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

• Published in: Genetics in medicine Vol. 14; no. 3; pp. 313 - 322
• Main Authors: Pehlivan, Davut, Hullings, Melanie, Carvalho, Claudia M.B., Gonzaga-Jauregui, Claudia G., Loy, Elizabeth, Jackson, Laird G., Krantz, Ian D., Deardorff, Matthew A., Lupski, James R.
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.03.2012; Elsevier Limited
• Subjects: 631/208/212; 631/208/737/1505; 692/699/375; Adolescent; Base Sequence; Biomedical and Life Sciences; Biomedicine; Breakpoints; Cell Cycle Proteins; Child; Child, Preschool; Chromosome Breakpoints; cohesin; Comparative Genomic Hybridization; Congenital defects; copy number; De Lange Syndrome - genetics; DNA microarrays; DNA Replication; Etiology; Exons; Facies; Female; Gene Deletion; Gene Order; Genetic Association Studies; genomics; haploinsufficiency; Hirsutism; Human Genetics; Humans; Hybridization analysis; Infant; Laboratory Medicine; Limbs; Male; Mental retardation; Molecular Sequence Data; Mutation; original-research-article; Phenotype; Proteins - genetics; Recombination, Genetic; Replication; Sequence Alignment; sister chromatids; genomic rearrangement; CNV; aCGH; CdLS
• ISSN: 1098-3600; 1530-0366; 1530-0366
• DOI: 10.1038/gim.2011.13

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. Genet Med 2012:14(3):313–322