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A severe clinical phenotype of Noonan syndrome with neonatal hypertrophic cardiomyopathy in the second case worldwide with RAF1 S259Y neomutation

Hager Jaouadi 1 Amel Ben Chehida 2, 3 Lilia Kraoua 4, 3 Heather Etchevers 5 Laurent Argiro 5 Nadia Kasdallah 6 Sonia Blibech 7 Valérie Delague 5 Nicolas Lévy 5 Neji Tebib 2, 3 Ridha Mrad 4, 3 Sonia Abdelhak 1 Rym Benkhalifa 8 Stéphane Zaffran 5, * 
* Corresponding author
1 LR11IPT05 - Laboratoire de Génomique Biomédicale et Oncogénétique - Biomedical Genomics and Oncogenetics Laboratory
2 Hôpital La Rabta [Tunis]
3 UTM - Université de Tunis El Manar
4 Hôpital Charles Nicolle [Tunis]
5 MMG - Marseille medical genetics - Centre de génétique médicale de Marseille
6 Hôpital militaire de Tunis
7 Military Hospital of Tunis
8 Laboratoire des Venins et Toxines, Institut Pasteur de Tunis
Abstract : Noonan syndrome and related disorders are a group of clinically and genetically heterogeneous conditions caused by mutations in genes of the RAS/MAPK pathway. Noonan syndrome causes multiple congenital anomalies, which are frequently accompanied by hypertrophic cardiomyopathy (HCM). We report here a Tunisian patient with a severe phenotype of Noonan syndrome including neonatal HCM, facial dysmorphism, severe failure to thrive, cutaneous abnormalities, pectus excavatum and severe stunted growth, who died in her eighth month of life. Using whole exome sequencing, we identified a de novo mutation in exon 7 of the RAF1 gene: c.776C > A (p.Ser259Tyr). This mutation affects a highly conserved serine residue, a main mediator of Raf-1 inhibition via phosphorylation. To our knowledge the c.776C > A mutation has been previously reported in only one case with prenatally diagnosed Noonan syndrome. Our study further supports the striking correlation of RAF1 mutations with HCM and highlights the clinical severity of Noonan syndrome associated with a RAF1 p.Ser259Tyr mutation.
Keywords : RAF1 mutation whole exome sequencing hypertrophic cardiomyopathy Noonan syndrome RAS/MAPK pathway
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Hager Jaouadi, Amel Ben Chehida, Lilia Kraoua, Heather Etchevers, Laurent Argiro, et al.. A severe clinical phenotype of Noonan syndrome with neonatal hypertrophic cardiomyopathy in the second case worldwide with RAF1 S259Y neomutation. Genetics Research, Cambridge University Press (CUP), 2019, 101, pp.e6. ⟨10.1017/S0016672319000041⟩. ⟨hal-02461305⟩

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