Genetic Architecture of Dilated Cardiomyopathy in Individuals of African and European Ancestry

Abstract

ImportanceBlack patients with dilated cardiomyopathy (DCM) have increased familial risk and worse outcomes than White patients, but most DCM genetic data are from White patients.ObjectiveTo compare the rare variant genetic architecture of DCM by genomic ancestry within a diverse population of patients with DCM.DesignCross-sectional study enrolling patients with DCM who self-identified as non-Hispanic Black, Hispanic, or non-Hispanic White from June 7, 2016, to March 15, 2020, at 25 US advanced heart failure programs. Variants in 36 DCM genes were adjudicated as pathogenic, likely pathogenic, or of uncertain significance.ExposurePresence of DCM.Main Outcomes and MeasuresVariants in DCM genes classified as pathogenic/likely pathogenic/uncertain significance and clinically actionable (pathogenic/likely pathogenic).ResultsA total of 505, 667, and 26 patients with DCM of predominantly African, European, or Native American genomic ancestry, respectively, were included. Compared with patients of European ancestry, a lower percentage of patients of African ancestry had clinically actionable variants (8.2% [95% CI, 5.2%-11.1%] vs 25.5% [95% CI, 21.3%-29.6%]), reflecting the lower odds of a clinically actionable variant for those with any pathogenic variant/likely pathogenic variant/variant of uncertain significance (odds ratio, 0.25 [95% CI, 0.17-0.37]). On average, patients of African ancestry had fewer clinically actionable variants in TTN (difference, −0.09 [95% CI, −0.14 to −0.05]) and other genes with predicted loss of function as a disease-causing mechanism (difference, −0.06 [95% CI, −0.11 to −0.02]). However, the number of pathogenic variants/likely pathogenic variants/variants of uncertain significance was more comparable between ancestry groups (difference, −0.07 [95% CI, −0.22 to 0.09]) due to a larger number of non-TTN non–predicted loss of function variants of uncertain significance, mostly missense, in patients of African ancestry (difference, 0.15 [95% CI, 0.00-0.30]). Published clinical case-based evidence supporting pathogenicity was less available for variants found only in patients of African ancestry (P < .001).Conclusion and RelevancePatients of African ancestry with DCM were less likely to have clinically actionable variants in DCM genes than those of European ancestry due to differences in genetic architecture and a lack of representation of African ancestry in clinical data sets.

Diversifying the Genetic Landscape of Heart Disease

“…This restricted approach represents the current clinical standard and is the appropriate place to start, but it does not capture the complete genetic landscape of DCM. In the analysis conducted by Jordan et al, 42% of probands of African ancestry and 35.5% of those of European ancestry did not carry a DCM variant in any of the 36 DCM genes, suggesting that the missing heritability of DCM in these patients may reside elsewhere in the genome, such as in noncoding regions of the curated DCM genes, and/or involve common and rare variants in other genes. Recent genome-wide association studies have indicated that the aggregate effects of common variants in noncoding regions can substantially influence risk of DCM and heart failure in general, and capturing this information in the form of polygenic risk scores may ultimately improve DCM genetic testing .…”

“…In this issue of JAMA , Jordan et al investigate the current approach to DCM genetic testing in a multicenter, cross-sectional study of DCM patients enrolled at 25 US heart failure centers. The authors compare burden and predicted pathogenicity of DCM variants in 36 DCM genes across ancestral groups inferred from common variant genotypes.…”

“…One of the key findings by Jordan et al is the inadequacy of the current genetic testing panel based on a well-curated set of 36 genes to assess DCM in individuals of African genetic ancestry. There are several potential explanations.…”

“…One of the limitations of this study is its focus on specific variants within a panel of 36 well-curated DCM genes, excluding other types of variants as well as other potential DCM genes. This restricted approach represents the current clinical standard and is the appropriate place to start, but it does not capture the complete genetic landscape of DCM.…”

“…In summary, the work of Jordan et al provides a compelling mandate to diversify the genetic landscape of heart disease. Doing so will require deliberate efforts to enrich recruitment of underrepresented populations and to enhance trust between researchers and participants.…”