Anti-CDKN1C monoclonal antibody, clone 58Q07

Beckwith-Wiedemann syndrome (BWS) is a model imprinting disorder resulting from mutations or epigenetic events affecting imprinted genes at 11p15.5. Most BWS cases are sporadic and result from imprinting errors (epimutations) involving either of the two 11p15.5 imprinting control regions (IC1 and IC2). Previously, we and other reported an association between sporadic BWS and assisted reproductive technologies (ARTs). In this study, we compared the clinical phenotype and molecular features of ART (IVF and ICSI) and non-ART children with sporadic BWS. A total of 25 patients with post-ART BWS were ascertained (12 after IVF and 13 after ICSI). Molecular genetic analysis revealed an IC2 epimutations (KvDMR1 loss of methylation) in 24 of the 25 children tested. Comparison of clinical features of children with post-ART BWS to those with non-ART BWS and IC2 defects revealed a lower frequency of exomphalos (43 versus 69%, P = 0.029) and a higher risk of neoplasia (two cases, P = 0.0014). As loss of methylation at imprinting control regions other than 11p15.5 might modify the phenotype of BWS patients with IC2 epimutations, we investigated differentially methylated regions (DMRs) at 6q24, 7q32 and 15q13 in post-ART and non-ART BWS IC2 cases (n = 55). Loss of maternal allele methylation at these DMRs occurred in 37.5% of ART and 6.4% of non-ART BWS IC2 defect cases. Thus, more generalized DMR hypomethylation is more frequent, but not exclusive to post-ART BWS. These findings provide further evidence that ART may be associated with disturbed normal genomic imprinting in a subset of children.

We report duplications of maternally derived chromosome 11p15 involving CDKN1C encoding a negative regulator for cell proliferation in three Japanese patients (cases 1 and 2 from family A and case 3 from family B) with Silver-Russell syndrome (SRS) phenotype lacking hemihypotrophy. Chromosome analysis showed 46,XX,der(16)t(11;16)(p15.3;q24.3)mat in case 1, 46, XY,der(16)t(11;16)(p15.3;q24.3)mat in case 2 and a de novo 46,XX,der(17)t(11;17)(p15.4;q25.3) in case 3. Genomewide oligonucleotide-based array comparative genomic hybridization, microsatellite analysis, pyrosequencing-based methylation analysis and direct sequence analysis revealed the presence of maternally derived extra copies of the distal chromosome 11p involving the wild-type CDKN1C (a similar to 7.98 Mb region in cases 1 and 2 and a similar to 4.43 Mb region in case 3). The results, in conjunction with the previous findings in patients with similar duplications encompassing CDKN1C and in those with intragenic mutations of CDKN1C, imply that duplications of CDKN1C, as well as relatively mild gain-of-function mutations of CDKN1C lead to SRS subtype that usually lack hemihypotrophy.