Spectrum of mutations in PTPN11 and genotype–phenotype correlation in 96 patients with Noonan syndrome and five patients with cardio-facio-cutaneous syndrome

Musante, Luciana; Kehl, Hans Gerd; Majewski, F.; Meinecke, Peter; Schweiger, Susann; Gillessen‐Kaesbach, Gabriele; Wieczorek, Dagmar; Hinkel, G. K.; Tinschert, S.; Hoeltzenbein, Maria; Ropers, Hans‐Hilger; Kalscheuer, Vera M.

doi:10.1038/sj.ejhg.5200935

Cited by 140 publications

(141 citation statements)

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“…The mutations and clinical features of four of these fetuses have also been described elsewhere; case 1 has been described by Bakker et al 24 and cases 9, 12 and 13 have been described by Houweling et al 27 Nine fetuses had a de novo mutation in PTPN11, three in RAF1 and one in KRAS. Eight of the 12 different mutations detected in this study have been described earlier in postnatally identified NS patients: PTPN11; c.174C4G (p.(Asn58Lys)), 28 c.182A4G (p.(Asp61Gly)), 4 c.184T4G (p.(Tyr62Asp)), 5 c.205G4C (p.(Glu69Gln)), 28 c,417G4C (p.(Glu139Asp)), 5 and c.854T4C (p.(Phe285Ser)), 5 RAF1 c.770C4T (p.(Ser257Leu)), 10 and KRAS c.173C4T (p.(Thr58Ile)). 6 One mutation has been previously described in a patient with the clinical diagnosis of LEOPARD syndrome: PTPN11 (c.1381G4A, p.(Ala461Thr)).…”

Section: Diagnostic Study Groupmentioning

confidence: 54%

Prenatal diagnostic testing of the Noonan syndrome genes in fetuses with abnormal ultrasound findings

et al. 2013

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In recent studies on prenatal testing for Noonan syndrome (NS) in fetuses with an increased nuchal translucency (NT) and a normal karyotype, mutations have been reported in 9-16% of cases. In this study, DNA of 75 fetuses with a normal karyotype and abnormal ultrasound findings was tested in a diagnostic setting for mutations in (a subset of) the four most commonly mutated NS genes. A de novo mutation in either PTPN11, KRAS or RAF1 was detected in 13 fetuses (17.3%). Ultrasound findings were increased NT, distended jugular lymphatic sacs (JLS), hydrothorax, renal anomalies, polyhydramnios, cystic hygroma, cardiac anomalies, hydrops fetalis and ascites. A second group, consisting of anonymized DNA of 60 other fetuses with sonographic abnormalities, was tested for mutations in 10 NS genes. In this group, five possible pathogenic mutations have been identified (in PTPN11 (n ¼ 2), RAF1, BRAF and MAP2K1 (each n ¼ 1)). We recommend prenatal testing of PTPN11, KRAS and RAF1 in pregnancies with an increased NT and at least one of the following additional features: polyhydramnios, hydrops fetalis, renal anomalies, distended JLS, hydrothorax, cardiac anomalies, cystic hygroma and ascites. If possible, mutation analysis of BRAF and MAP2K1 should be considered.

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Section: Diagnostic Study Groupmentioning

confidence: 54%

Prenatal diagnostic testing of the Noonan syndrome genes in fetuses with abnormal ultrasound findings

et al. 2013

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“…A role for SHP-2 in vertebrate heart development was demonstrated through the observation that missense mutations are often associated with Noonan syndrome, one of the most common human congenital heart diseases that leads to a number of cardiac developmental abnormalities, including atrial septal defects, ventricular septal defects, pulmonary stenosis and hypertrophic cardiomyopathy (Kosaki et al, 2002;Maheshwari et al, 2002;Noonan, 1968;Noonan, 1994;Tartaglia et al, 2002;Tartaglia et al, 2001). Interestingly, patients with acute myelogenous leukemia (AML), acute lymphoblastic leukemia (ALL), juvenile myelomonocytic leukemia (JMML) and LEOPARD syndrome frequently carry a second, somatically introduced subset of missense mutations in SHP-2 (Bentires- Alj et al, 2004;Digilio et al, 2002;Kratz et al, 2005;Legius et al, 2002;Loh et al, 2004;Musante et al, 2003;Tartaglia et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

