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. 2021 May;23(5):856-864.
doi: 10.1038/s41436-020-01049-x. Epub 2021 Jan 26.

Systematic large-scale assessment of the genetic architecture of left ventricular noncompaction reveals diverse etiologies

Francesco Mazzarotto  1   2   3   4 , Megan H Hawley  5 , Matteo Beltrami  1 , Leander Beekman  6 , Antonio de Marvao  7 , Kathryn A McGurk  3 , Ben Statton  7 , Beatrice Boschi  8 , Francesca Girolami  9 , Angharad M Roberts  3   4 , Elisabeth M Lodder  6 , Mona Allouba  10 , Soha Romeih  10 , Yasmine Aguib  10 , A John Baksi  3   4 , Antonis Pantazis  4 , Sanjay K Prasad  3   4 , Elisabetta Cerbai  11 , Magdi H Yacoub  10   12 , Declan P O'Regan  7 , Stuart A Cook  3   7   13   14 , James S Ware  3   4   7 , Birgit Funke  15 , Iacopo Olivotto  1   2 , Connie R Bezzina  6 , Paul J R Barton  3   4 , Roddy Walsh  16
Affiliations

Systematic large-scale assessment of the genetic architecture of left ventricular noncompaction reveals diverse etiologies

Francesco Mazzarotto et al. Genet Med. 2021 May.

Abstract

Purpose: To characterize the genetic architecture of left ventricular noncompaction (LVNC) and investigate the extent to which it may represent a distinct pathology or a secondary phenotype associated with other cardiac diseases.

Methods: We performed rare variant association analysis with 840 LVNC cases and 125,748 gnomAD population controls, and compared results to similar analyses on dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM).

Results: We observed substantial genetic overlap indicating that LVNC often represents a phenotypic variation of DCM or HCM. In contrast, truncating variants in MYH7, ACTN2, and PRDM16 were uniquely associated with LVNC and may reflect a distinct LVNC etiology. In particular, MYH7 truncating variants (MYH7tv), generally considered nonpathogenic for cardiomyopathies, were 20-fold enriched in LVNC cases over controls. MYH7tv heterozygotes identified in the UK Biobank and healthy volunteer cohorts also displayed significantly greater noncompaction compared with matched controls. RYR2 exon deletions and HCN4 transmembrane variants were also enriched in LVNC, supporting prior reports of association with arrhythmogenic LVNC phenotypes.

Conclusion: LVNC is characterized by substantial genetic overlap with DCM/HCM but is also associated with distinct noncompaction and arrhythmia etiologies. These results will enable enhanced application of LVNC genetic testing and help to distinguish pathological from physiological noncompaction.

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Conflict of interest statement

S.A.C. is a cofounder and director of Enleofen Bio PTE Ltd, a company that develops anti-IL-11 therapeutics. Enleofen Bio had no involvement in this study. J.S.W. and I.O. receive grant support and honoraria from Myokardia. Myokardia had no involvement in this study. The other authors declare no competing interests.

Figures

Fig. 1
Fig. 1. Significant genetic associations for LVNC and other cardiomyopathies.
(a,b) Comparison of the frequency of rare variants for the combined left ventricular noncompaction (LVNC) cohorts (y-axis) and gnomAD individuals (x-axis) for nontruncating variants (a) and truncating variants (b). Genes with a significant excess in LVNC (p < 0.0007 with Bonferroni correction) are highlighted in red. For nontruncating variants, data are restricted to the transmembrane region and pathogenic hotspot for HCN4 and RBM20 respectively, as described in the text. (c) Variant classes with a significant excess in LVNC cases versus gnomAD, with comparison to equivalent frequencies in dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM) cohorts. Variant classes are grouped according to which conditions display significant enrichment over gnomAD—LVNC and DCM, LVNC and HCM, all three indications, LVNC and arrhythmia phenotypes and LVNC only. Variant classes shown are truncating variants (TV), nontruncating variants (non-TV) and pathogenic hotspot for RBM20, transmembrane region (TM) for HCN4 and structural variants for RYR2.
Fig. 2
Fig. 2. Positional, molecular, and clinical characterization of MYH7 truncating variants (MYH7tv) in left ventricular noncompaction (LVNC) and in the population.
(a) Distribution of MYH7 nontruncating variants demonstrates distinct (though overlapping) enriched clusters in LVNC (blue band) and hypertrophic cardiomyopathy (HCM) (red band). MYH7tv are distributed throughout the transcript in LVNC and population cohorts but with a cluster around the c.732 splice region. (b) Details of the c.732 splice region and associated variants found in LVNC cases. (c) MaxEntScan scores for these variants (and the wild type sequence) with the reference exon base at c.732 and the c.732C>T common variant in cis. (d) Pedigree of the Italian family demonstrated segregation of the c.732+1G>A variant with noncompaction and/or varying degrees of myocardial hypertrabeculation. (e) MYH7tv are associated with higher noncompacted to compacted (NC/C) ratios in population cohorts. Maximum NC/C ratios of individuals identified with MYH7tv in population controls not selected for disease (see “Materials and Methods”), compared with age- and sex-matched individuals without MYH7tv drawn from the same populations. Boxplots show the median and interquartile range, red diamond indicates mean and the dashed line shows the diagnostic NC/C ratio of 2.3.
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