Novel Genetic Triggers and Genotype–Phenotype Correlations in Patients With Left Ventricular Noncompaction

Abstract

Background Left ventricular non-compaction (LVNC) is a genetically and phenotypically heterogeneous disease and, although increasingly recognized in clinical practice, there is a lack of widely accepted diagnostic criteria. We sought to identify novel genetic causes of LVNC and describe genotype-phenotype correlations. Methods and Results 190 patients from 174 families with left ventricular hypertrabeculation (LVHT) or LVNC were referred for cardiac magnetic resonance and whole exome sequencing. 425 control individuals were included to identify variants of interest (VOIs). We found an excess of 138 VOIs in 102 (59%) unrelated patients in 54 previously identified LVNC or other known cardiomyopathy genes. VOIs were found in 68 of 90 probands with LVNC and 34 of 84 probands with LVHT (76% and 40%, respectively; p<0.001). We identified 0, 1, and ≥2 VOIs in 72, 74, and 28 probands, respectively. We found increasing number of VOIs in a patient strongly correlated with several markers of disease severity, including ratio of non-compacted to compacted myocardium (p<0.001) and left ventricular ejection fraction (p=0.01). The presence of sarcomeric gene mutations was associated with increased occurrence of late gadolinium enhancement (p=0.004). Conclusions LVHT and LVNC likely represent a continuum of genotypic disease with differences in severity and variable phenotype explained, in part, by the number of VOIs and whether mutations are present in sarcomeric or non-sarcomeric genes. Presence of VOIs is common in patients with LVHT. Our findings expand the current clinical and genetic diagnostic approaches for patients with LVHT and LVNC.

Navigating Genetic and Phenotypic Uncertainty in Left Ventricular Noncompaction

“…18,19 Consistent with these observations, sarcomeric variants were observed frequently (32%) in the present study by Jefferies et al 4 Although the pathogenicity of many of these novel sarcomeric variants remains to be elucidated, the presence of sarcomeric variants was associated with increased trabeculations, late gadolinium enhancement, and a nonsignificant trend toward LV dysfunction. This is the first study suggesting the presence of sarcomeric variants as a predictor of worse clinical severity in LVNC.…”

“…In 2005, Petersen et al 8 proposed cardiac magnetic resonance criteria to diagnose pathological noncompaction based on the presence of bilayered myocardium with the noncompaction/compaction ratio is >2.3 at the end diastole. 8 In the absence of consensus criteria for the diagnosis of LVNC, the Petersen criteria have become the most widely adopted in both clinical and research settings and are the criteria used in the present study by Jefferies et al 4 Although many other criteria have since been proposed, including LV noncompacted mass >20% of the total mass, wide inconsistencies and poor specificity remain. For instance, in the MESA study (Multi-Ethnic Study of Atherosclerosis) which enrolled patients without clinically recognized cardiovascular disease, 9 ≤43% of participants satisfied LVNC diagnostic criteria, having at least 1 of 8 myocardial segments with a ratio >2.3.…”

“…15,16 To further delineate genetic causes of LVNC and establish genotype-phenotype relationships, Jefferies et al 4 performed whole exome sequencing along with detailed phenotypic/ magnetic resonance imaging characterization on 190 patients from 174 unrelated families with LVNC or LVHT, and 425 control subjects. In whole exome sequencing analysis of each individual, the authors searched for rare and predicted damaging variants falling in 54 LVNC-associated genes, or genes previously implicated in other cardiomyopathies.…”

“…Independent of its previous link to LVNC, Jefferies et al 4 find clear correlation between overall mutational burden and the severity of the disease phenotype. The patients with rare candidate variants in LVNC or cardiomyopathy genes, compared with those without, were more likely to have preexisting neuromuscular disease and LV dysfunction.…”

“…See Article by Author In this issue of Circulation: Cardiovascular Genetics, Jefferies et al 4 expand on the known genetic causes of LVNC and provide insights into the genetic landscape of LVNC and LV hypertrabeculation (LVHT) in the largest prospective cohort to date. By leveraging whole exome sequencing and cardiac magnetic resonance, the research team has assembled a deeply genotyped and phenotyped study population of 174 unrelated families with suspected or known LVNC.…”