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Spectrum of NIPBL gene mutations in Polish patients with Cornelia de Lange syndrome.

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.

SUBMITTER: Kuzniacka A

PROVIDER: S-EPMC3548104 | biostudies-literature |

REPOSITORIES: biostudies-literature

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De novo NIPBL Mutations in Vietnamese Patients with Cornelia de Lange Syndrome.

Project description:Cornelia de Lange Syndrome (CdLS) is a rare congenital genetic disease causing abnormal unique facial phenotypes, several defects in organs and body parts, and mental disorder or intellectual disorder traits. Main causes of CdLS have been reported as variants in cohesin complex genes, in which mutations in the NIPBL gene have been estimated to account for up to 80%. Our study included three Vietnamese patients with typical CdLS phenotypes. Whole exome sequencing revealed two known heterozygous mutations c.6697G>A (p.Val2233Met) and c.2602C>T (p.Arg868X), and a novel heterozygous mutation c.4504delG (p.Val1502fsX87) in the NIPBL gene of the three patients. In silico analyses of the identified mutations predicted possible damaging and truncating effects on the NIPBL protein. Inherited analyses in the patients' families showed that all of the mutations are de novo. Our results lead a definitive diagnosis of patients with CdLS and expand the spectrum of mutations in the NIPBL gene. These findings also confirm whole exome sequencing is an efficient tool for genetic screening of CdLS.

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[NIPBL gene mutations in two children with Cornelia de Lange syndrome].

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Functional characterization of NIPBL physiological splice variants and eight splicing mutations in patients with Cornelia de Lange syndrome.

Project description:Cornelia de Lange syndrome (CdLS) is a congenital developmental disorder characterized by distinctive craniofacial features, growth retardation, cognitive impairment, limb defects, hirsutism, and multisystem involvement. Mutations in five genes encoding structural components (SMC1A, SMC3, RAD21) or functionally associated factors (NIPBL, HDAC8) of the cohesin complex have been found in patients with CdLS. In about 60% of the patients, mutations in NIPBL could be identified. Interestingly, 17% of them are predicted to change normal splicing, however, detailed molecular investigations are often missing. Here, we report the first systematic study of the physiological splicing of the NIPBL gene, that would reveal the identification of four new splicing isoforms ΔE10, ΔE12, ΔE33,34, and B'. Furthermore, we have investigated nine mutations affecting splice-sites in the NIPBL gene identified in twelve CdLS patients. All mutations have been examined on the DNA and RNA level, as well as by in silico analyses. Although patients with mutations affecting NIPBL splicing show a broad clinical variability, the more severe phenotypes seem to be associated with aberrant transcripts resulting in a shift of the reading frame.

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Case Report: Novel <i>NIPBL</i> Variants Cause Cornelia de Lange Syndrome in Chinese Patients.

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Molecular characterization of two novel intronic variants of NIPBL gene detected in unrelated Cornelia de Lange syndrome patients.

Project description:BackgroundCornelia de Lange syndrome (CdLS), a rare, multisystemic disorder, has been linked to genetic alterations in NIPBL, SMC1A, SMC3, HDAC8, and RAD21 genes. Approximately 60% of CdLS patients harbor various NIPBL variants. Genetic changes predicted to affect NIPBL gene splicing represent 15% of all NIPBL genetic abnormalities. Yet, only a few studies have investigated the molecular consequences of such variants.Case presentationThis study reports two novel, intronic NIPBL genetic variants in unrelated CdLS patients with the characteristic phenotype. A c.6954 + 3A > C substitution and a c.5862 + 1delG deletion were identified, one of each, in a 6 year-old boy and 39 month-old girl. Further studies confirmed that both variants introduce premature termination codons, resulting in the formation of truncated proteins p.(Ser2255LeufsTer20) and p.(Leu1955Ter), respectively.ConclusionSingle nucleotide alterations located within the conserved splice-donor site of intronic regions of the NIPBL gene can give rise to a premature termination of the translation and cause significant changes in the sequence of mRNA transcripts and NIPBL protein structure and function. The latter underline development of Cornelia de Lange syndrome phenotype.