SHP-2 acts via ROCK to regulate the cardiac actin cytoskeleton

et al. 2012

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SUMMARYNoonan syndrome is one of the most common causes of human congenital heart disease and is frequently associated with missense mutations in the protein phosphatase SHP-2. Interestingly, patients with acute myelogenous leukemia (AML), acute lymphoblastic leukemia (ALL), juvenile myelomonocytic leukemia (JMML) and LEOPARD syndrome frequently carry a second, somatically introduced subset of missense mutations in SHP-2. To determine the cellular and molecular mechanisms by which SHP-2 regulates heart development and, thus, understand how Noonan-associated mutations affect cardiogenesis, we introduced SHP-2 encoding the most prevalent Noonan syndrome and JMML mutations into Xenopus embryos. Resulting embryos show a direct relationship between a Noonan SHP-2 mutation and its ability to cause cardiac defects in Xenopus; embryos expressing Noonan SHP-2 mutations exhibit morphologically abnormal hearts, whereas those expressing an SHP-2 JMML-associated mutation do not. Our studies indicate that the cardiac defects associated with the introduction of the Noonan-associated SHP-2 mutations are coupled with a delay or arrest of the cardiac cell cycle in M-phase and a failure of cardiomyocyte progenitors to incorporate into the developing heart. We show that these defects are a result of an underlying malformation in the formation and polarity of cardiac actin fibers and F-actin deposition. We show that these defects can be rescued in culture and in embryos through the inhibition of the Rho-associated, coiled-coil-containing protein kinase 1 (ROCK), thus demonstrating a direct relationship between SHP-2 N308D and ROCK activation in the developing heart.

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“…Different genes of the RAS/MAPK signaling pathway are responsible for NS (Table 1) (3)(4)(5)(6)(7)(8)(9)(10)(11). Mutation in the PTPN11, SOS1, RAF1 and KRAS genes, usually leading to a gain-of-function, is found in approximately 70% of NS (12) cases.…”

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confidence: 99%

Co-occurring PTPN11 and SOS1 gene mutations in Noonan syndrome: does this predict a more severe phenotype?

Brasil

Malaquias²,

Wanderley

et al. 2010

Arq Bras Endocrinol Metab

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Noonan syndrome (NS) is an autosomal dominant disorder, with variable phenotypic expression, characterized by short stature, facial dysmorphisms and heart disease. Different genes of the RAS/MAPK signaling pathway are responsible for the syndrome, the most common are: PTPN11, SOS1, RAF1, and KRAS. The objective of this study was to report a patient with Noonan syndrome presenting mutations in two genes of RAS/MAPK pathway in order to establish whether these mutations lead to a more severe expression of the phenotype. We used direct sequencing of the PTPN11, SOS1, RAF1, and KRAS genes. We have identified two described mutations in heterozygosity: p.N308D and p.R552G in the genes PTPN11 and SOS1, respectively. The patient has typical clinical features similar to the ones with NS and mutation in only one gene, even those with the same mutation identified in this patient. A more severe or atypical phenotype was not observed, suggesting that these mutations do not exhibit an additive effect.

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Spectrum of mutations in PTPN11 and genotype–phenotype correlation in 96 patients with Noonan syndrome and five patients with cardio-facio-cutaneous syndrome

Cited by 140 publications

References 22 publications

Prenatal diagnostic testing of the Noonan syndrome genes in fetuses with abnormal ultrasound findings

Prenatal diagnostic testing of the Noonan syndrome genes in fetuses with abnormal ultrasound findings

SHP-2 acts via ROCK to regulate the cardiac actin cytoskeleton

Co-occurring PTPN11 and SOS1 gene mutations in Noonan syndrome: does this predict a more severe phenotype?

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