Abstract:
The ability to discover causative genetic variants is becoming more important as the prevalence of neurodevelopmental disorders continues to increase. Many of these disorders show overlapping symptoms, which can create uncertainty in a patient’s diagnosis. Identifying the genetic cause of a condition not only results in a more precise diagnosis but can lead to a clearer understanding of the biology behind the disorder. In turn, this leads to more targeted treatment options and possible cures. The aim of this research project is to develop and subsequently employ a bioinformatic pipeline for the discovery of causative variants in children with severe neurodevelopmental disorders. Five family trios were recruited from the Minds for Minds databank or by referral from a clinician. The child in each case presented with a distinct, rare, undiagnosed neurodevelopmental disorder. DNA from each child was sequenced by whole genome sequencing and DNA from the parents were sequenced by whole exome sequencing. The sequenced short reads of each individual were separately mapped to the human reference genome and at loci where the reads differed, variant calls were made. The pipeline developed for this project then annotated, filtered and prioritised the variants. Variants were annotated with additional functional and biological information, which was then used to remove those that did not meet specific filter criteria. Variants were prioritised and interpreted manually for their potential to cause the child’s condition. Confirmation of putative causative candidates was carried out by Sanger Sequencing. In three of the five cases, the pipeline and interpretation methods were able to discover a causative variant in a gene involved with a developmentally important neuronal process. Each discovery led to a diagnosis for the family. It is hoped that in the future, these methods are used regularly to diagnose patients and similar projects can refine the techniques to make diagnosis as successful as possible.
