| Title: | Systematic large-scale assessment of the genetic architecture of left ventricular noncompaction reveals diverse etiologies |
| Journal: | Genetics in Medicine |
| Published: | 26 Jan 2021 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/33500567/ |
| DOI: | https://doi.org/10.1038/s41436-020-01049-x |
| URL: | http://www.gimjournal.org/article/S1098360021014349/pdf |
Publication 9546
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Abstract
PurposeTo 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.MethodsWe 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).ResultsWe 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.ConclusionLVNC 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.</p>
27 Authors
- Francesco Mazzarotto
- Megan H. Hawley
- Matteo Beltrami
- Leander Beekman
- Antonio de Marvao
- Kathryn A. McGurk
- Ben Statton
- Beatrice Boschi
- Francesca Girolami
- Angharad M. Roberts
- Elisabeth M. Lodder
- Mona Allouba
- Soha Romeih
- Yasmine Aguib
- A. John Baksi
- Antonis Pantazis
- Sanjay K. Prasad
- Elisabetta Cerbai
- Magdi H. Yacoub
- Declan P. O'Regan
- Stuart A. Cook
- James S. Ware
- Birgit Funke
- Iacopo Olivotto
- Connie R. Bezzina
- Paul J. R. Barton
- Roddy Walsh
1 Application
| Application ID | Title |
|---|---|
| 47602 | Understanding the genetic architecture of inherited cardiovascular conditions (ICCs) and cardio-renal disease |
Enabling scientific discoveries that improve human health