Molecular genetic testing of russian patients with suspected juvenile polyposis syndrome

AIM: to present the results of molecular genetic testing in patients with suspected juvenile polyposis syndrome (JPS). PATIENTS AND METHODS: molecular genetic testing was performed on 30 patients from 28 families (one family had three affected relatives) who were followed from 2012 to 2024. DNA was isolated from patients’ peripheral blood leukocytes. The initial step involved Sanger sequencing of the SMAD4 (NM_005359.6) and BMPR1A (NM_004329.3) genes, followed by screening for large rearrangements using MLPA (Multiplex Ligation-dependent Probe Amplification). Finally, patient DNA was analyzed by whole-exome sequencing (WES), with confirmation of identified variants by Sanger sequencing. RESULTS: pathogenic and likely pathogenic variants in the BMPR1A and SMAD4 genes were identified in 18 out of 28 families (64.3%). In the BMPR1A gene, 11 out of 18 (61.1%) germline variants were found, including three large deletions. In the SMAD4 gene, 7 out of 18 (38.9%) germline variants were detected, including one large deletion and one large duplication. Thus, 5 out of 18 (27.8%) germline variants in these genes were large rearrangements. In five families, previously unreported germline variants were identified (three in BMPR1A and two in SMAD4), all classified as likely pathogenic. CONCLUSION: all patients with suspected juvenile polyposis syndrome should be tested for SMAD4 and BMPR1A mutations using Sanger sequencing and MLPA. If the result is negative, high-throughput sequencing should be employed. For patients with 20 or more adenomatous colorectal neoplasms but no pathogenic/likely pathogenic variants in the APC and MUTYH genes, it is advisable to proceed directly to whole-exome sequencing.