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Cornelia de Lange Syndrome: A Newborn with Imperforate Anus and a NIPBL Mutation.

Project description:Cornelia de Lange syndrome is a dominantly inherited, genetically heterogeneous and clinically variable syndrome with multiple congenital anomalies and developmental delay. Gastrointestinal anomalies are common and an important cause of morbidity and mortality. We report on a newborn with a molecularly confirmed Cornelia de Lange syndrome who had an imperforate anus. This is the third report of Cornelia de Lange syndrome and imperforate anus.

| S-EPMC3529426 | biostudies-literature

Cornelia de Lange Syndrome: NIPBL haploinsufficiency downregulates canonical Wnt pathway in zebrafish embryos and patients fibroblasts.

Project description:Cornelia de Lange Syndrome is a severe genetic disorder characterized by malformations affecting multiple systems, with a common feature of severe mental retardation. Genetic variants within four genes (NIPBL (Nipped-B-like), SMC1A, SMC3, and HDAC8) are believed to be responsible for the majority of cases; all these genes encode proteins that are part of the 'cohesin complex'. Cohesins exhibit two temporally separated major roles in cells: one controlling the cell cycle and the other involved in regulating the gene expression. The present study focuses on the role of the zebrafish nipblb paralog during neural development, examining its expression in the central nervous system, and analyzing the consequences of nipblb loss of function. Neural development was impaired by the knockdown of nipblb in zebrafish. nipblb-loss-of-function embryos presented with increased apoptosis in the developing neural tissues, downregulation of canonical Wnt pathway genes, and subsequent decreased Cyclin D1 (Ccnd1) levels. Importantly, the same pattern of canonical WNT pathway and CCND1 downregulation was observed in NIPBL-mutated patient-specific fibroblasts. Finally, chemical activation of the pathway in nipblb-loss-of-function embryos rescued the adverse phenotype and restored the physiological levels of cell death.

| S-EPMC3824680 | biostudies-literature

Cerebellar Hypoperfusion in Two Patients with Cornelia de Lange Syndrome with Novel <i>NIPBL</i> Variants.

Project description:IntroductionCornelia de Lange syndrome (CdLS) is a rare congenital malformation characterized by distinctive facial features, short stature, and limb defects. In addition, half of the patients with CdLS exhibit repetitive self-injurious behaviors (SIBs) related to intellectual disability with autistic traits. CdLS is caused by pathogenic variants of genes encoding the cohesin complex pathway, with 70% of these variants identified in the nipped-B-like (NIPBL) gene.Case presentationWe report 2 patients with CdLS who exhibited repetitive SIBs. Patient 1, a 40-year-old male, carried a novel heterozygous duplication variant, c.1458dup, p.(Glu487*), in exon 9 of the NIPBL gene. Patient 2, a 49-year-old female, carried a novel heterozygous insertion variant, c.1751_1752ins[A;1652_1751], p.(Asp584Glufs*8), in exon 10 of the NIPBL gene. These variants were predicted to confer loss of function to the protein because of a premature stop codon. In both patients, single-photon emission computed tomography using N-isopropyl-p-[123I] iodoamphetamine (IMP-SPECT) revealed diffuse hypoperfusion in the cerebellum.DiscussionThis report identified 2 novel pathogenic variants in the NIPBL gene and the relationship between SIBs and cerebellar hypoperfusion in patients with CdLS. The cerebellar hypoperfusion might have been caused by the dysfunction of the cohesin complex via the downregulation of the NIPBL gene products. Further studies should be conducted to elucidate the contribution of the NIPBL gene to the development of the cerebello-cerebral cortical circuits associated with behavioral disorders.

| S-EPMC9911990 | biostudies-literature

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