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

Abstract

Aims: To study the frequency of methylation abnormalities among Estonian patients selected according to published clinical diagnostic scoring systems for Silver-Russell syndrome (SRS) and Beckwith-Wiedemann syndrome (BWS). Materials and Methods: Forty-eight patients with clinical suspicion of SRS (n = 20) or BWS (n = 28) were included in the study group, to whom methylation-specific multiplex ligation-dependant probe amplification analysis of 11p15 region was made. In addition, to patients with minimal diagnostic score for either SRS or BWS, multilocus methylation-specific single nucleotide primer extension assay was performed. Results: Five (38%) SRS patients with positive clinical scoring had abnormal methylation pattern at chromosome 11p15, whereas in the BWS group, only one patient was diagnosed with imprinting control region 2 (ICR2) hypomethylation (8%). An unexpected hypomethylation of the PLAGL1 (6q24) and IGF2R (6q25) genes in the patient with the highest BWS scoring was found. Conclusions: Compared to BWS, diagnostic criteria used for selecting SRS patients gave us a similar detection rate of 11p15 imprinting disorders as seen in other studies. A more careful selection of patients with possible BWS should be considered to improve the detection of molecularly confirmed cases. Genome-wide multilocus methylation tests could be used in routine clinical practice as it increases the detection rates of imprinting disorders.

Silver-Russell Syndrome and Beckwith-Wiedemann Syndrome: Opposite Phenotypes with Heterogeneous Molecular Etiology

“…They found that 22% of patients with diagnosed epimutations had methylation defects of additional imprinted loci, and among patients with clinical features of an imprinting disorder but no molecular diagnosis, methylation anomalies were diagnosed in 8%, including missed and unexpected molecular diagnoses. Vals et al [2015b] also detected the hypomethylation of PLAGL1 (6q24) and IGF2R (6q25) genes without 11p15 imprinting disorder and clinical features of 6q24-related transient neonatal diabetes mellitus in one patient with the highest BWS clinical scoring.…”

“…Other minor features are neonatal hypoglycemia, hemihyperplasia, and characteristic facial features. A rec- [Kotzot et al, 1995;Eggermann et al, 1997;Preece et al, 1997;Netchine et al, 2007;Abu-Amero et al, 2008;Binder et al, 2008] Methylation abnormality at ICR1 in the 11p15 region hypomethylation in 37 -63% [Netchine et al, 2007;Binder et al, 2008;Bartholdi et al, 2009;Bruce et al, 2009;Abu-Amero et al, 2010;Turner et al, 2010;Vals et al, 2015b] hypermethylation 5 -10% [Gaston et al, 2001;Cooper et al, 2005Cooper et al, , 2007Sasaki et al, 2007] Methylation abnormality at ICR2 in the 11p15 region few cases with the hypomethylation of both ICRs [Begemann et al, 2011] hypomethylation in 50 -60% [Gaston et al, 2001;Cooper et al, 2005;Weksberg et al, 2010;Begemann et al, 2012b] Duplication in the 11p15 region (may involve ICR1 and/or ICR2) maternal 1 -2% [Eggermann et al, 2010a[Eggermann et al, , 2014b paternal microdeletions involving ICR1 (~5%) and microduplications of ICR2 (<1%) [Niemitz et al, 2004;Sparago et al, 2004;Bliek et al, 2009b;Demars et al, 2011;Begemann et al, 2012b;Vals et al, 2015a] Other chromosomal aberrations (including cryptic) 2% (the most frequent are 1q21 microdeletion, 12q24 microdeletion, ring chromosome 15, and deletion 15qter) [Bruce et al, 2010;Spengler et al, 2012;Fuke et al, 2013;Fokstuen and Kotzot, 2014;Azzi et al, 2015] rare cases, maternally inherited balanced translocations/inversions …”

“…The genes within the second imprinted domain (CDKN1C and KCNQ1) are regulated by centromeric ICR2, which is mainly involved in the etiology of BWS [Weksberg et al, 2010]. Hypomethylation of ICR1 is found in 37-63% of SRS cases depending on the clinical criteria used for defining cases [Netchine et al, 2007;Binder et al, 2008;Bartholdi et al, 2009;Bruce et al, 2009;Abu-Amero et al, 2010;Turner et al, 2010;Vals et al, 2015b]. A mosaic distribution of the 11p15 epimutation is present in nearly all SRS patients, and this is due to a postfertilization error.…”

A retrospective analysis of the prevalence of imprinting disorders in Estonia from 1998 to 2016

“…MLPA data analysis was performed with the Coffalyser software (MRC-Holland). A detailed description of the methods has been previously published [36] and is available also on the manufacturer's website (MRC-Holland, https://mlpa.com).…”

Search for altered imprinting marks in Mayer–Rokitansky–Küster–Hauser patients

“…SRS belongs to the group of rare diseases, its incidence is estimated to range between 1 in 3,000 to 1 in 100,000 (Price, Stanhope, Garrett, Preece, & Trembath, 1999). In the Estonian population an incidence of 1 in 70,000 has been determined (Vals et al, 2015). MRKH as a comorbidity of SRS has been reported in five cases (Abraham et al, 2015;Bellver-Pradas et al, 2001;Bliek et al, 2006;Bruce et al, 2010), among them three with ICR1 hypomethylation, and it is therefore recommended to investigate girls with SRS and primary amenorrhoea for MRKH (Wakeling et al, 2017).…”