The Prevalence of Noonan Spectrum Disorders in Pediatric Patients with Pulmonary Valve Stenosis

Bell, Janet M.; Considine, Ellen M.; McCallen, Leslie M.; Chatfield, Kathryn C.

doi:10.1016/j.jpeds.2021.03.050

Cited by 13 publications

(10 citation statements)

References 33 publications

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“…[3][4][5] Our recently published retrospective study identified genetic diagnoses in 10% of 204 children with vPS, but also revealed that ≈20% of the cohort had extracardiac manifestations and had not received any genetic services. 11 Similar results were reported by Bell et al, 12 with 16% of 686 patients with vPS having a genetic diagnosis but without the entire cohort having received genetic testing. Noonan syndrome (NS), which is the second most common syndromic cause of CHD, is highly associated with vPS 13,14 and was the most common genetic diagnosis in both cohorts (6%-9%).…”

supporting

confidence: 74%

“…We described a large cohort of sequenced individuals with vPS, thus overcoming one of the most significant limitations of previously described cohorts. 11,12 We found that nearly 20% of our cohort had an identifiable molecular genetic diagnosis on exome or genome sequencing. Of the 22 patients we identified with molecular diagnoses, the majority (17/22, 77%) had a pathogenic or likely pathogenic variant in a RASopathy gene.…”

Section: Discussionmentioning

confidence: 88%

“…Noonan syndrome (NS), which is the second most common syndromic cause of CHD, is highly associated with vPS 13,14 and was the most common genetic diagnosis in both cohorts (6%-9%). 11,12 Individuals with NS frequently have extracardiac manifestations such as short stature, poor feeding, genitourinary anomalies, developmental delay, thrombocytopenia, and ocular anomalies as well as characteristic facial features. 13 However, the majority of vPS is identified in infancy or early childhood 15 when many of these extracardiac issues are not apparent or are still unknown.…”

mentioning

confidence: 99%

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Prevalence of Genetic Diagnoses in a Cohort With Valvar Pulmonary Stenosis

Weaver

Chen

Shikany

et al. 2022

Circ: Genomic and Precision Medicine

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Background: Valvar pulmonary stenosis (vPS) accounts for 8% to 12% of congenital heart disease cases. Multiple genetic syndromes are associated with vPS, most commonly Noonan syndrome, but the cause is unknown in most cases. We analyzed genomic data from a large cohort with vPS to determine the prevalence of genetic diagnosis. Methods: The Pediatric Cardiac Genomics Consortium database was queried to identify probands with vPS without complex congenital heart disease or aneuploidy and with existing whole exome or genome sequencing. A custom analysis workflow was used to identify likely pathogenic or pathogenic variants in disease-associated genes. Demographic and phenotypic characteristics were compared between groups with and without molecular diagnoses. Results: Data from 119 probands (105 trios) were included. A molecular diagnosis was identified in 22 (18%); 17 (14%) had Noonan syndrome or a related disorder. Extracardiac and neurodevelopmental comorbidities were seen in 67/119 (56%) of probands. Molecular diagnosis was more common in those with extracardiac and neurodevelopmental phenotypes than those without (18/67 versus 4/52, P =0.0086). Conclusions: Clinicians should have high suspicion for a genetic diagnosis in individuals with vPS, particularly if additional phenotypes are present. Our results suggest that clinicians should consider offering sequencing of at least the known congenital heart disease and RASopathy genes to all individuals with vPS, regardless of whether that individual has extracardiac or neurodevelopmental phenotypes present.

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supporting

confidence: 74%

Section: Discussionmentioning

confidence: 88%

mentioning

confidence: 99%

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Prevalence of Genetic Diagnoses in a Cohort With Valvar Pulmonary Stenosis

Weaver

Chen

Shikany

et al. 2022

Circ: Genomic and Precision Medicine

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“…PVS represents the most recurrent CHD, reported in about 50% of individuals affected by Noonan syndrome (Bell, Considine, McCallen, & Chatfield, 2021;Roberts, Allanson, Tartaglia, & Gelb, 2013).…”

Section: Cardiovascular Anomalies and Genotypephenotype Correlationmentioning

confidence: 99%

The heart in RASopathies

Delogu

Limongelli

Versacci

et al. 2022

American J of Med Genetics Pt C

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“…Pulmonary valve stenosis (PVS) represents the most recurrent CHD, (about 50% of affected individuals), and can be associated or not with dysplastic valves. In NS, as well as in the other RASopathies, supravalvular pulmonary stenosis (SVPS) can also occur, in the presence of valvular stenosis or as isolated anomaly (Bell et al, 2021). HCM is also common in patients with NS, being found roughly in 20% of patients.…”

Section: Introductionmentioning

confidence: 99%

Genotype‐cardiac phenotype correlations in a large single‐center cohort of patients affected by RASopathies: Clinical implications and literature review

Leoni

Blandino

Delogu

et al. 2021

American J of Med Genetics Pt A

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Congenital heart disease (CHD) and hypertrophic cardiomyopathy (HCM) are common features in patients affected by RASopathies. The aim of this study was to assess genotype‐ phenotype correlations, focusing on the cardiac features and outcomes of interventions for cardiac conditions, in a single‐center cohort of 116 patients with molecularly confirmed diagnosis of RASopathy, and compare these findings with previously published data. All enrolled patients underwent a comprehensive echocardiographic examination. Relevant information was also retrospectively collected through the analysis of clinical records. As expected, significant associations were found between PTPN11 mutations and pulmonary stenosis (both valvular and supravalvular) and pulmonary valve dysplasia, and between SOS1 mutations and valvular defects. Similarly, HRAS mutations were significantly associated with HCM. Potential associations between less prevalent mutations and cardiac defects were also observed, including RIT1 mutations and HCM, SOS2 mutations and septal defects, and SHOC2 mutations and septal and valve abnormalities. Patients with PTPN11 mutations were the most likely to require both a primary treatment (transcatheter or surgical) and surgical reintervention. Other cardiac anomalies less reported until recently in this population, such as isolated functional and structural mitral valve diseases, as well as a sigmoid‐shaped interventricular septum in the absence of HCM, were also reported. In conclusion, our study confirms previous data but also provides new insights on cardiac involvement in RASopathies. Further research concerning genotype/phenotype associations in RASopathies could lead to a more rational approach to surgery and the consideration of drug therapy in patients at higher risk due to age, severity, anatomy, and comorbidities.

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The Prevalence of Noonan Spectrum Disorders in Pediatric Patients with Pulmonary Valve Stenosis

Cited by 13 publications

References 33 publications

Prevalence of Genetic Diagnoses in a Cohort With Valvar Pulmonary Stenosis

Prevalence of Genetic Diagnoses in a Cohort With Valvar Pulmonary Stenosis

The heart in RASopathies

Genotype‐cardiac phenotype correlations in a large single‐center cohort of patients affected by RASopathies: Clinical implications and literature review

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