BACKGROUND AND AIMS: The European Society of Cardiology guidelines recommend a systematic search for diagnostic clues or 'red flags' (RFs) in patients with hypertrophic cardiomyopathy (HCM) to better tailor disease management. To date, the prevalence and clinical significance of RF associated with HCM phenotypes in different clinical settings are unknown. METHODS: The study cohort comprised 818 patients with a clinical diagnosis of HCM [479 (62%) males, mean age 49 ± 21 years] referred to four European centres. Pre-specified RFs were categorized into one of five domains: (i) family history
(ii) physical examination
(iii) electrocardiography
(iv) echocardiography
and (v) laboratory. RESULTS: A total of 318 (39%) patients had a pathogenic or likely pathogenic sarcomere gene variant
240 (29%) a TTR and GLA variant
154 (19%) a syndromic cause
and 106 (13%) no identifiable cause. In the overall cohort, 2979 RFs were identified. Of these, 1018 (34%) were identifiable from clinical history and examination alone (generalist setting) and 1961 (66%) by 12-lead electrocardiogram and echocardiography (cardiologist's office). Non-sarcomeric patients were diagnosed more often aged <
20 and after 60 years (476/500, 95%). Syndromic diseases such as Rasopathies, inherited metabolic disorders, and mitochondrial disorders were diagnosed in neonatal/early childhood (mean age 3 ± 2 years), whereas patients with Danon disease, Friedreich's ataxia, Noonan syndrome, and PRKAG2 cardiomyopathy were identified mostly during adolescence (mean age 16 ± 8 years). Non-cardiac RFs identified by clinical history, physical examination, and routine laboratory testing were most frequent in patients with HCM caused by Rasopathies, inherited metabolic disorders, and mitochondrial disorders (48%, 47%, and 57%, respectively). Physical RFs were almost exclusively observed in patients with a definite non-sarcomeric aetiology [348/350 (99%)]. On the contrary, most RFs associated with geno-positive and geno-negative HCM were derived from electrocardiogram and echocardiography [692/990 (70%) and 332/375 (88%), respectively]. CONCLUSIONS: Red flags are a common finding in patients presenting with HCM, most commonly non-cardiac in non-sarcomeric aetiology and cardiac in sarcomeric HCM. Over 34% of RF, most relevant to rare HCM phenocopies, can be potentially detected in a generalist setting. Investing in high-touch-low tech, widespread awareness for HCM-related RF may provide substantial advantage in terms of diagnostic yield and appropriate use of resources.