fig 5

Fig. 5 | Molecular diagnostic pathways for cornelia de Lange syndrome. In individuals with the classic Cornelia de Lange syndrome (CdLS) phenotype, the first-line molecular diagnostic approach should be next-generation sequencing (NGS)-based screening — either gene panel, whole-exome sequencing (WES) or whole-genome sequencing (WGS) — including currently known CdLS genes (NIPBL, SMC1A, SMC3, RAD21, BRD4, HDAC8 and ANKRD11). If NGS is not available, molecular testing should begin with targeted sequencing of NIPBL. In individuals with the non-classic CdLS phenotype, the phenotype itself may allow experienced clinicians to determine which candidate gene should be sequenced first; if this cannot be determined, WES or WGS can be performed. In the case of negative results, NIPBL and subsequently the other CdLS genes should be tested for mosaicism using tissues other than blood, for example, fibroblasts, buccal swabs or bladder epithelial cells from urine. Deletion and duplication testing of NIPBL can be carried out using multiplex ligation-dependent probe amplification (MLPA) or chromosome microarray if first-line testing is not WES or WGS, through which deletions and duplications can be readily detected. If WES or WGS are used for first-line testing, the data can be investigated further for variants in other genes.