SOS1 is the second most common Noonan gene but plays no major role in cardio-facio-cutaneous syndrome

Zenker, Martin; Horn, Denise; Wieczorek, Dagmar; Allanson, Judith; Pauli, Silke; Burgt, Ineke van der; Doerr, Helmuth‐Guenther-G.; Gaspar, Harald; Hofbeck, Michael; Gillessen‐Kaesbach, Gabriele; Koch, Andreas; Meinecke, Peter; Mundlos, Stefan; Nowka, Anja; Rauch, Anita; Reif, Silke; Schnakenburg, Christian von; Seidel, Heide; Wehner, Lars‐Erik-E.; Zweier, Christiane; Bauhuber, Susanne; Matejas, Verena; Kratz, Christian P.; Thomas, Christoph; Kutsche, Kerstin

doi:10.1136/jmg.2007.051276

Cited by 125 publications

(160 citation statements)

References 26 publications

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“…The mutation detection rate was lower than those reported in previous reports: 12/57 (21%) of cases with NS without PTPN11, KRAS and BRAF mutations (Roberts et al 2007), 22/129 (17%) patients with NS without PTPN11 and KRAS mutations (Tartaglia et al 2007), and 28% of patients with NS without mutations in PTPN11, KRAS, BRAF and MAP2K1/2 (Zenker et al 2007a). The lower detection rate in our study might be due to the smaller size of our cohorts.…”

Section: Discussioncontrasting

confidence: 68%

“…A c.2999G [ A (S1000 N) mutation was identified in a patient with CFC syndrome. The substitution was identified in an unaffected mother and may represent SNP or a weak allele (Roberts et al 2007;Tartaglia et al 2007;Zenker et al 2007a). A P655L, which has been reported as a SNP or a weak allele (Roberts et al 2007;Tartaglia et al 2007;Zenker et al 2007a), was found in 3 out of 14 CFC patients from France.…”

Section: Mutation Analysis In Patientsmentioning

confidence: 97%

“…2). R552S was located in the pleckstrin homology (PH) domain and has been identified in four patients with NS (Fig 3) (Tartaglia et al 2007;Zenker et al 2007a). E846 K in the RAS guanine nucleotide exchange factor (GEF) catalytic domain has been identified in eight NS patients (Fig.…”

Section: Mutation Analysis In Patientsmentioning

confidence: 99%

“…E846 K in the RAS guanine nucleotide exchange factor (GEF) catalytic domain has been identified in eight NS patients (Fig. 3) (Roberts et al 2007;Tartaglia et al 2007;Zenker et al 2007a). The in-frame 9-bp insertion in c.1442_1443 of exon 10 resulted in three amino-acid insertion (P481_G482insRLP).…”

Section: Mutation Analysis In Patientsmentioning

confidence: 99%

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Clinical manifestations in patients with SOS1 mutations range from Noonan syndrome to CFC syndrome

et al. 2008

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Noonan syndrome (NS) and cardio-facio-cutaneous (CFC) syndrome are autosomal dominant disorders characterized by heart defects, facial dysmorphism, ectodermal abnormalities, and mental retardation. There is a significant clinical overlap between NS and CFC syndrome, but ectodermal abnormalities and mental retardation are more frequent in CFC syndrome. Mutations in PTPN11 and KRAS have been identified in patients with NS and those in KRAS, BRAF and MAP2K1/2 have been identified in patients with CFC syndrome, establishing a new role of the RAS/MAPK pathway in human development. Recently, mutations in the son of sevenless gene (SOS1) have also -008-0320-0 been identified in patients with NS. To clarify the clinical spectrum of patients with SOS1 mutations, we analyzed 24 patients with NS, including 3 patients in a three-generation family, and 30 patients with CFC syndrome without PTPN11, KRAS, HRAS, BRAF, and MAP2K1/2 (MEK1/2) mutations. We identified two SOS1 mutations in four NS patients, including three patients in the above-mentioned three-generation family. In the patients with a CFC phenotype, three mutations, including a novel three amino-acid insertion, were identified in one CFC patient and two patients with both NS and CFC phenotypes. These three patients exhibited ectodermal abnormalities, such as curly hair, sparse eyebrows, and dry skin, and two of them showed mental retardation. Our results suggest that patients with SOS1 mutations range from NS to CFC syndrome.123 J Hum Genet (2008) 53:834-841 DOI 10.1007/s10038

