Classic Cornelia de Lange syndrome phenotype in a patient with a mosaic NIPBL variant absent in blood

Here we describe a 13-year-old female, the first living child of Brazilian consanguineous parents after two miscarriages, who presents classic Cornelia de Lange syndrome (CdLS) phenotype. Features include microcephaly, synophrys, thick eyebrows, short nose, upturned nasal tip, long and smooth philtrum, thin upper lip vermilion, downturned corners of the mouth, short fifth finger, small hands and feet, hirsutism, pre- and postnatal growth failure, and global developmental delay. She also exhibits gastrointestinal abnormalities and required hospitalization for pneumonia. She can speak a few words and recognize letters. Whole exome sequencing (WES) and RNA sequencing from peripheral blood revealed no clinically relevant variants (Aoi et al. 2019, 10.1038/s10038-019-0643-z; Seyama et al. 2022, 10.1016/j.ygeno.2022.110468). However, WES performed with DNA extracted from buccal cells revealed a novel likely pathogenic variant in the NIPBL gene. The variant was present in 28% of the reads and was confirmed by Sanger sequencing. Manual curation of the peripheral blood WES data confirmed the absence of this variant. In summary, this case highlights the importance of investigating multiple tissues in cases with classic CdLS phenotype, particularly when clinically relevant variants are not identified in molecular tests performed with peripheral blood.