TY - JOUR
T1 - TTR variants in patients with dilated cardiomyopathy
T2 - An investigation of the DCM Precision Medicine Study
AU - DCM Precision Medicine Study of the DCM Consortium
AU - Trachtenberg, Barry H.
AU - Jimenez, Javier
AU - Morris, Alanna A.
AU - Kransdorf, Evan
AU - Owens, Anjali
AU - Fishbein, Daniel P.
AU - Jordan, Elizabeth
AU - Kinnamon, Daniel D.
AU - Mead, Jonathan O.
AU - Huggins, Gordon S.
AU - Hershberger, Ray E.
AU - Haas, Garrie
AU - Fishbein, Daniel
AU - Gottlieb, Stephen S.
AU - Wheeler, Matthew T.
AU - Hofmeyer, Mark
AU - Tang, W. H.Wilson
AU - Owens, Anjali T.
AU - Moore, Charles K.
AU - Carcamo, Javier Jimenez
AU - Trachtenberg, Barry
AU - Sweitzer, Nancy K.
AU - Shah, Palak
AU - Lowes, Brian
AU - Stoller, Douglas
AU - Smart, Frank
AU - Wilcox, Jane
AU - Katz, Stuart
AU - Ewald, Gregory A.
AU - Aaronson, Keith D.
AU - Wang, Jessica J.
AU - Pamboukian, Salpy
AU - Judge, Daniel P.
AU - Kransdorf, Evan P.
AU - Garg, Sonia
AU - Desvigne-Nickens, Patrice
AU - Troendle, James
AU - Fu, Yi Ping
AU - Hindorff, Lucia
N1 - Funding Information:
We thank the families with dilated cardiomyopathy who have participated in this study, without whom this effort would not be possible. The DCM Precision Medicine Study is supported by computational infrastructure provided by The Ohio State University Division of Human Genetics Data Management Platform and the Ohio Supercomputer Center .
Funding Information:
Research reported in this publication was supported by a parent award from the National Heart, Lung, And Blood Institute of the National Institutes of Health under Award Number R01HL128857 (R.E.H.), which included a supplement from the National Human Genome Research Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Funding Information:
We thank the families with dilated cardiomyopathy who have participated in this study, without whom this effort would not be possible. The DCM Precision Medicine Study is supported by computational infrastructure provided by The Ohio State University Division of Human Genetics Data Management Platform and the Ohio Supercomputer Center. Research reported in this publication was supported by a parent award from the National Heart, Lung, And Blood Institute of the National Institutes of Health under Award Number R01HL128857 (R.E.H.), which included a supplement from the National Human Genome Research Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Conceptualization: B.H.T. J.J. R.E.H.; Data curation: E.J. D.D.K. J.O.M. R.E.H; Formal analysis: E.J. D.D.K. J.O.M. R.E.H; Funding acquisition; R.E.H.; Investigation: B.H.T. J.J. A.A.M. E.K. A.O. D.P.F. E.J. D.D.K. J.O.M. G.S.H. R.E.H; Methodology: E.J. D.D.K. R.E.H.; Project administration: D.D.K. R.E.H.; Resources: B.H.T. J.J. A.A.M. E.K. A.O. D.P.F. G.S.H. R.E.H.; Writing-original draft: B.H.T. J.J. E.J. D.D.K. J.O.M. R.E.H.; Writing-review and editing: B.H.T. J.J. A.A.M. E.K. A.O. D.P.F. E.J. D.D.K. J.O.M. G.S.H. R.E.H. All subjects provided informed consent, and study review and approval were obtained from the Institutional Review Board at the University of Pennsylvania.
Publisher Copyright:
© 2022 American College of Medical Genetics and Genomics
PY - 2022/7
Y1 - 2022/7
N2 - 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.
AB - 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.
KW - Dilated cardiomyopathy
KW - Genetic testing
KW - Genetics
KW - Hereditary transthyretin
KW - TTR
UR - http://www.scopus.com/inward/record.url?scp=85128627887&partnerID=8YFLogxK
U2 - 10.1016/j.gim.2022.03.011
DO - 10.1016/j.gim.2022.03.011
M3 - Article
C2 - 35438637
AN - SCOPUS:85128627887
SN - 1098-3600
VL - 24
SP - 1495
EP - 1502
JO - Genetics in Medicine
JF - Genetics in Medicine
IS - 7
ER -