Prenatal features of Noonan syndrome: prevalence and prognostic value

Baldassarre, Giuseppina; Mussa, Alessandro; Dotta, A.; Banaudi, Elena; Forzano, Serena; Marinosci, Annalisa; Rossi, Cesare; Tartaglia, Marco; Silengo, Margherita; Ferrero, Giovanni Battista

doi:10.1002/pd.2804

Cited by 45 publications

(55 citation statements)

References 24 publications

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“…The diagnosis of Noonan syndrome can also be made with this analysis in fetuses with normal karyotype and findings including pulmonary stenosis, polyhydramnios, and pleural effusions. 375 Other single-gene disorders with familial inheritance may also lend themselves to prenatal genetic testing, although this should be reserved in most cases for instances in which a family member has been previously confirmed to be affected.…”

Section: Incidencementioning

confidence: 99%

Diagnosis and Treatment of Fetal Cardiac Disease

Donofrio¹,

Moon-Grady²,

Hornberger³

et al. 2014

Circulation

979

543

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Background— The goal of this statement is to review available literature and to put forth a scientific statement on the current practice of fetal cardiac medicine, including the diagnosis and management of fetal cardiovascular disease. Methods and Results— A writing group appointed by the American Heart Association reviewed the available literature pertaining to topics relevant to fetal cardiac medicine, including the diagnosis of congenital heart disease and arrhythmias, assessment of cardiac function and the cardiovascular system, and available treatment options. The American College of Cardiology/American Heart Association classification of recommendations and level of evidence for practice guidelines were applied to the current practice of fetal cardiac medicine. Recommendations relating to the specifics of fetal diagnosis, including the timing of referral for study, indications for referral, and experience suggested for performance and interpretation of studies, are presented. The components of a fetal echocardiogram are described in detail, including descriptions of the assessment of cardiac anatomy, cardiac function, and rhythm. Complementary modalities for fetal cardiac assessment are reviewed, including the use of advanced ultrasound techniques, fetal magnetic resonance imaging, and fetal magnetocardiography and electrocardiography for rhythm assessment. Models for parental counseling and a discussion of parental stress and depression assessments are reviewed. Available fetal therapies, including medical management for arrhythmias or heart failure and closed or open intervention for diseases affecting the cardiovascular system such as twin–twin transfusion syndrome, lung masses, and vascular tumors, are highlighted. Catheter-based intervention strategies to prevent the progression of disease in utero are also discussed. Recommendations for delivery planning strategies for fetuses with congenital heart disease including models based on classification of disease severity and delivery room treatment will be highlighted. Outcome assessment is reviewed to show the benefit of prenatal diagnosis and management as they affect outcome for babies with congenital heart disease. Conclusions— Fetal cardiac medicine has evolved considerably over the past 2 decades, predominantly in response to advances in imaging technology and innovations in therapies. The diagnosis of cardiac disease in the fetus is mostly made with ultrasound; however, new technologies, including 3- and 4-dimensional echocardiography, magnetic resonance imaging, and fetal electrocardiography and magnetocardiography, are available. Medical and interventional treatments for select diseases and strategies for delivery room care enable stabilization of high-risk fetuses and contribute to improved outcomes. This statement highlights what is currently known and recommended on the basis of evidence and experience in the rapidly advancing and highly specialized field of fetal cardiac care.

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Section: Incidencementioning

confidence: 99%

Diagnosis and Treatment of Fetal Cardiac Disease

Donofrio¹,

Moon-Grady²,

Hornberger³

et al. 2014

Circulation

979

543

View full text Add to dashboard Cite

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“…The time reduction was of particular importance for prenatal genetic diagnosis. 4 For instance, the results of the screening of the 20 validation set cases were obtained within 5 days: 2 days for target enrichment and library preparation, 1 day for template preparation and sequencing and 2 days for data analysis and interpretation. In contrast, to screen the same 20 cases using Sanger sequencing, 90 days would have been needed: 2 days for target enrichment and enzymatic purification, 60 days to perform 6320 sequencing reactions and electrophoretic runs (158 amplicons per case in forward and reverse sequencing directions) and 30 days for data analysis and interpretation.…”

