Clinical features and outcome of hypertrophic cardiomyopathy associated with triple sarcomere protein gene mutations.
OBJECTIVE
The aim of this study was to describe the clinical profile associated with triple sarcomere gene mutations in a large hypertrophic cardiomyopathy (HCM) cohort.


BACKGROUND
In patients with HCM, double or compound sarcomere gene mutation heterozygosity might be associated with earlier disease onset and more severe outcome. The occurrence of triple mutations has not been reported.


METHODS
A total of 488 unrelated index HCM patients underwent screening for myofilament gene mutations by direct deoxyribonucleic acid sequencing of 8 genes, including myosin binding protein C (MYBPC3), beta-myosin heavy chain (MYH7), regulatory and essential light chains (MYL2, MYL3), troponin-T (TNNT2), troponin-I (TNNI3), alpha-tropomyosin (TPM1), and actin (ACTC).


RESULTS
Of the 488 index patients, 4 (0.8%) harbored triple mutations, as follows: MYH7-R869H, MYBPC3-E258K, and TNNI3-A86fs in a 32-year-old woman; MYH7-R723C, MYH7-E1455X, and MYBPC3-E165D in a 46-year old man; MYH7-R869H, MYBPC3-K1065fs, and MYBPC3-P371R in a 45-year old woman; and MYH7-R1079Q, MYBPC3-Q969X, and MYBPC3-R668H in a 50-year old woman. One had a history of resuscitated cardiac arrest, and 3 had significant risk factors for sudden cardiac death, prompting the insertion of an implantable cardioverter-defibrillator in all, with appropriate shocks in 2 patients. Moreover, 3 of 4 patients had a severe phenotype with progression to end-stage HCM by the fourth decade, requiring cardiac transplantation (n=1) or biventricular pacing (n=2). The fourth patient, however, had clinically mild disease.


CONCLUSIONS
Hypertrophic cardiomyopathy caused by triple sarcomere gene mutations was rare but conferred a remarkably increased risk of end-stage progression and ventricular arrhythmias, supporting an association between multiple sarcomere defects and adverse outcome. Comprehensive genetic testing might provide important insights to risk stratification and potentially indicate the need for differential surveillance strategies based on genotype.
Girolami
Francesca
F
Unit for Genetic Diagnosis, Careggi University Hospital, Florence, Italy.
Ho
Carolyn Y
CY
Semsarian
Christopher
C
Baldi
Massimo
M
Will
Melissa L
ML
Baldini
Katia
K
Torricelli
Francesca
F
Yeates
Laura
L
Cecchi
Franco
F
Ackerman
Michael J
MJ
Olivotto
Iacopo
I
D008841:Actin Cytoskeleton / Q000235:genetics*; D000328:Adult; D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D002312:Cardiomyopathy, Hypertrophic / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D012518:Sarcomeres / Q000235:genetics*