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De novo heterozygous mutations in SMC3 cause a range of Cornelia de Lange syndrome-overlapping phenotypes / Carolina Baquero Montoya  

Público ISBD Título : De novo heterozygous mutations in SMC3 cause a range of Cornelia de Lange syndrome-overlapping phenotypes Tipo de documento : documento electrónico Autores : Carolina Baquero Montoya, Fecha de publicación : 2015 Títulos uniformes : Human Mutation Idioma : Inglés (eng) Palabras clave : Cornelia de Lange syndrome  CdLS  SMC3  cohesin complex  CdLS-overlapping phenotypes  CdLS- like Resumen : Cornelia de Lange syndrome (CdLS) is characterized by facial dysmorphism, growth failure, intellectual disability, limb malformations, and multiple organ involvement. Mutations in five genes, encoding subunits of the cohesin complex (SMC1A, SMC3, RAD21) and its regulators (NIPBL, HDAC8), account for at least 70% of patients with CdLS or CdLS‐like phenotypes. To date, only the clinical features from a single CdLS patient with SMC3 mutation has been published. Here, we report the efforts of an international research and clinical collaboration to provide clinical comparison of 16 patients with CdLS‐like features caused by mutations in SMC3. Modeling of the mutation effects on protein structure suggests a dominant‐negative effect on the multimeric cohesin complex. When compared with typical CdLS, many SMC3‐associated phenotypes are also characterized by postnatal microcephaly but with a less distinctive craniofacial appearance, a milder prenatal growth retardation that worsens in childhood, few congenital heart defects, and an absence of limb deficiencies. While most mutations are unique, two unrelated affected individuals shared the same mutation but presented with different phenotypes. This work confirms that de novo SMC3 mutations account for ∼1%–2% of CdLS‐like phenotypes. Mención de responsabilidad : María Concepción Gil-Rodríguez, Matthew A Deardorff, Morad Ansari, Christopher A Tan, Ilaria Parenti, Carolina Baquero-Montoya, Lilian B Ousager, Beatriz Puisac, María Hernández-Marcos, María Esperanza Teresa-Rodrigo, Iñigo Marcos-Alcalde, Jan-Jaap Wesselink, Silvia Lusa-Bernal, Emilia K Bijlsma, Diana Braunholz, Inés Bueno-Martinez, Dinah Clark, Nicola S Cooper, Cynthia J Curry, Richard Fisher, Alan Fryer, Jaya Ganesh, Cristina Gervasini, Gabriele Gillessen-Kaesbach, Yiran Guo, Hakon Hakonarson, Robert J Hopkin, Maninder Kaur, Brendan J Keating, María Kibaek, Esther Kinning, Tjitske Kleefstra, Antonie D Kline, Ekaterina Kuchinskaya, Lidia Larizza, Yun R Li, Xuanzhu Liu, Milena Mariani, Jonathan D Picker, Ángeles Pié, Jelena Pozojevic, Ethel Queralt, Julie Richer, Elizabeth Roeder, Anubha Sinha, Richard H Scott, Joyce So, Katherine A Wusik, Louise Wilson, Jianguo Zhang, Paulino Gómez-Puertas, César H Casale, Lena Ström, Angelo Selicorni, Feliciano J Ramos, Laird G Jackson, Ian D Krantz Referencia : Hum Mutat. 2015 Apr;36(4):454-62. DOI (Digital Object Identifier) : 10.1002/humu.22761 PMID : 25655089 En línea : https://onlinelibrary.wiley.com/doi/abs/10.1002/humu.22761 Enlace permanente : https://hospitalpablotobon.cloudbiteca.com/pmb/opac_css/index.php?lvl=notice_display&id=3922 De novo heterozygous mutations in SMC3 cause a range of Cornelia de Lange syndrome-overlapping phenotypes [documento electrónico] / Carolina Baquero Montoya,  . - 2015. Obra : Human Mutation Idioma : Inglés (eng) Palabras clave : Cornelia de Lange syndrome  CdLS  SMC3  cohesin complex  CdLS-overlapping phenotypes  CdLS- like Resumen : Cornelia de Lange syndrome (CdLS) is characterized by facial dysmorphism, growth failure, intellectual disability, limb malformations, and multiple organ involvement. Mutations