Cardiovascular Abnormalities and Gene Mutations in Children With Noonan Syndrome

Abstract

Background: Common cardiac abnormalities in Noonan syndrome (NS) include congenital heart diseases (CHD), pulmonary valve stenosis and hypertrophic cardiomyopathy (HCM). Molecular diagnoses are enabling earlier and more precise diagnosis of patients who have a subtle or atypical presentation. The aims of this study were to investigate genotype-phenotype associations with respect to Noonan syndrome (NS)-associated cardiac abnormalities and catheter or surgery-based interventions conditions.Methods: From January 2019 to December 2021, 22 children with a confirmed molecular diagnosis of NS combined with cardiovascular abnormalities were consecutively enrolled into the current study. A comprehensive review was carried out of echocardiography and electrocardiogram results, second-generation whole-exome sequencing results and catheter or surgery-based interventions conditions.Results: The main manifestations of electrocardiogram abnormalities were QTc prolongation, abnormal Q wave in the precordial lead and limb lead, right ventricular hypertrophy and left or right deviation of the electrical axis. The most commonly detected abnormality was pulmonary valve dysplasia with stenosis, seen in 15 (68.2%) patients, followed by atrial septal defect in 11 (50%) patients. Seven genes (RAF1, RIT1, SOS1, PTPN11, BRAF, SOS2, and LZTR1) were found to contain disease-associated variants. The most commonly observed genetic mutations were PTPN11 (27%) and RAF1 (27%). Each genotype was associated with specific phenotypic findings. RIT1, SOS1, PTPN11, and SOS2 had common echocardiography features characterized by pulmonary valve stenosis, while RAF1 was characterized by HCM. Interestingly, patients with BRAF mutations were not only characterized by HCM, but also by pulmonary valve stenosis. In the cohort there was only one patient carrying a LZTR1 mutation characterized by left ventricle globose dilation. Ten cases underwent catheter or surgery-based interventions. All the operations had immediate results and high success rates. However, some of the cases had adverse outcomes during extended follow-up. Based on the genotype-phenotype associations observed during follow-up, BRAF and RAF1 genotypes seem to be poor prognostic factors, and multiple interventions may be required for NS patients with severe pulmonary stenosis or myectomy for HCM.Conclusions: The identification of causal genes in NS patients has enabled the evaluation of genotype-cardiac phenotype relationships and prognosis of the disease. This may be beneficial for the development of therapeutic approaches.

RASopathies and cardiac manifestations

“…Colquitt et al in 2014 demonstrated that in NS patients severe HCM has an early onset with an increased risk of long-term morbidities ( 74 ). Later many studies confirmed the early onset of HCM ( 75 , 76 ) as well as pulmonary valve stenosis and arterial septal defect in NS patients ( 77 ). In contrast, the prevalence of HCM in NF1 patients was only 2%, with a mean age of onset of 26 years.…”

“…Overall, 9% of the DCM cohort presenting in childhood or adolescence have RAF1 mutations ( 59 ) PTPN11 had common echocardiography features characterized by pulmonary valve stenosis, while HCM is characterized by RAF1 . RAF1 genotypes were shown as prognostic factors, eliciting multiple interventions that may be required for NS patients with severe pulmonary stenosis or myectomy for HCM ( 77 ). But a recent study indicated that the proportion of RIT1 mutation-positive patients who underwent intervention due to cardiovascular disease was significantly higher than that of patients with PTPN11 mutations ( 78 ).…”

Discovery of Potent SOS1 PROTACs with Effective Antitumor Activities against NCI-H358 Tumor Cells In Vitro/In Vivo

“…1 H NMR (400 MHz, DMSO-d 6 ) δ 11.09 (s, 1H), 7.90−7.82 (m, 1H), 7.65− 7.52 (m, 2H), 7.11−6.95 (m, 3H), 6.94−6.64 (m, 3H), 6.58 (s, 1H), 6.42 (dt, J = 18.0, 5.9 Hz, 1H), 5.59−5.50 (m, 1H), 5.32 (s, 2H), 5.05 (dd, J = 12.9, 5.4 Hz, 1H), 3.99−3.72 (m, 5H), 3.54−3.37 (m, 2H), 3.19−3.09 (m, 1H), 3.10−2.82 (m, 5H), 2.63−2.52 (m, 2H), 2.33 (d, J = 6.0 Hz, 3H), 2.23 (dt, J = 36.0, 7.4 Hz, 2H), 2.10−1.99 (m, 1H), 1.52 (d, J = 7.0 Hz, 3H), 1.43−1.22 (m, 4H), 1.21−0.91 (m, 4H), 0.76−0.58 (m, 4H). (14). Compound 14 was obtained using a similar procedure described for the preparation of PROTACs (steps e, f, and g).…”

“…Coupled with the rotation of the REM domain, it allows for Ras binding and nucleotide exchange. − Activated Ras plays an important role in cell proliferation, transformation, survival, and migration, while overactivation of Ras usually accompanies oncogenesis. − Human SOS proteins include hSOS1 and hSOS2 . Abnormal or mutated SOS1 causes leukemia, , Noonan syndrome, Costello syndrome, and neurofibromatosis. − Moreover, activation of SOS1 was shown to be a key mechanism for the development of adaptive resistance to MEK inhibitors . Therefore, inhibiting SOS1 provides a different strategy to suppress the activity of RAS mutants …”

Biallelic LZTR1 variants in a 49‐year‐old woman with hypertrophic cardiomyopathy: A clue for considering LZTR1 in adults

“…The early diagnosis of LZTR1 ‐related NS diseases can be challenging, mostly because of their variable expressivity, as well as their nonspecific prenatal presentation. Accordingly, very few adults with LZTR1 ‐related NS affected were reported to date and any of them seemed to be affected by HCM (Kraoua et al, 2022; Sun et al, 2022; Yamamoto et al, 2015).…”