title: A rasopathy phenotype with severe congenital hypertrophic obstructive cardiomyopathy associated with a PTPN11 mutation and a novel variant in SOS1.
abstract: The RAS-MAPK pathway is critical for human growth and development. Abnormalities at different steps of this signaling cascade result in neuro-cardio-facial-cutaneous syndromes, or the RASopathies, a group of disorders with overlapping yet distinct phenotypes. RASopathy patients have variable degrees of intellectual disability, poor growth, relative macrocephaly, ectodermal abnormalities, dysmorphic features, and increased risk for certain malignancies. Congenital heart disease, particularly hypertrophic cardiomyopathy (HCM) and pulmonic stenosis, are prominent features in these disorders. Significant locus heterogeneity exists for many of the RASopathies. Traditionally, these diseases were thought to be inherited in an autosomal dominant manner. However, recently patients with defects in two components of this pathway and overlapping features of various forms of Noonan syndrome and neurofibromatosis 1 and have been reported. Here we present a patient with severe, progressive neonatal HCM, elevated urinary catecholamine metabolites, and dysmorphic features in whom we identified a known LEOPARD syndrome-associated PTPN11 mutation (c.1403 C > T; p.T468M) and a novel, potentially pathogenic missense SOS1 variant (c.1018 C > T; p.P340S) replacing a rigid nonpolar imino acid with a polar amino acid at a highly conserved position. We describe detailed clinical manifestations, cardiac histopathology, and the molecular genetic findings. Oligogenic models of inheritance with potential synergistic effects should be considered in the RASopathies.
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA. jfahrne1@jhmi.edu
authors.forename: Jill A
authors.initials: JA
authors.lastname: Fahrner
authors.forename: Aisha
authors.initials: A
authors.lastname: Frazier
authors.forename: Suha
authors.initials: S
authors.lastname: Bachir
authors.forename: Michael F
authors.initials: MF
authors.lastname: Walsh
authors.forename: Carolyn D
authors.initials: CD
authors.lastname: Applegate
authors.forename: Reid
authors.initials: R
authors.lastname: Thompson
authors.forename: Marc K
authors.initials: MK
authors.lastname: Halushka
authors.forename: Anne M
authors.initials: AM
authors.lastname: Murphy
authors.forename: Meral
authors.initials: M
authors.lastname: Gunay-Aygun
mesh_terms: D000595:Amino Acid Sequence; D002312:Cardiomyopathy, Hypertrophic / Q000151:congenital* / Q000175:diagnosis / Q000235:genetics*; D005260:Female; D006801:Humans; D007223:Infant; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008969:Molecular Sequence Data; D009154:Mutation; D010641:Phenotype; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism; D020837:SOS1 Protein / Q000737:chemistry / Q000235:genetics*; D015398:Signal Transduction
chemical_list: D020837:SOS1 Protein; D020928:Mitogen-Activated Protein Kinases; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D016283:Proto-Oncogene Proteins p21(ras)