Exome sequencing and RNAseq in Left Ventricular Outflow Tract Obstruction

Genetics of “Left ventricular outflow tract obstruction” (LVOTO)

In a number of projects the group is working on the molecular genetics of structural congenital hearts defects. The category of left ventricular outflow tract obstruction (LVOTO) is of major interest to us. Major collaboration partners here are R. Siebert (Director of the Medical Genetics Department, Kiel), HH Kramer (Director of the Pediatric Cardiology Department), Kiel, AA Arndt (Berlin/Boston) /C MacRae (Boston), and MP Hitz/ M Hurles (Wellcome Trust Sanger Institute, Cambridge, UK).

The studies are a comprehensive analysis of disease-associated changes using a panel of state-of-the-art technologies including whole-transcriptome analysis (RNAseq), copy number variation (CNV) analysis and whole-exome sequencing (WES).

Contribution of copy number variants to congenital left-sided heart disease

In this collaborative study it was sought to determine the impact of structural genomic variation on left-sided congenital heart defects (CHD). In this first family-based CNV study of left-sided CHD, we found that both co-segregating and de novo events contribute to disease in a complex fashion at the structural genomic level. In our group we could confirm further that the CNVs in left-sided CHD were individual and rare.

Rare Variants in NR2F2 Cause Congenital Heart Defects in Humans

Nonsyndromic atrioventricular septal defects (AVSDs) are an important subtype of CHDs for which the genetic architecture is poorly understood. We performed exome sequencing in 13 parent-offspring trios and 112 unrelated individuals with nonsyndromic AVSDs and identified five rare missense variants (two of which arose de novo) in the highly conserved gene NR2F2. We identified three additional CHD-affected families, among them individuals with LVOTO with other variants in NR2F2.


Rare copy number variants contribute to congenital left-sided heart disease

Rare variants in NR2F2 cause congenital heart defects in humans

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