Natural history of MRAS-related Noonan syndrome: Evidence of mild adult-onset left ventricular hypertrophy and neuropsychiatric features |
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| Authors: | Manuela Priolo Cecilia Mancini Francesca Clementina Radio Luigi Chiriatti Andrea Ciolfi Camilla Cappelletti Viviana Cordeddu Letizia Pintomalli Alfredo Brusco Corrado Mammi Marco Tartaglia |
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| Affiliation: | 1. USD Genetica Medica, Grande Ospedale Metropolitano Bianchi-Melacrino-Morelli, Reggio Calabria, Italy;2. Molecular Genetics and Functional Genomics, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy;3. Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy;4. Department of Medical Sciences, University of Torino, Turin, Italy |
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| Abstract: | Gain of function pathogenic variants in MRAS have been found in a small subset of pediatric subjects presenting with Noonan syndrome (NS) associated with hypertrophic cardiomyopathy (HCM) and moderate to severe intellectual disability. These variants are considered to confer a high-risk for the development of severe HCM with poor prognosis and fatal outcome. We report on the natural history of the first adult subject with NS carrying the recurrent pathogenic p.Thr68Ile amino acid substitution. Different from what had previously been observed, he presented with a mild, late-onset left ventricular hypertrophy, and a constellation of additional symptoms rarely seen in NS. The present case provides evidence that HCM does not represent an obligatory, early-onset and severe complication in subjects with MRAS variants. It also adds new data about late-onset features suggesting that other unexpected complications might be observed in adult subjects providing anticipatory guidance for individuals of all age. |
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| Keywords: | genotype–phenotype correlations natural history Noonan syndrome RASopathies |
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