NIPBL Mutational Analysis in 120 Individuals with Cornelia de Lange Syndrome and Evaluation of Genotype-Phenotype Correlations

Division of Human Genetics and Molecular Biology, The Children's Hospital of Philadelphia, Philadelphia, PA 19104-4318, USA.
The American Journal of Human Genetics (Impact Factor: 10.93). 11/2004; 75(4):610-23. DOI: 10.1086/424698
Source: PubMed


The Cornelia de Lange syndrome (CdLS) is a multisystem developmental disorder characterized by facial dysmorphia, upper-extremity malformations, hirsutism, cardiac defects, growth and cognitive retardation, and gastrointestinal abnormalities. Both missense and protein-truncating mutations in NIPBL, the human homolog of the Drosophila melanogaster Nipped-B gene, have recently been reported to cause CdLS. The function of NIPBL in mammals is unknown. The Drosophila Nipped-B protein facilitates long-range enhancer-promoter interactions and plays a role in Notch signaling and other developmental pathways, as well as being involved in mitotic sister-chromatid cohesion. We report the spectrum and distribution of NIPBL mutations in a large well-characterized cohort of individuals with CdLS. Mutations were found in 56 (47%) of 120 unrelated individuals with sporadic or familial CdLS. Statistically significant phenotypic differences between mutation-positive and mutation-negative individuals were identified. Analysis also suggested a trend toward a milder phenotype in individuals with missense mutations than in those with other types of mutations.

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Available from: Michela Devoto, Jul 10, 2014
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    • "on chromosomes 5 (NIP-BL), 10 (SMC3) and X linked SMC1A and HDAC8 genes (Deardorff et al., 2007; Deardorff et al., 2012; Gillis et al., 2004; Krantz et al., 2004; Musio et al., 2006; Tonkin, et al., 2004). It is a malformation disorder with a distinctive physical appearance, small stature, medical complications and variable developmental and behavioral presentation. "
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    ABSTRACT: Little is known about the way in which the characteristics of autism spectrum disorder (ASD) develop and manifest across the age span in individuals with genetic syndromes. In this study we present findings from a two and a half year follow-up of the characteristics associated with ASD in three syndromes: Cornelia de Lange (CdLS), Fragile X (FXS), and Cri du Chat (CdCS). Parents and carers of 251 individuals (CdLS = 67, CdCS = 42, and FXS = 142) completed the Social Communication Questionnaire (SCQ) at Time 1 (T1) and again two and a half years later (T2). The FXS and CdLS groups were more likely to meet the cut-offs for both autism and ASD and show greater severity of ASD related behaviors, at both T1 and T2, compared to the CdCS group. Older individuals (>15yrs) with CdLS were more likely to meet the cut off for ASD than younger individuals (≤ 15yrs) with the syndrome and more likely to show greater severity of social impairments. In FXS repetitive behaviors were found to become less prominent with age and in CdCS social impairments were reported to be more severe with age. There were no significant changes between T1 and T2 in the severity of ASD characteristics in the CdCS and CdLS groups. The FXS group showed significantly fewer repetitive behaviors and less severe impairments in social interaction over this time frame. The findings suggest that while there may be similarities in overall severity and presentation of ASD characteristics in CdLS and FXS, these characteristics have divergent patterns of development within these groups. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
    Full-text · Article · May 2015 · American Journal of Medical Genetics Part C Seminars in Medical Genetics
    • "Cycling parameters were as follows: 36 cycles of: 94°C - 30 s; 55-62°C - 45 s, 72°C - 30 s; 72°C for 5 min final extension. The primer sequences were obtained from the study carried out by Gillis et al. 2004.[11] Table 1 shows primer sequences along with product size. "
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    ABSTRACT: Cornelia de Lange syndrome (CdLS) is a multisystem developmental disorder in children. The disorder is caused mainly due to mutations in Nipped-B-like protein. The molecular data for CdLS is available from developed countries, but not available in developing countries like India. In the present study, the hotspot region of NIPBL gene was screened by Polymerase Chain Reaction which includes exon 2, 22, 42, and a biggest exon 10, in six CdLS patients and ten controls. The method adopted in present study was amplification of the target exon by using polymerase chain reaction, qualitative confirmation of amplicons by Agarose Gel Electrophoresis and use of amplicons for Conformation Sensitive Gel Electrophoresis to find heteroduplex formation followed by sequencing. We report two polymorphisms in the studied region of gene NIPBL. The polymorphisms are in the region of intron 1 and in exon 10. The polymorphism C/A is present in intron 1 region and polymorphism T/G in exon 10. The intronic region polymorphism may have a role in intron splicing whereas the polymorphism in exon 10 results in amino acid change (Val to Gly). These polymorphisms are disease associated as these are found in CdLS patients only and not in controls.
    No preview · Article · Mar 2013 · Indian Journal of Human Genetics
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    • "In the current study, the mutation detection yield of 42 % was similar to the mean value observed in the previously published reports, although the mutation detection rate differs considerably between published studies, ranging from 26 to 70 % (Borck et al. 2004; Gillis et al. 2004; Miyake et al. 2005; Yan et al. 2006; Bhuiyan et al. 2006; Schoumans et al. 2007; Selicorni et al. 2007; Kline et al. 2007; Pié et al. 2010). The observed discrepancies between the studies could result from the size of the group, accuracy of clinical diagnosis, selection of patients for the study or even differences in methods used for molecular analysis. "
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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.
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