in five genes, encoding subunits of the cohesin complex (SMC1A, SMC3, RAD21) and its regulators (NIPBL, HDAC8), account for at least 70% of patients with CdLS or CdLS‐like phenotypes. To date, only the clinical features from a single CdLS patient with SMC3 mutation has been published. Here, we report the efforts of an international research and clinical collaboration to provide clinical comparison of 16 patients with CdLS‐like features caused by mutations in SMC3. Modeling of the mutation effects on protein structure suggests a dominant‐negative effect on the multimeric cohesin complex. When compared with typical CdLS, many SMC3‐associated phenotypes are also characterized by postnatal microcephaly but with a less distinctive craniofacial appearance, a milder prenatal growth retardation that worsens in childhood, few congenital heart defects, and an absence of limb deficiencies. While most mutations are unique, two unrelated affected individuals shared the same mutation but presented with different phenotypes. This work confirms that de novo SMC3 mutations account for ∼1%–2% of CdLS‐like phenotypes. Mención de responsabilidad : María Concepción Gil-Rodríguez, Matthew A Deardorff, Morad Ansari, Christopher A Tan, Ilaria Parenti, Carolina Baquero-Montoya, Lilian B Ousager, Beatriz Puisac, María Hernández-Marcos, María Esperanza Teresa-Rodrigo, Iñigo Marcos-Alcalde, Jan-Jaap Wesselink, Silvia Lusa-Bernal, Emilia K Bijlsma, Diana Braunholz, Inés Bueno-Martinez, Dinah Clark, Nicola S Cooper, Cynthia J Curry, Richard Fisher, Alan Fryer, Jaya Ganesh, Cristina Gervasini, Gabriele Gillessen-Kaesbach, Yiran Guo, Hakon Hakonarson, Robert J Hopkin, Maninder Kaur, Brendan J Keating, María Kibaek, Esther Kinning, Tjitske Kleefstra, Antonie D Kline, Ekaterina Kuchinskaya, Lidia Larizza, Yun R Li, Xuanzhu Liu, Milena Mariani, Jonathan D Picker, Ángeles Pié, Jelena Pozojevic, Ethel Queralt, Julie Richer, Elizabeth Roeder, Anubha Sinha, Richard H Scott, Joyce So, Katherine A Wusik, Louise Wilson, Jianguo Zhang, Paulino Gómez-Puertas, César H Casale, Lena Ström, Angelo Selicorni, Feliciano J Ramos, Laird G Jackson, Ian D Krantz Referencia : Hum Mutat. 2015 Apr;36(4):454-62. DOI (Digital Object Identifier) : 10.1002/humu.22761 PMID : 25655089 En línea : https://onlinelibrary.wiley.com/doi/abs/10.1002/humu.22761 Enlace permanente : https://hospitalpablotobon.cloudbiteca.com/pmb/opac_css/index.php?lvl=notice_display&id=3922

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Functional characterization of NIPBL physiological splice variants and eight splicing mutations in patients with Cornelia de Lange syndrome / Carolina Baquero Montoya    

Público ISBD Título : Functional characterization of NIPBL physiological splice variants and eight splicing mutations in patients with Cornelia de Lange syndrome Tipo de documento : documento electrónico Autores : Carolina Baquero Montoya, Fecha de publicación : 2014 Títulos uniformes : International Journal of Molecular Sciences Idioma : Inglés (eng) Palabras clave : CdLS  NIPBL  splicing mutations  physiological splicing Resumen : 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. Mención de responsabilidad : María E Teresa-Rodrigo, Juliane Eckhold, Beatriz Puisac, Andreas Dalski, María C Gil-Rodríguez, Diana Braunholz, Carolina Baquero, María Hernández-Marcos, Juan C de Karam, Milagros Ciero, Fernando Santos-Simarro, Pablo Lapunzina, Jolanta Wierzba, César H Casale, Feliciano J Ramos, Gabriele Gillessen-Kaesbach, Frank J Kaiser, Juan Pié Referencia : Int J Mol Sci. 2014 Jun 10;15(6):10350-64. DOI (Digital Object Identifier) : 10.3390/ijms150610350 PMID : 24918291 Derechos de uso : CC BY En línea : https://www.mdpi.com/1422-0067/15/6/10350 Enlace