New insights into the pathogenesis of beckwith-wiedemann and silver-russell syndromes: Contribution of small copy number variations to 11p15 imprinting defects

Abstract

The imprinted 11p15 region is organized in two domains, each of them under the control of its own imprinting control region (ICR1 for the IGF2/H19 domain and ICR2 for the KCNQ1OT1/CDKN1C domain). Disruption of 11p15 imprinting results in two fetal growth disorders with opposite phenotypes: the Beckwith-Wiedemann (BWS) and the Silver-Russell (SRS) syndromes. Various 11p15 genetic and epigenetic defects have been demonstrated in BWS and SRS. Among them, isolated DNA methylation defects account for approximately 60% of patients. To investigate whether cryptic copy number variations (CNVs) involving only part of one of the two imprinted domains account for 11p15 isolated DNA methylation defects, we designed a single nucleotide polymorphism array covering the whole 11p15 imprinted region and genotyped 185 SRS or BWS cases with loss or gain of DNA methylation at either ICR1 or ICR2. We describe herein novel small gain and loss CNVs in six BWS or SRS patients, including maternally inherited cis-duplications involving only part of one of the two imprinted domains. We also show that ICR2 deletions do not account for BWS with ICR2 loss of methylation and that uniparental isodisomy involving only one of the two imprinted domains is not a mechanism for SRS or BWS.

A maternal deletion upstream of the imprint control region 2 in 11p15 causes loss of methylation and familial Beckwith–Wiedemann syndrome

“…In both cases, the imprint at the ICR2 was not set after germline transmission, presumably caused by the lack of KCNQ1 transcription. The deletion described in our family as well as the duplication described by Demars et al 12 affect the 5′ part of KCNQ1 and probably interfere with its expression in the oocyte. That KCNQ1 is expressed in human and murine oocytes has already been shown.…”

“…12 There is recent evidence for imprinted loci on chromosomes 20 and 15 that transcription through the DMR is required for the establishment of the methylation imprint in the maternal germline. [24][25][26] It is possible that this is also true for the ICR2 on chromosome 11.…”

“…This is also the only deletion that not only removes the ICR2 but also the CDKN1C gene itself. Last, Demars et al 12 described a duplication of about 50 kb within the KCNQ1 gene that does not overlap with the ICR2, but leads to hypomethylation of the ICR2 and BWS.…”

Looking for CDKN1C enhancers

“…These regions may also be involved in imprinting control, as they are included in two maternal duplications ( Figure 1) associated with ICR2 hypomethylation and BWS. 12,13 Intriguingly, region 3 also harbors strong binding sites for CTCF (Supplementary Figure 1), which have been shown to interact with other CTCF binding sequences near CDKN1C, possibly forming higher-order chromatin structures or insulators that may be disrupted by the duplication and result in ICR2 imprinting alteration. 14 In conclusion, by integrating information on chromosome rearrangements and chromatin features, we have identified three sequences meeting the features predicted for CDKN1C enhancers that help explain the phenotypes associated with different 11p15.5 deletions.…”

DNA methylation in development

“…SRS is characterized by severe intrauterine and postnatal growth retardation, dysmorphic facial features, feeding difficulties, and body and limb asymmetry. DNA methylation defects account for approximately 60-70% of BWS and SRS patients (Demars, et al, 2011). Two imprinting control regions, ICR1 and ICR2, control the differential expression of imprinted genes at 11p15.5.…”