Section: Discussionmentioning

confidence: 99%

“…1,3 The diagnosis of such disorders is particularly difficult to perform in utero and in the first years of life, as most features manifest later during childhood. 4,5 Therefore, molecular analysis has become an important key for the verification of clinical diagnosis and represents a highly informative prognostic tool, with direct impact on the establishment of individual follow-up plans. 6,7 Heterozygous mutations in 11 genes associated with the RAS/MAPK signaling pathway have been causally linked to these disorders: PTPN11 (MIM 176876), SOS1 (MIM 182530), RAF1 (MIM 164760), BRAF (MIM 164757), MAP2K1 (MIM 176872), MAP2K2 (MIM601263), KRAS (MIM 190070), HRAS (MIM 190020), NRAS (MIM 164790), SHOC2 (MIM 602775) and CBL (MIM 165360).…”

Section: Introductionmentioning

confidence: 99%

Comprehensive massive parallel DNA sequencing strategy for the genetic diagnosis of the neuro-cardio-facio-cutaneous syndromes

et al. 2014

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Variants in 11 genes of the RAS/MAPK signaling pathway have been causally linked to the neuro-cardio-facio-cutaneous syndromes group (NCFCS). Recently, A2ML1 and RIT1 were also associated with these syndromes. Because of the genetic and clinical heterogeneity of NCFCS, it is challenging to define strategies for their molecular diagnosis. The aim of this study was to develop and validate a massive parallel sequencing (MPS)-based strategy for the molecular diagnosis of NCFCS. A multiplex PCR-based strategy for the enrichment of the 13 genes and a variant prioritization pipeline was established. Two sets of genomic DNA samples were studied using the Ion PGM System: (1) training set (n ¼ 15) to optimize the strategy and (2) validation set (n ¼ 20) to validate and evaluate the power of the new methodology. Sanger sequencing was performed to confirm all variants and low covered regions. All variants identified by Sanger sequencing were detected with our MPS approach. The methodology resulted in an experimental approach with a specificity of 99.0% and a maximum analytical sensitivity of Z98.2% with a confidence of 99%. Importantly, two patients (out of 20) harbored described disease-causing variants in genes that are not routinely tested (RIT1 and SHOC2). The addition of less frequently altered genes increased in E10% the diagnostic yield of the strategy currently used. The presented workflow provides a comprehensive genetic screening strategy for patients with NCFCS in a fast and cost-efficient manner. This approach demonstrates the potential of a combined MPS-Sanger sequencing-based strategy as an effective diagnostic tool for heterogeneous diseases.

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“…These entities, collectively named "RASopathies", share many clinical features, including facial dysmorphisms, a wide spectrum of congenital heart defects, postnatal growth failure, variable degrees of neurocognitive impairment, skeletal and ectodermal anomalies, and increased tumor risk . Prenatal findings include increased nuchal translucency, polyhydramnios, hydrothorax, cystic hygroma, and multiple effusions [Baldassarre et al, 2011;Baldassarre et al, 2013;Croonen et al, 2013]. Despite this clinical overlap, each RASopathy usually exhibits distinctive features, helping in the intricate differential diagnosis Zenker, 2011].…”

Section: Introductionmentioning

confidence: 94%

Phenotypic variability associated with the invariant SHOC2 c.4A>G (p.Ser2Gly) missense mutation

Baldassarre

Mussa

Banaudi

et al. 2014

American J of Med Genetics Pt A

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Noonan-like syndrome with loose anagen hair (NS/LAH; OMIM 607721) is a developmental disorder clinically related to Noonan syndrome (NS) and characterized by facial dysmorphisms, postnatal growth retardation, cardiac anomalies (in particular dysplasia of the mitral valve and septal defects), variable neurocognitive impairment, and florid ectodermal features. A distinctive trait of NS/LAH is its association with easily pluckable, slow growing, sparse, and thin hair. This rare condition is due to the invariant c.4A > G missense (p.Ser2Gly) change in SHOC2, which encodes a regulatory protein that participate in RAS signaling. Here we report two patients with molecularly confirmed NS/LAH, with extremely different phenotypic expression, in particular concerning the severity of the cardiac phenotype and neurocognitive profile. While the first available clinical records outlined a relatively homogeneous phenotype in NS/LAH, the present data emphasize that the phenotype spectrum associated with this invariant mutation is wider than previously recognized.

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Prenatal features of Noonan syndrome: prevalence and prognostic value

Cited by 45 publications

References 24 publications

Diagnosis and Treatment of Fetal Cardiac Disease

Diagnosis and Treatment of Fetal Cardiac Disease

Comprehensive massive parallel DNA sequencing strategy for the genetic diagnosis of the neuro-cardio-facio-cutaneous syndromes

Phenotypic variability associated with the invariant SHOC2 c.4A>G (p.Ser2Gly) missense mutation

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