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

Abstract

We report on a young woman admitted to our Cardiology Unit because of an episode of cardiac arrest related to a long-QT syndrome (LQTS). This manifestation was part of a broader phenotype, which was recognized as a mild form of BeckwithWiedemann syndrome (BWS). Molecular analysis confirmed the diagnosis of BWS owing to a maternally inherited deletion of the centromeric imprinting center, or ICR2, an extremely rare genetic mechanism in BWS. The deletion interval (198 kb) also included exons 11-16 of the KCNQ1 gene, known to be responsible for LQTS at locus LQT1. No concomitant mutations were found in any other of the known LQT genes. The proposita's mother carries the same deletion in her paternal chromosome and shows manifestations of the Silver-Russell syndrome (SRS). This report describes the smallest BWS-causing ICR2 deletion and provides the first evidence that a paternal deletion of ICR2 leads to a SRS-like phenotype. In addition, our observation strongly suggests that in cases of LQTS due to mutation of the KCNQ1 gene (LQT1), an accurate clinical genetic evaluation should be done in order to program the most appropriate genetic tests.

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

“…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. 8 However, the number of such families is small and more data are needed to find out if there is really a segregation distortion in favour of the mutated maternal allele. Figure 3 Results of the microsatellite analysis on chromosome 11.…”

“…250 kb Niemitz et al 2004 900 kb Zollino et al 2010 330 kb Algar et al 2010 330 kb Baskin et al 2013 0.9 kb Baskin et al 2013 198 kb Gurrieri et al 2013 Figure 2 Family pedigree. The mother (II-2) is a healthy carrier of the rearrangement, which is located on her paternal allele.…”

“…3,4 Other molecular causes of BWS include hypermethylation of the ICR1 (~5-10%), paternal uniparental disomy of chromosome 11p15 (~20-25%), paternal duplications (~1-2%) and point mutations in CDKN1C (~5%). 2,5 So far, only a few familial BWS cases caused by deletions or duplications affecting the centromeric imprinted region on 11p15.5 have been described in the literature (reviewed in Begemann et al, 6 Baskin et al 7 and Gurrieri et al 8 ). Although varying greatly in size, all deletions and all but one duplication include the ICR2 itself.…”

“…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. 8 Zollino et al 11 described the so far largest deletion, which spans about 900 kb. This is also the only deletion that not only removes the ICR2 but also the CDKN1C gene itself.…”

Epigenetics, fragile X syndrome and transcriptional therapy

“…In the second case the epimutation is localized to a specific gene or chromosomal region as in imprinting disorders, where microdeletions or mutations in the "imprinting centers" cause a local disturbance of gene transcription, resulting, for example, in Prader-Willi, Angelman or Beckwith-Wiedemann syndromes [Buiting, 2010;Choufani et al, 2010;Gurrieri et al, 2013]. As discussed below, also the hypermethylation of the FMR1 promoter is a local epigenetic defect, due to the expansion of a CGG repeat (genetic defect), and causing silencing of one gene.…”