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De novo heterozygous mutations in SMC3 cause a range of Cornelia de Lange syndrome-overlapping phenotypes.
- Source :
-
Human mutation [Hum Mutat] 2015 Apr; Vol. 36 (4), pp. 454-62. Date of Electronic Publication: 2015 Mar 17. - Publication Year :
- 2015
-
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.<br /> (© 2015 WILEY PERIODICALS, INC.)
- Subjects :
- Alleles
Cohort Studies
DNA Mutational Analysis
Exome
Facies
Female
Genotype
High-Throughput Nucleotide Sequencing
Humans
Male
Cell Cycle Proteins genetics
Chondroitin Sulfate Proteoglycans genetics
Chromosomal Proteins, Non-Histone genetics
De Lange Syndrome diagnosis
De Lange Syndrome genetics
Heterozygote
Mutation
Phenotype
Subjects
Details
- Language :
- English
- ISSN :
- 1098-1004
- Volume :
- 36
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Human mutation
- Publication Type :
- Academic Journal
- Accession number :
- 25655089
- Full Text :
- https://doi.org/10.1002/humu.22761