Phenotypes and genotypes in individuals with SMC1A variants

Sylvia Huisman; Paul A. Mulder; Egbert Redeker; Ingrid Bader; Anne Marie Bisgaard; Alice Brooks; Anna Cereda; Constanza Cinca; Dinah Clark; Valerie Cormier-Daire; Matthew A. Deardorff; Karin Diderich; Mariet Elting; Anthonie van Essen; David FitzPatrick; Cristina Gervasini; Gabriele Gillessen-Kaesbach; Katta M. Girisha; Yvonne Hilhorst-Hofstee; Saskia Hopman; Denise Horn; Mala Isrie; Sandra Jansen; Cathrine Jespersgaard; Frank J. Kaiser; Maninder Kaur; Tjitske Kleefstra; Ian D. Krantz; Phillis Lakeman; Annemiek Landlust; Davor Lessel; Caroline Michot; Jo Moss; Sarah E. Noon; Chris Oliver; Ilaria Parenti; Juan Pie; Feliciano J. Ramos; Claudine Rieubland; Silvia Russo; Angelo Selicorni; Zeynep Tümer; Rieneke Vorstenbosch; Tara L. Wenger; Ingrid van Balkom; Sigrid Piening; Jolanta Wierzba; Raoul C. Hennekam

doi:10.1002/ajmg.a.38279

Phenotypes and genotypes in individuals with SMC1A variants

Sylvia Huisman^*, Paul A. Mulder, Egbert Redeker, Ingrid Bader, Anne Marie Bisgaard, Alice Brooks, Anna Cereda, Constanza Cinca, Dinah Clark, Valerie Cormier-Daire, Matthew A. Deardorff, Karin Diderich, Mariet Elting, Anthonie van Essen, David FitzPatrick, Cristina Gervasini, Gabriele Gillessen-Kaesbach, Katta M. Girisha, Yvonne Hilhorst-Hofstee, Saskia HopmanDenise Horn, Mala Isrie, Sandra Jansen, Cathrine Jespersgaard, Frank J. Kaiser, Maninder Kaur, Tjitske Kleefstra, Ian D. Krantz, Phillis Lakeman, Annemiek Landlust, Davor Lessel, Caroline Michot, Jo Moss, Sarah E. Noon, Chris Oliver, Ilaria Parenti, Juan Pie, Feliciano J. Ramos, Claudine Rieubland, Silvia Russo, Angelo Selicorni, Zeynep Tümer, Rieneke Vorstenbosch, Tara L. Wenger, Ingrid van Balkom, Sigrid Piening, Jolanta Wierzba, Raoul C. Hennekam

^*Corresponding author for this work

Institute of Human Genetics

88 Citations (Scopus)

Abstract

SMC1A encodes one of the proteins of the cohesin complex. SMC1A variants are known to cause a phenotype resembling Cornelia de Lange syndrome (CdLS). Exome sequencing has allowed recognizing SMC1A variants in individuals with encephalopathy with epilepsy who do not resemble CdLS. We performed an international, interdisciplinary study on 51 individuals with SMC1A variants for physical and behavioral characteristics, and compare results to those in 67 individuals with NIPBL variants. For the Netherlands all known individuals with SMC1A variants were studied, both with and without CdLS phenotype. Individuals with SMC1A variants can resemble CdLS, but manifestations are less marked compared to individuals with NIPBL variants: growth is less disturbed, facial signs are less marked (except for periocular signs and thin upper vermillion), there are no major limb anomalies, and they have a higher level of cognitive and adaptive functioning. Self-injurious behavior is more frequent and more severe in the NIPBL group. In the Dutch group 5 of 13 individuals (all females) had a phenotype that shows a remarkable resemblance to Rett syndrome: epileptic encephalopathy, severe or profound intellectual disability, stereotypic movements, and (in some) regression. Their missense, nonsense, and frameshift mutations are evenly spread over the gene. We conclude that SMC1A variants can result in a phenotype resembling CdLS and a phenotype resembling Rett syndrome. Resemblances between the SMC1A group and the NIPBL group suggest that a disturbed cohesin function contributes to the phenotype, but differences between these groups may also be explained by other underlying mechanisms such as moonlighting of the cohesin genes.

