DNA studies in familial hypertrophic cardiomyopathy (FHC) have shown that it is caused by mutations in genes coding for proteins which make up the muscle sarcomere. The majority of mutations in the FHC genes result from missense changes, although one of the most recent genes to be identified (cardiac myosin binding protein C gene, MYBPC3) has predominantly DNA mutations which produce truncated proteins. Both dominant negative and haploinsufficiency models have been proposed to explain the molecular changes in FHC. This study describes two Australian families with FHC caused by different mutations in MYBPC3. The first produces a de novo Asn755Lys change in a cardiac specific domain of MYBPC3. The second is a Gln969X nonsense mutation which results in a truncated protein. Neither mutation has previously been found in the MYBPC3 gene. The consequences of DNA changes on the function of cardiac myosin binding protein C are discussed in relation to current molecular models for this disorder. (J Med Genet 1998;35:205-2 10)

LV hypertrophy is progressive, particularly in the septum, during adolescence and early adult life in patients with HCM. As progressive hypertrophy may continue after somatic growth has ceased, an abnormal myocardial response to physiological growth regulators is less likely to be the principal stimulus to hypertrophy. Gene-gene interactions, changes in haemodynamic load or environmental factors may modulate the development of hypertrophy. Serial measurements of ventricular wall thickness in the first two decades of life, and probably until the fourth decade of life are advisable in patients suspected of having HCM.

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DEAR EDITOR, Many countries have seen a dramatic increase in the reported incidence of cutaneous melanoma in recent decades, largely driven by increased diagnoses of melanoma in situ and thin invasive melanoma. The incidences of thick and metastatic melanomas, and melanoma mortality have remained relatively stable. While ageing populations could be Table 1 Evidence identified to support or reject a change to diagnostic thresholds and/or terminology used for melanoma in situ (MIS) and severely dysplastic naevus (SDN) Natural history studies: observation of MIS or SDN not actively treated or incompletely excised (partial or close margins) for ≥6 months. The collective 127 cases are underlined Study Country Study design Key findings Overall risk of bias Engeln, 2017 USA Retrospective chart review 286 people with SDN (140 with negative margins, 47 with close margins, 40 with positive margins, 3 with indeterminate margins, 56 margins not reported) observed for ≥5 years. 0 cases of invasive melanoma at same site, metastasis, or deaths from melanoma High

Background: Clinical studies of hypertrophic cardiomyopathy are over-represented by individuals of European ethnicity, with less known about other ethnic groups. We investigated differences between patients in a multiethnic Australian hypertrophic cardiomyopathy population. Methods: We performed a retrospective cohort study of 836 unrelated hypertrophic cardiomyopathy probands attending a specialized clinic between 2002 and 2020. Major ethnic groups were European (n=611), East Asian (n=75), South Asian (n=58), and Middle Eastern and North African (n=68). The minor ethnicity groups were Oceanian (n=9), People of the Americas (n=7), and African (n=8). One-way ANOVA with Dunnett post hoc test and Bonferroni adjustment were performed. Results: Mean age of the major ethnic groups was 54.9±16.9 years, and 527 (65%) were male. Using the European group as the control, East Asian patients had a lower body mass index (29 versus 25 kg/m 2 , P <0.0001). South Asians had a lower prevalence of atrial fibrillation (10% versus 31%, P =0.024). East Asians were more likely to have apical hypertrophy (23% versus 6%, P <0.0001) and Middle Eastern and North African patients more likely to present with left ventricular outflow tract obstruction (46% versus 34%, P =0.0003). East Asians were less likely to undergo genetic testing (55% versus 85%, P <0.0001) or have an implantable cardioverter-defibrillator implanted (19% versus 36%, P =0.037). East Asians were more likely to have a causative variant in a gene other than MYBPC3 or MYH7 , whereas Middle Eastern and North African and South Asians had the highest rates of variants of uncertain significance (27% and 21%, P <0.0001). Conclusions: There are few clinical differences based on ethnicity, but importantly, we identify health disparities relating to access to genetic testing and implantable cardioverter-defibrillator use. Unless addressed, these gaps will likely widen as we move towards precision-medicine–based care of individuals with hypertrophic cardiomyopathy.