January 1, 2021
Medical condition: Congenital hypotonia and global developmental delay
The Case: The POLR2A gene encodes a highly conserved RPB1 protein, which is the largest subunit of RNA polymerase II enzyme. This protein complex is responsible for the transcription of all protein-coding genes and has been shown to be associated with profound infantile-onset hypotonia (1). Variants located in POLR2A also have a range of classifications, VUS to Pathogenic, and can influence the severity of the phenotype depending on the given mutation. Furthermore, multi-nucleotide variants (MNVs) are an important class of genetic variation, but most tools do not accurately classify MNVs. In this example, a female displayed congenital hypotonia and global development delay, and a diagnosis were attempted with trio exome sequencing. These results were negative, so they implemented Whole-genome sequencing (WGS) and analysis using Geneyx.
Geneyx solution: Geneyx was utilized to analyze WGS results when exome analysis failed to provide candidate variants. WGS has the capability to be less sensitive to GC content and is more likely to provide complete coverage of the entire coding region of the genome.
Findings: WGS identified a likely pathogenic, de novo variant in POLR2A, which has a strong association with the phenotype displayed by the individual. The variant was adjacent to a polymorphism variant that was inherited from one of the parents, and this caused their in-house pipeline to misidentify it as an inherited MNV in the exome sequencing analysis. The WGS findings led to a positive finding that could be presented to the patient.
Prospective value: Geneyx Analysis has a strong WGS variant caller that is coupled with an intuitive ability to identify correctly MNVs and SNVs.
1. Hanneke Haijes, et al. “De Novo Heterozygous POLR2A Variants Cause a Neurodevelopmental Syndrome with Profound Infantile-Onset Hypotonia”. The American Journal of Human Genetics. 2019: 105;283-301.