Premature chromatid separation is not a useful diagnostic marker for Cornelia de Lange syndrome

Abstract

Cornelia de Lange syndrome (CdLS) is a rare, multiple congenital anomaly/mental retardation syndrome characterized by clinical variability and caused by mutations in the NIPBL (50-60%), SMC1L1 and SMC3 genes (5%), which encode for proteins involved in sister chromatid cohesion. Almost all of the studies of premature chromatid separation (PCS) in CdLS patients have failed to demonstrate that it is specific to CdLS, thus making its diagnostic use controversial. In order to verify the diagnostic usefulness of PCS screening in CdLS, we analysed metaphase spreads from 29 CdLS patients and 24 controls using a rigorous protocol to induce PCS, and precise criteria to score the affected chromosomes. Following exclusion of significant intra-sample variation we scored under blind conditions 150 spreads from a single preparation of each case and computed the ratio between the number of prematurely separated chromatids and the total number of chromatids. The results indicate the extreme variability of PCS in both cohorts (CdLS: mean 2.8 +/- 2.8%; controls: mean 4.0 +/- 5.4%) and highlight the difficulty of PCS monitoring, especially when selecting the control population. The absence of any difference in the frequency of PCS between the patients and controls, or between patients with different clinical or genetic backgrounds, precludes its potential use as an additional diagnostic tool.

Isolated NIBPL missense mutations that cause Cornelia de Lange syndrome alter MAU2 interaction

“…48 We have performed PSCS assays on available LCLs from patients with the NIPBL p.Gly15Arg, NIPBL p.Leu254Val and MAU2 p.Gln4_Ala8del and did not appreciate any abnormal sister chromatid separation.…”

Cohesin codes – interpreting chromatin architecture and the many facets of cohesin function

“…Cohesin and establishment mutations also result in developmental maladies, such as Roberts Syndrome/SC-phocomelia or Cornelia de Lange syndrome, that impart growth and mental retardation, severe limb reduction, and numerous facial abnormalities (Gordillo et al, 2008;Krantz et al, 2004;Musio et al, 2006;Tonkin et al, 2004;Vega et al, 2005;Deardorff et al, 2007;Deardorff et al, 2012b). A subset of cohesinopathies arise through deregulation of transcription programs (Gartenberg, 2009;Dorsett, 2011), based on the observation that cells from Cornelia de Lange patients can appear almost normal in terms of sister chromatid tethering (Castronovo et al, 2009;Revenkova et al, 2009). Cohesins similarly play a key role in DNA repair, and defective DNA repair in combination with transcription deregulation further impacts development (Dorsett and Ström, 2012).…”

DNA-dependent cohesin cleavage by separase

“…These findings helped to understand why mutations in cohesin subunits SMC1, SMC3 and cohesin loading protein SCC2 lead to an array of developmental defects, described as Cornelia De Lange syndrome, without having a detrimental effect on mitotic progression. [32][33][34][35] We hypothesize that in order to restore the transcriptional function of cohesin immediately after mitosis, a mechanism has evolved in vertebrates to protect most cohesin from separase cleavage, while allowing complete separation of sister chromatids at the same time. This mechanism includes three components (Fig.…”