Donders Institute for Brain, Cognition and Behaviour
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Thesis defense Jolanda Schieving (Donders Series 622)

27 September 2023

Promotors: Prof. dr. M.A.A.P. Willemsen and Prof. dr. L.E.L.M. Vissers

On genotyping and phenotyping in pediatric neurology. The role of whole exome sequencing in a tertiary setting for pediatric neurology and the relevance of careful clinical phenotyping

An important part of a pediatric neurologist's work is making an accurate diagnosis in a child referred with a pediatric neurological disorder. This diagnosis answers parents' questions about what is the etiology of the problems of their child, guides therapeutic options, and can be important for family planning.
Starting point for making an accurate diagnosis is, and always will be, a proper history taking and neurological examination. In this way, a classificatory diagnosis can often be made: there is a movement disorder, epilepsy, neuromuscular disease and/or a developmental delay, but this diagnosis is not specific enough for family planning or personalized medical treatment if possible.
In a large proportion of children with a childhood neurological disorder, a change in the hereditary material, the DNA, is suspected.

For this dissertation, we investigated the value of a new genetic technique called whole exome sequencing in the daily pediatric neurology practice of a university medical center.
In our study, performed between 2011 and 2015, in we looked at 150 children with a pediatric neurological disorder, highly likely caused by an underlying genetic defect, comparing the yield of definite diagnosis between the traditional investigations  and whole exome sequencing. The traditional pathway only succeeded in establishing a definitive etiological diagnosis in 7% of the children, while whole exome sequencing strategy succeeded in 2015 establishing an etiological diagnosis in 31% of the children. Whole exome sequencing was not only superior in establishing a definite diagnose, but was also cheaper, faster and less burdensome compared to the traditional techniques. This new whole exome sequencing technique thus deserves a place in pediatric neurology practice.
In 2020 we re-evaluated the cohort of 103 children for whom it had not been possible to establish a definitive etiological diagnosis in 2015. Thanks to this reanalysis approach, using new whole exome sequencing strategies, we increased the yield of definite diagnosis in the original 150 children to 53%. Thereby demonstrating that reanalysis of whole exome sequencing data is useful.
In part II of our study we showed that specific neurocutaneous features (like red colored spots) or biomarkers (like alpha-fetoprotein) can be helpful for a pediatric neurologist in establishing a correct diagnosis.
We emphasized the role of careful clinical phenotyping, for the purpose of gaining a better understanding of the whole clinical spectrum of recently discovered neurogenetic disorders.