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 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, Soma Das, Raoul C.M. Hennekam, Frank J. Kaiser, David R. FitzPatrick, Juan Pié

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 sixteen patients with CdLS-like features caused by mutations in SMC3. Modelling of the mutation effects on protein structure suggests a dominant-negative effect on the multimeric cohesin complex. When compared to 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. This article is protected by copyright. All rights reserved.