Chromosome Research

, Volume 17, Issue 6, pp 763–771

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

  • Paola Castronovo
  • Cristina Gervasini
  • Anna Cereda
  • Maura Masciadri
  • Donatella Milani
  • Silvia Russo
  • Angelo Selicorni
  • Lidia Larizza
Article

DOI: 10.1007/s10577-009-9066-6

Cite this article as:
Castronovo, P., Gervasini, C., Cereda, A. et al. Chromosome Res (2009) 17: 763. doi:10.1007/s10577-009-9066-6

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.

Keywords

Cornelia de Lange syndromepremature chromatid separationcohesin complexdiagnostic flowchart

Abbreviations

CdLS

Cornelia de Lange syndrome

CGH

comparative genomic hybridization

DHPLC

denaturing high-performance liquid chromatography

FISH

fluorescence in-situ hybridization

MLPA

multiple ligation-dependent probe amplification

MVA

multiple variegated aneuploidy

NIPBL

Nipped-B-like

PCS

premature chromatid separation

SCC2

sister chromatid cohesion protein 2

SMC

structural maintenance of chromosomes

Copyright information

© Springer Science+Business Media B.V. 2009

Authors and Affiliations

  • Paola Castronovo
    • 1
  • Cristina Gervasini
    • 1
  • Anna Cereda
    • 2
  • Maura Masciadri
    • 3
  • Donatella Milani
    • 2
  • Silvia Russo
    • 3
  • Angelo Selicorni
    • 2
  • Lidia Larizza
    • 1
    • 3
  1. 1.Division of Medical Genetics, San Paolo School of MedicineUniversity of MilanMilanItaly
  2. 2.I Clinica Pediatrica, Fondazione Policlinico Mangiagalli e Regina ElenaMilanItaly
  3. 3.Laboratory of Molecular Genetics, Istituto Auxologico ItalianoMilanItaly