Congenital heart defects in Noonan syndrome and RIT1 mutation

Calcagni, Giulio; Baban, Anwar; Lepri, Francesca Romana; Marino, Bruno; Tartaglia, Marco; Digilio, María Cristina

doi:10.1038/gim.2016.137

Cited by 17 publications

(10 citation statements)

References 3 publications

(1 reference statement)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In patients with RIT1 mutations, HCM (56%), atrial defects, and pulmonary stenosis are the more frequently reported clinical manifestations 25 . The clinical presentation of our patient was consistent with these published phenotypes and included cardiac anomalies and lymphatic complications 26 , 27 . Therefore, combining all of the evidence and functional analysis, we classified the two genetic variants RAF1 :p.R391S and RIT1 :p.D87H as likely pathogenic mutations, according to the latest guidelines 9 , 10 , 12 .…”

Section: Discussionsupporting

confidence: 86%

Integrating Functional Analysis in the Next-Generation Sequencing Diagnostic Pipeline of RASopathies

Leung

Luk

Tang

et al. 2018

Sci Rep

View full text Add to dashboard Cite

RASopathies are a group of heterogeneous conditions caused by germline mutations in RAS/MAPK signalling pathway genes. With next-generation sequencing (NGS), sequencing capacity is no longer a limitation to molecular diagnosis. Instead, the rising number of variants of unknown significance (VUSs) poses challenges to clinical interpretation and genetic counselling. We investigated the potential of an integrated pipeline combining NGS and the functional assessment of variants for the diagnosis of RASopathies. We included 63 Chinese patients with RASopathies that had previously tested negative for PTPN11 and HRAS mutations. In these patients, we performed a genetic analysis of genes associated with RASopathies using a multigene NGS panel and Sanger sequencing. For the VUSs, we evaluated evidence from genetic, bioinformatic and functional data. Twenty disease-causing mutations were identified in the 63 patients, providing a primary diagnostic yield of 31.7%. Four VUSs were identified in five patients. The functional assessment supported the pathogenicity of the RAF1 and RIT1 VUSs, while the significance of two VUSs in A2ML1 remained unclear. In summary, functional analysis improved the diagnostic yield from 31.7% to 36.5%. Although technically demanding and time-consuming, a functional genetic diagnostic analysis can ease the clinical translation of these findings to aid bedside interpretation.

show abstract

Section: Discussionsupporting

confidence: 86%

Integrating Functional Analysis in the Next-Generation Sequencing Diagnostic Pipeline of RASopathies

Leung

Luk

Tang

et al. 2018

Sci Rep

View full text Add to dashboard Cite

show abstract

“…Interesting to note, between the "new gene" recently discovered (15) (23791108), RIT1 mutation was reported only in one case in our populations. This data may be explained by the major cardiac involvement of RIT1 mutation, according to previous experience by our and other groups (33,34) (27101134, 27684039)…”

Section: ) (9805134 9048939)supporting

confidence: 69%

Atypical cardiac defects in patients with RASopathies: Updated data on CARNET study

Calcagni

Gagliostro

Limongelli

et al. 2020

Birth Defects Research

Self Cite

View full text Add to dashboard Cite

BackgroundRASopathies are a set of relatively common autosomal dominant clinically and genetically heterogeneous disorders. Cardiac outcomes in terms of mortality and morbidity for common heart defects (such as pulmonary valve stenosis and hypertrophic cardiomyopathy) have been reported. Nevertheless, also Atypical Cardiac Defects (ACDs) are described. The aim of the present study was to report both prevalence and cardiac outcome of ACDs in patients with RASopathies.MethodsA retrospective, multicentric observational study (CArdiac Rasopathy NETwork—CARNET study) was carried out. Clinical, surgical, and genetic data of the patients who were followed until December 2019 were collected.ResultsForty‐five patients out of 440 followed in CARNET centers had ACDs. Noonan Syndrome (NS), NS Multiple Lentigines (NSML) and CardioFacioCutaneous Syndrome (CFCS) were present in 36, 5 and 4 patients, respectively. Median age at last follow‐up was 20.1 years (range 6.9–47 years). Different ACDs were reported, including mitral and aortic valve dysfunction, ascending and descending aortic arch anomalies, coronary arteries dilation, enlargement of left atrial appendage and isolated pulmonary branches diseases. Five patients (11%) underwent cardiac surgery and one of them underwent a second intervention for mitral valve replacement and severe pericardial effusion. No patients died in our cohort until December 2019.ConclusionsPatients with RASopathies present a distinct CHD spectrum. Present data suggest that also ACDs must be carefully investigated for their possible impact on the clinical outcome. A careful longitudinal follow up until the individuals reach an adult age is recommended.

show abstract

“…In previous studies, mutations in RAF1 are highly associated with hypertrophic CMP, reaching 75% (Ezquieta et al, ; Ko, Kim, Kim, & Yoo, ; Kobayashi et al, ; Pandit et al, ; Razzaque et al, ; Yaoita et al, ). However, it has been also described in RIT1 (56%) and PTPN11 (9%) (Calcagni et al, ; Kobayashi et al, ; Yaoita et al, ). No specific report is available in literature regarding the spectrum of CMPs in SOS1 mutations.…”

Section: Introductionmentioning

confidence: 93%

SOS1 mutations in Noonan syndrome: Cardiomyopathies and not only congenital heart defects! Report of six patients including two novel variants and literature review

Baban

Olivini

Lepri

et al. 2019

American J of Med Genetics Pt A

Self Cite

View full text Add to dashboard Cite

Noonan syndrome (NS) is caused by mutations in more than 10 genes, mainly PTPN11, SOS1, RAF1, and RIT1. Congenital heart defects and cardiomyopathy (CMP) are associated with significant morbidity and mortality in NS. Although hypertrophic CMP has "classically" been reported in association to RAF1, RIT1, and PTPN11 variants, SOS1 appears to be poorly related to CMP. Patients with NS attending our Center from January 2013 to June 2018 were eligible for inclusion if they carried SOS1 variants and presented with-or developed-CMP. Literature review describing the co-existence of SOS1 mutation and CMP was also performed. We identified six patients with SOS1 variants and CMP (male to female ratio 2:1) including two novel variants. CMP spectrum encompassed: (a) dilated CMP, (b) nonobstructive hypertrophic CMPs, and (c) obstructive hypertrophic CMPs. Survival is 100%. Literature review included 16 SOS1 mutated in CMP. CMP, mainly hypertrophic, has been often reported in association to RAF1, RIT1, and PTPN11 variants. Differently from previous reports, due to the frequent association of SOS1 variants and CMP in our single center experience, we suggest potential underestimated proportion of SOS1 in pediatric CMPs. K E Y W O R D Scardiomyopathy, RASopathies, SOS1

show abstract

Congenital heart defects in Noonan syndrome and RIT1 mutation

Cited by 17 publications

References 3 publications

Integrating Functional Analysis in the Next-Generation Sequencing Diagnostic Pipeline of RASopathies

Integrating Functional Analysis in the Next-Generation Sequencing Diagnostic Pipeline of RASopathies

Atypical cardiac defects in patients with RASopathies: Updated data on CARNET study

SOS1 mutations in Noonan syndrome: Cardiomyopathies and not only congenital heart defects! Report of six patients including two novel variants and literature review

Contact Info

Product

Resources

About