Original language	English
Journal	American Journal of Medical Genetics, Part A
Volume	173
Issue number	8
Pages (from-to)	2108-2125
Number of pages	18
ISSN	1552-4825
DOIs	https://doi.org/10.1002/ajmg.a.38279
Publication status	Published - 08.2017

Funding

We are exceptionally grateful to the patients with SMC1A variants and their families who participated in this study. We are very grateful to the Prinsenstichting for funding in part the work of SH, and to the Dutch and Polish CdLS Associations for cooperation in the development of detailed clinical data NIPBL positive patients. We sincerely thank Dr Alina Kuzniacka and Natalia Krawczy?ska from Department of Biology and Genetics, Medical University in Gda?sk for molecular analysis. This work was supported by National Institutes of Health Grants UMO-2014/15/B/NZ5/03503. This work was supported by the Spanish Ministry of Health ? ISCIII, Fondo de Investigaci?n Sanitaria (FIS) [Ref: PI15/00707] and the Diputaci?n General de Arag?n [Grupo Consolidado B20], European Social Fund (?Construyendo Europa desde Arag?n?) to FJRF and JPJ. This work was funded by the German Federal Ministry of Education and Research (BMBF, CHROMATIN-Net) to FJK and GG-K. We dedicate this manuscript to the excellent clinician and caregiver, a colleague and a friend, Ton van Essen, who died during the preparation of the manuscript.

Research Areas and Centers

Research Area: Medical Genetics

DFG Research Classification Scheme

2.22-03 Human Genetics

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1002/ajmg.a.38279

Cite this

Huisman, S., Mulder, P. A., Redeker, E., Bader, I., Bisgaard, A. M., Brooks, A., Cereda, A., Cinca, C., Clark, D., Cormier-Daire, V., Deardorff, M. A., Diderich, K., Elting, M., van Essen, A., FitzPatrick, D., Gervasini, C., Gillessen-Kaesbach, G., Girisha, K. M., Hilhorst-Hofstee, Y., ... Hennekam, R. C. (2017). Phenotypes and genotypes in individuals with SMC1A variants. American Journal of Medical Genetics, Part A, 173(8), 2108-2125. https://doi.org/10.1002/ajmg.a.38279

@article{f437c0c0a50a43f7b463116c629e4606,

title = "Phenotypes and genotypes in individuals with SMC1A variants",

abstract = "SMC1A encodes one of the proteins of the cohesin complex. SMC1A variants are known to cause a phenotype resembling Cornelia de Lange syndrome (CdLS). Exome sequencing has allowed recognizing SMC1A variants in individuals with encephalopathy with epilepsy who do not resemble CdLS. We performed an international, interdisciplinary study on 51 individuals with SMC1A variants for physical and behavioral characteristics, and compare results to those in 67 individuals with NIPBL variants. For the Netherlands all known individuals with SMC1A variants were studied, both with and without CdLS phenotype. Individuals with SMC1A variants can resemble CdLS, but manifestations are less marked compared to individuals with NIPBL variants: growth is less disturbed, facial signs are less marked (except for periocular signs and thin upper vermillion), there are no major limb anomalies, and they have a higher level of cognitive and adaptive functioning. Self-injurious behavior is more frequent and more severe in the NIPBL group. In the Dutch group 5 of 13 individuals (all females) had a phenotype that shows a remarkable resemblance to Rett syndrome: epileptic encephalopathy, severe or profound intellectual disability, stereotypic movements, and (in some) regression. Their missense, nonsense, and frameshift mutations are evenly spread over the gene. We conclude that SMC1A variants can result in a phenotype resembling CdLS and a phenotype resembling Rett syndrome. Resemblances between the SMC1A group and the NIPBL group suggest that a disturbed cohesin function contributes to the phenotype, but differences between these groups may also be explained by other underlying mechanisms such as moonlighting of the cohesin genes.",

author = "Sylvia Huisman and Mulder, \{Paul A.\} and Egbert Redeker and Ingrid Bader and Bisgaard, \{Anne Marie\} and Alice Brooks and Anna Cereda and Constanza Cinca and Dinah Clark and Valerie Cormier-Daire and Deardorff, \{Matthew A.\} and Karin Diderich and Mariet Elting and \{van Essen\}, Anthonie and David FitzPatrick and Cristina Gervasini and Gabriele Gillessen-Kaesbach and Girisha, \{Katta M.\} and Yvonne Hilhorst-Hofstee and Saskia Hopman and Denise Horn and Mala Isrie and Sandra Jansen and Cathrine Jespersgaard and Kaiser, \{Frank J.\} and Maninder Kaur and Tjitske Kleefstra and Krantz, \{Ian D.\} and Phillis Lakeman and Annemiek Landlust and Davor Lessel and Caroline Michot and Jo Moss and Noon, \{Sarah E.\} and Chris Oliver and Ilaria Parenti and Juan Pie and Ramos, \{Feliciano J.\} and Claudine Rieubland and Silvia Russo and Angelo Selicorni and Zeynep T{\"u}mer and Rieneke Vorstenbosch and Wenger, \{Tara L.\} and \{van Balkom\}, Ingrid and Sigrid Piening and Jolanta Wierzba and Hennekam, \{Raoul C.\}",

