De novo heterozygous mutations in SMC3 cause a range of cornelia de lange syndrome-overlapping phenotypes

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 FisherAlan 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 Debra 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, Soma Das, Raoul C M Hennekam, Frank J. Kaiser, David R. Fitzpatrick, Juan Pié

Research output: Contribution to journalArticle

Abstract

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. Cornelia de Lange syndrome (CdLS) is a multisystem developmental disorder caused by mutation in five genes encoding subunits or regulators of the cohesin complex. To date, only the clinical features of the unique mildly affected CdLS male with SMC3 mutation have been published. Here, we report a series of 16 probands with 15 different intragenic mutations in SMC3 that provide a significant advance in our understanding of the clinical and molecular basis of Cornelia de Lange syndrome and overlapping phenotypes.

Original languageEnglish (US)
Pages (from-to)454-462
Number of pages9
JournalHuman Mutation
Volume36
Issue number4
DOIs
StatePublished - Apr 1 2015

Fingerprint

De Lange Syndrome
Phenotype
Mutation
Extremities
Microcephaly
Congenital Heart Defects
Growth
Intellectual Disability
Genes

Keywords

  • CdLS
  • CdLS-like
  • CdLS-overlapping phenotypes
  • Cohesin complex
  • Cornelia de Lange syndrome
  • SMC3

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Medicine(all)

Cite this

Gil-Rodríguez, M. C., Deardorff, M. A., Ansari, M., Tan, C. A., Parenti, I., Baquero-Montoya, C., ... Pié, J. (2015). De novo heterozygous mutations in SMC3 cause a range of cornelia de lange syndrome-overlapping phenotypes. Human Mutation, 36(4), 454-462. https://doi.org/10.1002/humu.22761

De novo heterozygous mutations in SMC3 cause a range of cornelia de lange syndrome-overlapping phenotypes. / Gil-Rodríguez, María Concepción; Deardorff, Matthew A.; Ansari, Morad; Tan, Christopher A.; Parenti, Ilaria; Baquero-Montoya, Carolina; Ousager, Lilian B.; Puisac, Beatriz; Hernández-Marcos, María; Teresa-Rodrigo, María Esperanza; Marcos-Alcalde, Iñigo; Wesselink, Jan Jaap; Lusa-Bernal, Silvia; Bijlsma, Emilia K.; Braunholz, Diana; Bueno-Martinez, Inés; Clark, Dinah; Cooper, Nicola S.; Curry, Cynthia J.; Fisher, Richard; Fryer, Alan; Ganesh, Jaya; Gervasini, Cristina; Gillessen-Kaesbach, Gabriele; Guo, Yiran; Hakonarson, Hakon; Hopkin, Robert J.; Kaur, Maninder; Keating, Brendan J.; Kibaek, María; Kinning, Esther; Kleefstra, Tjitske; Kline, Antonie Debra; Kuchinskaya, Ekaterina; Larizza, Lidia; Li, Yun R.; Liu, Xuanzhu; Mariani, Milena; Picker, Jonathan D.; Pié, Ángeles; Pozojevic, Jelena; Queralt, Ethel; Richer, Julie; Roeder, Elizabeth; Sinha, Anubha; Scott, Richard H.; So, Joyce; Wusik, Katherine A.; Wilson, Louise; Zhang, Jianguo; Gómez-Puertas, Paulino; Casale, César H.; Ström, Lena; Selicorni, Angelo; Ramos, Feliciano J.; Jackson, Laird G.; Krantz, Ian D.; Das, Soma; Hennekam, Raoul C M; Kaiser, Frank J.; Fitzpatrick, David R.; Pié, Juan.

In: Human Mutation, Vol. 36, No. 4, 01.04.2015, p. 454-462.

