Many rare diseases display highly variable and often overlapping symptoms, which makes the diagnostic process challenging. Modern sequencing technologies have, however, revolutionised the diagnostics of genetic diseases and increased our understanding of the genetic and phenotypic heterogeneity of rare diseases.
The main aim of M.Sc. Luca Trotta’s thesis entitled "Genetics of primaryimmunodeficiency in Finland", was to characterize the molecular genetic basis of primary immunodeficiency (PIDs), a broad and heterogeneous group of inborn immunity errors. Luca defended his doctoral dissertation in the Faculty of Biological and Environmental Sciences 24 January. His thesis was supervised by FIMM Research Director Janna Saarela and Docent Mikko Seppänen from the HUS Rare Disease Center.
Luca graduated from the University of Milan in 2005. He finished his licentiate degree in medical genetics in 2010 after working as a medical geneticist in a local hospital for seven years. Thus, his knowledge in disease genetics was already very well developed when joining Janna Saarela’s group at FIMM in 2012.
Luca’s first project concentrated on multiple sclerosis, a common autoimmune disease. When Janna Saarela’s research focus changed more towards the rare immune diseases, Luca and Janna started to work to develop whole-exome sequencing based diagnostics for clinical samples at FIMM.
In his thesis work, Luca wanted to further depict the genetics of PIDs, targeting the possible disease-causing variants in Finnish patients with a suspicion of immune and/or haematological disorder but lacking a clinical diagnosis.
The broader goal that motivated me throughout the thesis work was to develop methods that could improve routine genetic diagnostics of these patients, so that as many of them as possible could get a prompt diagnosis and more accurate prognostic information.
- Luca Trotta
Luca’s thesis consists of three publications. In two of these, he was able to identify a Finnish enriched founder mutation. In the first study, mutation in the AICDA gene was found in patients affected by a primary antibody deficiency disease called hyper-IgM syndrome type 2. This mutation has accounted for all the thus far identified Finnish cases.
In the second study, bialllelic ADA2 mutations that cause a deficiency of adenosine deaminase 2 (DADA2) were identified in seven PID patients. All these patients shared one common mutation, enriched in Finland, either as homozygous or in combination with a second mutation. The phenotypic spectrum of the patients was surprisingly wide and included lymphoproliferative features novel to this syndrome.
The third publication focused on telomere biology disorders –associated genes. Among the sequenced cases, four undiagnosed patients with seemingly distinct features were shown to have novel mutations affecting the function of telomerase and leading to shortened telomere lengths.
In this thesis, I focused on patients with unexplained, rare and atypical forms of PIDs. For these patients and their parents reaching the genetic diagnosis is very valuable. The findings allowed us to expand the phenotypic spectrum of the studied diseases and to offer accurate genetic counselling for the families. Correct molecular diagnosis can also, in some cases, lead to more efficient treatment opportunities.
Luca is grateful for the experience he gained at FIMM, especially the possibility to work at the frontier of genomic research and diagnostics. He highly values the close collaboration Janna Saarela’s research group has with the clinicians treating the patients.
This project is a beautiful example of what can be achieved when you meet with the right people at the right time.
At the moment, Luca is living in Switzerland and working at the R&D department of a small start-up company, designing and implementing new diagnostic sequencing kits. He feels that working in the private sector is a valuable experience and acknowledges the fact that he can utilize the sequencing data interpretation skills and the “customer viewpoint” he developed during his thesis work.
The public examination of Luca Trotta’s thesis took place on 24 January 2019. Docent Asbjorg Stray-Pedersen (Oslo University Hospital, Norway) served as the opponent and Professor Minna Nyström as the custos. The dissertation is also available in electronic form.