Mikko Muona's doctoral thesis demonstrates the power of whole-exome sequencing in the gene discovery of rare diseases
Modern sequencing technologies have revolutionized the diagnostics of genetic diseases. However, there is still lot to do since the underlying genetic defects of thousands of rare diseases are not yet known. The main aim of M.Sc. Mikko Muona’s thesis entitled "Identification of new genetic syndromes with epilepsy by whole-exome sequencing", was to characterize the molecular genetic basis of severe epilepsy syndromes utilizing whole-exome sequencing.

Mikko graduated from the University of Helsinki in 2011 with human genetics as his major subject. He started working at FIMM already as a third-year student and received a funded graduate school position in 2011. Mikko has done his thesis work both at FIMM and at Folkhälsan Institute of Genetics, under the supervision of Professors Aarno Palotie and Anna-Elina Lehesjoki.

In his thesis work, Mikko studied 84 patients with progressive myoclonic epilepsy and 30 Finnish patients with severe infantile epilepsy. Since many of the study subjects had been previously screened for some of the most likely disease causing mutations, the team hypothesized that the cohort may be enriched for novel disease genes.

Given the rarity of the diseases we study, international collaboration and data sharing is of huge importance. The progressive myoclonus epilepsy patients I have studied are mainly of European and Asian origin, and collected through long-lasting international collaboration.

Mikko’s thesis consists of two publications and one manuscript which is in press. In the first publication of the thesis, published in the high-profile journal Nature Genetics, he was able to identify a single mutation in a potassium channel encoding gene KCNC1 which explained a significant proportion of unsolved cases. Interestingly, in most studied families this mutation is not inherited from the parents but is a newly arising (de novo) mutation.

In the two other publications two more epilepsy genes were established. Recessively inherited mutations in the UBA5 gene were found in five families and loss-of-function mutations in ADAM22 in one patient with infantile-onset epilepsy. The pathogenicity of the mutations was confirmed by functional assays.

We made the decision not to use time in setting up the functional studies by ourselves but to ask the international collaborators with existing assays to do this for us. This has been very efficient and can be considered as a win-win situation for both parties.

Overall, the thesis work made substantial progress in understanding the genetic causes and molecular basis of the epilepsy syndromes studied.

We focused on patients with unexplained, rare, devastating forms of epileptic syndromes. For these patients and their parents reaching the genetic diagnosis is very valuable. Furthermore, it is the first step on the way to develop targeted therapies to the disease, Mikko concludes.

Mikko has enjoyed working at FIMM and is grateful for the great team spirit and the supportive environment of the Human Genomics wing.

At the moment, Mikko is working in Blueprint Genetics, a Finnish company specialized in developing next generation sequencing-based diagnostics services. He feels that working in the private sector is a valuable experience and likes the fact that he can utilize the sequencing data analysis and interpretation skills he has developed during his thesis work.

The public examination of Mikko Muona’s thesis will take place on 22 June 2016 at 12 o’clock noon in the lecture hall 2 of Biomedicum Helsinki 1, Haartmaninkatu 8. Professor Joris Veltman (Radboud University Medical Center, Nijmegen, the Netherlands) will serve as the opponent and Professor Päivi Peltomäki as the custos.

The dissertation is also available in electronic form and can be downloaded here.