Correspondence on “ACMG SF v3.0 list for reporting of secondary findings in clinical exome and genome sequencing: a policy statement of the American College of Medical Genetics and Genomics (ACMG)” by Miller et al

Identification of an increased lifetime risk of major adverse cardiovascular events in UK Biobank participants with scoliosis

“…The first occurrence of health outcomes summary data in the UKB is reported using ICD10 codes[13]. The fields analysed for the major adverse cardiovascular events (MACE) composite trait were as follows: cardiac arrest, I46*; atrial fibrillation and flutter/arrhythmia: I48* and I49*; heart failure, I50*; and stroke, I64*, as previously published[20]. The survival analysis was conducted using MACE and death as the primary outcome.…”

First Steps of Population Genomic Medicine in the Arrhythmia World: Pros and Cons

“…Nevertheless, penetrance for specific genes/conditions was surprisingly high and indicates that focused approaches that target definitively pathogenic variants (using stringent ACMG guidelines and functional validation where feasible) in penetrant genes (identified though EHR associations) could effectively help address underdiagnosis in inherited cardiac conditions (Figure [ challenging, however, particularly for genes with lossof-function mechanisms. For example, low penetrance in population cohorts has been demonstrated for truncating variants in TTN 14 (recently added to the ACMG secondary findings gene list 1 ) and desmosomal genes. 15 These findings suggest that there would be a risk of substantial overdiagnosis if such variants were returned after population screening, at least until our understanding of the genetic and nongenetic factors that underlie variable penetrance and expressivity markedly improves.…”

“…Expanding population genetic screening to other cardiac conditions such as cardiomyopathies may prove more challenging, however, particularly for genes with loss-of-function mechanisms. For example, low penetrance in population cohorts has been demonstrated for truncating variants in TTN 14 (recently added to the ACMG secondary findings gene list 1 ) and desmosomal genes. 15 These findings suggest that there would be a risk of substantial overdiagnosis if such variants were returned after population screening, at least until our understanding of the genetic and nongenetic factors that underlie variable penetrance and expressivity markedly improves.…”

Dilated cardiomyopathy – details make the difference

“…5 The use of large-scale, intensively phenotyped population datasets, such as the UK Biobank, 12 will help us understand the role of rare and common genetic variation in disease expression. Recent large-scale population efforts to analyse variant carriers of predicted (likely) pathogenic variants in DCM-associated genes have emphasized reduced penetrance across the general population, 13,14 and our understanding of this -the probability of disease when carrying a DNA variant -must be a focus of future genetic research to fully utilize genetics to individualize the risk of developing disease. In turn, large prospective genetic studies in well-phenotyped disease cohorts will continue to improve our understanding around the association between rare and common genetic variation and adverse arrhythmic and heart failure outcomes in patients with DCM.…”