Copy number variants in Ebstein anomaly

PLoS One. 2017 Dec 7;12(12):e0188168. doi: 10.1371/journal.pone.0188168. eCollection 2017.


Background: Ebstein anomaly (EA) is a rare congenital defect characterized by apical displacement of the septal tricuspid leaflets and atrialization of the right ventricle. The etiology of EA is unclear; however, recurrence in families and the association of EA with genetic syndromes and copy number variants (CNVs) suggest a genetic component.

Objective: We performed a population-based study to search for recurrent and novel CNVs in a previously unreported set of EA cases.

Methods: We genotyped 60 EA cases identified from all live births (2,891,076) from selected California counties (1991-2010) using the Illumina HumanOmni2.5-8 array. We identified 38 candidate CNVs in 28 (46%) cases and prioritized and validated 11 CNVs based on the genes included.

Results: Five CNVs (41%) overlapped or were close to genes involved in early myocardial development, including NODAL, PDLIM5, SIX1, ASF1A and FGF12. We also replicated a previous association of EA with CNVs at 1p34.1 and AKAP12. Finally, we identified four CNVs overlapping or in close proximity to the transcription factors HES3, TRIM71, CUX1 and EIF4EBP2.

Conclusions: This study supports the relationship of genetic factors to EA and demonstrates that defects in cardiomyocytes and myocardium differentiation may play a role. Abnormal differentiation of cardiomyocytes and how genetic factors contribute should be examined for their association with EA.

MeSH terms

  • Adolescent
  • Adult
  • Chromosome Mapping
  • DNA Copy Number Variations*
  • Ebstein Anomaly / genetics*
  • Female
  • Genotype
  • Humans
  • Infant, Newborn
  • Male
  • Maternal Age
  • Young Adult