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Publicatie

The search of novel genetic causes of dominantly inherited Charcot-Marie-Tooth disease

Boek - Dissertatie

Charcot-Marie-Tooth disease (CMT) is the most common inherited peripheral neuropathy and it is well-known for its incredible genetic and phenotypic heterogeneity. Recent advances in sequencing technologies and genome annotation have led to an explosion of known CMT- causes with mutations in over 80 genes so far described. Despite this, the overall rate of underlying genetic defect identification of in patients ranges from 18.5%-63.2% suggesting that we are still missing a large part of the disease aetiology. In this thesis we illuminated part of this missing heritability of dominantly inherited CMT and explored where the unknown part could lie. We show that an unbiased approach combining next generation sequencing technologies with positional cloning and filtering based on the online genomic databases is very potent method in CMT-causing gene discovery. As a result, we were one of the first to report mutations in PMP2 as a novel cause of CMT and later expanded on this by adding novel mutations and associated phenotypes. Also, through close collaboration with clinical scientists we were able to redefine a known genetic entity CMT2G to CMT2P by identifying a missense mutation in LRSAM1. A broader analysis of the current literature revealed LRSAM1 involvement in other neurodegenerative diseases blurring the divide between them and CMT. Finally, we explored the contribution of non-protein coding parts of the genome by analysing the long-standing locus on 10q24.1-q25.1 attributed to dominant intermediate CMT type A. We interrogated this region for structural variants using third generation sequencing as well as studied the possible functional implications of identified non-coding variants. In particular, one variant in the PAX2 3’UTR sequence was predicted to have an effect on a possible regulatory element. Unfortunately, we were not able to verify the functional relevance of that sequence exemplifying the difficulty in studying the contribution of the non- coding genome to human pathology. Still, the DI-CMTA family remains the prime candidate for a discovery of novel CMT-causing variant in the non-coding part of the genome.
Aantal pagina's: 174
Jaar van publicatie:2019
Trefwoorden:Doctoral thesis
Toegankelijkheid:Closed