Finding the Cause of Hereditary Disease in a Family with Adenomatous Polyposis: Why It Is Important to Accumulate Whole Exome Sequencing Data in the Russian Population

With the aim to find the genetic cause of adenomatous polyposis, DNA samples from six members of the same family (three affected patients, two healthy individuals, and one individual with unknown disease status) were examined via whole exome sequencing and segregation analysis. Previously, no APC/MutYH mutations were found in one patient by Sanger sequencing despite all the symptoms of adenomatous polyposis syndrome. As a result of bioinformatic analysis of data obtained from four blood relatives (three affected patients and one individual with unknown disease status), the mutation in the NSUN7 gene was observed, which was not previously associated with the development of adenomatous polyposis. However, subsequently, the population frequency of this genetic variant in Russia appeared to be significantly higher than the incidence of adenomatous polyposis itself. Additional bioinformatic analysis of copy number variation (CNV) revealed previously undescribed large heterozygous deletion in three patients, which included exons 2–16 of the APC gene and regions of the SRP19 and REEP5 genes, which was subsequently confirmed by Multiplex Ligation-dependent Probe Amplification (MLPA). The conducted molecular-genetic study demonstrated the need to develop and constantly update the national database with variants detected under high-throughput sequencing. In addition, the necessity to search for large deletions in the APC gene in Russian patients with adenomatous polyposis has also been established.