Unravelling monogenic diseases

To make a difference is the key driving force for Anna Wedell. Her research focuses on severe but often treatable diseases affecting metabolism, and her patients are often young children. Thanks to infrastructure available at SciLifeLab, she and her team are translating ground-breaking technology developments into improved clinical diagnostics, with dramatic consequences for affected families.

Anna Wedell

Anna Wedell has been devoted to human genetics her whole career. She graduated from Karolinska Institutet in 1988 and has been working at KI and at the Karolinska University Hospital ever since, except for a few months in La Jolla in the USA. Her specialty is medical and clinical genetics focusing on inborn errors of endocrinology and metabolism (IEM), an area where clinical work and research are highly integrated.

Anna is head of the Centre for Inherited Metabolic Diseases at Karolinska University Hospital, an expert centre providing laboratory diagnostics and expert advice on IEM throughout the country. The clinic has collaborated intimately with SciLifeLab from the start in 2010, in particular in establishing the Clinical Genomics facility in Stockholm.

Developed a unique routine test
As IEM are potentially treatable and since initial symptoms often are unspecific, wide screening methods are required to diagnose patients in time to initiate treatment and avoid irreversible damage, particularly of the brain.

Anna and her colleagues have adapted massively parallel DNA sequencing for clinical diagnostics. By developing a bioinformatics analysis pipeline, a stringent and rapid clinical test has been developed, enabling diagnosis of all monogenic disorders in one step. Anna has built a multidisciplinary team with clinical, technical and molecular competence, enabling direct translation of genetic findings into individual treatment for affected patients. Furthermore, by building a database containing all around 600 known genes of proven pathogenetic significance in IEM, analysis is restricted to genes of proven relevance for their patients, reducing the risk of ambiguous results and incidental findings.

“It has been crucial for our work to be close to the platform so that we can be intimately involved in developing tailored ways to work with these questions and to really customize the workflow to meet our needs.”

Clinical implementation started in 2014, with dramatic consequences as larger numbers of patients now receive correct diagnoses in early disease stages, enabling early treatment and reducing irreversible brain damage and death. Importantly, the team has developed their workflow such that it can be adopted to any genetic disease area, and teams focussing on other disease areas are now implementing the technology.

Many unknown mutations to discover
More than ten thousand monogenic diseases are known, but the responsible disease genes have been identified in less than half of these.

“We have a unique patient material, which is very well characterized both clinically and biochemically. In cases where known mechanisms cannot explain the disease, whole genome sequencing can reveal novel disease mechanisms. The possibility to combine high-throughput genetics with functional, biochemical measurements is a powerful way of validating novel findings, and also allows deep mechanistic investigations”.

The group has discovered several novel disease genes that have shed light on novel metabolic pathways important for normal brain function and disease. Newly discovered genes are gradually incorporated into the clinical diagnostic pipeline.

“The technology is still comparatively new, but it is already clear that a completely new landscape of monogenic disorders is emerging. This provides us with a unique opportunity to understand disease mechanisms that are important also for more common disorders. The long-term goal will be to develop new treatments.”

Many of Anna’s patients are severely ill and their families are desperate for help but in some cases there is nothing Anna and her colleagues can do. Still, Anna doesn’t find it hard to go to work in the morning.

“It is extremely rewarding to be able to transfer these powerful new techniques directly to the patients. The benefit is enormous for affected families, and scientifically we are making important discoveries. I am also extremely fortunate to work with an outstanding team of colleagues. The true multidisciplinary nature of our work is very stimulating and we have really shown the power of joining forces across disciplines towards a common goal”.

Research group