note = "Funding Information: We are exceptionally grateful to the patients with SMC1A variants and their families who participated in this study. We are very grateful to the Prinsenstichting for funding in part the work of SH, and to the Dutch and Polish CdLS Associations for cooperation in the development of detailed clinical data NIPBL positive patients. We sincerely thank Dr Alina Kuzniacka and Natalia Krawczy?ska from Department of Biology and Genetics, Medical University in Gda?sk for molecular analysis. This work was supported by National Institutes of Health Grants UMO-2014/15/B/NZ5/03503. This work was supported by the Spanish Ministry of Health ? ISCIII, Fondo de Investigaci?n Sanitaria (FIS) [Ref: PI15/00707] and the Diputaci?n General de Arag?n [Grupo Consolidado B20], European Social Fund (?Construyendo Europa desde Arag?n?) to FJRF and JPJ. This work was funded by the German Federal Ministry of Education and Research (BMBF, CHROMATIN-Net) to FJK and GG-K. We dedicate this manuscript to the excellent clinician and caregiver, a colleague and a friend, Ton van Essen, who died during the preparation of the manuscript. Publisher Copyright: {\textcopyright} 2017 Wiley Periodicals, Inc. Copyright: Copyright 2017 Elsevier B.V., All rights reserved.",

year = "2017",

month = aug,

doi = "10.1002/ajmg.a.38279",

language = "English",

volume = "173",

pages = "2108--2125",

journal = "American Journal of Medical Genetics, Part A",

issn = "1552-4825",

publisher = "John Wiley and Sons Inc",

number = "8",

}

Huisman, S, Mulder, PA, Redeker, E, Bader, I, Bisgaard, AM, Brooks, A, Cereda, A, Cinca, C, Clark, D, Cormier-Daire, V, Deardorff, MA, Diderich, K, Elting, M, van Essen, A, FitzPatrick, D, Gervasini, C, Gillessen-Kaesbach, G, Girisha, KM, Hilhorst-Hofstee, Y, Hopman, S, Horn, D, Isrie, M, Jansen, S, Jespersgaard, C, Kaiser, FJ, Kaur, M, Kleefstra, T, Krantz, ID, Lakeman, P, Landlust, A, Lessel, D, Michot, C, Moss, J, Noon, SE, Oliver, C, Parenti, I, Pie, J, Ramos, FJ, Rieubland, C, Russo, S, Selicorni, A, Tümer, Z, Vorstenbosch, R, Wenger, TL, van Balkom, I, Piening, S, Wierzba, J & Hennekam, RC 2017, 'Phenotypes and genotypes in individuals with SMC1A variants', American Journal of Medical Genetics, Part A, vol. 173, no. 8, pp. 2108-2125. https://doi.org/10.1002/ajmg.a.38279

TY - JOUR

T1 - Phenotypes and genotypes in individuals with SMC1A variants

AU - Huisman, Sylvia

AU - Mulder, Paul A.

AU - Redeker, Egbert

AU - Bader, Ingrid

AU - Bisgaard, Anne Marie

AU - Brooks, Alice

AU - Cereda, Anna

AU - Cinca, Constanza

AU - Clark, Dinah

AU - Cormier-Daire, Valerie

AU - Deardorff, Matthew A.

AU - Diderich, Karin

AU - Elting, Mariet

AU - van Essen, Anthonie

AU - FitzPatrick, David

AU - Gervasini, Cristina

AU - Gillessen-Kaesbach, Gabriele

AU - Girisha, Katta M.

AU - Hilhorst-Hofstee, Yvonne

AU - Hopman, Saskia

AU - Horn, Denise

AU - Isrie, Mala

AU - Jansen, Sandra

AU - Jespersgaard, Cathrine

AU - Kaiser, Frank J.

AU - Kaur, Maninder

AU - Kleefstra, Tjitske

AU - Krantz, Ian D.

AU - Lakeman, Phillis

AU - Landlust, Annemiek

AU - Lessel, Davor

AU - Michot, Caroline

AU - Moss, Jo

AU - Noon, Sarah E.

AU - Oliver, Chris

AU - Parenti, Ilaria

AU - Pie, Juan

AU - Ramos, Feliciano J.

AU - Rieubland, Claudine

AU - Russo, Silvia

AU - Selicorni, Angelo

AU - Tümer, Zeynep

AU - Vorstenbosch, Rieneke

AU - Wenger, Tara L.

AU - van Balkom, Ingrid

AU - Piening, Sigrid

AU - Wierzba, Jolanta

AU - Hennekam, Raoul C.

