This poster (#2776T) will be presented at the ASHG Annual Meeting by Agata Minor, our molecular fellow, Thursday October 24: 11:30am-12:30pm. Stop by and learn more.

Cornelia de Lange syndrome (CdLS) is a developmental disorder characterized by limb reduction defects, characteristic facial features and impaired cognitive development. In the majority of cases mutations in NIPBL can be identified. However, additional genes have been implicated in the disorder. Recently, 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 expand the RAD21 mutational spectrum by reporting the first intragenic deletion and the first frame shift mutation identified in two patients presenting with a mild form of CdLS. Patient 1 is a 2 ½ year old boy with developmental delay, hypospadias, inguinal hernia and some dysmorphic features that included mild synophrys, coarse facial features, 5th finger clinodactyly and overlapping of toes two over three. Patient 2 is a 12 year old boy who was diagnosed with CdLS at around a year of life on the basis of developmental delays, characteristic facial features, hirsuitism, and hand and feet anomalies. In patient 1, an intragenic deletion involving RAD21 exon 13 was identified by exon-targeted array comparative genomic hybridization.  Breakpoint junction sequence analysis identified a five base pair region of microhomology around the deletion breakpoints, suggesting that the deletion arose through a microhomology-mediated repair mechanism. In patient 2, sequence analysis of the RAD21 coding region revealed a two base-pair duplication in exon 6, c.592_593dup. This frameshift duplication causes premature stop codon at amino acid position 203. mRNA sequences that contain a premature stop codon may be targeted for nonsense mediated decay. The single exonic deletion and the frame shift mutation of RAD21 identified in our patients were associated with a mild presentation of CdLS.  As supported by previous literature reports, our data confirm that RAD21 mutation analysis is indicated in patients presenting with milder phenotypes of CdLS.