024-01643-6
pii: 10.1038/s41431-024-01643-6
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
© 2024. The Author(s), under exclusive licence to European Society of Human Genetics.
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