Prevalence and severity of "benign" mutations in the beta-myosin heavy chain, cardiac troponin T, and alpha-tropomyosin genes in hypertrophic cardiomyopathy.
BACKGROUND
Genotype-phenotype correlative studies have implicated 8 particular mutations that cause hypertrophic cardiomyopathy (HCM) as "benign defects," associated with near-normal survival: N232S, G256E, F513C, V606M, R719Q, and L908V of beta-myosin heavy chain (MYH7); S179F of troponin T (TNNT2); and D175N of alpha-tropomyosin (TPM1). Routine genetic screening of HCM patients for specific mutations is anticipated to provide important diagnostic and prognostic information. The frequency and associated phenotype of these mutations in a large, unselected cohort of HCM is unknown.


RESULTS
A total of 293 unrelated HCM patients were genotyped for the presence of a benign mutation. DNA was obtained after informed consent; specific MHY7, TNNT2, and TPM1 fragments were amplified by polymerase chain reaction; and the mutations were detected by denaturing high-performance liquid chromatography and automated DNA sequencing. Only 5 (1.7%) of the 293 patients possessed a benign mutation. Moreover, all 5 subjects with an ascribed benign mutation had already manifested clinically severe expression of HCM, with all 5 requiring surgical myectomy, 3 of the 5 having a family history of sudden cardiac death, and 1 adolescent requiring an orthotopic heart transplant.


CONCLUSIONS
These findings demonstrate the rarity of specific mutations in HCM and challenge the notion of mutation-specific clinical outcomes. Fewer than 2% of the subjects harbored a benign mutation, and those patients with a benign mutation experienced a very serious clinical course.
Van Driest
Sara L
SL
Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minn 55905, USA.
Ackerman
Michael J
MJ
Ommen
Steve R
SR
Shakur
Rameen
R
Will
Melissa L
ML
Nishimura
Rick A
RA
Tajik
A Jamil
AJ
Gersh
Bernard J
BJ
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002312:Cardiomyopathy, Hypertrophic / Q000453:epidemiology / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D018450:Disease Progression; D005260:Female; D005838:Genotype; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008875:Middle Aged; D008910:Minnesota / Q000453:epidemiology; D009154:Mutation; D018995:Myosin Heavy Chains / Q000235:genetics*; D011237:Predictive Value of Tests; D015995:Prevalence; D014335:Tropomyosin / Q000235:genetics*; D020107:Troponin T / Q000235:genetics*; D024723:Ventricular Myosins / Q000235:genetics*
D014335:Tropomyosin; D020107:Troponin T; D024723:Ventricular Myosins; D018995:Myosin Heavy Chains