Postma group – Uncovering genetic causes in rare (congenital) diseases

We aim to identify the underlying genetic causes in rare (congenital) diseases in order to better understand the pathophysiology of the disease and help improve genetic counseling and therapy. To this end we employ state-of-the-art genomic and bioinformatics techniques.

Contact: A.V. Postma (

Research overview

1. Genetics of Congenital Heart Disease

Congenital heart disease (CHD) is the most common type of birth defect, accounting for one-third of all major congenital anomalies. Worldwide, 1.35 million infants are born with CHD each year. In the Netherlands, CHD occurs in 7 per 1000 live births. A broad phenotypic spectrum exists for CHDs. Conotruncal cardiac defects are among the most prevalent and severe. They are associated with severe late complications, requiring lifelong medical care. Tetralogy of Fallot (TOF, consisting of a ventricular septal defect, obstruction of the right ventricular outflow tract, override of the ventricular septum by the aortic root, and right ventricular hypertrophy) and Transposition of the Great Arteries (TGA, characterised by ventriculo-arterial discordance, where the pulmonary artery arises from a morphological left ventricle and the aorta arises from a morphological right ventricle), account for more than half of conotruncal cardiac defects and 5-10% of all CHDs. Although there have been tremendous advances in diagnosis and treatment of congenital heart disease (CHD), our knowledge of causes of CHD is very limited. Recent clinical and basic research has shown the importance of genetic factors in causation of CHD. The novel high-throughput DNA sequencing technologies that have lately become available (namely next-generation sequencing, NGS) provide the impetus for further CHD gene discovery, even in cases with sporadic (non-familial) presentation. Some recent successful examples of this approach are the identification of a loss-of-function mutations in PLD1 in patients with congenital right-sided cardiac valve defects and neonatal cardiomyopathy. The discovery that mutations in the VEGFR2 gene (KDR) can give rise to tetralogy of Fallot, and our recent GWAS study on the common genetics of TGA and the implication of WNT5A gene in its pathogenesis.

Current major focusses of our group for CHD genetics are:

  • Transposition of the Great Arteries
  • Tetralogy of Fallot
  • Ebstein anomaly
  • Familial (consanguineous) CHD

2. Genetics of rare developmental syndromes/diseases

Congenital cardiac and neural tube defects account for 21 percent of late stage fetal or neonatal loss. Chromosomal aberrations commonly contributing to fetal demise are routinely identified via karyotype or comparative genome hybridization (CGH) array analysis; however, these techniques do not identify single nucleotide changes, thus many affected pregnancies remain without a genetic diagnosis. To understand what the genetic cause is for these syndromes we use traditional genetic methods such as linkage analysis or homozygosity analysis, coupled to whole exome or genome sequencing (WES/WGS) and other data sources in the hope to uncover the causal variant(s). Case in point, we were able to link the SIRT6 gene, a chromatin-associated protein, to a syndrome involving perinatal loss of life due to a number of severe neurodevelopmental and cardiac anomalies. Another recent success was the finding that loss-of-function variants in myocardin, an essential gene in smooth muscle (SM) and cardiac muscle development, cause congenital megabladder in humans.

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Figure 1. Schematic representation of a human heart with Transposition of the Great Arteries (TGA). Newborns with TGA have two separate blood flow circuits — one that circulates oxygen-poor (blue) blood from the body back to the body, and another that recirculates oxygen-rich (red) blood from the lungs back to the lungs, which is usually a fatal situation if not operated on immediately.

Figure 2. Graphical abstract highlighting the genomewide signal on chromosome 3 for patients with TGA. The signal overlaps an enhancer close to the WNT5a gene and we demonstrated that this enhancer is regulating WNT5A expression through involvement of TBX20.

Figure 3. Example of a study in which we used mice and human genetics to identify loss-of-function mutations in myocardin (an essential smooth muscle transcription factor) that cause megabladder and perinatal lethality.


Aho Ilgun
Doris Milosavljevic
Rob Zwart


For publications by this research group, click here.