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The Capital Region of Denmark - a part of Copenhagen University Hospital
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Delineation of phenotypes and genotypes related to cohesin structural protein RAD21

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  • Lianne C Krab
  • Iñigo Marcos-Alcalde
  • Melissa Assaf
  • Meena Balasubramanian
  • Janne Bayer Andersen
  • Anne-Marie Bisgaard
  • David R Fitzpatrick
  • Sanna Gudmundsson
  • Sylvia A Huisman
  • Tugba Kalayci
  • Saskia M Maas
  • Francisco Martinez
  • Shane McKee
  • Leonie A Menke
  • Paul A Mulder
  • Oliver D Murch
  • Michael Parker
  • Juan Pie
  • Feliciano J Ramos
  • Claudine Rieubland
  • Jill A Rosenfeld Mokry
  • Emanuela Scarano
  • Marwan Shinawi
  • Paulino Gómez-Puertas
  • Raoul C Hennekam
  • Zeynep Tümer
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RAD21 encodes a key component of the cohesin complex, and variants in RAD21 have been associated with Cornelia de Lange Syndrome (CdLS). Limited information on phenotypes attributable to RAD21 variants and genotype-phenotype relationships is currently published. We gathered a series of 49 individuals from 33 families with RAD21 alterations [24 different intragenic sequence variants (2 recurrent), 7 unique microdeletions], including 24 hitherto unpublished cases. We evaluated consequences of 12 intragenic variants by protein modelling and molecular dynamic studies. Full clinical information was available for 29 individuals. Their phenotype is an attenuated CdLS phenotype compared to that caused by variants in NIPBL or SMC1A for facial morphology, limb anomalies, and especially for cognition and behavior. In the 20 individuals with limited clinical information, additional phenotypes include Mungan syndrome (in patients with biallelic variants) and holoprosencephaly, with or without CdLS characteristics. We describe several additional cases with phenotypes including sclerocornea, in which involvement of the RAD21 variant is uncertain. Variants were frequently familial, and genotype-phenotype analyses demonstrated striking interfamilial and intrafamilial variability. Careful phenotyping is essential in interpreting consequences of RAD21 variants, and protein modeling and dynamics can be helpful in determining pathogenicity. The current study should be helpful when counseling families with a RAD21 variation.

Original languageEnglish
JournalHuman Genetics
Volume139
Issue number5
Pages (from-to)575-592
Number of pages18
ISSN0340-6717
DOIs
Publication statusPublished - May 2020

    Research areas

  • Adolescent, Adult, Cell Cycle Proteins/chemistry, Child, Child, Preschool, Chromosome Deletion, DNA-Binding Proteins/chemistry, De Lange Syndrome/genetics, Female, Genetic Association Studies, Genotype, Humans, Infant, Infant, Newborn, Male, Middle Aged, Molecular Dynamics Simulation, Mutation, Phenotype, Protein Conformation, Young Adult

ID: 59748458