TY - JOUR
T1 - Coding sequence rare variants identified in MYBPC3, MYH6, TPM1, TNNC1, and TNNI3 from 312 patients with familial or idiopathic dilated cardiomyopathy
AU - Hershberger, Ray E.
AU - Norton, Nadine
AU - Morales, Ana
AU - Li, Duanxiang
AU - Siegfried, Jill D.
AU - Gonzalez-Quintana, Jorge
PY - 2010/4
Y1 - 2010/4
N2 - Background-Rare variants in >30 genes have been shown to cause idiopathic or familial dilated cardiomyopathy (DCM), but the frequency of genetic causation remains poorly understood. We have previously resequenced 9 genes in a cohort of idiopathic or familial DCM probands for rare variants, and now we report resequencing results for 5 more genes with established relationships to DCM. Methods and Results-Blood samples were collected, and DNA specimens were prepared from 312 patients, 181 with familial DCM and 131 with idiopathic DCM. Genomic DNA underwent bidirectional sequencing, and DNA of additional family members underwent analysis when a rare variant was identified. We identified rare variants in 34 probands (10.9% overall), including 29 unique protein-altering rare variants and 2 splicing variants that were absent in 246 control subjects (492 chromosomes). These variants were 12 MYBPC3 (myosin-binding protein C) in 13 (4.2%) probands, 8 MYH6 (α-myosin heavy chain) in 10 (3.2%), 6 TPM1 (tropomyosin) in 6 (1.9%), 4 TNNC1 (cardiac troponin C) in 4 (1.3%), and 1 TNNI3 (cardiac troponin I) in 2 (0.6%). Variants were classified as likely or possibly disease causing in 13 and 20 probands, respectively (n=33; 10.6% overall). One MYH6 variant was classified as unlikely to be disease causing. Conclusion-Rare variants in these 5 genes likely or possibly caused 10.6% of DCM in this cohort. When combined with our prior resequencing reports, ≈27% of DCM probands had possible or likely disease-causing variants identified. (Circ Cardiovasc Genet. 2010;3:155-161.)
AB - Background-Rare variants in >30 genes have been shown to cause idiopathic or familial dilated cardiomyopathy (DCM), but the frequency of genetic causation remains poorly understood. We have previously resequenced 9 genes in a cohort of idiopathic or familial DCM probands for rare variants, and now we report resequencing results for 5 more genes with established relationships to DCM. Methods and Results-Blood samples were collected, and DNA specimens were prepared from 312 patients, 181 with familial DCM and 131 with idiopathic DCM. Genomic DNA underwent bidirectional sequencing, and DNA of additional family members underwent analysis when a rare variant was identified. We identified rare variants in 34 probands (10.9% overall), including 29 unique protein-altering rare variants and 2 splicing variants that were absent in 246 control subjects (492 chromosomes). These variants were 12 MYBPC3 (myosin-binding protein C) in 13 (4.2%) probands, 8 MYH6 (α-myosin heavy chain) in 10 (3.2%), 6 TPM1 (tropomyosin) in 6 (1.9%), 4 TNNC1 (cardiac troponin C) in 4 (1.3%), and 1 TNNI3 (cardiac troponin I) in 2 (0.6%). Variants were classified as likely or possibly disease causing in 13 and 20 probands, respectively (n=33; 10.6% overall). One MYH6 variant was classified as unlikely to be disease causing. Conclusion-Rare variants in these 5 genes likely or possibly caused 10.6% of DCM in this cohort. When combined with our prior resequencing reports, ≈27% of DCM probands had possible or likely disease-causing variants identified. (Circ Cardiovasc Genet. 2010;3:155-161.)
KW - Cardiomyopathy
KW - Dilated cardiomyopathy
KW - Genetics
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U2 - 10.1161/CIRCGENETICS.109.912345
DO - 10.1161/CIRCGENETICS.109.912345
M3 - Article
C2 - 20215591
AN - SCOPUS:77953023261
SN - 1942-325X
VL - 3
SP - 155
EP - 161
JO - Circulation: Cardiovascular Genetics
JF - Circulation: Cardiovascular Genetics
IS - 2
ER -