NIPBL mutations and genetic heterogeneity in Cornelia de Lange syndrome

INSERM U393 and Département de Génétique Médicale, Hôpital Necker - Enfants Malades, Paris, France.
Journal of Medical Genetics (Impact Factor: 6.34). 01/2005; 41(12):e128. DOI: 10.1136/jmg.2004.026666
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Available from: Damien Sanlaville, Oct 06, 2015
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    • "The genomic technology of array Comparative Genomic Hybridisation (aCGH), which monitors losses or gains in chromosome regions that may harbour novel candidate genes, is not yet a standard test for investigation of NIPBL- and SMC1A-mutation-negative CdLS patients [11,18,34,35], but results obtained with the technique to date are consistent with those of > 30 conventional cytogenetic and FISH-targeted studies that have shown chromosomal abnormalities associated with the CdLS phenotype involving almost all of the chromosomes (reviewed [36]). One study has used aCGH to study probands with CdLS-like features, who had been previously screened for mutations in the two major causative genes; however, this was performed in a relatively small patient cohort [35]. "
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    ABSTRACT: Background Cornelia de Lange syndrome (CdLS) is a rare autosomal-dominant disorder characterised by facial dysmorphism, growth and psychomotor developmental delay and skeletal defects. To date, causative mutations in the NIPBL (cohesin regulator) and SMC1A (cohesin structural subunit) genes account for > 50% and 6% of cases, respectively. Methods We recruited 50 patients with a CdLS clinical diagnosis or with features that overlap with CdLS, who were negative for mutations at NIPBL and SMC1A at molecular screening. Chromosomal rearrangements accounting for the clinical diagnosis were screened for using array Comparative Genomic Hybridisation (aCGH). Results Four patients were shown to carry imbalances considered to be candidates for having pathogenic roles in their clinical phenotypes: patient 1 had a 4.2 Mb de novo deletion at chromosome 20q11.2-q12; patient 2 had a 4.8 Mb deletion at chromosome 1p36.23-36.22; patient 3 carried an unbalanced translocation, t(7;17), with a 14 Mb duplication of chromosome 17q24.2-25.3 and a 769 Kb deletion at chromosome 7p22.3; patient 4 had an 880 Kb duplication of chromosome 19p13.3, for which his mother, who had a mild phenotype, was also shown to be a mosaic. Conclusions Notwithstanding the variability in size and gene content of the rearrangements comprising the four different imbalances, they all map to regions containing genes encoding factors involved in cell cycle progression or genome stability. These functional similarities, also exhibited by the known CdLS genes, may explain the phenotypic overlap between the patients included in this study and CdLS. Our findings point to the complexity of the clinical diagnosis of CdLS and confirm the existence of phenocopies, caused by imbalances affecting multiple genomic regions, comprising 8% of patients included in this study, who did not have mutations at NIPBL and SMC1A. Our results suggests that analysis by aCGH should be recommended for CdLS spectrum cases with an unexplained clinical phenotype and included in the flow chart for diagnosis of cases with a clinical evaluation in the CdLS spectrum.
