Missense mutations in the myozenin 2 (MYOZ2) gene (S48P and I246M) cosegregated with hypertrophic cardiomyopathy and were absent in controls, identifying MYOZ2 as a novel causal gene for human HCM.
Observational (n=1,703)
Is the MYOZ2 gene a causal gene for human hypertrophic cardiomyopathy?
MYOZ2 is identified as a novel causal gene for human hypertrophic cardiomyopathy, expanding the genetic understanding of the disease.
Effect estimate: LOD score 2.03
p-value: p=0.005
Hypertrophic cardiomyopathy (HCM) is a genetic disorder caused by mutations in sarcomeric proteins (excluding phenocopy). The causal genes in approximately one-third of the cases remain unknown. We identified a family comprised of 6 clinically affected members. The phenotype was characterized by early onset of symptoms, pronounced cardiac hypertrophy, and cardiac arrhythmias. We excluded MYH7, MYBPC3, TNNT2, and ACTC1 as the causal gene either by direct sequencing or by haplotype analysis. To map the putative candidate sarcomeric gene, we perforbold locus-specific haplotyping to detect cosegregation of the locus haplotype with the phenotype, followed by mutation screening. We genotyped 5 short-tandem-repeat markers that spanned a 4.4-centimorgan region on 4q26-q27 locus and encompassed myozenin 2 (MYOZ2), a Z-disk protein. The maximum logarithm of odds score was 2.03 (P=0.005). All affected members shared a common haplotype, implicating MYOZ2 as the causal gene. To detect the causal mutation, we sequenced all exons and exon-intron boundaries of MYOZ2 in 10 family members and identified a T-->C missense mutation corresponding to S48P substitution, which cosegregated with inheritance of HCM (N=6). It was absent in 4 clinically normal family members and in 658 additional normal individuals. To determine frequency of the MYOZ2 mutations in HCM, we sequenced MYOZ2 in 516 HCM probands and detected another missense mutation (I246M). It was absent in 2 normal family members and 517 controls. Both mutations affect highly conserved amino acids. We conclude MYOZ2 is a novel causal gene for human HCM.
Osio et al. (Fri,) conducted a observational in Hypertrophic cardiomyopathy (n=1,703). MYOZ2 mutations (S48P and I246M) vs. Absence of mutation (normal individuals) was evaluated on Cosegregation of MYOZ2 mutations with HCM phenotype (LOD score 2.03, p=0.005). Missense mutations in the myozenin 2 (MYOZ2) gene (S48P and I246M) cosegregated with hypertrophic cardiomyopathy and were absent in controls, identifying MYOZ2 as a novel causal gene for human HCM.