Identification of novel gene variants associated with heritable phenotypes

The project involves phenotyping and next generation sequencing to identify gene variants associated with human diseases and traits.

Our aim is to identify novel associations between high-penetrant gene variants and human phenotypes. Disease associated gene variants may serve as the starting point to unravel molecular pathways and targets for therapeutic interventions. We focus mainly on heritable disorders of the central nervous system but also a few other phenotypes.

Disorders caused by single genes (i.e. Mendelian or monogenic disorders) are extremely heterogeneous and affect approximately 5-6% of the population in Western societies. The approximately 8,000 Mendelian entities described to date constitute a major socioeconomic burden worldwide. The identification of causative gene variants is crucial not only for our understanding of developmental processes, organ function and development of novel therapies, but also for accurate diagnosis, appropriate follow-up and counseling to patients/families.

Sequencing patient samples to identify disease causes

We apply whole genome sequencing, whole exome sequencing, targeted resequencing and transcriptome sequencing (Illumina and Ion Proton sequencing platforms) on samples from selected and clinically well-characterized patients/families/cohorts. To date, we have identified the genetic causes of a number of unique phenotypes/disorders and additional clinical entities are continuously identified.

Novel and disease associated gene variants are immediately used in diagnostic settings and pave the path for understanding disease mechanisms. Selected novel gene variants/genes causing Mendelian traits are further examined and validated in biological systems derived from induced pluripotent stem cells (iPSC) to recapitulate pathophysiology.

Micorscope image of skeletal muscle pathology
Skeletal muscle pathology in a patient with Welander distal myopathy (progressive peripheral
muscle weakness). The disease is caused by a missense mutation in the gene encoding the
RNA binding protein TIA1 identified by our group. The mutation, now routinely used as a
diagnostic marker for the disease, results in perturbed splicing and cellular stress resulting
in inclusion bodies in skeletal muscle fibers.