Long-term clinical benefit of mavacamten for hypertrophic cardiomyopathy in a patient with RAF1-associated Noonan syndrome—case report

Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiomyopathy and is frequently complicated by left ventricular outflow tract (LVOT) obstruction. While most cases are caused by sarcomeric mutations, up to 10% represent non-sarcomeric or syndromic phenocopies, including Noonan syndrome (NS). Noonan syndrome is a RASopathy in which mutations in genes such as RAF1 predispose to HCM through dysregulation of the Ras/MAPK pathway and are often associated with severe LVOT obstruction. Cardiac myosin inhibitors have demonstrated efficacy in sarcomeric obstructive HCM, but patients with syndromic HCM were excluded from pivotal clinical trials.

We report a 29-year-old woman with long-standing obstructive HCM and NYHA class III symptoms, angina, and dizziness. Multimodality imaging demonstrated asymmetric septal hypertrophy (maximal wall thickness 20 mm), focal intramural late gadolinium enhancement, and dynamic LVOT obstruction reaching 55 mmHg during exercise. Owing to progressive obstruction, the patient was enrolled in the EXPLORER-HCM trial. During follow-up exceeding 5 years, treatment resulted in sustained reduction of LVOT gradients, improvement in functional status to NYHA class II, and complete resolution of angina and presyncope, without adverse effects. Genetic testing performed during trial participation identified a heterozygous likely pathogenic RAF1 variant, confirming Noonan syndrome-associated HCM.

This case report demonstrates durable clinical and haemodynamic benefit of myosin inhibition in RAF1-associated Noonan syndrome HCM. This finding suggests that possible downstream hypercontractility may represent a shared and therapeutically targetable mechanism across sarcomeric HCM and selected syndromic phenocopies.