Coding sequence mutations identified in MYH7, TNNT2, SCN5A, CSRP3, LBD3, and TCAP from 313 patients with familial or idiopathic dilated cardiomyopathy.
BACKGROUND
More than 20 genes have been reported to cause idiopathic and familial dilated cardiomyopathy (IDC/FDC), but the frequency of genetic causation remains poorly understood.


RESULTS
Blood samples were collected and DNA prepared from 313 patients, 183 with FDC and 130 with IDC. Genomic DNA underwent bidirectional sequencing of six genes, and mutation carriers were followed up by evaluation of additional family members. We identified in 36 probands, 31 unique protein-altering variants (11.5% overall) that were not identified in 253 control subjects (506 chromosomes). These included 13 probands (4.2%) with 12 beta-myosin heavy chain (MYH7) mutations, nine probands (2.9%) with six different cardiac troponin T (TNNT2) mutations, eight probands (2.6%) carrying seven different cardiac sodium channel (SCN5A) mutations, three probands (1.0%) with three titin-cap or telethonin (TCAP) mutations, three probands (1.0%) with two LIM domain binding 3 (LDB3) mutations, and one proband (0.3%) with a muscle LIM protein (CSRP3) mutation. Four nucleotide changes did not segregate with phentoype and/or did not alter a conserved amino acid and were therefore considered unlikely to be disease-causing. Mutations in 11 probands were assessed as likely disease-causing, and in 21 probands were considered possibly disease-causing. These 32 probands included 14 of the 130 with IDC (10.8%) and 18 of 183 with FDC (9.8%)


CONCLUSIONS
Mutations of these six genes each account for a small fraction of the genetic cause of FDC/IDC. The frequency of possible or likely disease-causing mutations in these genes is similar for IDC and FDC.
Hershberger
Ray E
RE
Division of Cardiovascular Medicine, Department of Medicine, Oregon Health & Science University, Portland, Oregon, USA. rhershberger@med.miami.edu
Parks
Sharie B
SB
Kushner
Jessica D
JD
Li
Duanxiang
D
Ludwigsen
Susan
S
Jakobs
Petra
P
Nauman
Deirdre
D
Burgess
Donna
D
Partain
Julie
J
Litt
Michael
M
D024722:Cardiac Myosins / Q000235:genetics*; D002311:Cardiomyopathy, Dilated / Q000235:genetics*; D064211:Connectin; D004252:DNA Mutational Analysis; D005006:Ethnicity; D005091:Exons; D005192:Family Health; D006801:Humans; D007438:Introns; D060588:LIM Domain Proteins; D009124:Muscle Proteins / Q000235:genetics*; D009154:Mutation; D018995:Myosin Heavy Chains / Q000235:genetics*; D062554:NAV1.5 Voltage-Gated Sodium Channel; D017434:Protein Structure, Tertiary; D015222:Sodium Channels / Q000235:genetics*; D020107:Troponin T / Q000235:genetics*
D064211:Connectin; D060588:LIM Domain Proteins; C501641:MYH7 protein, human; D009124:Muscle Proteins; D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; D015222:Sodium Channels; C577292:TCAP protein, human; C545568:TNNT2 protein, human; D020107:Troponin T; C090114:cysteine and glycine-rich protein 3; D024722:Cardiac Myosins; D018995:Myosin Heavy Chains