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Journal article
De Novo Heterozygous Mutations in SMC3 Cause a Range of Cornelia de Lange Syndrome-Overlapping Phenotypes
Human mutation, v 36(4), pp 454-462
01 Apr 2015
PMID: 25655089
Featured in Collection : UN Sustainable Development Goals @ Drexel
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 approximate to 1%-2% of CdLS-like phenotypes.
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- Title
- De Novo Heterozygous Mutations in SMC3 Cause a Range of Cornelia de Lange Syndrome-Overlapping Phenotypes
- Creators
- Maria Concepcion Gil-Rodriguez - University of ZaragozaMatthew A. Deardorff - University of PennsylvaniaMorad Ansari - University of EdinburghChristopher A. Tan - University of ChicagoIlaria Parenti - University of LübeckCarolina Baquero-Montoya - University of ZaragozaLilian B. Ousager - Odense University HospitalBeatriz Puisac - University of ZaragozaMaria Hernandez-Marcos - University of ZaragozaMaria Esperanza Teresa-Rodrigo - Univ Zaragoza, Sch Med, Unit Clin Genet & Funct Genom, Dept Pharmacol Physiol,CIBERER GCV, E-50009 Zaragoza, SpainInigo Marcos-Alcalde - Spanish National Research CouncilJan-Jaap Wesselink - Biomol Informat SL Campus UAM, Madrid, SpainSilvia Lusa-Bernal - Biomol Informat SL Campus UAM, Madrid, SpainEmilia K. Bijlsma - Leiden UniversityDiana Braunholz - University of LübeckInes Bueno-Martinez - University of ZaragozaDinah Clark - Children's Hospital of PhiladelphiaNicola S. Cooper - Birmingham Womens Hosp, Clin Genet Unit, Birmingham, W Midlands, EnglandCynthia J. Curry - University of California, San FranciscoRichard Fisher - James Cook University HospitalAlan Fryer - Boston Children's HospitalJaya Ganesh - University of PennsylvaniaCristina Gervasini - University of MilanGabriele Gillessen-Kaesbach - University of LübeckYiran Guo - Children's Hospital of PhiladelphiaHakon Hakonarson - University of PennsylvaniaRobert J. Hopkin - Cincinnati Children's Hospital Medical CenterManinder Kaur - Children's Hospital of PhiladelphiaBrendan J. Keating - University of PennsylvaniaMaria Kibaek - Boston Children's HospitalEsther Kinning - Southern General HospitalTjitske Kleefstra - Radboud University Nijmegen Medical CentreAntonie D. Kline - Greater Baltimore Medical CenterEkaterina Kuchinskaya - Linköping UniversityLidia Larizza - University of MilanYun R. Li - University of PennsylvaniaXuanzhu Liu - BGI Shenzhen, Shenzhen, Peoples R ChinaMilena Mariani - University of Milano-BicoccaJonathan D. Picker - Boston Children's HospitalAngeles Pie - University of ZaragozaJelena Pozojevic - University of LübeckEthel Queralt - Inst Invest Biomed Bellvitge IDIBELL LHospitalet, Cell Cycle Grp, Canc Epigenet & Biol Program PEBC, Barcelona, SpainJulie Richer - Children's Hospital of Eastern OntarioElizabeth Roeder - The University of Texas at San AntonioAnubha Sinha - Birmingham Womens Hosp, Clin Genet Unit, Birmingham, W Midlands, EnglandRichard H. Scott - UCL Institute of Child HealthJoyce So - University of TorontoKatherine A. Wusik - Cincinnati Children's Hospital Medical CenterLouise Wilson - Great Ormond Street HospitalJianguo Zhang - BGI Shenzhen, Shenzhen, Peoples R ChinaPaulino Gomez-Puertas - Spanish National Research CouncilCesar H. Casale - National University of Río CuartoLena Stroem - Karolinska Inst, Dept Cell & Mol Biol, Stockholm, SwedenAngelo Selicorni - University of Milano-BicoccaFeliciano J. Ramos - University of ZaragozaLaird G. Jackson - Drexel UniversityIan D. Krantz - University of PennsylvaniaSoma Das - University of ChicagoRaoul C. M. Hennekam - University of AmsterdamFrank J. Kaiser - University of LübeckDavid R. FitzPatrick - University of EdinburghJuan Pie - University of ZaragozaYixin Guo - Mathematics
- Publication Details
- Human mutation, v 36(4), pp 454-462
- Publisher
- Wiley
- Number of pages
- 9
- Grant note
- European Social Fund ("Construyendo Europa desde Aragon") K08HD055488; P01 HD052860 / National Institutes of Health Grants (NICHD) MC_PC_U127561093 / Medical Research Council; UK Research & Innovation (UKRI); Medical Research Council UK (MRC); European Commission University of Lubeck (Schwerpunktprogramm, Medizinische Genetik: Von seltenen Varianten zur Krankheitsentstehung) Fundacion Severo Ochoa K08HD055488 / EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH &HUMAN DEVELOPMENT; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD) Medical Research Council (UK); UK Research & Innovation (UKRI); Medical Research Council UK (MRC) U54HD086984 / EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD) 2012059 / Doris Duke Charitable Foundation; Doris Duke Charitable Foundation (DDCF) PI12/01318 / Spanish Ministry of Health - Fondo de Investigacion Sanitaria (FIS); Instituto de Salud Carlos III European Social Fund; European Social Fund (ESF) German Federal Ministry of Education and Research; Federal Ministry of Education & Research (BMBF) PIF-UZ_2009-BIO-02 / University of Zaragoza 1013EXPFMTV3 / Fundacio La Marato de TV3 USA CdLS Foundation B20 / Diputacion General de Aragon (Grupo Consolidado) IPT2011-0964-900000; SAF2011-13156-E / Spanish Ministerio de Economia y Competitividad; Spanish Government MC_PC_U127561093 / MRC; UK Research & Innovation (UKRI); Medical Research Council UK (MRC)
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Mathematics
- Web of Science ID
- WOS:000352304200010
- Scopus ID
- 2-s2.0-84925845145
- Other Identifier
- 991019173702604721
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- Domestic collaboration
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- Web of Science research areas
- Genetics & Heredity