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Section: Discussioncontrasting

confidence: 68%

Section: Mutation Analysis In Patientsmentioning

confidence: 97%

Section: Mutation Analysis In Patientsmentioning

confidence: 99%

Section: Mutation Analysis In Patientsmentioning

confidence: 99%

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Clinical manifestations in patients with SOS1 mutations range from Noonan syndrome to CFC syndrome

et al. 2008

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“…The analysis of SOS1 illustrates the individualized approach for each syndrome and mutation. Since Roberts et al [2007] listed each patient allowing complete analysis, and Zenker et al [2007b] provided a summary table useful for many data points, both references were used in a complementary fashion; a smaller series [Narumi et al, 2008] was omitted as per general methods. A condensed comparison is shown in Table VI based on study patient data only.…”

Section: Comparison With Rasopathiesmentioning

confidence: 99%

Clinical, pathological, and molecular analyses of cardiovascular abnormalities in Costello syndrome: A Ras/MAPK pathway syndrome

Lin

Alexander

Colan

et al. 2011

American J of Med Genetics Pt A

117

106

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Cardiovascular abnormalities are important features of Costello syndrome and other Ras/MAPK pathway syndromes (“RASopathies”). We conducted clinical, pathological and molecular analyses of 146 patients with an HRAS mutation including 61 enrolled in an ongoing longitudinal study and 85 from the literature. In our study, the most common (84%) HRAS mutation was p.G12S. A congenital heart defect (CHD) was present in 27 of 61 patients (44%), usually non‐progressive valvar pulmonary stenosis. Hypertrophic cardiomyopathy (HCM), typically subaortic septal hypertrophy, was noted in 37 (61%), and 5 also had a CHD (14% of those with HCM). HCM was chronic or progressive in 14 (37%), stabilized in 10 (27%), and resolved in 5 (15%) patients with HCM; follow‐up data was not available in 8 (22%). Atrial tachycardia occurred in 29 (48%). Valvar pulmonary stenosis rarely progressed and atrial septal defect was uncommon. Among those with HCM, the likelihood of progressing or remaining stable was similar (37%, 41% respectively). The observation of myocardial fiber disarray in 7 of 10 (70%) genotyped specimens with Costello syndrome is consistent with sarcomeric dysfunction. Multifocal atrial tachycardia may be distinctive for Costello syndrome. Potentially serious atrial tachycardia may present in the fetus, and may continue or worsen in about one‐fourth of those with arrhythmia, but is generally self‐limited in the remaining three‐fourths of patients. Physicians should be aware of the potential for rapid development of severe HCM in infants with Costello syndrome, and the need for cardiovascular surveillance into adulthood as the natural history continues to be delineated. © 2011 Wiley‐Liss, Inc.

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Noonan Syndrome

Tartaglia¹,

Gelb²

2011

Encyclopedia of Life Sciences

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Noonan syndrome is a genetic disorder inherited as an autosomal trait or occurring sporadically, characterised by short stature, dysmorphic facies, webbed neck, congenital heart disease or hypertrophic cardiomyopathy, skeletal anomalies, cryptorchidism and developmental delay. Missense mutations in the PTPN11 gene, encoding the protein tyrosine phosphatase SHP2, cause approximately 50% of cases. SHP2 is a positive regulator of RAS/mitogen‐activated protein kinase (MAPK) signal transduction. Noonan syndrome‐associated PTPN11 mutations typically have gain‐of‐function effects on SHP2 and RAS/MAPK signalling. Missense mutations in other genes encoding proteins in the RAS/MAPK pathway, including SOS1 , KRAS , NRAS , RAF1 , BRAF and possibly MEK1 , also cause Noonan syndrome. In aggregate, mutations in these seven genes account for approximately 70–75% of Noonan syndrome. Genotype–phenotype associations have been established with respect to particular genes and even mutations underlying this disorder. Key Concepts: Noonan syndrome is an autosomal dominant, pleomorphic trait characterised by short stature, typical facial dysmorphia and cardiovascular defects. Noonan syndrome is a genetically heterogeneous trait, caused by missense mutations in genes encoding proteins in the RAS/mitogen‐activated protein kinase pathway. Most mutations causing Noonan syndrome have gain‐of‐function effects resulting in increased RAS signalling. Strong genotype–phenotype associations exist for genes and even specific alleles for Noonan syndrome. The seven Noonan syndrome genes identified to date account for approximately 70–75% of cases.

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SOS1 is the second most common Noonan gene but plays no major role in cardio-facio-cutaneous syndrome

Cited by 125 publications

References 26 publications

Clinical manifestations in patients with SOS1 mutations range from Noonan syndrome to CFC syndrome

Clinical manifestations in patients with SOS1 mutations range from Noonan syndrome to CFC syndrome

Clinical, pathological, and molecular analyses of cardiovascular abnormalities in Costello syndrome: A Ras/MAPK pathway syndrome

Noonan Syndrome

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