This poster (#3090F) will be presented at the 62nd Annual Meeting of the American Society of Human Genetics by Yu-Wei Cheng, our molecular fellow, Friday November 9: 3:15pm-4:15pm.  Stop by and learn more.

Background: Cornelia de Lange syndrome (CdLS) is a genetically heterogeneous disorder characterized by severe growth retardation, intellectual disability, upper-limb abnormalities, hirsutism and characteristic facial features.    Heterozygous mutations in the NIPBL, SMC1A and SMC3 cohesin-associated genes account for approximately 65% of patients with a diagnosis of CdLS; the majority of them have been found in NIPBL. Recent studies have shown that intragenic deletions and duplications in NIPBL are present in approximately 2-5% of patient with CdLS. 

Methods: In this study we explored the occurrence of intragenic NIPBL deletions and duplications in a large cohort of 510 NIPBL sequencing negative CdLS cases referred to our laboratory for NIBPL deletion/duplication testing.  Copy number analysis was performed by custom exon-targeted oligonucleotide array-CGH and/or MLPA. Whole-genome SNP array was used to further characterize rearrangements extending beyond the NIPBL gene.

Results: NIPBL copy number alterations were detected in 14 out of 510 (3%) patients, including 11 intragenic single- or multi-exon deletions, two duplications, and a deletion of exons 12 to 14 in a mosaic state. Clinical information was collected for 11out of14 patients and the clinical phenotype of these patients suggest that the majority have facial and physical features consistent with classic CdLS.

Conclusions: Our experience contribute to the growing amount of data on NIPBL-related copy number variations in patients with CdLS, supports the clinical usage of NIPBL deletion/duplication analysis in patients with negative NIPBL results by sequencing and widens the mutational spectrum of NIPBL mutations.