How to Cite this Article: Fahrner JA, Frazier A, Bachir S, Walsh MF, Applegate CD, Thompson R, Halushka MK, Murphy, AM, Gunay-Aygun M. 2012. A rasopathy phenotype with severe congenital hypertrophic obstructive cardiomyopathy associated with a PTPN11 mutation and a novel variant in SOS1. Am J Med Genet Part A. 158A:1414–1421.
A rasopathy phenotype with severe congenital hypertrophic obstructive cardiomyopathy associated with a PTPN11 mutation and a novel variant in SOS1†
Version of Record online: 14 MAY 2012
Copyright © 2012 Wiley Periodicals, Inc.
American Journal of Medical Genetics Part A
Volume 158A, Issue 6, pages 1414–1421, June 2012
How to Cite
Fahrner, J. A., Frazier, A., Bachir, S., Walsh, M. F., Applegate, C. D., Thompson, R., Halushka, M. K., Murphy, A. M. and Gunay-Aygun, M. (2012), A rasopathy phenotype with severe congenital hypertrophic obstructive cardiomyopathy associated with a PTPN11 mutation and a novel variant in SOS1. Am. J. Med. Genet., 158A: 1414–1421. doi: 10.1002/ajmg.a.35363
- Issue online: 17 MAY 2012
- Version of Record online: 14 MAY 2012
- Manuscript Accepted: 3 MAR 2012
- Manuscript Received: 19 AUG 2011
- hypertrophic cardiomyopathy;
- LEOPARD syndrome;
- Noonan syndrome;
- Noonan syndrome-multiple lentigines;
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. © 2012 Wiley Periodicals, Inc.