Precocious sister chromatid separation (PSCS) in Cornelia de Lange syndrome

Abstract

The Cornelia de Lange syndrome (CdLS) (OMIM# 122470) is a dominantly inherited multisystem developmental disorder. The phenotype consists of characteristic facial features, hirsutism, abnormalities of the upper extremities ranging from subtle changes in the phalanges and metacarpal bones to oligodactyly and phocomelia, gastroesophageal dysfunction, growth retardation, and neurodevelopmental delay. Prevalence is estimated to be as high as 1 in 10,000. Recently, mutations in NIPBL were identified in sporadic and familial CdLS cases. To date, mutations in this gene have been identified in over 45% of individuals with CdLS. NIPBL is the human homolog of the Drosophila Nipped-B gene. Although its function in mammalian systems has not yet been elucidated, sequence homologs of Nipped-B in yeast (Scc2 and Mis4) are required for sister chromatid cohesion during mitosis, and a similar role was recently demonstrated for Nipped-B in Drosophila. In order to evaluate NIPBL role in sister chromatid cohesion in humans, metaphase spreads on 90 probands (40 NIPBL mutation positive and 50 NIPBL mutation negative) with CdLS were evaluated for evidence of precocious sister chromatid separation (PSCS). We screened 50 metaphases from each proband and found evidence of PSCS in 41% (compared to 9% in control samples). These studies indicate that NIPBL may play a role in sister chromatid cohesion in humans as has been reported for its homologs in Drosophila and yeast.

Fig. 1

Full face and profile of a child with typical facial features of Cornelia de Lange syndrome. Note ptosis, synophrys, long eyelashes, depressed nasal bridge with upturned nasal tip, posterior-rotated ears, thin upper lip with down-turned corners and a small chin.

Fig. 2

Metaphase spreads in individuals with CdLS and unaffected controls. A: Control metaphase spread stained with giemsa. B: Control C-stained metaphase. C–E: Metaphase spread from three individuals with CdLS stained with giemsa demonstrating PSCS. Note separated sister chromatids and centromeres present in practically all sister chromatids. F–H: C-stained metaphases from individuals with CdLS demonstrating the premature division and separation of the centromeres in the majority of sister chromatids. I: A metaphase form an individual with CdLS demonstrating apparent chromatid breaks (arrowheads).