Novel frameshift mutation in PURA gene causes severe encephalopathy of unclear cause

BACKGROUND: The etiology of many genetic diseases is challenging. This is especially true for developmental disorders of the central nervous system, since several genes can be involved. Many of such pathologies are considered rare diseases, since they affect less than 1 in 2000 people. Due to their low frequency, they present several difficulties for patients, from the delay in the diagnosis to the lack of treatments. Next‐generation sequencing techniques have improved the search for diagnosis in several pathologies. Many studies have shown that the use of whole‐exome/genome sequencing in rare Mendelian diseases has a diagnostic yield between 30% and 50% depending on the disease. METHODS: Here, we present the case of an undiagnosed 6‐year‐old boy with severe encephalopathy of unclear cause, whose etiological diagnosis was achieved by whole‐genome sequencing. RESULTS: We found a novel variant that has not been previously reported in patients nor it has been described in GnomAD. Segregation analysis supports a de novo mutation, since it is not present in healthy parents. The change is predicted to be harmful to protein function, since it falls in the first quarter of the protein producing an altered reading frame and generating a premature stop codon. Additionally, the variant is classified as pathogenic according to ACMG criteria (PVS1, PM2, and PP3). Furthermore, there are several reported frameshift mutations in nearby codons as well as nonsense mutations that are predicted as pathogenic in other studies. CONCLUSION: We found a novel de novo frameshift mutation in the PURA gene (MIM number 600473), c.151_161del, with sufficient evidence of its pathogenicity.