Barry H Trachtenberg1, Javier Jimenez2, Alanna A Morris3, Evan Kransdorf4, Anjali Owens5, Daniel P Fishbein6, Elizabeth Jordan7, Daniel D Kinnamon7, Jonathan O Mead7, Gordon S Huggins8, Ray E Hershberger9. 1. Houston Methodist DeBakey Heart & Vascular Center, J.C. Walter Jr Transplant Center, Houston Methodist, Houston, TX. Electronic address: btrachtenberg@houstonmethodist.org. 2. Miami Cardiac & Vascular Institute, Baptist Health South Florida, Miami, FL. 3. Emory University School of Medicine, Emory University, Atlanta, GA. 4. Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA. 5. Center for Inherited Cardiovascular Disease, Division of Cardiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA. 6. University of Washington, Seattle, WA. 7. Division of Human Genetics, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH. 8. Tufts University School of Medicine, Boston, MA. 9. Division of Human Genetics, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH; Division of Cardiovascular Medicine, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH. Electronic address: Ray.Hershberger@osumc.edu.
Abstract
PURPOSE: The cardiac phenotype of hereditary transthyretin amyloidosis (hTTR) usually presents as a restrictive or hypertrophic cardiomyopathy, and, although rarely observed as dilated cardiomyopathy (DCM), TTR is routinely included in DCM genetic testing panels. However, the prevalence and phenotypes of TTR variants in patients with DCM have not been reported. METHODS: Exome sequences of 729 probands with idiopathic DCM were analyzed for TTR and 35 DCM genes. RESULTS: Rare TTR variants were identified in 2 (0.5%; 95% CI = 0.1%-1.8%) of 404 non-Hispanic White DCM probands; neither of them had features of hTTR. In 1 proband, a TTR His110Asn variant and a variant of uncertain significance in DSP were identified, and in the other proband, a TTR Val50Met variant known to cause hTTR and a likely pathogenic variant in FLNC were identified. The TTR Val142Ile variant was identified in 8 (3.0%) non-Hispanic Black probands, comparable with African/African American Genome Aggregation Database controls (OR = 1.01; 95% CI = 0.46-1.99). CONCLUSION: Among the 729 DCM probands, 2 had rare TTR variants identified without the features of hTTR, and both had other plausible genetic causes of DCM. Moreover, the frequency of TTR Val142Ile was comparable to a control sample. These findings suggest that hTTR variants may have a limited role in patients with DCM without TTR-specific findings.
PURPOSE: The cardiac phenotype of hereditary transthyretin amyloidosis (hTTR) usually presents as a restrictive or hypertrophic cardiomyopathy, and, although rarely observed as dilated cardiomyopathy (DCM), TTR is routinely included in DCM genetic testing panels. However, the prevalence and phenotypes of TTR variants in patients with DCM have not been reported. METHODS: Exome sequences of 729 probands with idiopathic DCM were analyzed for TTR and 35 DCM genes. RESULTS: Rare TTR variants were identified in 2 (0.5%; 95% CI = 0.1%-1.8%) of 404 non-Hispanic White DCM probands; neither of them had features of hTTR. In 1 proband, a TTR His110Asn variant and a variant of uncertain significance in DSP were identified, and in the other proband, a TTR Val50Met variant known to cause hTTR and a likely pathogenic variant in FLNC were identified. The TTR Val142Ile variant was identified in 8 (3.0%) non-Hispanic Black probands, comparable with African/African American Genome Aggregation Database controls (OR = 1.01; 95% CI = 0.46-1.99). CONCLUSION: Among the 729 DCM probands, 2 had rare TTR variants identified without the features of hTTR, and both had other plausible genetic causes of DCM. Moreover, the frequency of TTR Val142Ile was comparable to a control sample. These findings suggest that hTTR variants may have a limited role in patients with DCM without TTR-specific findings.