Genomic Context Differs Between Human Dilated Cardiomyopathy and Hypertrophic Cardiomyopathy

Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease

Samuel D. Kearns¹  Anthony M. Gacita¹  Megan J. Puckelwartz¹  Lisa M. Dellefave‐Castillo¹  Avery C. Robinson¹  Zachary J. Schoppen¹  Elizabeth M. McNally¹  Tess D. Pottinger¹  Wenyu Pan¹  Lorenzo L. Pesce¹  Sharlene M. Day²  Euan A. Ashley³  Jane E. Wilcox³  Allen S. Anderson³  Gene Kim⁴  Matthew T. Wheeler⁵  Thomas Cappola⁶  Gerald W. Dorn⁷ 

[1] Center for Genetic Medicine Northwestern University Feinberg School of Medicine Chicago IL;Department of Internal Medicine The University of Michigan Ann Arbor MI;Department of Medicine Bluhm Cardiovascular InstituteNorthwestern University Chicago IL;Department of Medicine University of Chicago Chicago IL;Department of Medicine/Cardiovascular Medicine Stanford University Stanford CA;Perelman School of Medicine Division of Cardiovascular Medicine and Penn Cardiovascular Institute and Department of MedicineUniversity of Pennsylvania Philadelphia PA;Washington University School of Medicine St. Louis MO;

关键词: dilated cardiomyopathy;    hypertrophic cardiomyopathy;    modifier genes;    variable expressivity;    variant burden;   

DOI  :  10.1161/JAHA.120.019944

来源: DOAJ

【 摘 要 】

Background Inherited cardiomyopathies display variable penetrance and expression, and a component of phenotypic variation is genetically determined. To evaluate the genetic contribution to this variable expression, we compared protein coding variation in the genomes of those with hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM). Methods and Results Nonsynonymous single‐nucleotide variants (nsSNVs) were ascertained using whole genome sequencing from familial cases of HCM (n=56) or DCM (n=70) and correlated with echocardiographic information. Focusing on nsSNVs in 102 genes linked to inherited cardiomyopathies, we correlated the number of nsSNVs per person with left ventricular measurements. Principal component analysis and generalized linear models were applied to identify the probability of cardiomyopathy type as it related to the number of nsSNVs in cardiomyopathy genes. The probability of having DCM significantly increased as the number of cardiomyopathy gene nsSNVs per person increased. The increase in nsSNVs in cardiomyopathy genes significantly associated with reduced left ventricular ejection fraction and increased left ventricular diameter for individuals carrying a DCM diagnosis, but not for those with HCM. Resampling was used to identify genes with aberrant cumulative allele frequencies, identifying potential modifier genes for cardiomyopathy. Conclusions Participants with DCM had more nsSNVs per person in cardiomyopathy genes than participants with HCM. The nsSNV burden in cardiomyopathy genes did not correlate with the probability or manifestation of left ventricular measures in HCM. These findings support the concept that increased variation in cardiomyopathy genes creates a genetic background that predisposes to DCM and increased disease severity.

【 授权许可】

Unknown