TY - JOUR
T1 - Two novel RAD21 mutations in patients with mild Cornelia de Lange syndrome-like presentation and report of the first familial case
AU - Minor, Agata
AU - Shinawi, Marwan
AU - Hogue, Jacob S.
AU - Vineyard, Marisa
AU - Hamlin, Damara R.
AU - Tan, Christopher
AU - Donato, Kirsten
AU - Wysinger, Latrice
AU - Botes, Shaun
AU - Das, Soma
AU - Del Gaudio, Daniela
PY - 2014/3/10
Y1 - 2014/3/10
N2 - 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.
AB - 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.
KW - Cornelia de Lange syndrome
KW - Exonic copy number variants
KW - Frameshift mutation
KW - Germline mutation
KW - RAD21
UR - http://www.scopus.com/inward/record.url?scp=84893674218&partnerID=8YFLogxK
U2 - 10.1016/j.gene.2013.12.045
DO - 10.1016/j.gene.2013.12.045
M3 - Article
C2 - 24378232
AN - SCOPUS:84893674218
VL - 537
SP - 279
EP - 284
JO - Gene
JF - Gene
SN - 0378-1119
IS - 2
ER -