Incidence and clinical features of X-linked Cornelia de Lange syndrome due toSMC1L1 mutations

Borck, Guntram; Zarhrate, Mohamed; Bonnefont, Jean‐Paul; Münnich, Arnold; Cormier‐Daire, Valérie; Colleaux, Laurence

doi:10.1002/humu.9478

Cited by 68 publications

(65 citation statements)

References 19 publications

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“…Mutations in SMC1A and SMC3 result in a phenotype with few structural anomalies, but moderate-to-severe mental retardation. [11][12][13][14] NIPBL function The NIPBL gene encodes a highly conserved protein, NIPBL or delangin, which contains HEAT-repeat protein interaction motifs, a glutamine-rich domain and a predicted bipartite nuclear localization signal. 6,8,15 Upon the identification of its role in CdLS, it was noted to have homology to Drosophila Nipped-B, 16 identified as a transcriptional regulator, and yeast Scc2, a key component of sister chromatid cohesion.…”

Section: Cdlsmentioning

confidence: 99%

Isolated NIBPL missense mutations that cause Cornelia de Lange syndrome alter MAU2 interaction

et al. 2011

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Cornelia de Lange syndrome (CdLS; or Brachmann-de Lange syndrome) is a dominantly inherited congenital malformation disorder with features that include characteristic facies, cognitive delays, growth retardation and limb anomalies. Mutations in nearly 60% of CdLS patients have been identified in NIPBL, which encodes a regulator of the sister chromatid cohesion complex. NIPBL, also known as delangin, is a homolog of yeast and amphibian Scc2 and C. elegans PQN-85. Although the exact mechanism of NIPBL function in sister chromatid cohesion is unclear, in vivo yeast and C. elegans experiments and in vitro vertebrate cell experiments have demonstrated that NIPBL/Scc2 functionally interacts with the MAU2/Scc4 protein to initiate loading of cohesin onto chromatin. To test the significance of this model in the clinical setting of CdLS, we fine-mapped the NIPBL-MAU2 interaction domain and tested the functional significance of missense mutations and variants in NIPBL and MAU2 identified in these minimal domains in a cohort of patients with CdLS. We demonstrate that specific novel mutations at the N-terminus of the MAU2-interacting domain of NIPBL result in markedly reduced MAU2 binding, although we appreciate no consistent clinical difference in the small group of patients with these mutations. These data suggest that factors in addition to MAU2 are essential in determining the clinical features and severity of CdLS.

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Section: Cdlsmentioning

confidence: 99%

Isolated NIBPL missense mutations that cause Cornelia de Lange syndrome alter MAU2 interaction

et al. 2011

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“…Since the identification of SMC1A [Musio et al, 2006] and the provision of a genetic test to clinically evaluate Cornelia de Lange patients that are negative for mutations of the major (and first identified) gene NIPBL, only 44 CdLS cases harboring 29 different SMC1A mutations have been described worldwide [Borck et al, 2007;Deardorff et al, 2007;Liu et al, 2009;Limongelli et al, 2010;Mannini et al, 2010;Pie et al, 2010;Hoppman-Chaney et al, 2011; http://grenada.lumc.nl/LOVD2/CDLS/home.php? select_db¼SMC1A].…”

Section: Discussionmentioning

confidence: 99%

“…Mutations in SMC1A (Structural Maintenance of Chromosomes 1A) (OMIM 300040), located at Xp11.22 and reported to escape X-inactivation in humans [Brown et al, 1995], account for about 5% of clinically diagnosed CdLS patients who are characterized by phenotypic features similar to, but usually milder than those of the much more numerous (up to 65%) CdLS patients with NIBPL mutations [Borck et al, 2007;Deardorff et al, 2007;Limongelli et al, 2010;Pié et al, 2010;Rohatgi et al, 2010;Hoppman-Chaney et al, 2011]. To date, 44 CdLS individuals harboring 29 unique SMC1A mutations (23 missense and six in-frame deletions) have been described: 33 sporadic and 11 belonging to four families, with a 2:1 female:male ratio (29 females and 14 males plus one patient whose sex was not specified) [Borck et al, 2007;Deardorff et al, 2007;Liu et al, 2009;Limongelli et al, 2010;Mannini et al, 2010;Pié et al, 2010;Hoppman-Chaney et al, 2011, http://grenada.lumc.nl/LOVD2/CDLS/home.php?select_db¼SMC1A].…”

Section: Introductionmentioning

confidence: 99%

“…To date, 44 CdLS individuals harboring 29 unique SMC1A mutations (23 missense and six in-frame deletions) have been described: 33 sporadic and 11 belonging to four families, with a 2:1 female:male ratio (29 females and 14 males plus one patient whose sex was not specified) [Borck et al, 2007;Deardorff et al, 2007;Liu et al, 2009;Limongelli et al, 2010;Mannini et al, 2010;Pié et al, 2010;Hoppman-Chaney et al, 2011, http://grenada.lumc.nl/LOVD2/CDLS/home.php?select_db¼SMC1A]. A few generalities about life-permissive SMC1A mutations have emerged, which are invariably missense and in-frame deletions and that apparently affect all the following protein domains: the N-and C-ATP-binding heads, the coiled-coils, and the coiled-coil/hinge junctions.…”

