Dataset Information

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

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

SUBMITTER: Pehlivan D

PROVIDER: S-EPMC3556738 | biostudies-literature | 2012 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Pehlivan Davut D Hullings Melanie M Carvalho Claudia M B CM Gonzaga-Jauregui Claudia G CG Loy Elizabeth E Jackson Laird G LG Krantz Ian D ID Deardorff Matthew A MA Lupski James R JR

Genetics in medicine : official journal of the American College of Medical Genetics 20120105 3

<h4>Purpose</h4>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 th ...[more]

PMID: 22241092

Similar Datasets

Project description:BackgroundCornelia de Lange (CdLS) is a rare genetic disorder that affects most body systems. Variants in multiple genes including NIPBL and SMC1A, can cause the syndrome. To date, literature on genotype-phenotype associations in individuals with CdLS is extremely limited, although studies suggest some differences in clinical phenotype severity across variants. This study aimed to examine and compare neurobehavioral differences and developmental variability across CdLS genes, specifically NIPBL and SMC1A, and identify genotype-phenotype correlations.Participants and methodsThis patient-reported outcomes study included accessing data from the Coordination of Rare Diseases registry at Sanford. Parents of a total of 26 children/adults with CdLS and a known variant in NIPBL (Mean age = 20.46 years, SD = 11.21) and 12 with a known variant in SMC1A (Mean age = 11.08 years, SD = 9.04) completed a series of questionnaires regarding their child's developmental history. This included attainment of common language and motor milestones, intervention history, and behavior functioning. Developmental history and reported behavior regulation difficulties were compared across variant groups.ResultsOverall, individuals with a pathogenic variant in NIPBL or SMC1A were similarly delayed across motor and language milestones with about 70% not using phrase speech and 30-50% not walking by 5 years of age. However, those with NIPBL variants showed more severity in behavioral phenotype, namely with more repetitive behaviors, tantrums, and withdrawn behaviors. In addition, these individuals were more likely than those with SMC1A variants to demonstrate self-injurious behaviors, and anxiety. Both groups yielded a similar proportion of participants who participated in speech and occupational therapy, however those with SMC1A variants were more likely to engage in physical therapy. Both clinical groups report low rate of communicative or assistive device use despite a large proportion of participants never mastering single word or sentence use.ConclusionsStudy results are consistent with recent investigations highlighting more severe behavioral phenotype, particularly autistic features, anxiety, and behavior regulation challenges, among those with NIPBL variants albeit comparable developmental milestones. Both groups endorsed very elevated attention problems. Findings highlight importance of early interventions, including behavioral health services.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets