Cornelia de Lange syndrome (CdLS) is a multi-system developmental disorder with heterogeneous phenotype and genotype of the patients. Pathogenic genetic variants associated with this syndrome can be detected in genes encoding the cohesive complex. This complex plays an extremely important role in many intracellular processes, including control of sister chromatids cohesion during cell division, regulation of gene expression and repair of DNA breaks.

Currently, one of the basic criteria for the diagnosis of CdLS is the detection of a pathogenic variant in one of the five genes associated with the syndrome: NIPBL, SMC1A, SMC3, HDAC8, RAD21. However, in about 30% of patients with a clinical diagnosis of CdLS, analysis of these genes does not confirm the clinical diagnosis. This is caused by the phenomenon of cellular mosaicism, which is a consequence of the negative selection of cells in relation to the pathogenic change and by the possibility of occurring pathogenic variants in different genes.

As part of this research project, comprehensive genetic tests were carried out using modern molecular biology methods in a group of patients with a clinical diagnosis of CdLS. The performed research allowed simultaneous analysis of the coding sequence and adjacent intron sequences of 24 genes whose protein products participate in the construction and functioning of the cohesin complex. To identify genetic variants, DNA isolated from peripheral blood and swab from the inner cheek of patients with CdLS was used. This methodology allowed the identification of both germinal and mosaic variants in the examined group of patients. In addition, selected genetic variants were analyzed at the RNA level to determine their possible effect on the disruption of the mRNA assembly process.

The obtained results allowed to state that the use of high-throughput and sensitive molecular methods and the use of DNA isolated from various germ layers allows the identification of the molecular basis in a larger number of patients with CdLS. In addition, analysis at the RNA level allows determining the pathogenicity and the correct classification of detected intron variants. The obtained results, published in three international journals, contributed to the deepening of knowledge on the molecular mechanisms responsible for the phenotypic and genotypic heterogeneity of patients with CdLS.