Research output: Contribution to journalArticle

Gil-Rodríguez, MC, Deardorff, MA, Ansari, M, Tan, CA, Parenti, I, Baquero-Montoya, C, Ousager, LB, Puisac, B, Hernández-Marcos, M, Teresa-Rodrigo, ME, Marcos-Alcalde, I, Wesselink, JJ, Lusa-Bernal, S, Bijlsma, EK, Braunholz, D, Bueno-Martinez, I, Clark, D, Cooper, NS, Curry, CJ, Fisher, R, Fryer, A, Ganesh, J, Gervasini, C, Gillessen-Kaesbach, G, Guo, Y, Hakonarson, H, Hopkin, RJ, Kaur, M, Keating, BJ, Kibaek, M, Kinning, E, Kleefstra, T, Kline, AD, Kuchinskaya, E, Larizza, L, Li, YR, Liu, X, Mariani, M, Picker, JD, Pié, Á, Pozojevic, J, Queralt, E, Richer, J, Roeder, E, Sinha, A, Scott, RH, So, J, Wusik, KA, Wilson, L, Zhang, J, Gómez-Puertas, P, Casale, CH, Ström, L, Selicorni, A, Ramos, FJ, Jackson, LG, Krantz, ID, Das, S, Hennekam, RCM, Kaiser, FJ, Fitzpatrick, DR & Pié, J 2015, 'De novo heterozygous mutations in SMC3 cause a range of cornelia de lange syndrome-overlapping phenotypes', Human Mutation, vol. 36, no. 4, pp. 454-462. https://doi.org/10.1002/humu.22761
Gil-Rodríguez MC, Deardorff MA, Ansari M, Tan CA, Parenti I, Baquero-Montoya C et al. De novo heterozygous mutations in SMC3 cause a range of cornelia de lange syndrome-overlapping phenotypes. Human Mutation. 2015 Apr 1;36(4):454-462. https://doi.org/10.1002/humu.22761
Gil-Rodríguez, María Concepción ; Deardorff, Matthew A. ; Ansari, Morad ; Tan, Christopher A. ; Parenti, Ilaria ; Baquero-Montoya, Carolina ; Ousager, Lilian B. ; Puisac, Beatriz ; Hernández-Marcos, María ; Teresa-Rodrigo, María Esperanza ; Marcos-Alcalde, Iñigo ; Wesselink, Jan Jaap ; Lusa-Bernal, Silvia ; Bijlsma, Emilia K. ; Braunholz, Diana ; Bueno-Martinez, Inés ; Clark, Dinah ; Cooper, Nicola S. ; Curry, Cynthia J. ; Fisher, Richard ; Fryer, Alan ; Ganesh, Jaya ; Gervasini, Cristina ; Gillessen-Kaesbach, Gabriele ; Guo, Yiran ; Hakonarson, Hakon ; Hopkin, Robert J. ; Kaur, Maninder ; Keating, Brendan J. ; Kibaek, María ; Kinning, Esther ; Kleefstra, Tjitske ; Kline, Antonie Debra ; Kuchinskaya, Ekaterina ; Larizza, Lidia ; Li, Yun R. ; Liu, Xuanzhu ; Mariani, Milena ; Picker, Jonathan D. ; Pié, Ángeles ; Pozojevic, Jelena ; Queralt, Ethel ; Richer, Julie ; Roeder, Elizabeth ; Sinha, Anubha ; Scott, Richard H. ; So, Joyce ; Wusik, Katherine A. ; Wilson, Louise ; Zhang, Jianguo ; Gómez-Puertas, Paulino ; Casale, César H. ; Ström, Lena ; Selicorni, Angelo ; Ramos, Feliciano J. ; Jackson, Laird G. ; Krantz, Ian D. ; Das, Soma ; Hennekam, Raoul C M ; Kaiser, Frank J. ; Fitzpatrick, David R. ; Pié, Juan. / De novo heterozygous mutations in SMC3 cause a range of cornelia de lange syndrome-overlapping phenotypes. In: Human Mutation. 2015 ; Vol. 36, No. 4. pp. 454-462.
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T1 - De novo heterozygous mutations in SMC3 cause a range of cornelia de lange syndrome-overlapping phenotypes

AU - Gil-Rodríguez, María Concepción

AU - Deardorff, Matthew A.

AU - Ansari, Morad

AU - Tan, Christopher A.

AU - Parenti, Ilaria

AU - Baquero-Montoya, Carolina

AU - Ousager, Lilian B.

AU - Puisac, Beatriz

AU - Hernández-Marcos, María

AU - Teresa-Rodrigo, María Esperanza

AU - Marcos-Alcalde, Iñigo

AU - Wesselink, Jan Jaap

AU - Lusa-Bernal, Silvia

AU - Bijlsma, Emilia K.

AU - Braunholz, Diana

AU - Bueno-Martinez, Inés

AU - Clark, Dinah

AU - Cooper, Nicola S.

AU - Curry, Cynthia J.

AU - Fisher, Richard

AU - Fryer, Alan

AU - Ganesh, Jaya

AU - Gervasini, Cristina

AU - Gillessen-Kaesbach, Gabriele

AU - Guo, Yiran

AU - Hakonarson, Hakon

AU - Hopkin, Robert J.

AU - Kaur, Maninder

AU - Keating, Brendan J.

AU - Kibaek, María

AU - Kinning, Esther

AU - Kleefstra, Tjitske

AU - Kline, Antonie Debra

AU - Kuchinskaya, Ekaterina

AU - Larizza, Lidia

AU - Li, Yun R.

AU - Liu, Xuanzhu

AU - Mariani, Milena

AU - Picker, Jonathan D.

AU - Pié, Ángeles

AU - Pozojevic, Jelena

AU - Queralt, Ethel

AU - Richer, Julie

AU - Roeder, Elizabeth

AU - Sinha, Anubha

AU - Scott, Richard H.

AU - So, Joyce

AU - Wusik, Katherine A.

AU - Wilson, Louise

AU - Zhang, Jianguo

AU - Gómez-Puertas, Paulino

AU - Casale, César H.

AU - Ström, Lena

AU - Selicorni, Angelo

AU - Ramos, Feliciano J.

AU - Jackson, Laird G.

AU - Krantz, Ian D.

AU - Das, Soma

AU - Hennekam, Raoul C M

AU - Kaiser, Frank J.

AU - Fitzpatrick, David R.

AU - Pié, Juan

PY - 2015/4/1

Y1 - 2015/4/1

N2 - 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. Cornelia de Lange syndrome (CdLS) is a multisystem developmental disorder caused by mutation in five genes encoding subunits or regulators of the cohesin complex. To date, only the clinical features of the unique mildly affected CdLS male with SMC3 mutation have been published. Here, we report a series of 16 probands with 15 different intragenic mutations in SMC3 that provide a significant advance in our understanding of the clinical and molecular basis of Cornelia de Lange syndrome and overlapping phenotypes.

AB - 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. Cornelia de Lange syndrome (CdLS) is a multisystem developmental disorder caused by mutation in five genes encoding subunits or regulators of the cohesin complex. To date, only the clinical features of the unique mildly affected CdLS male with SMC3 mutation have been published. Here, we report a series of 16 probands with 15 different intragenic mutations in SMC3 that provide a significant advance in our understanding of the clinical and molecular basis of Cornelia de Lange syndrome and overlapping phenotypes.

KW - CdLS

KW - CdLS-like

KW - CdLS-overlapping phenotypes

KW - Cohesin complex

KW - Cornelia de Lange syndrome

KW - SMC3

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