Additional molecular findings in 11p15-associated imprinting disorders: an urgent need for multi-locus testing

Abstract

Molecular disturbances in patients with imprinting disorders are often not restricted to the disease-specific locus but also affect other chromosomal regions. These additional disturbances include methylation defects, uniparental disomies as well as chromosomal imbalances. The identification of these additional alterations is mandatory for a well-directed genetic counseling. Furthermore, these findings help to decipher the complex regulation of imprinting.

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

“…As patients with a clinical presentation of BWS and Silver-Russel syndrome sometimes harbour multilocus imprinting disturbances, 16 we tested the methylation status of the twins by further MS-MLPA analyses for imprinted loci on chromosomes 6, 7, 14 and 15 (III-5 and III-6) but no aberrant methylation could be detected for the loci studied (data not shown). Furthermore, array-based DNA methylation analyses were conducted in one of the twins (III-6).…”

Congenital imprinting disorders: Application of multilocus and high throughput methods to decipher new pathomechanisms and improve their management

“…Molecular testing was not restricted to the 11p15 imprinted loci, but also encompassed differentially methylated regions (DMRs) on chromosomes 6, 7, 14 and 15 [13].…”

“…Another example for the impact of multilocus testing in IDs is the growing number of reports on BWS patients with a mosaic genome-wide paternal diploidy meaning that a significant ratio of cells carry chromosomes exclusively derived from the father. It turns out that a considerable number of BWS patients diagnosed to have an UPD(11p15)pat carry this unusual aberration [13], Considering that UPD(11p15)pat accounts for nearly 20% of BWS patients, and that carriers of a mosaic genome-wide paternal diploidy exhibit particularly unusual tumor histories which are not covered by the already existing surveillance programs for classical BWS [28], every case of UPD(11)pat warrants testing for genome-wide uniparental diploidy [29].…”

“…In particular in the 11p15-associated disorders (BWS and SRS), nearly all patients with epimutations and UPD show mosaicism (for review: [13]). As a consequence of mosaicism, the molecular alterations currently often escape diagnostic detection in case of a low level mosaicism [30], an unequal distribution in different tissues [15], or an insufficient sensitivity of assays [31,32].…”

The Frequency of Methylation Abnormalities Among Estonian Patients Selected by Clinical Diagnostic Scoring Systems for Silver–Russell Syndrome and Beckwith–Wiedemann Syndrome

“…In our group, 5 of 13 (38%) SRS patients with positive clinical scoring had abnormal methylation in chromosome 11p15. In the BWS group, of all the patients who met the clinical criteria, only one patient was diagnosed with ICR2 hypomethylation (8%), whereas in other studies, the detection rate for imprinting disorders in 11p15 has been 28-72% (Gaston et al, 2001;Calvello et al, 2013;Mussa et al, 2013;Baskin et al, 2014;Eggermann et al, 2014). When we compared the symptoms of our BWS group patients with recent criteria by Ibrahim et al (2014), eight patients met the minimum score for BWS, but nevertheless the detection rate remained low (12.5%).…”