Mutations and variants in the cohesion factor genes NIPBL, SMC1A, and SMC3 in a cohort of 30 unrelated patients with Cornelia de Lange syndrome

Pié, Juan; Gil-Rodríguez, María Concepción; Ciero, Milagros; López-Viñas, Eduardo; Ribate, María Pilar; Arnedo, María; Deardorff, Matthew A.; Puisac, Beatriz; Legarreta, Jesús; Karam, Juan C. de; Rubio, Encarnación Sonia Soriano; Bueno, Inés; Baldellou, A; Calvo, M.; Casals, Núria; Olivares, José L.; Losada, Ana; Hegardt, Fausto G.; Krantz, Ian D.; Gómez‐Puertas, Paulino; Ramos, Feliciano J.

doi:10.1002/ajmg.a.33348

Cited by 76 publications

(73 citation statements)

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“…The intragenic exon 3 deletion of patient 3 (which cDNA analysis indicates as predicting protein truncation) deserves comment because this exon encodes a delangin domain that interacts with the Mau-2 protein required for the binding of cohesin to chromosomes. 22 The consequence of the deletion (p.Leu22GlnfsX3) is the same as that predicted by the nonsense mutation described in the literature 23,24 and the splicing mutation (c.65-5A.G) found in two of our CdLS patients 7 (plus unpublished data). Patients 2 and 3, whose deletions skip exons within the NIPBL amino terminus, have a very mild phenotype (clinical scores of 20 and 18) even though it is predicted that they are haploinsufficient for the protein.…”

Section: Discussionsupporting

confidence: 87%

Intragenic and large NIPBL rearrangements revealed by MLPA in Cornelia de Lange patients

et al. 2012

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Cornelia de Lange syndrome (CdLS) is a rare multisystemic congenital anomaly disorder that is characterised by intellectual disability and growth retardation, congenital heart defects, intestinal anomalies, facial dysmorphism (including synophyris and high arched eyebrows) and limb reduction defects. Mutations in three cohesin-associated genes encoding a key regulator (NIPBL, chr 5p13.2) and one structural component of the cohesin ring (SMC1A, chr Xp11) occur in about 65% of CdLS patients. NIPBL is the major causative gene, and accounts for 40-60% of CdLS patients as shown by a number of mutational screening studies that indicate a wide mutational repertoire of mainly small deletions and point mutations. Only a few data are available concerning the occurrence of large NIPBL rearrangements or intragenic deletions or duplications involving whole exons. We used multiplex ligation-dependent probe amplification (MLPA) to study 132 CdLS patients negative to the standard mutation NIPBL test out of a cohort of 200 CdLS patients. A total of 7 out of 132 patients were found to carry NIPBL alterations, including two large gene deletions extending beyond the gene, four intragenic multi-or single-exon deletions and one singleexon duplication. These findings show that MLPA leads to a 5.3% increase in the detection of mutations when used in addition to the standard NIPBL scan, and contributes per se to the molecular diagnosis of 3.5% (7/200) of clinically diagnosed CdLS patients. It is recommended that MLPA be included in the CdLS diagnostic flow chart.

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Section: Discussionsupporting

confidence: 87%

Intragenic and large NIPBL rearrangements revealed by MLPA in Cornelia de Lange patients

et al. 2012

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“…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%

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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“…Es importante mencionar que en la última década se han podido establecer los genes causales de varias enfermedades genéticas mediante la resonancia magnética (26)(27)(28)(29), lo que hace cada vez más expedita la confirmación de enfermedades con diagnóstico clínico.…”

Section: Discussionunclassified

Etiología del retardo mental en la infancia: experiencia en dos centros de tercer nivel

2013

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Introducción. De 1 a 3 % de la población mundial tiene retardo mental. Este trastorno constituye un motivo de consulta y diagnóstico frecuente en los servicios de Neuropediatría. Objetivo. Determinar la etiología en pacientes con retraso mental que asisten a la consulta de Neuropediatría en dos centros hospitalarios de tercer nivel. Materiales y métodos. Se incluyeron pacientes pediátricos con diagnóstico de retardo mental, para cuya evaluación se empleó el algoritmo diagnóstico propuesto por el Comité de Genética Médica y Academia de Pediatría. Los datos se registraron en una base de Excel ™ y posteriormente se analizaron en SPSS ™ , versión 1.5. La causa etiológica de la discapacidad cognitiva se clasificó en cinco categorías. Resultados. Se incluyeron 239 pacientes. Según la gravedad, 39 % de los pacientes presentaron retardo mental leve, 37,7 %, moderado, 13,4%, grave, y 9,6 %, profundo. Entre las manifestaciones clínicas se destacó la presencia de anomalías menores en el 70,3 %, hallazgos que al encontrarse en más de dos sugirieron una causa de origen genético. La etiología definitiva del retardo mental se determinó en el 64,4 %. Las causas ambientales explicaron el 36,4% de esta discapacidad, en la cual la hipoxia perinatal fue la más frecuente. Las causas genéticas explicaron el 23,8 % de los casos. Finalmente, el 23,8 % persistieron sin diagnóstico específico. Conclusiones. La hipoxia perinatal es la causa más frecuente de discapacidad cognitiva. Es por esto que el tratamiento precoz de las enfermedades concomitantes del recién nacido prematuro pueden causar un impacto en el resultado final, disminuyendo la discapacidad motora y cognitiva. La segunda causa de retardo mental es la genética. La proporción de pacientes sin diagnóstico específico posiblemente podría disminuirse si el acceso de esta población a estudios de genética fuera mayor y los estudios pudieran ser cubiertos, en cualquiera de sus afiliaciones, por el sistema de salud del país.Palabras clave: discapacidad intelectual/etiología, anoxia, genética. doi: http://dx.doi.org/10.7705/biomedica.v33i3.785

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Mutations and variants in the cohesion factor genes NIPBL, SMC1A, and SMC3 in a cohort of 30 unrelated patients with Cornelia de Lange syndrome

Cited by 76 publications

References 21 publications

Intragenic and large NIPBL rearrangements revealed by MLPA in Cornelia de Lange patients

Intragenic and large NIPBL rearrangements revealed by MLPA in Cornelia de Lange patients

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

Etiología del retardo mental en la infancia: experiencia en dos centros de tercer nivel

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