Abstract 14425: Exome Sequencing Reveals a Low Frequency Variant in BMPER in a Pedigree With Recurrence of Left Ventricular Outflow Tract Obstruction Defects
Introduction: Bicuspid aortic valve (BAV) is the most common congenital heart defect affecting 1-2% of the population and is etiologically related to more severe left ventricular outflow tract (LVOTO) defects such as congenital AS, COA or HLHS. Family and population studies suggest that LVOTO defects are associated with significant heritability, yet only few genes have been associated with LVOTO in humans and explain only a minority of cases.
Methods: In a Finnish population of 120 patients with LVOTO and their family members (total n=248) we sought to discover novel genes and variants associated with disease using exome sequencing. Exome sequencing was performed at Personalis Inc. and UW-CMG. Variant calling was performed with the Realtime Genomic Package (RTG version 3.4) in reference to the UCSC reference sequence (hg19).
Results: In a family with two affected members, a biologically plausible heterozygous missense snp (rs144030074) was identified in BMPER, a BMP-pathway inhibitor. The proband has BAV and COA, and his maternal grandmother has BAV and AS. The mother and three siblings of the proband have the same variant with a normal phenotype, The variant has a MAF of 0.0007 in the ethnically matched Finnish Sequencing Initiative Suomi population (N= 10,474). Among the other sequenced patients with LVOTO (N=49) the identical variant was found in one unrelated individual with HLHS (p=0.03, Exact Binomial test).
BMPER is present in the developing mouse aortic valve at E9.5-E11.5. BMP proteins are essential for early heart development and variants in genes interacting with this pathway (ACVR1, NOTCH1, SMAD6) are associated with LVOTO defects in mammals. The variant N74D is located in the first cysteine rich repeat of the protein, a site that binds to BMP proteins. An in vitro transfection experiment in HUVEC cells comparing wild type and the mutant suggests altered activation of 6 of 56 tested BMP signaling targets (BMP4, COL1A2, FST, ID1, SMAD7, TGFB2, cutoff p=0.001, phyper test p=8.80e-06) when cells are exposed to flow conditions.
Conclusion: We have identified a low frequency BMPER-variant likely causal with LVOTO defects. Confirmation of the findings with an allele specific BMPER N74D knockin mouse-model and confirmation in large sequenced cohorts is ongoing.
Author Disclosures: E. Helle: None. T. Ojala: None. M. Perola: None. E. Ashley: Ownership Interest; Significant; Personalis Inc.. J.R. Priest: None.
- © 2016 by American Heart Association, Inc.