    BMC Medical Genetics 04/2013; 14(1):41. DOI:10.1186/1471-2350-14-41 · 2.08 Impact Factor
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    • "De novo Classic 9 c.1012_1016delCAGAG p.Gln338* This study (novel) Unknown Classic 9 c.1051C>A p.Pro351Ser This study (novel) De novo Mild 9 c.1071A>C p.Lys357Asn This study (novel) De novo Classic 10 c.2296delA p.Arg766Glyfs*27 This study (novel) Unknown Classic 10 c.2322_2323delGA p.Lys776Thrfs*2 Yan et al. (2006) De novo Classic 10 c.2485_2486dupTG p.Glu829Valfs*19 This study (novel) Unknown Classic 10 c.2603G>A p.Arg868Gln This study (novel) De novo Classic 10 c.2920_2921delAA p.Lys974Glufs*19 Yan et al. (2006) De novo Classic 10 c.3060_3063delAGAG p.Glu1021Thrfs*22 This study (previously reported by Gillis et al. 2004; unknown ethnicity, and by Bhuiyan et al. 2006; Dutch patient) Unknown Classic 13 c.3525dupA p.Glu1176Argfs*10 Yan et al. (2006) De novo Classic 14 c.3619G>A p.Glu1207Lys This study (novel) De novo Classic 17 c.4015T>C p.Tyr1339His This study (novel) Unknown Mild 19 c.4306A>C p.Lys1436Gln This study (novel) Unknown Classic 20 c.4321G>T p.(Phe1442Lysfs*3, Val1441Leu) This study (previously reported by Pé et al. 2010 in a Spanish patient) De novo Mild 21 c.4450delC p.Pro1484Serfs*137 This study (novel) Unknown Classic 24 c.4873G>T p.Val1625Phe This study (novel) Unknown Mild 24 c.4909A>C p.Ile1637Leu This study (novel) De novo Mild 26 c.5167C>T p.Arg1723* Yan et al. (2006) (previously reported by Gillis et al. 2004 in two patients) De novo Classic 26 c.5164A>C p.Asn1722His This study (novel) De novo Classic 26 c.5207_5222del16 p.Ser1736* This study (novel) Unknown Classic 37 c.6409_6412delAAAC p.Lys2137Glnfs*33 This study (novel) Unknown Classic 37 c.6475G>T p.Glu2159* Yan et al. (2006) Unknown Classic 39 c.6653_6655delATA p.Asn2218del Yan et al. (2006) [previously reported by Borck et al. 2004 "
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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 · 1.48 Impact Factor
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    • "Recently, a second locus on the X-linked SMC1L1 gene, which encodes a different *Correspondence to: L. S. Chitty, Clinical Molecular Genetics Unit, Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK. E-mail: subunit of the cohesin complex, has been associated with BDLS (Musio et al., 2006; Borck et al., 2004) in less than 5% of cases (Gervasini et al., 2008). Many of the features of BDLS are potentially detectable before birth by fetal ultrasound examination; however, because of the variable presentation, the sporadic inheritance of the syndrome and the subtlety of the diagnostic findings, accurate prenatal diagnosis is rarely achieved (Golsby et al., 1995; Ackerman and Gilbert- Barness, 1997; Ranzini et al., 1997; Boog et al., 1999; Le Vaillant et al., 2004; Hulinsky et al., 2005; Lalatta et al., 2007; Barisic et al., 2008; Sepulveda et al., 2009). "
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    ABSTRACT: The objective was to improve the prenatal diagnosis of Brachmann-de Lange syndrome (BDLS) by defining the sonographic criteria. Retrospective review of Fetal Medicine Unit (FMU) notes from 1998 to 2009 to identify all cases seen with a final diagnosis of BDLS. Literature review undertaken to ascertain all cases where sonographic features of BDLS had been described. Information was pooled to define the most common features. Seven cases were identified from review of FMU records. The diagnosis was suspected prenatally in four of the seven. All had asymmetrical forearm defects with oligodactyly/polydactyly, five had intrauterine growth restriction (IUGR) and five had abnormal facial features including micrognathia and/or a long overhanging philtrum. A further 28 cases were identified in the literature, but the diagnosis was only suspected prenatally in nine. Overall the most common feature was IUGR (80%); upper limb anomalies were detected in nearly half of cases. Other common features included facial anomalies (40%), diaphragmatic hernia (34%), increased nuchal translucency/fold (37%) and cardiac anomalies (14%). Identification of asymmetrical oligodactyly with or without forearm anomalies associated with microcephaly and/or IUGR or diaphragmatic hernia are findings that should arouse suspicion of BDLS, although definitive diagnosis at present would have to await delivery in the majority of cases.
    Prenatal Diagnosis 09/2010; 30(9):865-72. DOI:10.1002/pd.2577 · 3.27 Impact Factor
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