Phenotype/Genotype Relationship in Left Ventricular Noncompaction: Ion Channel Gene Mutations Are Associated With Preserved Left Ventricular Systolic Function and Biventricular Noncompaction: Phenotype/Genotype of Noncompaction

https://doi.org/10.1016/j.cardfail.2021.01.007Get rights and content

Abstract

Background

Few data exist concerning genotype–phenotype relationships in left ventricular noncompaction (LVNC).

Methods and Results

From a multicenter French Registry, we report the genetic and clinical spectrum of 95 patients with LVNC, and their genotype–phenotype relationship. Among the 95 LVNC, 45 had at least 1 mutation, including 14 cases of mutation in ion channel genes. In a complementary analysis including 16 additional patients with ion channel gene mutations, for a total of 30 patients with ion channel gene mutation, we found that those patients had higher median LV ejection fraction (60% vs 40%; P < .001) and more biventricular noncompaction (53.1% vs 18.5%; P < .001) than the 81 other patients with LVNC. Among them, both the 19 patients with an HCN4 mutation and the 11 patients with an RYR2 mutation presented with a higher LV ejection fraction and more frequent biventricular noncompaction than the 81 patients with LVNC but with no mutation in the ion channel gene, but only patients with HCN4 mutation presented with a lower heart rate.

Conclusions

Ion channel gene mutations should be searched systematically in patients with LVNC associated with either bradycardia or biventricular noncompaction, particularly when LV systolic function is preserved. Identifying causative mutations is of utmost importance for genetic counselling of at-risk relatives of patients affected by LVNC.

Section snippets

Patients

From 2012 to 2013, 95 patients newly diagnosed with LVNC were included. This study complies with the Declaration of Helsinki and was approved by our institutional review board. Written informed consent was obtained from all patients. Since the end of the inclusion period (2013), 16 additional new cases of ion channel gene mutations were identified, giving a total of 111 patients with LVNC. Finally, the echocardiographic characteristics of 30 patients with channel gene mutations were compared

Analysis of the Data From the Registry

Characteristics at diagnosis of the 95 unrelated patients with LVNC are presented in Supplementary Table 1. Mean age at diagnosis was 47.0 ± 15.4 years, and 54 patients (56.8%) were male. The median LVEF was 41% (interquartile range, 32–57), 32 patients (34%) had an LVEF of 50% or greater and 19 patients (20%) had an LVEF of less than 30%. The median number of NC segments was 5 (interquartile range, 4–6) and the mean NC/compacted ratio in end-systole was 2.2 ± 0.3. The most frequent

Discussion

LVNC is a rare cardiomyopathy characterized by clinical and genetic heterogeneity. Recent studies reported that mutations in the HCN4 gene could be associated with LVNC.2, 3, 4 However, the significance of such mutations has been debated6, 7, 8, 9 and if those patients present with a different phenotype than other patients with LVNC is unknown.

We recently reported our experience of a targeted panel sequencing in a prospective series of LVNC and found that LVNC was basically a genetic disease in

Conclusions

Ion channel mutations should be systematically searched in patients with LVNC associated with biventricular noncompaction, particularly when LV systolic function is preserved. HCN4 mutation should be particularly suspected in the presence of additional bradycardia. Identifying causative mutations is of utmost importance for genetic counselling in at-risk relatives of patients affected by LVNC.

Conflict of Interest Statement

None.

Financial Disclosure

None.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Cited by (0)

Supported by grants from the PHRC (projet hospitalier de recherche clinique) PHRC 2011-A-00987-34.

#

Marie Cambon-Viala, Hilla Gerard, and Karine Nguyen equally contributed to the paper and are equal first authors.

Gilbert Habib and Philippe Charron are equal last authors.

View full text