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Cornelia de Lange syndrome is caused by mutations in NIPBL, the human homolog of Drosophila melanogaster Nipped-B. Nat Genet

Division of Human Genetics and Molecular Biology, The Children's Hospital of Philadelphia and The University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
Nature Genetics (Impact Factor: 29.65). 07/2004; 36(6):631-5. DOI: 10.1038/ng1364
Source: PubMed

ABSTRACT Cornelia de Lange syndrome (CdLS; OMIM 122470) is a dominantly inherited multisystem developmental disorder characterized by growth and cognitive retardation; abnormalities of the upper limbs; gastroesophageal dysfunction; cardiac, ophthalmologic and genitourinary anomalies; hirsutism; and characteristic facial features. Genital anomalies, pyloric stenosis, congenital diaphragmatic hernias, cardiac septal defects, hearing loss and autistic and self-injurious tendencies also frequently occur. Prevalence is estimated to be as high as 1 in 10,000 (ref. 4). We carried out genome-wide linkage exclusion analysis in 12 families with CdLS and identified four candidate regions, of which chromosome 5p13.1 gave the highest multipoint lod score of 2.7. This information, together with the previous identification of a child with CdLS with a de novo t(5;13)(p13.1;q12.1) translocation, allowed delineation of a 1.1-Mb critical region on chromosome 5 for the gene mutated in CdLS. We identified mutations in one gene in this region, which we named NIPBL, in four sporadic and two familial cases of CdLS. We characterized the genomic structure of NIPBL and found that it is widely expressed in fetal and adult tissues. The fly homolog of NIPBL, Nipped-B, facilitates enhancer-promoter communication and regulates Notch signaling and other developmental pathways in Drosophila melanogaster.

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    • "Cornelia de Lange syndrome (CdLS; OMIM #122470, #300590, and #610759), a cohesinopathy, is caused by single mutations in cohesin complex genes [Krantz et al., 2004; Tonkin et al., 2004; Musio et al., 2006]. Among cohesin genes, mutations in NIPBL (5p13) account for up to 50% of cases, while those in SMC3 (10q25) and SMC1A (Xp11) appear to cause a smaller proportion of instances of CdLS. "
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    ABSTRACT: Cornelia de Lange syndrome (CdLS) is a cohesinopathy causing delayed growth and limb deficits. Individuals with CdLS have mild to profound intellectual disability and autistic features. This study characterizes the behavioral phenotype of children with CdLS, focusing on autistic features, maladaptive behaviors, and impact of age. Children with CdLS (5–18 years) were administered normed instruments to characterize autism features (Childhood Autism Rating Scale, CARS), maladaptive behaviors (Aberrant Behavior Checklist), and adaptive skills (Vineland Adaptive Behaviors Scales). CdLS features and severity were rated with Diagnostic Criteria for CdLS. Forty-one children with CdLS (23 females, 18 males) were classified as having “no autism” (n = 7; 17.1%), “mild autism” (n = 17; 41.4%), and “severe autism” (n = 17; 41.4%), using CARS scores. Characteristic items were abnormal emotional response, stereotypies, odd object use, rigidity, lack of verbal communication, and low intellectual functioning. Verbal communication deficits and repetitive behaviors were higher compared to sensory, social cognition, and behavior abnormalities (P ≤ 0.0001). Maladaptive behaviors associated with autism traits were stereotypies (P = 0.003), hyperactivity (P = 0.01), and lethargy (P = 0.03). Activities of daily living were significantly affected; socialization adaptive skills were a relative strength. However, with advancing age, both socialization (P < 0.0001) and communication (P = 0.001) domains declined significantly. CdLS is characterized by autistic features, notably excessive repetitive behaviors and expressive language deficits. While other adaptive skills are impacted, socialization adaptive skills are less affected. Advancing age can worsen communication and socialization deficits relative to neurotypical peers. © 2014 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part A 06/2014; 164(6). DOI:10.1002/ajmg.a.36573 · 2.05 Impact Factor
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    • "The disorder is referred to as a cohesinopathy, since it is caused by alterations in genes involved in the proper interaction of the cohesin complex, such as NIPBL, PDS5 (coding cohesion regulators) and SMC1, SMC3, RAD21 (coding proteins of the core of the cohesin complex) (Krantz et al. 2004; Tonkin et al. 2004; Zhang et al. 2009; Musio et al. 2006; Deardorff et al. 2007; Deardorff et al. 2012a). The primary function of the cohesin complex is to regulate chromosome segregation during cell division; however, cohesion is also implicated in the regulation of gene expression and DNA repair (Dorsett and Krantz 2009; Feeney et al. 2010). "
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    ABSTRACT: Cornelia de Lange syndrome (CdLS) is a rare multi-system genetic disorder characterised by growth and developmental delay, distinctive facial dysmorphism, limb malformations and multiple organ defects. The disease is caused by mutations in genes responsible for the formation and regulation of cohesin complex. About half of the cases result from mutations in the NIPBL gene coding delangin, a protein regulating the initialisation of cohesion. To date, approximately 250 point mutations have been identified in more than 300 CdLS patients worldwide. In the present study, conducted on a group of 64 unrelated Polish CdLS patients, 25 various NIPBL sequence variants, including 22 novel point mutations, were detected. Additionally, large genomic deletions on chromosome 5p13 encompassing the NIPBL gene locus were detected in two patients with the most severe CdLS phenotype. Taken together, 42 % of patients were found to have a deleterious alteration affecting the NIPBL gene, by and large private ones (89 %). The review of the types of mutations found so far in Polish patients, their frequency and correlation with the severity of the observed phenotype shows that Polish CdLS cases do not significantly differ from other populations.
    Journal of applied genetics 12/2012; 54(1). DOI:10.1007/s13353-012-0126-9 · 1.90 Impact Factor
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    • "The diagnosis of Cornelia de Lange syndrome (CdLS) can be made clinically based on distinctive craniofacial appearance, limb deformities, hirsutism, and growth failure with significant developmental delays and intellectual disability. To date, three genes, NIPBL, SMC1A, and SMC3, all involved in the regulation or structure of the cohesin complex, have been identified to cause CdLS when mutated [Krantz et al., 2004; Tonkin et al., 2004; Musio et al., 2006; Deardorff et al., 2007]. Mutations are detected in approximately 60% of patients. "
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    ABSTRACT: Congenital heart disease (CHD) has been reported to occur in 14-70% of individuals with Cornelia de Lange syndrome (CdLS, OMIM 122470) and accounts for significant morbidity and mortality when present. Charts from a cohort of 479 patients with CdLS were reviewed for cardiac evaluations, gene testing and information to determine phenotypic severity. Two hundred fifty-nine individuals had either documented structural defects or minor cardiac findings. The presence of CHD was then quantified as a function of mutation status and severity of CdLS: mild, moderate, or severe. Different types of CHD were also evaluated by mutation status to assess for any genotype-phenotype correlation. NIPBL, SMC1A, and SMC3 mutation-positive patients were equally likely to have CHD, although the number of SMC1A and SMC3 mutation-positive patients were small in comparison. Structural CHDs were more likely to be present in individuals with moderate and severe CdLS than in the mild phenotype. This study evaluates the trends of CHD seen in the CdLS population and correlates these findings with genotype. © 2012 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part A 10/2012; 158A(10):2499-505. DOI:10.1002/ajmg.a.35582 · 2.05 Impact Factor
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