Noonan syndrome due to RIT1 mutations: further clinical and molecular delineation in 32 cases. A. Verloes1,2, A. Caye1, A. Dieux Coeslier3, C. Baumann1, C. Vincent-Delorme4, P. Bouvagnet5, A. David6, D. Lacombe7, P. Blanchet8, B. Isidor6, M. Rio9, D. Héron10, S. Sauvion11, J. L. Alessandri12, V. Drouin-Garraud13, B. Doray12, N. Pouvreau13, A. Cavé1,14 1) 1.Department of Genetics, APHP - Robert Debré University Hospital and Denis-Diderot-Robert DEBRE University Hopital and Paris VII University Medical School, Paris, France; 2) INSERM UMR 1141, Robert DEBRE Hospital, Paris, France; 3) Dept of Genetics, Jeanne de Flandre University Hospital, Lille; 4) Dept of Genetics, Regional Hospital, Arras; 5) Dept of Cardiology, University Hospital, Lyon; 6) Dept of Genetics, University Hospital, Nantes; 7) Dept of Genetics, University Hospital, Bordeaux; 8) Dept of Genetics, University Hospital, Montpellier; 9) Dept of Genetics, APHP - Necker-Enfants Malades Hospital, Paris; 10) Dept of Genetics, APHP - La Pitié-Salpétrière Hospital, Paris; 11) Dept of Pediatrics, Jean Verdier Hospital, Bondy; 12) Dept of Genetics, University hospital, Saint Denis de la Réunion; 13) Dept of genetics, University Hospital, Rouen; 14) INSERM U 1131, APHP - Saint Louis University Hospital, Paris.
Noonan syndrome is a heterogeneous dominant disorder, due to mutations in at least 8 different genes involved in the RAS/MAPK signaling pathway. Recently, RIT1 was shown to be involved in the pathogenesis of some Noonan patients. We report a series of 32 patients from 22 pedigrees with mutations in RIT1. The patients show a typical Noonan Gestalt and facial phenotype. Among the 22 probands, 5 % showed postnatal growth retardation, 71 % had congenital heart defect, 37 % had hypertrophic cardiomyopathy, 52% had speech delay, 62 % have learning difficulties, but only 10% had intellectual disability. None of them has major skin anomalies. Compared to the canonic Noonan syndrome phenotype linked to PTPN11 mutations, RIT1 mutants appear to be less severely growth retarded and intellectually impaired. Incidence of cardiomyopathy was lower than previously observed. Based on our experience, we estimate that RIT1 may be the cause of 3 to 5 % of Noonan syndrome, and should be prioritized in patients with normal growth and cognitive development.
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