One Family's Story: How exome sequencing opened the door to understanding and research

Often with rare genetic diseases, families must endure a frustrating, expensive, and exceptionally lengthy course to find an etiology for the clinical symptoms found in a patient - the diagnostic odyssey. This study examines the impact of exome sequencing on finding the cause of two siblings' global delay and ataxia and the treatments and research resulting from the diagnosis. Included is a glimpse at how pipelines can influence diagnosis.For this study, the medical history of two affected siblings was used to consider the exome sequence results with regard to clinical symptoms and mitochondrial respiratory chain enzyme analysis. Due to the differing phenotypes of the siblings, the exome data was scoured for possible modifier genes to explain this variation. Finally, the FASTQ files were processed through an alternate pipeline to determine if filtering can play a role in discordant variant calling.Exome testing diagnosed Complex I deficiency. Each girl had one allele with a common mutation in the NUBPL gene and a novel mutation in trans. Neither sibling had a polymorphism in cis with the common mutation. These are the first reported symptomatic patients with compound heterozygous mutations lacking the polymorphism in cis with the common mutation. The siblings were started on treatment, and clinical trials have been appropriately examined for qualifications. In the more affected sibling, both pipelines found two mutations in the SYNE1 gene, a gene associated with spinocerebellar ataxia. A second pipeline found only one mutation in each sibling's NUBPL gene, therefore missing this diagnosis