Male infant with Noonan syndrome with<i>RAF-1</i>gene mutation who survived hypertrophic cardiomyopathy-induced fatal heart failure and uncontrollable arrhythmias

Hagino, Mao; Ota, Chiharu; Onoki, Takehiko; Iwasawa, Shinya

doi:10.1136/bcr-2022-250342

Cited by 3 publications

(1 citation statement)

References 11 publications

(33 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Studies have suggested that males with NS may be more likely to have more severe cardiac manifestations, including a higher incidence of hypertrophic cardiomyopathy and aortic valve stenosis, compared to females with NS (3,35,65). Similarly, few studies indicated that males had a higher incidence of pathogenic variants in the RAF1 gene, a less common genetic mutation associated with NS (66)(67)(68)(69). However, other studies suggested no significant sex differences in the prevalence or severity of cardiac abnormalities in NS patients (16,70).…”

Section: Sex Dimorphism In Rasopathy-induced Cardiomyopathy In Ns And...mentioning

confidence: 99%

RASopathies and cardiac manifestations

Hilal

Chen

et al. 2023

Front. Cardiovasc. Med.

View full text Add to dashboard Cite

As binary switches, RAS proteins switch to an ON/OFF state during signaling and are on a leash under normal conditions. However, in RAS-related diseases such as cancer and RASopathies, mutations in the genes that regulate RAS signaling or the RAS itself permanently activate the RAS protein. The structural basis of this switch is well understood; however, the exact mechanisms by which RAS proteins are regulated are less clear. RAS/MAPK syndromes are multisystem developmental disorders caused by germline mutations in genes associated with the RAS/mitogen-activated protein kinase pathway, impacting 1 in 1,000–2,500 children. These include a variety of disorders such as Noonan syndrome (NS) and NS-related disorders (NSRD), such as cardio facio cutaneous (CFC) syndrome, Costello syndrome (CS), and NS with multiple lentigines (NSML, also known as LEOPARD syndrome). A frequent manifestation of cardiomyopathy (CM) and hypertrophic cardiomyopathy associated with RASopathies suggest that RASopathies could be a potential causative factor for CM. However, the current supporting evidence is sporadic and unclear. RASopathy-patients also display a broad spectrum of congenital heart disease (CHD). More than 15 genes encode components of the RAS/MAPK signaling pathway that are essential for the cell cycle and play regulatory roles in proliferation, differentiation, growth, and metabolism. These genes are linked to the molecular genetic pathogenesis of these syndromes. However, genetic heterogeneity for a given syndrome on the one hand and alleles for multiple syndromes on the other make classification difficult in diagnosing RAS/MAPK-related diseases. Although there is some genetic homogeneity in most RASopathies, several RASopathies are allelic diseases. This allelism points to the role of critical signaling nodes and sheds light on the overlap between these related syndromes. Even though considerable progress has been made in understanding the pathophysiology of RASopathy with the identification of causal mutations and the functional analysis of their pathophysiological consequences, there are still unidentified causal genes for many patients diagnosed with RASopathies.

show abstract