Abstract
Background: Cornelia de Lange Syndrome (CdLS) is a heterogeneous disorder. Diverse expression of clinical symptoms can be caused by a variety of pathogenic variants located within the sequence of different genes correlated with the cohesin complex.Methods: Sixty-nine patients with confirmed clinical diagnosis of CdLS were enrolled in the study. Blood and buccal swab samples were collected for molecular studies. Mutational analysis was performed using the Next Generation (deep) Sequencing (NGS) covering 24 genes. In addition, the MLPA technique was applied to detect large rearrangements of NIPBL.Results: MLPA and NGS analysis were performed in 66 (95,7%) and 67 (97,1%) patients, respectively. Large rearrangements of NIPBL were not identified in the studied group. Germline pathogenic variants were detected in 18 (26,1%) patients. Fourteen variants (20,3%) were identified in NIPBL, two (2,9%) in SMC1A, and two (2,9%) in HDAC8. In total, 13 (18,8%) buccal swabs were suitable for deep sequencing. Mosaic variants were found in four (30,8%; 4/13) patients negative for germline alterations. Three mosaic substitutions were detected in NIPBL while one in KMT2A gene.Conclusions: Comprehensive and sensitive molecular techniques allow detecting novel pathogenic variants responsible for the molecular basis of CdLS. In addition, molecular testing of different tissues should be applied since such an approach allows detect mosaic variants specific for a subgroup of CdLS patients. Finally, to test possible pathogenicity of intronic variants, RNA analysis should be conducted.
Highlights
Cornelia de Lange Syndrome (CdLS; OMIM# 1227470, 300590, 610759, 614701, and 300882) is a heterogeneous disorder in relation to both patients’ phenotype and genotype [1, 2]
Current data suggest that these functions of the complex may be impaired in a group of CdLS patients
It is accepted that genetic variants are more frequently detected in CdLS patients with classic phenotype than in those with a mild phenotype
Summary
Cornelia de Lange Syndrome (CdLS; OMIM# 1227470, 300590, 610759, 614701, and 300882) is a heterogeneous disorder in relation to both patients’ phenotype and genotype [1, 2]. Alterations in genes encoding subunits or regulators of the cohesin complex, especially those in NIPBL, are detected in the majority of CdLS patients. The basic function of the cohesin complex is to control sister chromatids separation during mitosis and meiosis [3]. More recent studies indicate the involvement of the cohesin complex in other chromatin-related processes, namely in mediating sister chromatid cohesion, chromatin. Current data suggest that these functions of the complex may be impaired in a group of CdLS patients. Cornelia de Lange Syndrome (CdLS) is a heterogeneous disorder. Diverse expression of clinical symptoms can be caused by a variety of pathogenic variants located within the sequence of different genes correlated with the cohesin complex
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