title: De novo heterozygous mutations in SMC3 cause a range of Cornelia de Lange syndrome-overlapping phenotypes.
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.
authors: Unit of Clinical Genetics and Functional Genomics, Departments of Pharmacology-Physiology and Pediatrics, Medical School, University of Zaragoza, CIBERER-GCV and ISS-Aragon, Zaragoza, Spain.
authors: María Concepción
authors: MC
authors: Gil-Rodríguez
authors: Matthew A
authors: MA
authors: Deardorff
authors: Morad
authors: M
authors: Ansari
authors: Christopher A
authors: CA
authors: Tan
authors: Ilaria
authors: I
authors: Parenti
authors: Carolina
authors: C
authors: Baquero-Montoya
authors: Lilian B
authors: LB
authors: Ousager
authors: Beatriz
authors: B
authors: Puisac
authors: María
authors: M
authors: Hernández-Marcos
authors: María Esperanza
authors: ME
authors: Teresa-Rodrigo
authors: Iñigo
authors: I
authors: Marcos-Alcalde
authors: Jan-Jaap
authors: JJ
authors: Wesselink
authors: Silvia
authors: S
authors: Lusa-Bernal
authors: Emilia K
authors: EK
authors: Bijlsma
authors: Diana
authors: D
authors: Braunholz
authors: Inés
authors: I
authors: Bueno-Martinez
authors: Dinah
authors: D
authors: Clark
authors: Nicola S
authors: NS
authors: Cooper
authors: Cynthia J
authors: CJ
authors: Curry
authors: Richard
authors: R
authors: Fisher
authors: Alan
authors: A
authors: Fryer
authors: Jaya
authors: J
authors: Ganesh
authors: Cristina
authors: C
authors: Gervasini
authors: Gabriele
authors: G
authors: Gillessen-Kaesbach
authors: Yiran
authors: Y
authors: Guo
authors: Hakon
authors: H
authors: Hakonarson
authors: Robert J
authors: RJ
authors: Hopkin
authors: Maninder
authors: M
authors: Kaur
authors: Brendan J
authors: BJ
authors: Keating
authors: María
authors: M
authors: Kibaek
authors: Esther
authors: E
authors: Kinning
authors: Tjitske
authors: T
authors: Kleefstra
authors: Antonie D
authors: AD
authors: Kline
authors: Ekaterina
authors: E
authors: Kuchinskaya
authors: Lidia
authors: L
authors: Larizza
authors: Yun R
authors: YR
authors: Li
authors: Xuanzhu
authors: X
authors: Liu
authors: Milena
authors: M
authors: Mariani
authors: Jonathan D
authors: JD
authors: Picker
authors: Ángeles
authors: Á
authors: Pié
authors: Jelena
authors: J
authors: Pozojevic
authors: Ethel
authors: E
authors: Queralt
authors: Julie
authors: J
authors: Richer
authors: Elizabeth
authors: E
authors: Roeder
authors: Anubha
authors: A
authors: Sinha
authors: Richard H
authors: RH
authors: Scott
authors: Joyce
authors: J
authors: So
authors: Katherine A
authors: KA
authors: Wusik
authors: Louise
authors: L
authors: Wilson
authors: Jianguo
authors: J
authors: Zhang
authors: Paulino
authors: P
authors: Gómez-Puertas
authors: César H
authors: CH
authors: Casale
authors: Lena
authors: L
authors: Ström
authors: Angelo
authors: A
authors: Selicorni
authors: Feliciano J
authors: FJ
authors: Ramos
authors: Laird G
authors: LG
authors: Jackson
authors: Ian D
authors: ID
authors: Krantz
authors: Soma
authors: S
authors: Das
authors: Raoul C M
authors: RC
authors: Hennekam
authors: Frank J
authors: FJ
authors: Kaiser
authors: David R
authors: DR
authors: FitzPatrick
authors: Juan
authors: J
authors: Pié
mesh_terms: D000483:Alleles; D018797:Cell Cycle Proteins / Q000235:genetics*; D011508:Chondroitin Sulfate Proteoglycans / Q000235:genetics*; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics*; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D003635:De Lange Syndrome / Q000175:diagnosis* / Q000235:genetics*; D059472:Exome; D019066:Facies; D005260:Female; D005838:Genotype; D006579:Heterozygote; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D009154:Mutation; D010641:Phenotype
chemical_list: D018797:Cell Cycle Proteins; D011508:Chondroitin Sulfate Proteoglycans; D002868:Chromosomal Proteins, Non-Histone; C492318:SMC3 protein, human
keywords: CdLS; CdLS-like; CdLS-overlapping phenotypes; Cornelia de Lange syndrome; SMC3; cohesin complex