Short communication: the cardiac myosin binding protein C Arg502Trp mutation: a common cause of hypertrophic cardiomyopathy.
BACKGROUND
The myosin-binding protein C isoform 3 (MYBPC3) variant Arg502Trp has been identified in multiple hypertrophic cardiomyopathy (HCM) cases, but compelling evidence to support or refute the pathogenicity of this variant is lacking.


OBJECTIVE
To determine the prevalence, origin and clinical significance of the MYBPC3 Arg502Trp variant.


RESULTS
The prevalence of MYBPC3 Arg502Trp was ascertained in 1414 sequential HCM patients of primarily European descent. MYBPC3 Arg502Trp was identified in 34 of these 1414 unrelated HCM patients. Segregation of MYBPC3 Arg502Trp with clinical status was assessed in family members. Disease haplotypes were examined in 17 families using two loci flanking MYBPC3. Family studies identified an additional 43 variant carriers, many with manifest disease, yielding a calculated odds ratio of 11 000:1 for segregation of MYBPC3 Arg502Trp with HCM. Analyses in 17 families showed at least 4 independent haplotypes flanked MYBPC3 Arg502Trp. Eight individuals (4 probands and 4 family members) also had another sarcomere protein gene mutation. Major adverse clinical events occurred in approximately 30% of MYBPC3 Arg502Trp carriers by age 50; these were significantly more likely (P<0.0001) when another sarcomere mutation was present.


CONCLUSIONS
MYBPC3 Arg502Trp is the most common and recurrent pathogenic mutation in a diverse primarily European descent HCM cohort, occurring in 2.4% of patients. MYBPC3 Arg502Trp conveys a 340-fold increased risk for HCM by 45 years of age, when more than 50% of carriers have overt disease. HCM prognosis worsens when MYBPC3 Arg502Trp occurs in the setting of another sarcomere protein gene mutation.
Saltzman
Adam J
AJ
Department of Medicine, Columbia University, New York, NY, USA.
Mancini-DiNardo
Debora
D
Li
Chumei
C
Chung
Wendy K
WK
Ho
Carolyn Y
CY
Hurst
Stephanie
S
Wynn
Julia
J
Care
Melanie
M
Hamilton
Robert M
RM
Seidman
Gregor W
GW
Gorham
Joshua
J
McDonough
Barbara
B
Sparks
Elizabeth
E
Seidman
J G
JG
Seidman
Christine E
CE
Rehm
Heidi L
HL
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002312:Cardiomyopathy, Hypertrophic / Q000175:diagnosis / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D006801:Humans; D007223:Infant; D008875:Middle Aged; D017354:Point Mutation; D055815:Young Adult; D000099163:Myosin Binding Protein C
D002352:Carrier Proteins; D000099163:Myosin Binding Protein C