Year: 2016
Type: dissertation
Abstract: In the era of precision medicine, understanding genetic variation has grown from a topic of research interest into a tangible source of therapeutic benefit for patients. As the list of confirmed links between genetic lesions and disease continues to grow, so does the list of actionable genetic diagnoses.\n\nThe workup of a childhood-onset schizophrenia case provides a useful foil for discussion of current methods for genomic diagnostics, both to demonstrate some of the important available analyses, and to highlight areas of ongoing need. In brief, the stages of this case as pertains to the general diagnostic process are: clinical workup, sequencing and technical processing, analysis and interpretation of results, and follow-up research study.\n\nThe patient in this case presented with command auditory hallucinations at age 6 and began empirical treatment for schizophrenia; he was subsequently found to have a novel de novo heterozygous missense mutation in ATP1A3 NM_152296.4 c.385G>A, predicted to cause the coding change p.V129M. This gene codes for a neuron-specific isoform of the alpha subunit of the sodium-potassium pump complex that helps establish transmembrane ion gradients necessary for neuronal function. The variant found in this case is now being replicated in a patient-derived iPS-neuron model to seek greater insight into the mechanism of disease and possible therapeutic opportunities.\n\nGeneralizing from this case, researchers and clinicians hoping to replicate or improve upon this patient-centric genomics workflow can benefit from reviewing technical and infrastructural best practices. This case may also help illustrate some of the key difficulties in connecting genomic evidence with appropriate functional validation and other clinical markers to support well-informed decision-making.
Author: Niklas Smedemark-Margulies
Language: English
Topic: Genomics and Rare Diseases
Subfield: Genetics
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2759372980