title: Two novel RAD21 mutations in patients with mild Cornelia de Lange syndrome-like presentation and report of the first familial case.
abstract: Cornelia de Lange syndrome (CdLS) is a developmental disorder characterized by limb reduction defects, characteristic facial features and impaired cognitive development. Mutations in the NIPBL gene predominate; however, mutations in other cohesin complex genes have also been implicated, particularly in atypical and mild CdLS cases. Missense mutations and whole gene deletions in RAD21 have been identified in children with growth retardation, minor skeletal anomalies and facial features that overlap findings in individuals with CdLS. We report the first intragenic deletion and frameshift mutations identified in RAD21 in two patients presenting with atypical CdLS. One patient had an in-frame deletion of exon 13, while the second patient had a c.592_593dup frameshift mutation. The first patient presented with developmental delay, hypospadias, inguinal hernia and dysmorphic features while, the second patient presented with developmental delay, characteristic facial features, hirsutism, and hand and feet anomalies, with the first patient being milder than the second. The in-frame deletion mutation was found to be inherited from the mother who had a history of melanoma and other unspecified medical problems. This study expands the spectrum of RAD21 mutations and emphasizes the clinical utility of performing RAD21 mutation analysis in patients presenting with atypical forms of CdLS. Moreover, the variability of clinical presentation within families and low penetrance of mutations as well as the significance of performing molecular genetic testing in mildly affected patients are discussed.
authors.affiliation: Department of Human Genetics, University of Chicago, Chicago, IL, USA.
authors.forename: Agata
authors.initials: A
authors.lastname: Minor
authors.affiliation: Department of Pediatrics, Division Genetics and Genomic Medicine, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Marwan
authors.initials: M
authors.lastname: Shinawi
authors.affiliation: Department of Pediatrics, San Antonio Military Medical Center, Fort Sam Houston, TX, USA.
authors.forename: Jacob S
authors.initials: JS
authors.lastname: Hogue
authors.affiliation: Department of Pediatrics, Division Genetics and Genomic Medicine, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Marisa
authors.initials: M
authors.lastname: Vineyard
authors.affiliation: Department of Pediatrics, San Antonio Military Medical Center, Fort Sam Houston, TX, USA.
authors.forename: Damara R
authors.initials: DR
authors.lastname: Hamlin
authors.affiliation: Department of Human Genetics, University of Chicago, Chicago, IL, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Tan
authors.affiliation: Department of Human Genetics, University of Chicago, Chicago, IL, USA.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Donato
authors.affiliation: Department of Human Genetics, University of Chicago, Chicago, IL, USA.
authors.forename: Latrice
authors.initials: L
authors.lastname: Wysinger
authors.affiliation: Department of Human Genetics, University of Chicago, Chicago, IL, USA.
authors.forename: Shaun
authors.initials: S
authors.lastname: Botes
authors.affiliation: Department of Human Genetics, University of Chicago, Chicago, IL, USA.
authors.forename: Soma
authors.initials: S
authors.lastname: Das
authors.affiliation: Department of Human Genetics, University of Chicago, Chicago, IL, USA. Electronic address: ddelgaudio@bsd.uchicago.edu.
authors.forename: Daniela
authors.initials: D
authors.lastname: Del Gaudio
mesh_terms: D000328:Adult; D018797:Cell Cycle Proteins; D002675:Child, Preschool; D004268:DNA-Binding Proteins; D003635:De Lange Syndrome / Q000209:etiology* / Q000235:genetics; D002658:Developmental Disabilities / Q000235:genetics; D005091:Exons; D005260:Female; D016368:Frameshift Mutation; D006628:Hirsutism / Q000235:genetics; D006801:Humans; D008297:Male; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics*; D010375:Pedigree; D010750:Phosphoproteins / Q000235:genetics*
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D010750:Phosphoproteins; C429022:RAD21 protein, human
keywords: CdLS; Cornelia de Lange Syndrome; Cornelia de Lange syndrome; Exonic copy number variants; Frameshift mutation; Germline mutation; OFC; RAD21; comparative threshold cycle method; ddCt; occipitofrontal circumference