N1 - Funding Information: We are exceptionally grateful to the patients with SMC1A variants and their families who participated in this study. We are very grateful to the Prinsenstichting for funding in part the work of SH, and to the Dutch and Polish CdLS Associations for cooperation in the development of detailed clinical data NIPBL positive patients. We sincerely thank Dr Alina Kuzniacka and Natalia Krawczy?ska from Department of Biology and Genetics, Medical University in Gda?sk for molecular analysis. This work was supported by National Institutes of Health Grants UMO-2014/15/B/NZ5/03503. This work was supported by the Spanish Ministry of Health ? ISCIII, Fondo de Investigaci?n Sanitaria (FIS) [Ref: PI15/00707] and the Diputaci?n General de Arag?n [Grupo Consolidado B20], European Social Fund (?Construyendo Europa desde Arag?n?) to FJRF and JPJ. This work was funded by the German Federal Ministry of Education and Research (BMBF, CHROMATIN-Net) to FJK and GG-K. We dedicate this manuscript to the excellent clinician and caregiver, a colleague and a friend, Ton van Essen, who died during the preparation of the manuscript. Publisher Copyright: © 2017 Wiley Periodicals, Inc. Copyright: Copyright 2017 Elsevier B.V., All rights reserved.

PY - 2017/8

Y1 - 2017/8

N2 - SMC1A encodes one of the proteins of the cohesin complex. SMC1A variants are known to cause a phenotype resembling Cornelia de Lange syndrome (CdLS). Exome sequencing has allowed recognizing SMC1A variants in individuals with encephalopathy with epilepsy who do not resemble CdLS. We performed an international, interdisciplinary study on 51 individuals with SMC1A variants for physical and behavioral characteristics, and compare results to those in 67 individuals with NIPBL variants. For the Netherlands all known individuals with SMC1A variants were studied, both with and without CdLS phenotype. Individuals with SMC1A variants can resemble CdLS, but manifestations are less marked compared to individuals with NIPBL variants: growth is less disturbed, facial signs are less marked (except for periocular signs and thin upper vermillion), there are no major limb anomalies, and they have a higher level of cognitive and adaptive functioning. Self-injurious behavior is more frequent and more severe in the NIPBL group. In the Dutch group 5 of 13 individuals (all females) had a phenotype that shows a remarkable resemblance to Rett syndrome: epileptic encephalopathy, severe or profound intellectual disability, stereotypic movements, and (in some) regression. Their missense, nonsense, and frameshift mutations are evenly spread over the gene. We conclude that SMC1A variants can result in a phenotype resembling CdLS and a phenotype resembling Rett syndrome. Resemblances between the SMC1A group and the NIPBL group suggest that a disturbed cohesin function contributes to the phenotype, but differences between these groups may also be explained by other underlying mechanisms such as moonlighting of the cohesin genes.

AB - SMC1A encodes one of the proteins of the cohesin complex. SMC1A variants are known to cause a phenotype resembling Cornelia de Lange syndrome (CdLS). Exome sequencing has allowed recognizing SMC1A variants in individuals with encephalopathy with epilepsy who do not resemble CdLS. We performed an international, interdisciplinary study on 51 individuals with SMC1A variants for physical and behavioral characteristics, and compare results to those in 67 individuals with NIPBL variants. For the Netherlands all known individuals with SMC1A variants were studied, both with and without CdLS phenotype. Individuals with SMC1A variants can resemble CdLS, but manifestations are less marked compared to individuals with NIPBL variants: growth is less disturbed, facial signs are less marked (except for periocular signs and thin upper vermillion), there are no major limb anomalies, and they have a higher level of cognitive and adaptive functioning. Self-injurious behavior is more frequent and more severe in the NIPBL group. In the Dutch group 5 of 13 individuals (all females) had a phenotype that shows a remarkable resemblance to Rett syndrome: epileptic encephalopathy, severe or profound intellectual disability, stereotypic movements, and (in some) regression. Their missense, nonsense, and frameshift mutations are evenly spread over the gene. We conclude that SMC1A variants can result in a phenotype resembling CdLS and a phenotype resembling Rett syndrome. Resemblances between the SMC1A group and the NIPBL group suggest that a disturbed cohesin function contributes to the phenotype, but differences between these groups may also be explained by other underlying mechanisms such as moonlighting of the cohesin genes.

UR - https://www.scopus.com/pages/publications/85019761292

U2 - 10.1002/ajmg.a.38279

DO - 10.1002/ajmg.a.38279

M3 - Journal articles

C2 - 28548707

AN - SCOPUS:85019761292

SN - 1552-4825

VL - 173

SP - 2108

EP - 2125

JO - American Journal of Medical Genetics, Part A

JF - American Journal of Medical Genetics, Part A

IS - 8

ER -

Phenotypes and genotypes in individuals with SMC1A variants

Abstract

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DFG Research Classification Scheme

UN SDGs

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