Section: Introductionmentioning

confidence: 99%

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Cornelia de Lange individuals with new and recurrent SMC1A mutations enhance delineation of mutation repertoire and phenotypic spectrum

Gervasini

Russo

Cereda

et al. 2013

American J of Med Genetics Pt A

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We report on the clinical and molecular characterization of eight patients, one male and seven females, with clinical diagnosis of Cornelia de Lange syndrome (CdLS), who were found to carry distinct mutations of the SMC1A gene. Five of the eight mutations are novel, with two involving amino acid residues previously described as altered in a different way. The other three have been reported each in a single case. Comparison of pairs of individuals with the same mutation indicates only partial overlap of their clinical phenotypes. The following novel missense mutations, all affecting highly conserved amino acid residues, were found: p.R398G in the N‐terminal coiled‐coil domain, p.V651M in the C‐terminal coiled‐coil/hinge junction, p.R693G in the C‐terminal coiled‐coil, and p.N1166T and p.L1189F in the C‐terminal ABC cassette. The latter is localized in the H‐loop, and represents the first mutation involving a functional motif of SMC1A protein. The effect of the mutations on SMC1A protein function has been predicted using four bioinformatic tools. All mutations except p.V651M were scored as pathogenic by three or four of the tools. p.V651M was found in the only male individual of our cohort, who presented with the most severe phenotype. This raises the issue of gender effect when addressing mutation‐phenotype correlation for genes such as SMC1A, which incompletely escapes X‐inactivation. Our clinical and molecular findings expand the total number of characterized SMC1A‐mutated patients (from 44 to 52) and the restricted repertoire of SMC1A mutations (from 29 to 34), contributing to the molecular and clinical signature of SMC1A‐based CdLS. © 2013 Wiley Periodicals, Inc.

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“…35,36 This is a clinically heterogeneous developmental disorder characterized by malformations affecting multiple systems, including dysmorphic facial features, distal limb defects, cleft palate growth retardation and developmental delay. [35][36][37][38][39][40][41] Mutations in HUWE1 cause XLID with moderate-to-severe ID often coupled with disturbances to speech development. 20,42,43 Of the ID genes in this cluster, HUWE1 is the only one known to be dosage-sensitive, with twofold overexpression in males leading to mild-to-profound cognitive impairment in syndromic XLID, Turner type.…”

Section: Xp112 Microduplications C Moey Et Almentioning

confidence: 99%

Xp11.2 microduplications including IQSEC2, TSPYL2 and KDM5C genes in patients with neurodevelopmental disorders

et al. 2015

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Copy number variations are a common cause of intellectual disability (ID). Determining the contribution of copy number variants (CNVs), particularly gains, to disease remains challenging. Here, we report four males with ID with sub-microscopic duplications at Xp11.2 and review the few cases with overlapping duplications reported to date. We established the extent of the duplicated regions in each case encompassing a minimum of three known disease genes TSPYL2, KDM5C and IQSEC2 with one case also duplicating the known disease gene HUWE1. Patients with a duplication encompassing TSPYL2, KDM5C and IQSEC2 without gains of nearby SMC1A and HUWE1 genes have not been reported thus far. All cases presented with ID and significant deficits of speech development. Some patients also manifested behavioral disturbances such as hyperactivity and attention-deficit/ hyperactivity disorder. Lymphoblastic cell lines from patients show markedly elevated levels of TSPYL2, KDM5C and SMC1A, transcripts consistent with the extent of their CNVs. The duplicated region in our patients contains several genes known to escape X-inactivation, including KDM5C, IQSEC2 and SMC1A. In silico analysis of expression data in selected gene expression omnibus series indicates that dosage of these genes, especially IQSEC2, is similar in males and females despite the fact they escape from X-inactivation in females. Taken together, the data suggest that gains in Xp11.22 including IQSEC2 cause ID and are associated with hyperactivity and attention-deficit/hyperactivity disorder, and are likely to be dosage-sensitive in males.

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Incidence and clinical features of X-linked Cornelia de Lange syndrome due toSMC1L1 mutations

Cited by 68 publications

References 19 publications

Isolated NIBPL missense mutations that cause Cornelia de Lange syndrome alter MAU2 interaction

Isolated NIBPL missense mutations that cause Cornelia de Lange syndrome alter MAU2 interaction

Cornelia de Lange individuals with new and recurrent SMC1A mutations enhance delineation of mutation repertoire and phenotypic spectrum

Xp11.2 microduplications including IQSEC2, TSPYL2 and KDM5C genes in patients with neurodevelopmental disorders

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