permanente : https://hospitalpablotobon.cloudbiteca.com/pmb/opac_css/index.php?lvl=notice_display&id=3782 Functional characterization of NIPBL physiological splice variants and eight splicing mutations in patients with Cornelia de Lange syndrome [documento electrónico] / Carolina Baquero Montoya,  . - 2014. Obra : International Journal of Molecular Sciences Idioma : Inglés (eng) Palabras clave : CdLS  NIPBL  splicing mutations  physiological splicing Resumen : 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. Mención de responsabilidad : María E Teresa-Rodrigo, Juliane Eckhold, Beatriz Puisac, Andreas Dalski, María C Gil-Rodríguez, Diana Braunholz, Carolina Baquero, María Hernández-Marcos, Juan C de Karam, Milagros Ciero, Fernando Santos-Simarro, Pablo Lapunzina, Jolanta Wierzba, César H Casale, Feliciano J Ramos, Gabriele Gillessen-Kaesbach, Frank J Kaiser, Juan Pié Referencia : Int J Mol Sci. 2014 Jun 10;15(6):10350-64. DOI (Digital Object Identifier) : 10.3390/ijms150610350 PMID : 24918291 Derechos de uso : CC BY En línea : https://www.mdpi.com/1422-0067/15/6/10350 Enlace permanente : https://hospitalpablotobon.cloudbiteca.com/pmb/opac_css/index.php?lvl=notice_display&id=3782

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Severe ipsilateral musculoskeletal involvement in a Cornelia de Lange patient with a novel NIPBL mutation / Carolina Baquero Montoya  

Público ISBD Título : Severe ipsilateral musculoskeletal involvement in a Cornelia de Lange patient with a novel NIPBL mutation Tipo de documento : documento electrónico Autores : Carolina Baquero Montoya, Fecha de publicación : 2014 Títulos uniformes : European Journal of Medical Genetics Idioma : Inglés (eng) Palabras clave : Cornelia de Lange syndrome  CdLS  HEAT repeat  ipsilateral  musculoskeletal involvement  NIPBL mutation  BHLHA9 duplication  exome sequencing Resumen : Cornelia de Lange Syndrome (CdLS) is a congenital autosomal dominant ( NIPBL , SMC3 and RAD21 ) or X-linked ( SMC1A and HDAC8 ) disorder characterized by facial dysmorphism, pre and postnatal growth retardation, developmental delay and/or intellectual disability, and multiorgan involvement. Musculoskeletal malformations are usually bilateral and affect mainly the upper limbs; the range goes from brachyclinodactyly to severe reduction defects. Instead lower extremities are usually less and mildly involved. Here, we report on a 3-year-old Senegalese boy with typical craniofacial CdLS features, pre and postnatal growth retardation, atrial septal defect, developmental delay and right ipsilateral limb malformations, consistent with oligodactyly of the 3rd and 4th fingers, tibial agenesis and fibula hypoplasia. Exome sequencing and Sanger sequencing showed a novel missense mutation in NIPBL gene (c.6647A>G; p.(Tyr2216Cys)), which affects a conserved residue located within NIPBL HEAT repeat elements. Pyrosequencing analysis of NIPBL gene, disclosed similar levels of wild-type and mutated alleles in DNA and RNA samples from all tissues analyzed (oral mucosa epithelial cells, peripheral blood leukocytes and fibroblasts). These findings indicated the absence of somatic mosaicism, despite of the segmental asymmetry of the limbs, and confirmed biallelic expression for NIPBL transcripts, respectively. Additionally, conditions like Split-hand/foot malformation with long-bone deficiency secondary to duplication of BHLHA9 gene have been ruled out by the array-CGH and MLPA analysis. To our knowledge, this is the first CdLS patient described with major ipsilateral malformations of both the upper and lower extremities, that even though this finding could be due to a random event, expands the spectrum of limb reduction defects in CdLS. Mención de responsabilidad : Carolina Baquero-Montoya, María-Concepción Gil-Rodríguez, María Hernández-Marcos, María-Esperanza Teresa-Rodrigo, Alicia Vicente-Gabas, María-Luisa Bernal, Cesar-Horacio Casale, Gloria Bueno-Lozano, Inés Bueno-Martínez, Ethel Queralt, Olaya Villa, Cristina Hernando-Davalillo, Lluís Armengol, Paulino Gómez-Puertas, Beatriz Puisac, Angelo Selicorni, Feliciano J Ramos, Juan Pié Referencia : Eur J Med Genet. 