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Genet Med. 2012 Mar;14(3):313-22. doi: 10.1038/gim.2011.13. Epub 2012 Jan 5.

NIPBL rearrangements in Cornelia de Lange syndrome: evidence for replicative mechanism and genotype-phenotype correlation.

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  • 1Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.

Abstract

PURPOSE:

Cornelia de Lange syndrome (CdLS) is a multisystem congenital anomaly disorder characterized by mental retardation, limb abnormalities, distinctive facial features, and hirsutism. Mutations in three genes involved in sister chromatid cohesion, NIPBL, SMC1A, and SMC3, account for ~55% of CdLS cases. The molecular etiology of a significant fraction of CdLS cases remains unknown. We hypothesized that large genomic rearrangements of cohesin complex subunit genes may play a role in the molecular etiology of this disorder.

METHODS:

Custom high-resolution oligonucleotide array comparative genomic hybridization analyses interrogating candidate cohesin genes and breakpoint junction sequencing of identified genomic variants were performed.

RESULTS:

Of the 162 patients with CdLS, for whom mutations in known CdLS genes were previously negative by sequencing, deletions containing NIPBL exons were observed in 7 subjects (~5%). Breakpoint sequences in five patients implicated microhomology-mediated replicative mechanisms-such as serial replication slippage and fork stalling and template switching/microhomology-mediated break-induced replication-as a potential predominant contributor to these copy number variations. Most deletions are predicted to result in haploinsufficiency due to heterozygous loss-of-function mutations; such mutations may result in a more severe CdLS phenotype.

CONCLUSION:

Our findings suggest a potential clinical utility to testing for copy number variations involving NIPBL when clinically diagnosed CdLS cases are mutation-negative by DNA-sequencing studies.

PMID:
22241092
[PubMed - indexed for MEDLINE]
PMCID:
PMC3556738
Free PMC Article
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