Identification of genetic variants and chromosomal abnormalities associated with Ebstein anomaly

Background/Hypothesis: Ebstein Anomaly (EA) is an infrequent congenital heart defect (CHD) with considerable phenotypic heterogeneity in which right ventricle, tricuspid valve and electrical abnormalities prevail. Phenotypic diversity likely reflects an underlying genetic heterogeneity, which combined with studies based on small cohorts, has hindered high-confidence associations with genetic variants. Although a few chromosomal abnormalities and mutations have been linked to the disease, genetic etiologies have not been identified in most cases. Our Cardiovascular Care Center, a referral institution for CHD, has an unusually large cohort of EA patients that allows a comprehensive study of EA genetics. Materials and Methods: We carried out a thorough phenotypic characterization of 147 EA patients, followed by unsupervised two-step cluster analysis to classify patients according to the presence or absence of comorbidities. Selected syndromic/familial cases were subjected to whole exome sequencing and/or comparative genomic hybridization. Variant filtering was accomplished using family members to identify high confidence associations with identified variants. Results: In the cohort analysis, we identified a large proportion of syndromic (10.9%) and familial cases (11.6%). Molecular testing revealed high likelihood causative variants/abnormalities in most of the syndromic/familial cases studied. Our results suggest a novel association of EA with a rare chromosomal abnormality, the identification of a single gene in the 1p36 EA-associated region, as well as novel variants in familial cases with high likelihood of causality. Cluster analysis identified homogeneous endophenotypes that possibly reflect different underlying genetic etiologies. We are currently expanding our analysis to isolated cases. Conclusions: Our data suggest that major causative genetic variants/ chromosomal abnormalities can be found in a significant proportion of EA cases with thorough phenotypic evaluations and genome-scale molecular testing, raising the possibility of a role for genetic testing in the management of EA.

• Fecha de publicación: 2017
• Institución: Universidad del Rosario
• Repositorio: Repositorio EdocUR - U. Rosario
• Idioma: eng
• OAI Identifier: oai:repository.urosario.edu.co:10336/26456
• Acceso en línea: https://doi.org/10.1017/s104795111700110x; https://repository.urosario.edu.co/handle/10336/26456
• Palabra clave: Cardiorespiratory Medicine and Haematology; Medical and Health Sciences
• License: http://purl.org/coar/access_right/c_14cb