2014 Sep;57(9):503-9. DOI (Digital Object Identifier) : 10.1016/j.ejmg.2014.05.006 PMID : 24874887 En línea : https://linkinghub.elsevier.com/retrieve/pii/S0041-1345(12)01403-0 Enlace permanente : https://hospitalpablotobon.cloudbiteca.com/pmb/opac_css/index.php?lvl=notice_display&id=3795 Severe ipsilateral musculoskeletal involvement in a Cornelia de Lange patient with a novel NIPBL mutation [documento electrónico] / Carolina Baquero Montoya,  . - 2014. Obra : European Journal of Medical Genetics Idioma : Inglés (eng) Palabras clave : Cornelia de Lange syndrome  CdLS  HEAT repeat  ipsilateral  musculoskeletal involvement  NIPBL mutation  BHLHA9 duplication  exome sequencing Resumen : Cornelia de Lange Syndrome (CdLS) is a congenital autosomal dominant ( NIPBL , SMC3 and RAD21 ) or X-linked ( SMC1A and HDAC8 ) disorder characterized by facial dysmorphism, pre and postnatal growth retardation, developmental delay and/or intellectual disability, and multiorgan involvement. Musculoskeletal malformations are usually bilateral and affect mainly the upper limbs; the range goes from brachyclinodactyly to severe reduction defects. Instead lower extremities are usually less and mildly involved. Here, we report on a 3-year-old Senegalese boy with typical craniofacial CdLS features, pre and postnatal growth retardation, atrial septal defect, developmental delay and right ipsilateral limb malformations, consistent with oligodactyly of the 3rd and 4th fingers, tibial agenesis and fibula hypoplasia. Exome sequencing and Sanger sequencing showed a novel missense mutation in NIPBL gene (c.6647A>G; p.(Tyr2216Cys)), which affects a conserved residue located within NIPBL HEAT repeat elements. Pyrosequencing analysis of NIPBL gene, disclosed similar levels of wild-type and mutated alleles in DNA and RNA samples from all tissues analyzed (oral mucosa epithelial cells, peripheral blood leukocytes and fibroblasts). These findings indicated the absence of somatic mosaicism, despite of the segmental asymmetry of the limbs, and confirmed biallelic expression for NIPBL transcripts, respectively. Additionally, conditions like Split-hand/foot malformation with long-bone deficiency secondary to duplication of BHLHA9 gene have been ruled out by the array-CGH and MLPA analysis. To our knowledge, this is the first CdLS patient described with major ipsilateral malformations of both the upper and lower extremities, that even though this finding could be due to a random event, expands the spectrum of limb reduction defects in CdLS. Mención de responsabilidad : Carolina Baquero-Montoya, María-Concepción Gil-Rodríguez, María Hernández-Marcos, María-Esperanza Teresa-Rodrigo, Alicia Vicente-Gabas, María-Luisa Bernal, Cesar-Horacio Casale, Gloria Bueno-Lozano, Inés Bueno-Martínez, Ethel Queralt, Olaya Villa, Cristina Hernando-Davalillo, Lluís Armengol, Paulino Gómez-Puertas, Beatriz Puisac, Angelo Selicorni, Feliciano J Ramos, Juan Pié Referencia : Eur J Med Genet. 2014 Sep;57(9):503-9. DOI (Digital Object Identifier) : 10.1016/j.ejmg.2014.05.006 PMID : 24874887 En línea : https://linkinghub.elsevier.com/retrieve/pii/S0041-1345(12)01403-0 Enlace permanente : https://hospitalpablotobon.cloudbiteca.com/pmb/opac_css/index.php?lvl=notice_display&id=3795

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