As part of its work to better understand and find novel treatments for sudden death, especially in young people, the Sudden Death Genomics Laboratory studies genotype-phenotype relationships in hypertrophic cardiomyopathy (HCM).
Hypertrophic cardiomyopathy is one of the most common heritable cardiovascular diseases and the most common cause of sudden death in young people, especially in young athletes. Hypertrophic cardiomyopathy is a disease underscored by profound phenotypic and genetic heterogeneity.
Since the sentinel discovery of mutations in MYH7-encoded beta myosin heavy chain as a pathogenetic basis for HCM, hundreds of mutations scattered over at least 20 genes that encode essential sarcomeric, calcium regulation and structural proteins have been identified.
The Sudden Death Genomics Laboratory completed comprehensive mutational analysis of the eight most common myofilament genes in the largest assembled cohort of unrelated patients diagnosed with hypertrophic cardiomyopathy.
As Dr. Ackerman and other researchers in the lab discovered, established HCM-associated mutations are present for only 38 percent of these unrelated patients, and the two most common genotypes — myosin binding protein C-HCM and beta myosin heavy chain-HCM — are phenotypically indistinguishable. In addition, specific mutations didn't carry prognostic significance among unrelated index cases.
Interestingly, the lab determined that when classified by the morphology of the heart's ventricular septum, 79 percent of patients with reversed septal curvature (reverse curve-HCM) tested positive. Only 8 percent of patients with a sigmoidal-shaped septum (sigmoidal-HCM) had an HCM-causing mutation (p < 0.0001).
Recent attention has been focused on proteins outside the cardiac myofilament, in particular the cardiac Z-disc, which is involved in the cytoarchitecture and cardiac stretch sensor mechanism of the cardiomyocyte.
In the lab's cohort, mutations in three such proteins — CSRP3-encoded muscle LIM protein (MLP), TCAP-encoded telethonin, and the cardiac specific insert (exon 19) of VCL-encoded vinculin that yields metavinculin — have already been associated with hypertrophic cardiomyopathy.
In contrast, patients with myofilament genotype negative-HCM were older, had less hypertrophy and were less likely to have reverse curve-HCM compared with the 143 patients with myofilament-HCM.
The Sudden Death Genomics Lab has now completed genetic analyses for more than 1,000 patients with hypertrophic cardiomyopathy, which has enabled the lab to:
- Strengthen the initial genotype-phenotype correlations
- Develop a phenotype-driven score that can help physicians, providers and genetic counselors predict the outcome of the HCM genetic test
As previously observed, the lab determined that genotype-positive patients with hypertrophic cardiomyopathy were younger at diagnosis, had more hypertrophy, were more likely to have a family history of HCM or sudden cardiac death (SCD) and were more likely to have reverse-curve HCM.
Based on this, the Sudden Death Genomics Lab created a simple score by which any of these parameters would receive 1 point:
- Younger than age 45 at diagnosis
- Maximum wall thickness greater than 20 millimeters
- Family history of hypertrophic cardiomyopathy or sudden cardiac death
- Reverse-curve HCM
The lab subsequently showed that the higher the score, the higher the likelihood that the genetic test would come back positive for an HCM-causing mutation (Figure 1).
New gene discovery in the pathogenesis of hypertrophic cardiomyopathy
The Sudden Death Genomics Laboratory has discovered seven HCM-susceptibility genes. The lab also has discovered two novel genes associated with the pathogenesis of Noonan syndrome with concomitant left ventricular hypertrophy with RAF1 and MRAS.
With the advent of next-generation sequencing techniques, novel gene discovery has moved from candidate gene strategies to whole-exome and whole-genome sequencing platforms. This advance has resulted in several causative and putative candidate genes in the pathogenesis of hypertrophic cardiomyopathy.
In addition, sudden death research in Dr. Ackerman's lab has expanded to other studies:
- The study of transcriptome and proteomic pathways in tissue from patients with hypertrophic cardiomyopathy who have undergone surgical myectomy
- Cellular characterization studies in cardiomyocytes derived from patient-specific induced pluripotent stem cells