An 11p15 Imprinting Centre Region 2 Deletion in a Family with Beckwith Wiedemann Syndrome Provides Insights into Imprinting Control at CDKN1C

Abstract

We report a three generation family with Beckwith Wiedemann syndrome (BWS) in whom we have identified a 330 kb deletion within the KCNQ1 locus, encompassing the 11p15.5 Imprinting Centre II (IC2). The deletion arose on the paternal chromosome in the first generation and was only associated with BWS when transmitted maternally to subsequent generations. The deletion on the maternal chromosome was associated with a lower median level of CDKN1C expression in the peripheral blood of affected individuals when compared to a cohort of unaffected controls (p<0.05), however was not significantly different to the expression levels in BWS cases with loss of methylation (LOM) within IC2 (p<0.78). Moreover the individual with a deletion on the paternal chromosome did not show evidence of elevated CDKN1C expression or features of Russell Silver syndrome. These observations support a model invoking the deletion of enhancer elements required for CDKN1C expression lying within or close to the imprinting centre and importantly extend and validate a single observation from an earlier study. Analysis of 94 cases with IC2 loss of methylation revealed that KCNQ1 deletion is a rare cause of loss of maternal methylation, occurring in only 3% of cases, or in 1.5% of BWS overall.

Mild Beckwith-Wiedemann and severe long-QT syndrome due to deletion of the imprinting center 2 on chromosome 11p

“…A similar ICR2 deletion was also reported in a second family in which maternal transmission led to a BWS phenotype in the offspring because of underexpression of CDKN1C. 8 This gene is commonly expressed by the maternal chromosome in which ICR2 is methylated, thus preventing chromatin insulator formation and allowing a distant enhancer cisactivity on CDKN1C transcription. It has been speculated that the maternal ICR2 deletion either exposes CDKN1C to repression in trans by the paternal KCNQ10T1 antisense, or removes a cis-acting distant enhancer of CDKN1C expression.…”

“…A more proximal enhancer with milder effect on CDKN1C transcription is predicted at 3 0 of KCNQ1. If the position in intron 3 of the distant enhancer is correct, then this enhancer should not be deleted in our proposita; however, we propose that the deletion interval in our patient includes this strong enhancer thus suggesting a different position, not in intron 3, as previously proposed, 8 but rather to a more restricted interval, between intron 10 and 15. The loss of a strong enhancer and the maintenance of a weak one might explain the mild expression of the BWS phenotype related to some residual expression of CDKN1C.…”

“…This postulated enhancer has been tentatively located within intron 3 of the KCNQ1 gene. 8 Both pathogenic mechanisms are likely to occur in our BWS patient: we speculate that absence of the maternal KCNQ1 transcript does not protect the flanking CDKN1C from the silencing effect of the paternal antisense transcript. According to this hypothesis, a cis-protection effect preventing downregulation might be exerted by ICR2 on flanking genes in the maternal chromosome.…”

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

“…In the first family described at least three out of four children were affected. 9 Additionally, two of two siblings in the second family 10 and three to four out of five children in the third family 7 have inherited the deletion from their respective mother. In the three remaining families, two deletions occurred de novo in the patients, 7,11 and in the last family only one child was reported.…”

“…A similar deletion of~330 kb also abolishing the ICR2 has been reported a few years later. 10 Another deletion encompassing again about 330 kb within the KCNQ1 gene and abolishing the ICR2 has been described by Baskin et al 7 They also identified a second, much smaller deletion spanning only about 0.9 kb, but deleting a large part of the ICR2 as well. Another BWS patient with a mild phenotype together with cardiac problems has a 198 kb deletion that removes the 3′ part of KCNQ1 including the ICR2.…”