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

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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.

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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

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Acknowledgements

The authors thank the patients’ and the healthy controls’ families for participating in this study. In particular, they thank the Associazione Italiana di Volontariato Sindrome di Cornelia de Lange and the Mariani Foundation for their support and collaboration. This study was supported by grants from the Istituto Superiore di Sanità: ‘Rare Diseases’ Grant 526/A27 to L.L. (Istituto Auxologico Italiano) and ‘Rare Disease’ Grant to A.S. (Fondazione Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena).

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Authors and Affiliations

  1. Division of Medical Genetics, San Paolo School of Medicine, University of Milan, via A. di Rudinì 8, 20142, Milan, Italy

    Paola Castronovo, Cristina Gervasini & Lidia Larizza

  2. I Clinica Pediatrica, Fondazione Policlinico Mangiagalli e Regina Elena, Milan, Italy

    Anna Cereda, Donatella Milani & Angelo Selicorni

  3. Laboratory of Molecular Genetics, Istituto Auxologico Italiano, Milan, Italy

    Maura Masciadri, Silvia Russo & Lidia Larizza

Authors
  1. Paola Castronovo
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  2. Cristina Gervasini
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  3. Anna Cereda
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  4. Maura Masciadri
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  5. Donatella Milani
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  6. Silvia Russo
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  7. Angelo Selicorni
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  8. Lidia Larizza
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Corresponding author

Correspondence to Lidia Larizza.

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Responsible Editor: Wendy Bickmore.

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Castronovo, P., Gervasini, C., Cereda, A. et al. Premature chromatid separation is not a useful diagnostic marker for Cornelia de Lange syndrome. Chromosome Res 17, 763–771 (2009). https://doi.org/10.1007/s10577-009-9066-6

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  • DOI: https://doi.org/10.1007/s10577-009-9066-6

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