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De Novo Heterozygous Mutations in SMC3 Cause a Range of Cornelia de Lange Syndrome-Overlapping Phenotypes
University of Zaragoza, Spain; University of Zaragoza, Spain; ISS Aragon, Spain.
Childrens Hospital Philadelphia, PA 19104 USA; University of Penn, PA 19104 USA.
University of Edinburgh, Scotland.
University of Chicago, IL 60637 USA.
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2015 (English)In: Human Mutation, ISSN 1059-7794, E-ISSN 1098-1004, Vol. 36, no 4, 454-462 p.Article in journal (Refereed) Published
Abstract [en]

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 approximate to 1%-2% of CdLS-like phenotypes.

Place, publisher, year, edition, pages
Wiley: 12 months , 2015. Vol. 36, no 4, 454-462 p.
Keyword [en]
Cornelia de Lange syndrome; CdLS; SMC3; cohesin complex; CdLS-overlapping phenotypes; CdLS-like
National Category
Clinical Medicine
URN: urn:nbn:se:liu:diva-117795DOI: 10.1002/humu.22761ISI: 000352304200010PubMedID: 25655089OAI: diva2:811269

Funding Agencies|Spanish Ministry of Health - Fondo de Investigacion Sanitaria (FIS) [PI12/01318]; Diputacion General de Aragon (Grupo Consolidado) [B20]; European Social Fund ("Construyendo Europa desde Aragon"); Spanish Ministerio de Economia y Competitividad [IPT2011-0964-900000, SAF2011-13156-E]; University of Zaragoza [PIF-UZ_2009-BIO-02]; Fundacio La Marato de TV3 [1013EXPFMTV3]; University of Lubeck (Schwerpunktprogramm, Medizinische Genetik: Von seltenen Varianten zur Krankheitsentstehung); German Federal Ministry of Education and Research; Medical Research Council (UK); National Institutes of Health Grants (NICHD) [K08HD055488, P01 HD052860]; USA CdLS Foundation; Doris Duke Charitable Foundation [2012059]; Fundacion Severo Ochoa; European Social Fund

Available from: 2015-05-11 Created: 2015-05-08 Last updated: 2015-05-11

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Kuchinskaya, Ekaterina
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Division of Cell BiologyFaculty of Health Sciences
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