Author + information
- Lauren Northa,b,
- Donna Mahnkea,b,
- Karl Stamma,b,
- Huan Ling Lianga,b,
- Richard J. Willesa,b,
- Michele Frommelta,b,
- Michael Mitchella,b and
- Aoy Tomita-Mitchella,b
Background: Ebstein's Anomaly (EA) is a complex congenital heart defect (CHD) of the tricuspid valve that has significant morbidity and mortality. Most cases are of sporadic origin, however several familial cases have been described. It has been associated with myosin heavy chain 7 (MYH7), transcription factor NKX2.5, and recently, alpha-tropomyosin (TPM1). Our study describes a family spanning three generations with six members affected by EA.
Methods: Echocardiography was performed to characterize cardiac anatomy. Whole exome sequencing (WES) was performed on five family members: three affected and two unaffected. INDEL and SNP variants were detected and annotated. Genetic variants were filtered for rarity (≤1% Exome Variant Server, NHLBI GO Exome Sequencing Project), predicted deleterious/damaging effect, and observed expression and/or association with cardiac or muscle development. Variants were further evaluated with Sanger Sequencing in all family members (n=12) to determine inheritance pattern.
Results: Our investigation revealed six family members with EA, of which all also had left ventricular noncompaction (LVNC) and three also had atrial septal defect (ASD). Additionally, there were two non-viable pregnancies due to known CHD detected prenatally. WES and Sanger sequencing revealed neighboring variants on KLHL26 and TMEM59L, both located on chromosome 19, which followed an autosomal dominant inheritance pattern in coordination with EA phenotype (p<0.05 Fisher exact test).
Conclusions: Never before has such a large familial study of Ebstein's Anomaly occurring with Left Ventricular Noncompaction been described. Through WES we have identified two rare variants in KLHL26 and TMEM59L that segregate with EA. Multiple family members affected by EA were found to also have LVNC, which supports reports in the literature of these two phenotypes occurring together. The ability to genetically characterize this family will aid in future diagnosis and management of multiple family members. Our approach validates the importance of translational research in medicine when approaching complex diseases.
Poster Hall, Hall C
Saturday, March 18, 2017, 3:45 p.m.-4:30 p.m.
Session Title: Congenital Heart Disease: New Diagnostic Approaches in Congenital Heart Disease
Abstract Category: 10. Congenital Heart Disease: Pediatric
Presentation Number: 1231-010
- 2017 American College of Cardiology Foundation