Risk of Sudden Death in Patients With RASopathy Hypertrophic Cardiomyopathy

Lynch, Áine; Tatangelo, Mark; Ahuja, Sachin; Fan, Chun‐Po Steve; Min, Sandar; Lafrenière-Roula, Myriam; Papaz, Tanya; Zhou, Vivian; Armstrong, Kathryn; Aziz, Peter F.; Benson, Lee; Butts, Ryan J.; Dragulescu, Andréea; Gardin, Letizia; Godown, Justin; Jeewa, Aamir; Kantor, Paul F.; Kaufman, Beth D.; Lal, Ashwin K.; Parent, John J.; Richmond, Marc E.; Russell, Mark W.; Balaji, Seshadri; Stephenson, Elizabeth A.; Villa, Chet; Jefferies, John L.; Whitehill, Robert; Conway, Jennifer; Howard, Taylor S.; Rossano, Joseph W.; Weintraub, Robert G.; Mital, Seema

doi:10.1016/j.jacc.2023.01.012

Cited by 17 publications

(11 citation statements)

References 18 publications

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“…RAS‐HCM carries a significant risk of mortality in infancy and a higher incidence of SCD during adolescence compared to primary hypertrophic cardiomyopathy (P‐HCM) (Lynch et al, 2023). In RAS‐HCM patients, the presence of sustained ventricular tachycardia (VT) is common and correlated with an increased risk of SCD (Aydin et al, 2011; Eichhorn et al, 2019; Petrin et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

“…Factors such as a history of VT or cardiac arrest, unexplained syncope, nonsustained VT, or extensive LVH are associated with a higher SCD risk and may warrant consideration of implantable cardioverter‐defibrillator (ICD) implantation (Ommen et al, 2020). Interestingly, in a cohort study comparing pediatric RAS‐HCM patients and P‐HCM patients, the 10‐year cumulative incidence of ICD insertions was five times lower in RAS‐HCM than in P‐HCM (Lynch et al, 2023). Better risk stratification is needed to guide ICD practices in RAS‐HCM along with monitoring for heart failure and timely consideration of advanced heart failure therapies.…”

Section: Discussionmentioning

confidence: 99%

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RAF1 mutation leading to hypertrophic cardiomyopathy in a Chinese family with a history of sudden cardiac death: A diagnostic insight into Noonan syndrome

Zheng,

Peng,

Cheng

et al. 2023

Molec Gen & Gen Med

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BackgroundHypertrophic cardiomyopathy (HCM) is predominantly caused by mutations in sarcomeric genes. However, a subset of cases is attributed to genetic disorders unrelated to sarcomeric genes, such as Noonan syndrome (NS) and other RASopathies. In this study, we present a family with a history of sudden cardiac death (SCD) and focus on two adults with syndromic left ventricular hypertrophy (LVH).MethodsClinical evaluations, including echocardiography, were conducted to assess cardiac manifestations. Whole‐exome sequencing was performed to identify potential genetic variants underlying syndromic LVH in the study participants.ResultsWhole‐exome sequencing revealed a missense variant in the RAF1 gene, c.782C>T (p.Pro261Leu). This variant confirmed the diagnosis of NS in the affected individuals.ConclusionThe findings of this study underscore the importance of family history investigation and genetic testing in diagnosing syndromic LVH. By identifying the underlying genetic cause, clinicians can better understand the etiology of RAS‐HCM and its association with SCD in young adults.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

RAF1 mutation leading to hypertrophic cardiomyopathy in a Chinese family with a history of sudden cardiac death: A diagnostic insight into Noonan syndrome

Zheng,

Peng,

Cheng

et al. 2023

Molec Gen & Gen Med

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“…Recent work from a pediatric population demonstrated an equal risk of sudden cardiac death in RASopathy HCM patients compared with nonsyndromic HCM, which highlights the importance of a genetic diagnosis for nonsarcomeric HCM. 1 This article now implicates the CRD of RAF1 in HCM and Noonan-spectrum disorders. We provide functional evidence of increased MAPK signaling secondary to the RAF1 T145M and F151L variants.…”

mentioning

confidence: 82%

“…One major contributor to nonsarcomeric HCM is the RASopathies, which often present with Noonan syndrome. 1 RAF1 , a RASopathy gene, encodes a Ras-activated serine/threonine kinase. Activated RAF1 stimulates the MAPK (mitogen-activated protein kinase) pathway through phosphorylation of MEK (MAPK/ERK [extracellular signal-regulated kinase]).…”

mentioning

confidence: 99%

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Hypertrophic Cardiomyopathy Secondary to RAF1 Cysteine-Rich Domain Variants

Fullenkamp,

Jorgensen,

Leach

et al. 2023

Circ: Genomic and Precision Medicine

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Natural history and outcomes in paediatric RASopathy‐associated hypertrophic cardiomyopathy

Boleti,

Norrish,

Field

et al. 2024

ESC Heart Failure

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AimsThis study aimed to describe the natural history and predictors of all‐cause mortality and sudden cardiac death (SCD)/equivalent events in children with a RASopathy syndrome and hypertrophic cardiomyopathy (HCM).Methods and resultsThis is a retrospective cohort study from 14 paediatric cardiology centres in the United Kingdom and Ireland. We included children <18 years with HCM and a clinical and/or genetic diagnosis of a RASopathy syndrome [Noonan syndrome (NS), NS with multiple lentigines (NSML), Costello syndrome (CS), cardiofaciocutaneous syndrome (CFCS), and NS with loose anagen hair (NS‐LAH)]. One hundred forty‐nine patients were recruited [111 (74.5%) NS, 12 (8.05%) NSML, 6 (4.03%) CS, 6 (4.03%) CFCS, 11 (7.4%) Noonan‐like syndrome, and 3 (2%) NS‐LAH]. NSML patients had higher left ventricular outflow tract (LVOT) gradient values [60 (36–80) mmHg, P = 0.004]. Over a median follow‐up of 197.5 [inter‐quartile range (IQR) 93.58–370] months, 23 patients (15.43%) died at a median age of 24.1 (IQR 5.6–175.9) months. Survival was 96.45% [95% confidence interval (CI) 91.69–98.51], 90.42% (95% CI 84.04–94.33), and 84.12% (95% CI 75.42–89.94) at 1, 5, and 10 years, respectively, but this varied by RASopathy syndrome. RASopathy syndrome, symptoms at baseline, congestive cardiac failure (CCF), non‐sustained ventricular tachycardia (NSVT), and maximal left ventricular wall thickness were identified as predictors of all‐cause mortality on univariate analysis, and CCF, NSVT, and LVOT gradient were predictors for SCD or equivalent event.ConclusionsThese findings highlight a distinct category of patients with Noonan‐like syndrome with a milder HCM phenotype but significantly worse survival and identify potential predictors of adverse outcome in patients with RASopathy‐related HCM.

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Risk of Sudden Death in Patients With RASopathy Hypertrophic Cardiomyopathy

Cited by 17 publications

References 18 publications

RAF1 mutation leading to hypertrophic cardiomyopathy in a Chinese family with a history of sudden cardiac death: A diagnostic insight into Noonan syndrome

RAF1 mutation leading to hypertrophic cardiomyopathy in a Chinese family with a history of sudden cardiac death: A diagnostic insight into Noonan syndrome

Hypertrophic Cardiomyopathy Secondary to RAF1 Cysteine-Rich Domain Variants

Natural history and outcomes in paediatric RASopathy‐associated hypertrophic cardiomyopathy

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