Digital Public Defence: Waduwawatte Lekamalage Dulika Sanjeewani Sumathipala

MSc, MD Waduwawatte Lekamalage Dulika Sanjeewani Sumathipala at Institute of Clinical Medicine will be defending the thesis “Using high throughput sequencing technologies to study genetic causes of ultra-rare neurological diseases” for the degree of PhD (Philosophiae Doctor).

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Photo: Jeff Dowling, European Bioinformatics Institute (EMBL-EBI)

The public defence will be held as a video conference over Zoom.

The defence will follow regular procedure as far as possible, hence it will be open to the public and the audience can ask ex auditorio questions when invited to do so.

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Due to copyright reasons, an electronic copy of the thesis must be ordered from the faculty. In order for the faculty to have time to process the order, it must be received by the faculty no later than 2 days prior to the public defence. Orders received later than 2 days before the defence will not be processed. Inquiries regarding the thesis after the public defence must be addressed to the candidate.

Digital Trial Lecture – time and place

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Adjudication committee

  • First opponent: Clinical Geneticist Karin Writzl, University Medical Centre Ljubljana, Slovenia
  • Second opponent: Professor Øivind Nilssen, The Arctic University of Norway (UiT)
  • Third member and chair of the evaluation committee: Associate Professor Anette Ramm-Pettersen, University of Oslo

Chair of the Defence

Professor Mathias Toft, University of Oslo

Principal Supervisor

Professor Eirik Frengen, University of Oslo


Rare diseases affect less than 1 in 2000, whereas ultra-rare diseases affect less than 1 in 50,000 people. Such diseases have often a genetic basis and efficient diagnostic tools are required.

In my PhD project we studied 33 families suffering from ultra-rare neurological disorders with a likely monogenic cause in which previous whole exome sequencing (WES) did not identify the disease-causing genetic variants. We reanalyzed the existing WES data using updated databases, improved bioinformatics, and recent literature. In the WES data analysis, we identified the disease-causing variants in seven of the 33 families, emphasizing the value of data reanalysis due to the increasing knowledge about genes associated with diseases. In unsolved cases, we performed whole genome sequencing (WGS).  The WGS data analyses identified pathogenic deletions sized 6-8 kb in TBCK and KIAA0586 causing a lysosomal storage disease and a ciliopathy, respectively. Thus, WGS has the potential to detect deletions below the size resolution for standard diagnostic microarray-based analyses, bridging the resolution gap between these analyses and WES.

We further studied functionally putative pathogenic variants detected in two previously unrecognized human disease-causing genes, ZBTB11 and CBY1. We demonstrated that the mutant transcriptional regulator ZBTB11 caused reduced expression of genes involved in mitochondrial functions and RNA processing, resulting in the disease in the patients. We also documented that loss of function variants in CBY1 caused primary cilia defects in patient fibroblasts and in a zebrafish model. We concluded that CBY1 mutations cause Joubert syndrome, a primary ciliopathy.

This project used extensive analysis of sequence data and functional studies to detect pathogenic variants and further reveal knowledge about the molecular mechanisms causing novel diseases.

Additional information

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Published Mar. 7, 2022 1:58 PM - Last modified Mar. 30, 2022 1:27 PM