Journal article
NIPBL rearrangements in Cornelia de Lange syndrome: evidence for replicative mechanism and genotype-phenotype correlation
Genetics in medicine, v 14(3), pp 313-322
01 Mar 2012
PMID: 22241092
Featured in Collection : UN Sustainable Development Goals @ Drexel
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 similar to 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 (similar to 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.
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Details
- Title
- NIPBL rearrangements in Cornelia de Lange syndrome: evidence for replicative mechanism and genotype-phenotype correlation
- Creators
- Davut Pehlivan - Baylor College of MedicineMelanie Hullings - Children's Hospital of PhiladelphiaClaudia M. B. Carvalho - Baylor College of MedicineClaudia G. Gonzaga-Jauregui - Baylor College of MedicineElizabeth Loy - Children's Hospital of PhiladelphiaLaird G. Jackson - Drexel UniversityIan D. Krantz - Children's Hospital of PhiladelphiaMatthew A. Deardorff - University of PennsylvaniaJames R. Lupski - Baylor College of Medicine
- Publication Details
- Genetics in medicine, v 14(3), pp 313-322
- Publisher
- Springer Nature
- Number of pages
- 10
- Grant note
- P01 HD052860 / National Institute of Child Health and Human Development (NICHD); United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD) M01RR000188 / NATIONAL CENTER FOR RESEARCH RESOURCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Center for Research Resources (NCRR) P01HD052860 / EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD) US CdLS Foundation K08HD055488 / National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA R01NS058529 / NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Neurological Disorders & Stroke (NINDS) K08HD055488 / EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH &HUMAN DEVELOPMENT; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD) 6-FY09-504 / Children's Hospital of Philadelphia
- Resource Type
- Journal article
- Language
- English
- Web of Science ID
- WOS:000301475100005
- Scopus ID
- 2-s2.0-84857885510
- Other Identifier
- 991019350675004721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Genetics & Heredity