TY - JOUR
T1 - A rasopathy phenotype with severe congenital hypertrophic obstructive cardiomyopathy associated with a PTPN11 mutation and a novel variant in SOS1
AU - Fahrner, Jill A.
AU - Frazier, Aisha
AU - Bachir, Suha
AU - Walsh, Michael F.
AU - Applegate, Carolyn D.
AU - Thompson, Reid
AU - Halushka, Marc
AU - Murphy, Anne M
AU - Gunay-Aygun, Meral
PY - 2012/6
Y1 - 2012/6
N2 - 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.
AB - 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.
KW - Hypertrophic cardiomyopathy
KW - LEOPARD syndrome
KW - Myectomy
KW - Myotomy
KW - Noonan syndrome
KW - Noonan syndrome-multiple lentigines
KW - PTPN11
KW - RASopathy
KW - SOS1
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U2 - 10.1002/ajmg.a.35363
DO - 10.1002/ajmg.a.35363
M3 - Article
C2 - 22585553
AN - SCOPUS:84861225184
SN - 1552-4825
VL - 158 A
SP - 1414
EP - 1421
JO - American Journal of Medical Genetics, Part A
JF - American Journal of Medical Genetics, Part A
IS - 6
ER -